TW202216682A - Alk5 inhibitors, conjugates, and uses thereof - Google Patents

Abstract

ALK5 inhibitor compounds, conjugates, and pharmaceutical compositions for use in the treatment of disease, such as cancer, are disclosed herein. Additionally, compounds incorporated into a conjugate with an antibody construct are described herein. The disclosed compounds and conjugates are useful, among other things, in the treating of cancer and fibrosis and modulating ALK5.

Description

ALK5 inhibitors, conjugates and uses thereof

none

One of the leading causes of death in the United States is cancer. Conventional approaches to cancer treatment, such as chemotherapy, surgery, or radiation therapy, tend to be highly toxic or nonspecific for cancer, or both, resulting in limited efficacy and deleterious side effects. However, the immune system has the potential to be a powerful, specific tool in the fight against cancer. In many cases, tumors can specifically express genes whose products are required to induce or maintain a malignant state. These proteins can be used as antigen markers for developing and building more specific anti-cancer immune responses. This enhancement of the immune response has the potential to be a powerful anticancer therapy that can be more effective and have fewer side effects than conventional cancer treatments.

Fibrosis is the formation of excess fibrous connective or scar tissue within an organ or tissue during repair or response. Fibrosis can occur in many tissues in the body, often resulting in inflammation or damage, including the lungs, liver, heart, and brain. Scar tissue can clog arteries, fix joints and damage internal organs, wreaking havoc with the body's ability to maintain vital functions. Every year, millions of people are hospitalized due to the devastating effects of fibrosis. However, current therapies for the treatment of fibrotic diseases are lacking or have shortcomings. Accordingly, there remains a considerable need for alternative or improved treatments for fibrotic diseases.

The Sequence Listing pertaining to this application is in textual form in lieu of a printed copy, and is hereby incorporated by reference into this specification. The text file containing the sequence listing is named 860234_403TW_ST25.txt. The text file is 1149 KB and was created on June 29, 2021.

(I) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、互變異構物、同位素、或鹽類，其中： L為-[CR’ ₂]p-L’-[CH ₂]q-； L’係不存在、-S-、-O-、或-NH-； A係不存在、碳環、或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、鹵、C _1-3烷基、或C _1-3鹵烷基； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3； n為0-5； p為1-3；且 q為0-3。 In particular embodiments, provided compounds have the structure of formula (I):

(I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein: L is -[CR' ₂ ]p-L' -[CH ₂ ]q-; L' is absent, -S-, -O-, or -NH-; A is absent, carbocyclic, or heterocyclic; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, halogen, C _1-3 alkyl, or C _1-3 haloalkyl ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halogen, C _{1- 3} alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is on each occurrence are independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N( R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R' , -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P( O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is in each occurrence independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; n is 0-5; p is 1 -3; and q is 0-3.

In some embodiments, the compounds disclosed herein are linked to a linker to form a compound-linker.

In some embodiments, the compounds disclosed herein are covalently bound to an antibody construct or target moiety, optionally via a linker.

In some embodiments, the compounds disclosed herein are covalently bound to an antibody construct or target moiety, the antibody or antigen-binding domain thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), Wherein: (i) VH comprises a CDR1 (VH-CDR1) containing the amino acid sequence of SEQ ID NO: 364, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 365, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 365, a VH-CDR3 of the amino acid sequence of 366; and VL comprising a CDR1 containing the amino acid sequence of SEQ ID NO:367 (VL-CDR1), a VL-CDR2 containing the amino acid sequence of SEQ ID NO:368 , and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 369; (ii) VH comprising a CDR1 (VH-CDR1) containing the amino acid sequence of SEQ ID NO: 364, a VL-CDR1 containing the amino acid sequence of SEQ ID NO: 364; VH-CDR2 of the amino acid sequence of 370, a VH-CDR3 containing the amino acid sequence of SEQ ID NO:366; and VL comprising a CDR1 containing the amino acid sequence of SEQ ID NO:367 (VL-CDR1) , a VL-CDR2 containing the amino acid sequence of SEQ ID NO:368, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:369; (iii) VH comprising an amine containing SEQ ID NO:371 CDR1 (VH-CDR1) of amino acid sequence, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 372, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 373; and VL comprises a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 373; CDR1 (VL-CDR1) of the amino acid sequence of SEQ ID NO:374, a VL-CDR2 containing the amino acid sequence of SEQ ID NO:375, and a VL containing the amino acid sequence of SEQ ID NO:376 -CDR3; (iv) VH comprises a CDR1 containing the amino acid sequence of SEQ ID NO:364 (VH-CDR1), a CDR1 containing an amino group selected from any one of SEQ ID NOS:370, 377, or 365 VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 366; and VL comprising a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 367, a VL-CDR2 derived from the amino acid sequence of any one of SEQ ID NOS: 368, 378, or 379, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 369; (v) the VH comprises a CDR1 containing the amino acid sequence of SEQ ID NO: 371 (VH-CDR1), a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:372, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:373; and VL comprises a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:374 CDR1 (VL-CDR1) of the amino acid sequence of the VL-CDR3; (vi) VH comprises a CDR1 (VH-CDR1) containing the amino acid sequence of SEQ ID NO: 381, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 382, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 382 The VH-CDR3 of the amino acid sequence of NO:383; and the VL comprises a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO:384, a VL containing the amino acid sequence of SEQ ID NO:385 -CDR2, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 386; (vii) VH comprising a CDR1 (VH-CDR1) containing the amino acid sequence of SEQ ID NO: 387, a VL-CDR1 containing the amino acid sequence of SEQ ID NO: 387 VH-CDR2 of the amino acid sequence of NO:388, a VH-CDR3 containing the amino acid sequence of SEQ ID NO:389; and VL comprising a CDR1 (VL-CDR1 of the amino acid sequence of SEQ ID NO:390) CDR1), a VL-CDR2 containing the amino acid sequence selected from any one of SEQ ID NOS: 391-393, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 394; or (viii ) VH comprises a CDR1 (VH-CDR1) containing the amino acid sequence of SEQ ID NO: 395, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 396, an amino group containing SEQ ID NO: 397 and VL comprises a CDR1 containing the amino acid sequence of SEQ ID NO:398 (VL-CDR1), a VL-CDR2 containing the amino acid sequence of SEQ ID NO:399, and a VL-CDR2 containing the amino acid sequence of SEQ ID NO:399 VL-CDR3 of the amino acid sequence of SEQ ID NO:400.

(I)； 其中：A'為抗ASGR1抗體或其抗原結合片段，L為連接子；D _x為本發明之化合物；n係選自於1至20；且z係選自於1至20。在一些具體實施例中，n為1至約10、或1至約5之整數，或為1或2，或為1。在一些具體實施例中，n為1至10、或1至5之整數，或為1或2，或為1。在一些具體實施例中，n為1、2、3、4、5、6、7、8、9、或10。在一些具體實施例中，z為1至約10，或1至約9，或1至約8，或2至約6，或約3至約5，或約4。在一些具體實施例中，z為1至10，或1至9，或1至8，或2至6，或約3至5，或4。在一些具體實施例中，z為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、或20。 In some specific embodiments, the conjugate is represented by formula (I):

(I); wherein: A' is an anti-ASGR1 antibody or an antigen-binding fragment thereof, L is a linker; _Dx is a compound of the present invention; n is selected from 1 to 20; and z is selected from 1 to 20. In some embodiments, n is an integer from 1 to about 10, or 1 to about 5, or 1 or 2, or 1. In some embodiments, n is an integer from 1 to 10, or 1 to 5, or 1 or 2, or 1. In some specific embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some specific embodiments, z is 1 to about 10, or 1 to about 9, or 1 to about 8, or 2 to about 6, or about 3 to about 5, or about 4. In some specific embodiments, z is 1 to 10, or 1 to 9, or 1 to 8, or 2 to 6, or about 3 to 5, or 4. In some specific embodiments, z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

， 其中抗體為抗ASGR1抗體，其包含選自於SEQ ID NOS:401-409之任一者之輕鏈可變區胺基酸序列所示之輕鏈CDR1、CDR2、及CDR3，以及選自於SEQ ID NOS:410-461之任一者之重鏈可變區胺基酸序列所示之重鏈CDR1、CDR2、及CDR3；選自於SEQ ID NOS:462-465之任一者之輕鏈可變區胺基酸序列所示之輕鏈CDR1、CDR2、及CDR3，以及選自於SEQ ID NOS:466-470之任一者之重鏈可變區胺基酸序列所示之重鏈CDR1、CDR2、及CDR3；選自於SEQ ID NOS:471-477之任一者之輕鏈可變區胺基酸序列所示之輕鏈CDR1、CDR2、及CDR3，以及選自於SEQ ID NOS:478-490之任一者之重鏈可變區胺基酸序列所示之重鏈CDR1、CDR2、及CDR3；選自於SEQ ID NOS:491-494之任一者之輕鏈可變區胺基酸序列所示之輕鏈CDR1、CDR2、及CDR3，以及選自於SEQ ID NOS:495-503之任一者之重鏈可變區胺基酸序列所示之重鏈CDR1、CDR2、及CDR3；或SEQ ID NO:504之輕鏈可變區胺基酸序列所示之輕鏈CDR1、CDR2、及CDR3，以及選自於SEQ ID NOS:505-514之任一者之重鏈可變區胺基酸序列所示之重鏈CDR1、CDR2、及CDR3；如通過Kabat索引確定，且L ³-D為連接子-化合物。 The present invention provides a conjugate or a salt thereof, which is represented by the following formula:

, wherein the antibody is an anti-ASGR1 antibody comprising a light chain CDR1, CDR2, and CDR3 selected from the light chain variable region amino acid sequence shown in any one of SEQ ID NOS: 401-409, and selected from Heavy chain CDR1, CDR2, and CDR3 shown in the heavy chain variable region amino acid sequence of any one of SEQ ID NOS: 410-461; selected from the light chain of any one of SEQ ID NOS: 462-465 The light chain CDR1, CDR2, and CDR3 shown in the variable region amino acid sequence, and the heavy chain CDR1 shown in the heavy chain variable region amino acid sequence selected from any one of SEQ ID NOS: 466-470 , CDR2, and CDR3; selected from the light chain CDR1, CDR2, and CDR3 shown in the light chain variable region amino acid sequence of any one of SEQ ID NOS: 471-477, and selected from SEQ ID NOS: Heavy chain CDR1, CDR2, and CDR3 shown in the heavy chain variable region amino acid sequence of any one of 478-490; selected from the light chain variable region amines of any one of SEQ ID NOS: 491-494 The light chain CDR1, CDR2, and CDR3 shown in the amino acid sequence, and the heavy chain CDR1, CDR2, and CDR2 shown in the heavy chain variable region amino acid sequence selected from any one of SEQ ID NOS: 495-503 CDR3; or the light chain CDR1, CDR2, and CDR3 shown in the light chain variable region amino acid sequence of SEQ ID NO: 504, and a heavy chain variable selected from any of SEQ ID NOS: 505-514 The heavy chain CDR1, CDR2, and CDR3 shown in the amino acid sequences of the regions; as determined by the Kabat index, and L3 ^- D is the linker-compound.

Also disclosed herein are pharmaceutical compositions of the compounds or conjugates described herein.

In some aspects, the present invention provides a method for treating cancer comprising administering to a subject in need thereof a compound, conjugate, or pharmaceutical composition described herein.

In some aspects, the invention provides a method for enhancing an immune response (eg, an anticancer immune response) in a subject comprising administering to a subject in need thereof a compound, conjugate, or pharmacy described herein composition.

In some aspects, the present invention provides a method for treating fibrosis comprising administering to a subject in need thereof a compound, conjugate, or pharmaceutical composition described herein. In some aspects, fibrosis is associated with cancer. In some aspects, fibrosis is not associated with cancer. In one aspect, the fibrosis is scleroderma. In another aspect, the fibrosis is systemic fibrosis. In one aspect, the fibrotic disease is steatohepatitis, such as nonalcoholic steatohepatitis (NASH).

Activin receptor-like kinase 5 (ALK5), also commonly known as transforming growth factor beta receptor 1 (TGF-βR1), is a serine Acid/threonine kinase transmembrane receptor. It is part of the TGFβ signaling pathway and is involved in the transmission of messages from the cell surface to the cytoplasm. The TGFβ signaling pathway regulates gene expression of genes involved in cellular processes such as differentiation, apoptosis, wound healing, and cell growth. ALK5 is used interchangeably with TGF-βR1.

In the absence of TGF[beta] ligand, ALK5 remains a homodimeric cell surface receptor. However, ligand binding to TGFβ receptor type 2 (TGFβR2) induces the formation of the TGFβR1/TGFβR2 complex, which results in the mothers against decapentaplegic homolog 2 (Smad2) and the parental anti-Dpp homolog Phosphorylation of Mothers Against Decapentaplegic homolog 3 (Smad3) and subsequent regulation of some downstream signaling targets involved in the regulation of gene expression. Therefore, inhibitors of ALK5 can be used to alter or modulate the expression of genes involved in cancer, thereby being useful in the treatment and prevention of cancer.

As used herein, a "modulator" of ALK5 is a compound that, when administered to a patient, provides the desired modulation of the target receptor. For example, by interacting directly or indirectly with the target receptor, a compound can act as a full or partial antagonist or synergist of the receptor. The present invention provides compounds, linkers, conjugates, and pharmaceutical compositions for use in the treatment of diseases. In certain embodiments, the compounds of the present invention modulate activin-like receptor kinase type 5 (ALK5). In certain embodiments, the compounds of the present invention act as ALK5 inhibitors. definition

Before describing the present invention in more detail, definitions of specific terms to be used herein are provided to assist in their understanding. Other definitions are also set forth throughout this disclosure. Unless specifically defined otherwise, technical terms used herein have their normal meanings as understood in the art. The following explanations of terms and methods are provided to better describe the compounds, compositions, and methods of the present invention, and to guide those of ordinary skill in the art to practice the present invention. It is also to be understood that the terminology used in the present disclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting.

As used in the specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. It is to be understood that the terms "a" and "one" as used herein mean "one or more" of the listed components.

The use of alternatives (eg "or") should be understood to mean one, both, or any combination of the alternatives. As used herein, the words "including" and "including" are synonymous. Thus, the phrase "comprising A or B" is meant to include A, B, or both A and B.

When the phrase "at least one of" is followed by a list of items or elements, it is intended to mean an open-ended collection of one or more of the elements in the list, which may, but need not, include more than one element.

The word "about" as used herein, in the context of a number, means a range centered on the number that is 15% less and 15% greater than the number. The word "about" used in the context of a range means an extended range that is 15% less than the lowest number listed in the range and 15% greater than the highest number listed in the range.

In this specification, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range and, where appropriate, fractions thereof (such as tenths and hundredths of an integer) part), whether or not a specific value or a specific sub-range is expressly stated. Furthermore, unless otherwise indicated, any numerical range described herein in relation to any physical characteristic (eg, polymer subunit, size, or thickness) should be understood to include any integer within the range.

The phrase "target moiety" means a structure that has selective affinity for or selectively binds to a target molecule relative to other non-target molecules. Targeting moieties can include, for example, antibodies, antibody constructs, peptides, polypeptides, ligands, carbohydrates, polynucleotides, oligonucleotides, or receptor or binding portions thereof. Target biomolecules can be biological receptors of cells or other structures (eg, tumor antigens).

The term "antibody" as used herein means an immunoglobulin molecule that specifically binds or is immunologically reactive to a specific antigen. The portion of an antibody that binds a specific antigen may be referred to as an "antigen-binding domain." Antibodies can include, for example, polyclonal, monoclonal, and genetically engineered antibodies, as well as antigen-binding fragments thereof. Antibodies can be, for example, murine, chimeric, humanized, heteroconjugate, bispecific, diabodies, tribodies, or tetrabodies.

As used herein, an "antigen-binding domain" means a region of a molecule that can specifically bind to an antigen. An antigen-binding domain can be the antigen-binding portion of an antibody or antibody fragment. An antigen binding domain can be one or more fragments of an antibody that retain the ability to specifically bind to an antigen. An antigen-binding domain can be an antigen-binding fragment. In some embodiments, the antigen binding domain recognizes a single antigen. An antigen binding domain can recognize, for example, two or three antigens. Antigen-binding fragments can include, for example, Fab, F(ab) ₂ , Fab, Fv, rIgG, scFv, hcAbs (heavy chain antibodies), single domain antibodies, _VHHs , _VNARs , sdAbs, or Nanobodies.

As used herein, "specifically binds" and the like means that the specificity between an antigen-binding domain and an antigen is associated or specific binding. In some embodiments, the dissociation constant (KD) of the antigen binding domain that recognizes or specifically binds to the antigen is <<100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (eg, ^10-8 M or less, such as about ^10-8 M to about ^10-13 M, such as about ^10-9 M to about ^10-13 M). Specific binding does not require that the antigen binding domain is not associated or bound to any other antigen, but preferentially associates or binds to the target antigen of interest as opposed to off-target association or binding to an unrelated antigen.

As used herein, "antibody construct" means a molecule (eg, protein, peptide, antibody, or portion thereof) that contains an antigen binding domain and an Fc region (eg, an Fc domain within an Fc region).

As used herein, an "Fc domain" can be derived from the Fc region of an antibody or from within the domain of a non-antibody molecule, which can bind to an Fc receptor.

As used herein, a "tumor antigen" can be an antigenic substance that is associated with a tumor or cancer cell and can trigger a host immune response.

"Identity" or "identity" as used herein means between a DNA, RNA, nucleotide, amino acid, or protein sequence and another DNA, RNA, nucleotide, amino acid, or protein sequence similarity. Identity can be expressed as percent sequence identity between the first sequence and the second sequence. The percent (%) sequence identity relative to the reference DNA sequence may be the percentage of DNA nucleotides in the candidate sequence that, after aligning the sequences, are identical to the DNA nucleotides in the reference DNA sequence. Percent (%) sequence identity relative to the reference amino acid sequence, which can be the percentage of amino acid residues in the candidate sequence that, after aligning the sequences and introducing gaps, is the same as the amino acid in the reference amino acid sequence Residues are identical, as required, to achieve the maximum percent sequence identity, and any retained substitutions are not considered as part of the sequence identity. In a specific embodiment, the percent sequence identity value system is generated using NCBI BLAST 2.0 software, as defined by Altschul et al ., Nucleic Acids Res. 25 :3389-3402, 2007, wherein the parameters are all set to default values.

Compounds or salts of the invention used herein, such as formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or (VI) Compounds, or pharmaceutically acceptable isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts thereof, may be referred to as "ALK5 inhibitors", drugs "D" ", compound, or payload "P", especially when referenced as part of a conjugate. In some embodiments, the ALK5 inhibitor inhibits about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, compared to ALK5 activity in the absence of the inhibitor %, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, Or 100% ALK5 enzyme activity. In some embodiments, the ALK5 inhibitor inhibits 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% of ALK5 activity in the absence of the inhibitor , 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% ALK5 enzymatic activity.

As used herein, "LP", "linker-payload", "LD", "linker-ALK5 inhibitor", "linker-drug", or "linker-compound" may be used herein to mean binding to linker of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or (VI) compound, or a pharmacy thereof The above acceptable isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts.

"Conjugate" as used herein means that a compound of the invention is conjugated to an antibody, antibody construct, or target moiety, either directly or through a linker group.

， 其中A'為抗體、抗體構築體、或標靶部分；L為連接子；D為式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、或(VI)化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類；且z為1至約20。在一些具體實施例中，z之範圍為1至約10、1至約9、1至約8、2至約8、1至約6、1至約3、或約3至約5。在特定具體實施例中，z為2、約3、約4、約5、約6、約7、或約8。在一些具體實施例中，z為1至20。在一些具體實施例中，z之範圍為1至10、1至9、1至8、2至8、1至6、1至3、3至5。在特定具體實施例中，z為2、3、4、5、6、7、或8。在進一步之具體實施例中，共軛物係以下式表示：

， 其中A'為抗體、抗體構築體、或標靶部分；D為式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、或(VI)化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類；且z之範圍為1至約20。在一些具體實施例中，z之範圍為1至約10、1至約9、1至約8、2至約8、1至約6、1至約3、或約3至約5。在特定具體實施例中，z為2、約3、約4、約5、約6、約7、或約8。在一些具體實施例中，z為1至20。在一些具體實施例中，z之範圍為1至10、1至9、1至8、2至8、1至6、1至3、3至5。在特定具體實施例中，z為2、3、4、5、6、7、或8。在諸如組成物或製劑中發現的一群共軛物將具有平均DAR。在一些具體實施例中，組成物或製劑之共軛物的平均DAR範圍為1至約10、1至約9、1至約8、1至約6、1至約3、約2至約8、約2至約6、約2.5至約5.5、約2.5至約4.5、約2至約4、約3.5至約5.5、約3至約5、約3.5至約4.5、或約3至約4。在特定具體實施例中，組成物或製劑之共軛物的平均DAR為約1.5、約2、約2.5、約3、約3.5、約4、約4.5、約5、約5.5、約6、約6.5、約7、約7.5、或約8。在一些具體實施例中，組成物或製劑之共軛物的平均DAR範圍為1至10、1至9、1至8、1至6、1至3、2至8、2至6、2.5至5.5、2.5至4.5、2至4、3.5至5.5、3至5、3.5至4.5、或3至4。在特定具體實施例中，組成物或製劑之共軛物的平均DAR為1.5、2、2.5、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、或8。 "Drug to Antibody Ratio"("DAR") as used herein means a compound that is covalently bound or linked directly or indirectly (via a linker) to an antibody, antibody construct, or conjugate of a target moiety ( ALK5 inhibitors). For conjugates with more than one compound covalently bound or linked, the linked compounds can be the same or different. In certain specific embodiments, the conjugate is represented by the formula:

, wherein A' is an antibody, an antibody construct, or a target moiety; L is a linker; D is a formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), ( VI'), (VI''), or (VI) compound, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; and z is 1 to about 20. In some embodiments, z ranges from 1 to about 10, 1 to about 9, 1 to about 8, 2 to about 8, 1 to about 6, 1 to about 3, or about 3 to about 5. In certain specific embodiments, z is 2, about 3, about 4, about 5, about 6, about 7, or about 8. In some specific embodiments, z is 1-20. In some embodiments, z ranges from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 1 to 6, 1 to 3, 3 to 5. In certain specific embodiments, z is 2, 3, 4, 5, 6, 7, or 8. In a further specific embodiment, the conjugate is represented by the following formula:

, wherein A' is an antibody, an antibody construct, or a target moiety; D is a formula (I'), (I''), (I), (II'), (II''), (II), ( III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), ( VI''), or compound (VI), or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; and z ranges from 1 to about 20. In some embodiments, z ranges from 1 to about 10, 1 to about 9, 1 to about 8, 2 to about 8, 1 to about 6, 1 to about 3, or about 3 to about 5. In certain specific embodiments, z is 2, about 3, about 4, about 5, about 6, about 7, or about 8. In some specific embodiments, z is 1-20. In some embodiments, z ranges from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 1 to 6, 1 to 3, 3 to 5. In certain specific embodiments, z is 2, 3, 4, 5, 6, 7, or 8. A population of conjugates found in, for example, a composition or formulation will have an average DAR. In some embodiments, the conjugates of the composition or formulation have an average DAR ranging from 1 to about 10, 1 to about 9, 1 to about 8, 1 to about 6, 1 to about 3, about 2 to about 8 , about 2 to about 6, about 2.5 to about 5.5, about 2.5 to about 4.5, about 2 to about 4, about 3.5 to about 5.5, about 3 to about 5, about 3.5 to about 4.5, or about 3 to about 4. In particular embodiments, the conjugate of the composition or formulation has an average DAR of about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8. In some embodiments, the conjugates of the composition or formulation have an average DAR ranging from 1 to 10, 1 to 9, 1 to 8, 1 to 6, 1 to 3, 2 to 8, 2 to 6, 2.5 to 5.5, 2.5 to 4.5, 2 to 4, 3.5 to 5.5, 3 to 5, 3.5 to 4.5, or 3 to 4. In particular embodiments, the conjugate of the composition or formulation has an average DAR of 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8.

Compounds or salts of the invention used herein, such as formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or (VI) Compounds, or pharmaceutically acceptable isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts thereof, may refer to ALK5 inhibitors, drugs (D), compounds , or payload, especially when referenced as part of a conjugate. "LP", "L-P", or "Linker-Payload" are used interchangeably herein to mean Formula (I'), (I''), (I), (II'), (II' '), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V ), (VI'), (VI''), or (VI) compound, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof class, which can be conjugated to the linker (L).

As used herein, "alkyl" or "lower alkyl" means having 1 to 12 carbon atoms, in some embodiments 1 to 10 carbon atoms, and in some embodiments 1 to 8 carbon atoms atoms, in some embodiments 1 to 6 carbon atoms, in some embodiments 1 to 4 carbon atoms, and in some embodiments 1 to 3 carbon atoms straight or branched alkyl. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, isobutyl, tertiary butyl, tertiary butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl.

As used herein, "alkenyl" or "lower alkenyl" means having 2 to 10 carbon atoms, in some embodiments 2 to 8 carbon atoms, and in some embodiments 2 to 6 carbon atoms atoms, in some embodiments, 2 to 4 carbon atoms, and in some embodiments, straight or branched chain alkenyl groups of 2 to 3 carbon atoms. Alkenyl groups are unsaturated hydrocarbons containing at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

As used herein, "alkynyl" or "lower alkynyl" means having 2 to 10 carbon atoms, in some embodiments 2 to 8 carbon atoms, and in some embodiments 2 to 6 carbon atoms atoms, in some embodiments, 2 to 4 carbon atoms, and in some embodiments, straight or branched chain alkynyl groups of 2 to 3 carbon atoms. Alkynyl groups are unsaturated hydrocarbons containing at least one carbon-carbon bond. Examples of lower alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

"Halo" or "halogen" means fluorine, chlorine, bromine, and iodine.

"Hydroxy" means -OH.

"Cyano" means -CN.

"Haloalkyl" or "lower haloalkyl" means lower alkyl as defined above wherein one or more hydrogen atoms are replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CHF2, and the like.

"Haloalkenyl" or "lower haloalkenyl" means lower alkenyl as defined above wherein one or more hydrogen atoms are replaced with halogen.

"Haloalkynyl" or "lower haloalkynyl" means a lower alkynyl group as defined above wherein one or more hydrogen atoms are replaced with halogen.

"Hydroxyalkyl" or "lower hydroxyalkyl" means a lower alkyl group as defined above wherein one or more hydrogen atoms are replaced with hydroxy groups. Examples of lower hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, and the like.

"Alkoxy" or "lower alkoxy" means that a lower alkyl group, as defined above, is attached through an oxygen atom (ie -O-(lower alkyl). Examples of lower alkoxy include, but are not limited to, methoxy group, ethoxy, n-propoxy, n-butoxy, isopropoxy, secondary butoxy, tertiary butoxy, and the like.

"Haloalkoxy" or "lower haloalkoxy" means a lower haloalkyl group, as defined above, attached through an oxygen atom (ie -O-(lower haloalkyl). Examples of lower haloalkoxy include, but do not Limited to, -OCF3 and its analogs.

"Cycloalkyl" means an alkyl group that forms a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or fully unsaturated wherein, if unsaturation is present, there are pi electrons on the ring The conjugation does not produce aromaticity. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl further includes polycyclic cycloalkyl, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl, and fused rings such as, but not limited to, decalinyl and the like.

"Aryl" is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptenyl, biphenyl, indenyl, indenyl, phenanthryl, triphenylene, pyrenyl, tetraphenyl, pyrenyl (chrysenyl), biphenylene, anthracenyl, and naphthyl. In some embodiments, aryl groups contain 6-14 carbons in the ring portion of the group. The terms "aryl" and "aryl group" include fused rings in which at least one, but not necessarily all of the rings are aromatic, such as fused aromatic-aliphatic ring systems (eg, indenyl, tetrahydro naphthyl, and its analogs). In one embodiment, aryl is phenyl or naphthyl, and in another embodiment, aryl is phenyl.

"Carbocyclyl", "carbocycle", or "carbocyclic" means an alkyl group that forms a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or fully unsaturated , in which if there is unsaturation, the conjugation of π electrons on the ring can produce aromaticity. In a specific embodiment, the carbocycle includes a cycloalkyl group as defined above. In another specific embodiment, the carbocycle includes an aryl group as defined above.

"Heterocyclyl", "heterocycle", or "heterocyclic" means aromatic and non-aromatic ring moieties containing three or more ring members, one or more of which are heteroatoms, such as but not limited to In, N, O, S, or P. In some embodiments, heterocyclyl groups include 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but each ring of a polycyclic ring system need not contain a heteroatom. For example, both dioxolanyl rings and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are heterocyclyl groups within the meaning herein.

Heterocyclyl also includes fused ring species, including those having fused aromatic and non-aromatic groups. Heterocyclyl also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl, and also includes substituted heterocyclyls, including, but not limited to, alkyl, halo , amine, hydroxyl, cyano, carboxyl, nitro, thio, or alkoxy, which are bonded to one of the ring members. A heterocyclyl group as defined herein can be a heteroaryl group or a partially or fully saturated cyclic group including at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazole base, oxazolyl, isoxazolyl, thiazolyl, pyridyl, thiophenyl, benzothiophene, benzofuranyl, dihydrobenzofuranyl, indolyl, indoline, nitrogen Heteroindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl , thianaphthalenyl, purine, xanthine, adenine, guanopurine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoline, and quinazoline.

"Heteroaryl" means an aromatic ring moiety containing five or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, for example, pyrrolyl, pyrazolyl, pyridyl, pyridyl, pyrimidinyl, pyrazinyl, pyrimidinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazolyl 𠯤, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophene, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, nitrogen Heterobenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thinaphthyl, purinyl, xanthine, adeninyl , guanopurinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinolinyl, and quinazolinyl. The terms "heteroaryl" and "heteroaryl group" include fused ring compounds, for example, in which at least one, but not necessarily all of the rings are aromatic, including tetrahydroquinolyl, tetrahydroisoquinolyl, indole base, and 2,3-indoline.

The term "optionally substituted" as used herein means a group ( such as alkyl, carbocyclic, or heterocyclic). Substituents include, but are not limited to, -ORa, -NRaRb, -S(O)2Ra or -S(O)2ORa, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, Carbocycloalkyl, or heterocycloalkyl, wherein each Ra and Rb are independently H, alkyl, haloalkyl, carbocycle, or heterocycle, or Ra and Rb together form 3-8 membered carbocyclic or heterocyclic ring.

As used herein, "isomers" encompass all chiral, non-spiroisomeric, or racemic forms of a structure unless a specific stereochemistry or isomeric form is specifically indicated. Such compounds may be enriched or resolved optical isomers at any or all asymmetric atoms in any degree of enrichment, as apparent from the description. Racemic and non-enantiomer mixtures, as well as individual optical isomers, can be synthesized so as to be substantially free of their enantiomer or non-enantiomer partners and fall within the scope of this invention within the scope of specific examples. Isomers due to the presence of a chiral center contain a pair of non-superimposable isomers called "enantiomers". A single enantiomer of a pure compound is optically active (ie, it rotates the plane of the plane polarizer and is designated R or S).

"Isolated optical isomer" means a compound substantially purified from the corresponding optical isomer of the same molecular formula. For example, the isolated isomer can be at least about 80%, at least 80%, or at least 85% pure by weight. In other specific embodiments, the isolated isomers are at least 90% pure, or at least 98% pure, or at least 99% pure, by weight.

Purity by "substantially enantiomer or non-spideromer" means the level of enantiomer or non-spideromer enrichment of one enantiomer relative to other enantiomers or non-spideromers is at least about 80%, and more specifically more than 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%.

The terms "racemate" and "racemic mixture" mean an equal mixture of two enantiomers. The racemate is labeled "(±)" because it is not optically active (ie, does not rotate plane polarized light in either direction, because its constituent mirror-image isomers cancel each other out). All compounds with an asterisk (*) adjacent to the tertiary or quaternary carbon are optically active isomers, which can be purified from the respective racemates and/or by appropriate chiral synthesis reactions synthesis.

Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds may exist in the Z- or E-form (or cis or trans). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise indicated, the compounds described herein are also intended to include all Z-, E-, and tautomeric forms.

"Tautomer" means a molecule in which a proton may be transferred from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. Tautomers will exist in chemical equilibrium under circumstances where tautomerism is likely to occur. The exact ratio of tautomers depends on a number of factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

A "hydrate" is a compound that exists in combination with water molecules. The combination may include stoichiometric amounts of water, such as monohydrate or dihydrate, or may include random amounts of water. The term "hydrate" as used herein refers to the solid form; that is, although a compound in an aqueous solution may be hydrated, it is not a hydrate as used herein.

A "solvate" is similar to a hydrate, except that a solvent other than water is present. For example, methanol or ethanol can form "alcoholates," which can also be stoichiometric or non-stoichiometric. As used herein, "solvate" means solid form; that is, although a compound in a solvent solution may be solvated, it is not a solvate as used herein.

"Isotope" means atoms having the same number of protons but different numbers of neutrons, and isotopes of compounds of formula (I) include any such compounds in which one or more atoms are replaced by isotopes of atoms. For example, carbon 12 is the most common form of carbon with six protons and six neutrons, while carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). Although fluorine has multiple isotopes, fluorine 19 has the longest lifespan. Thus, isotopes of compounds of formula (I) include, but are not limited to, compounds of formula (I) wherein one or more carbon 12 atoms are replaced by carbon 13 atoms and/or carbon 14 atoms, wherein one or more hydrogen atoms Atoms are replaced by deuterium and/or tritium, and/or one or more of the fluorine atoms are replaced by fluorine 19.

"Salt" generally means an organic compound, such as a carboxylic acid or an amine, in ionic form combined with a counterion. For example, salts formed between an acid in an anionic form and a cation are referred to as "acid addition salts". Conversely, salts formed between a base in cationic form and an anion are referred to as "base addition salts". ALK5 inhibitor compounds

(I’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、互變異構物、同位素、或鹽類，其中： L為-[CR’ ₂]p-L’-[CH ₂]q- L’係不存在、-S-、-O-、或-NH-； A係不存在、碳環、或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、鹵、C _1-3烷基、或C _1-3鹵烷基； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3； n為0-5； p為1-3；且 q為0-3。 In particular embodiments, provided compounds have the structure of formula (I'):

(I') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein: L is -[CR' ₂ ]p-L '-[CH ₂ ]q- L' is absent, -S-, -O-, or -NH-; A is absent, carbocyclic, or heterocyclic; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, halogen, C _1-3 alkyl, or C _1-3 haloalkyl ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halogen, C _{1- 3} alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is on each occurrence are independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N( R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R' , -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P( O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is in each occurrence independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; n is 0-5; p is 1 -3; and q is 0-3.

(I’’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、互變異構物、同位素、或鹽類，其中： L為-[CR’ ₂]p-L’-[CH ₂]q- L’係不存在、-S-、-O-、或-NH-； A係不存在、碳環、或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3； n為0-5； p為1-3；且 q為0-3。 In particular embodiments, provided compounds have the structure of formula (I''):

(I'') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein: L is -[CR' ₂ ]p- L'-[CH ₂ ]q- L' is absent, -S-, -O-, or -NH-; A is absent, carbocyclic, or heterocyclic; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl; R ² in each occurrence are independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 Alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy ; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independently halo, -OR at each occurrence ', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N( R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR ', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each represented by 0- 3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; n is 0-5; p is 1-3; and q is 0- 3.

(I) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、互變異構物、同位素、或鹽類，其中： L為-[CR’ ₂]p-L’-[CH ₂]q- L’係不存在、-S-、-O-、或-NH-； A係不存在、碳環、或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3； n為0-5； p為1-3；且 q為0-3。 In particular embodiments, provided compounds have the structure of formula (I):

(I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein: L is -[CR' ₂ ]p-L' -[CH ₂ ]q- L' is absent, -S-, -O-, or -NH-; A is absent, carbocyclic, or heterocyclic; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl; R ² is independent at each occurrence is halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ³ is H, halogen, C _1-3 alkyl , C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halogen, C _1-3 alkyl, C _1-3 haloalkane base, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N(R')C(O)R',-C(O)OR',-OC(O)R',-S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP (O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _{2 -5} haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ is 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane m is _0-3 ; n is _0-5 ; p is 1-3; and q is _0-3 .

(I) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、互變異構物、同位素、或鹽類，其中： L為-[CR’ ₂]p-L’-[CH ₂]q- L’係不存在、-S-、-O-、或-NH-； A係不存在、碳環、或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3； n為0-5； p為1-3；且 q為0-3。 In certain other specific embodiments, the provided compounds have the structure of formula (I):

(I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein: L is -[CR' ₂ ]p-L' -[CH ₂ ]q- L' is absent, -S-, -O-, or -NH-; A is absent, carbocyclic, or heterocyclic; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl; R ² is independent at each occurrence is halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ³ is H, halogen, C _1-3 alkyl , C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halogen, C _1-3 alkyl, C _1-3 haloalkane base, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O) OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP (O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _{2 -5} haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ is 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane m is _0-3 ; n is _0-5 ; p is 1-3; and q is _0-3 .

In particular embodiments, provided compounds have the structure of formula (I'), formula (I''), or formula (I), or a pharmaceutically acceptable isomer, racemate, hydrated compounds, solvates, tautomers, isotopes, or salts in which the L' system is absent. In other specific embodiments, L' is -S-. In other specific embodiments, L' is -O-. In yet other specific embodiments, L' is -NH-.

In certain embodiments, provided compounds have the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof class, where p is 1. In some specific embodiments, p is 2. In other specific embodiments, p is 3.

In certain embodiments, provided compounds have the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof class, where q is 0. In other specific embodiments, q is 1. In yet other specific embodiments, q is 2. In a further specific embodiment, q is 3.

(II’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (II'):

(II') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkane group, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl , or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _1-6 hydroxyalkyl, - C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S (O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 ring Alkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' independently at each occurrence hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II’’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (II"):

(II'') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is Substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 Haloalkoxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is on each occurrence are independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N( R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R' , -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P( O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is in each occurrence independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (II):

(II) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is 0 -3 R ¹⁰ substitutions; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkane oxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _{1 -3} haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H , halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independent at each occurrence is halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R' ) ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', - S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O) (OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _{1 -4} haloalkyl, _C2-5 haloalkenyl, _C2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ series are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is independently in each occurrence is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain other specific embodiments, provided compounds have the structure of formula (II):

(II) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is 0 -3 R ¹⁰ substitutions; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkane oxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _{1 -3} haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H , halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independent at each occurrence Halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O) R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O) (OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _{1 -4} haloalkyl, _C2-5 haloalkenyl, _C2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ series are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is independently in each occurrence is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II’’-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (II''-A):

(II''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N(R')C(O)R', -C(O) OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _{1 -6} alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independent at each occurrence is C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (II-A):

(II-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR' , -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 Alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain other specific embodiments, the provided compounds have the structure of formula (II-A):

(II-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II’’-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (II''-B):

(II''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in Each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _{1-6hydroxyalkyl} , -C( O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O ) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl , -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _{2- 5} alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0- 3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (II-B):

(II-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in each When they appear, they are all independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _{1-6hydroxyalkyl} , -C(O) N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, - P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkyne group, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each with 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane group, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain other specific embodiments, the provided compounds have the structure of formula (II-B):

(II-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in each Occurs independently as halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R') C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', - P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkyne group, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each with 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane group, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(II’’-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (II''-C):

(II''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N(R')C(O)R', -C(O) OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _{1 -6} alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy at each occurrence or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 halo alkyl; m is 0-3; and n is 0-5.

(II-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)O-C _1-6羥烷基、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-C(O)NHS(O) ₂-C _1-6烷基、-C(O)NHS(O) ₂-C _3-8環烷基、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (II-C):

(II-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR' , -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 Alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl ; m is 0-3; and n is 0-5.

(II-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain other specific embodiments, the provided compounds have the structure of formula (II-C):

(II-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl ; m is 0-3; and n is 0-5.

(III’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (III'):

(III') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkane group, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl , or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N (R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' independently at each occurrence hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, or _C1-6 haloalkyl; m is 0-3; and n is 0-5.

(III’’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (III''):

(III'') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is Substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 Haloalkoxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is on each occurrence are independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C( O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P( O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is in each occurrence independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(III) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (III):

(III) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is 0 -3 R ¹⁰ substitutions; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkane oxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _{1 -3} haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H , halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independent at each occurrence Halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O) R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O) (OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _{1 -4} haloalkyl, _C2-5 haloalkenyl, _C2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ series are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is independently in each occurrence is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(III’’-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (III''-A):

(III''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independent at each occurrence is C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(III-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (III-A):

(III-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(III’’-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (III''-B):

(III''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in Halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R at each occurrence independently ')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR' , -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _{2- 5} alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0- 3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(III-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (III-B):

(III-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in each Occurs independently as halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R') C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', - P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkyne group, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each with 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane group, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(III’’-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (III''-C):

(III''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy at each occurrence or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 halo alkyl; m is 0-3; and n is 0-5.

(III-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (III-C):

(III-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl ; m is 0-3; and n is 0-5.

(IV’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (IV'):

(IV') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkane group, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl , or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N (R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' independently at each occurrence hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(IV’’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (IV''):

(IV'') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is Substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 Haloalkoxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is on each occurrence are independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C( O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P( O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is in each occurrence independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(IV) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (IV):

(IV) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is 0 -3 R ¹⁰ substitutions; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkane oxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _{1 -3} haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H , halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independent at each occurrence Halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O) R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O) (OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _{1 -4} haloalkyl, _C2-5 haloalkenyl, _C2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ series are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is independently in each occurrence is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(IV’’-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (IV''-A):

(IV''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independent at each occurrence is C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(IV-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (IV-A):

(IV-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(IV’’-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (IV''-B):

(IV''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in Halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R at each occurrence independently ')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR' , -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _{2- 5} alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0- 3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(IV-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (IV-B):

(IV-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in each Occurs independently as halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R') C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', - P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkyne group, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each with 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane group, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(IV’’-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In specific embodiments, provided compounds have the structure of formula (IV''-C):

(IV''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy at each occurrence or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 halo alkyl; m is 0-3; and n is 0-5.

(IV-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (IV-C):

(IV-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl ; m is 0-3; and n is 0-5.

(V _aʹ) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (V _a ʹ):

(V _a ʹ) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 halogen Alkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkane group, or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _{1- 3} alkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; ^R9 is at each occurrence independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , - N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R ' is independently at each occurrence hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n 0-5.

(V _a’’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (V _a ''):

(V _a '') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 halo Alkyl, or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo , C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _{1 -3} alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody ; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O ) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl , C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy at each occurrence; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V _a) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (V _a ):

(V _a ) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkane group, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl , or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N (R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' independently at each occurrence hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, or _C1-6 haloalkyl; m is 0-3; and n is 0-5.

(V _a’’-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (V _a ''-A):

(V _a ''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen , C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; R ⁹ is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', - S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkyne wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V _a-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (V _a -A):

(V _a -A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is A reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C (O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S( O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , = O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, Carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkane base; m is 0-3; and n is 0-5.

(V _a’’-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (V _a ''-B):

(V _a ''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen , C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; R ⁹ Halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N( R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR ', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _{2 -5} alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0 -3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1 -6} alkyl, _C2-6 alkenyl, _C2-6 alkynyl, or _C1-6 haloalkyl; m is 0-3; and n is 0-5.

(V _a-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (V _a -B):

(V _a -B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in each Each occurrence is independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R',-C(O)OR',-OC(O)R',-S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 Alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0-3 R ¹⁰ is substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' is independently hydrogen, C _1-6 at every occurrence alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V _a’’-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (V _a ''-C):

(V _a ''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen , C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; R ⁹ is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', - S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkyne wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V _a-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (Va-C ₎ :

(V _a -C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is A reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C (O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S( O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , = O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, Carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkane base; m is 0-3; and n is 0-5.

(V’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (V'):

(V') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkane group, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl , or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N (R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' independently at each occurrence hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V’’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (V''):

(V'') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is Substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 Haloalkoxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is on each occurrence are independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C( O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P( O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is in each occurrence independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (V):

(V) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is 0 -3 R ¹⁰ substitutions; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkane oxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _{1 -3} haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H , halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independent at each occurrence Halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O) R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O) (OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _{1 -4} haloalkyl, _C2-5 haloalkenyl, _C2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ series are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is independently in each occurrence is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V’’-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (V''-A):

(V''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy at each occurrence or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 halo alkyl; m is 0-3; and n is 0-5.

(V-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (VA):

(VA) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 Alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkane oxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of connecting with A sub-linked reactive moiety or a reactive moiety capable of being linked to an antibody; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C(O) R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R ', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, - CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocyclic, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1- at each occurrence ₃ haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V’’-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (V''-B):

(V''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in Halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R at each occurrence independently ')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR' , -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _{2- 5} alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0- 3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (VB):

(VB) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 Alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkane oxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; R ⁹ at each occurrence are independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C( O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P( O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each with 0-3 R ¹⁰ Substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(V’’-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (V''-C):

(V''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy at each occurrence or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 halo alkyl; m is 0-3; and n is 0-5.

(V-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： A為碳環或雜環； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (VC):

(VC) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 Alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkane oxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of connecting with A sub-linked reactive moiety or a reactive moiety capable of being linked to an antibody; ^R9 at each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C(O) R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R ', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, - CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocyclic, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1- at each occurrence ₃ haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(VI’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； Q ⁷為C或N； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In certain embodiments, provided compounds have the structure of formula (VI'):

(VI') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is 0 -3 R ¹⁰ substitutions; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkane oxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _{1 -3} haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H , halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independent at each occurrence Halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O) R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O) (OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _{1 -4} haloalkyl, _C2-5 haloalkenyl, _C2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ series are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is independently in each occurrence is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(VI’’) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (VI"):

(VI'') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halogen, C _{1- 3} alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independently halo, -OR at each occurrence ', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C( O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each represented by 0- 3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(VI) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： Q ³為N或CR ³； Q ⁴為N或CR ⁴； Q ⁵為N或CR ⁵； Q ⁶為N或CR ⁶； R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ³為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁴為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁵為H、鹵、C _1-3烷基、C _1-3鹵烷基、或C _1-3烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (VI):

(VI) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halogen, C _1-3 alkoxy group, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O) OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP (O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _{2 -5} haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ is 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane group, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(VI’’-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (VI''-A):

(VI''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reaction capable of connecting with a linker A reactive moiety or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', - C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S (O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _{1 -4} alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy at each occurrence base; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3 ; and n is 0-5.

(VI-A) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (VI-A):

(VI-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _{1 -3} haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C( O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O ) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy at each occurrence; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(VI’’-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (VI''-B):

(VI''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; R ⁹ is independently at each occurrence Halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R' , -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR ') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(VI-B) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (VI-B):

(VI-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _{1 -3} haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', - C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkane group, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is in each Each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl at each occurrence , C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

(VI’’-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In particular embodiments, provided compounds have the structure of formula (VI''-C):

(VI''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reaction capable of connecting with a linker A reactive moiety or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', - C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S (O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _{1 -4} alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy at each occurrence base; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3 ; and n is 0-5.

(VI-C) 或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其中： R ¹為氫、C _1-3烷基、或C _1-3鹵烷基，其中R ¹係以0-3個R ¹⁰取代； R ²在每次出現時皆獨立地為鹵、C _1-3烷基、C _1-3烷氧基、C _1-3鹵烷基、或C _1-3鹵烷氧基； R ⁶為H、鹵、C _1-3烷基、或C _1-3烷氧基； R ⁷為能與連接子連接的反應性部分或能與抗體連接的反應性部分； R ⁹在每次出現時皆獨立地為鹵、-OR’、-SR’、-N(R’) ₂、-C(O)R’、-C(O)N(R’) ₂、-N(R’)C(O)R’、-C(O)OR’、-OC(O)R’、-S(O)R’、-S(O) ₂R’、-S(O) ₂OR’、-P(O)(OR’) ₂、-OP(O)(OR’) ₂、-NO ₂、=O、-CN、C _1-4烷基、C _2-5烯基、C _2-5炔基、C _1-4鹵烷基、C _2-5鹵烯基、C _2-5鹵炔基、碳環、或雜環； 其中R ¹、R ²、R ⁶、及R ⁹係各以0-3個R ¹⁰取代； R ¹⁰在每次出現時皆獨立地為C _1-3烷氧基或C _1-3鹵烷氧基； R’在每次出現時皆獨立地為氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、或C _1-6鹵烷基； m為0-3；且 n為0-5。 In specific embodiments, provided compounds have the structure of formula (VI-C):

(VI-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _{1 -3} haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C( O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O ) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy at each occurrence; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ¹ is hydrogen. In other specific embodiments, R ¹ is unsubstituted C _1-3 alkyl. In certain specific embodiments, R ¹ is methyl. In other embodiments, R ¹ is C _1-3 alkyl substituted with 1-3 R ¹⁰ . In certain specific embodiments, R ¹ is -CH ₂ OCH ₃ . In another specific embodiment, R ¹ is unsubstituted C _1-3 haloalkyl. In certain specific embodiments, R ¹ is -CF ₃ .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ¹ is hydrogen. In other specific embodiments, R ¹ is unsubstituted C _1-3 alkyl. In certain specific embodiments, R ¹ is methyl. In other embodiments, R ¹ is C _1-3 alkyl substituted with 1-3 R ¹⁰ . In certain specific embodiments, R ¹ is -CH ₂ OCH ₃ . In another specific embodiment, R ¹ is unsubstituted C _1-3 haloalkyl. In certain specific embodiments, R ¹ is -CF ₃ . In certain specific embodiments, R ¹ is -CHF ₂ .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ¹ is hydrogen. In other specific embodiments, R ¹ is halo. In other specific embodiments, R ¹ is Cl. In other specific embodiments, R ¹ is unsubstituted C _1-3 alkyl. In certain specific embodiments, R ¹ is methyl. In other embodiments, R ¹ is C _1-3 alkyl substituted with 1-3 R ¹⁰ . In certain specific embodiments, R ¹ is -CH ₂ OCH ₃ . In another specific embodiment, R ¹ is unsubstituted C _1-3 haloalkyl. In certain specific embodiments, R ¹ is -CF ₃ . In certain specific embodiments, R ¹ is -CHF ₂ .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein m is 0. In other specific embodiments, m is 1-3. In certain specific embodiments, m is one.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ² is halo . In some embodiments, at least one R ² is F.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein A is a heterocycle.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein A is a heterocycle. In certain specific embodiments, A is pyridyl. In certain specific embodiments, A is pyrimidinyl.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein A is a carbocycle. In certain specific embodiments, A is phenyl. In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein n is 0. In some specific embodiments, n is 1-5. In other specific embodiments, n is 1 or 2.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is halogen . In some embodiments, at least one R ⁹ is F or Cl.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is halogen . In some embodiments, at least one R ⁹ is F, Cl, or Br.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - OR'. In some embodiments, R' of at least one -OR' is C _1-6 alkyl.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is C _1-4 alkyl. In some embodiments, at least one R ⁹ is methyl.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - EN.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - C(O)N(R') ₂ . In some embodiments, at least one R ⁹ is -C(O)N(CH ₃ ) ₂ .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - C(O)N(R') ₂ . In some embodiments, at least one R ⁹ is -C(O)N(CH ₃ ) ₂ . In some embodiments, at least one R ⁹ is -C(O)NH ₂ .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - N(R') ₂ . In some embodiments, at least one R ⁹ is -N(CH ₃ ) ₂ .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - NO ₂ .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - C(O)ORʹ. In some embodiments, at least one R ⁹ is -C(O)OCH ₃ . In some embodiments, at least one R ⁹ is -C(O)OH.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - C(O)OC _1-6 hydroxyalkyl. In some embodiments, at least one R ⁹ is --C(O)OCH ₂ CH ₂ OH.

、

、或

。 In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - C(O)NHS(O) ₂ -C _1-6 alkyl. In some embodiments, at least one R ⁹ is

,

,or

.

。 In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R ⁹ is - C(O)NHS(O) ₂ - _{C3-8cycloalkyl} . In some embodiments, at least one R ⁹ is

.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ⁶ is H.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ⁶ is halo. In some specific embodiments, R ⁶ is F or Cl.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ⁶ is C _{1- 3} alkyl. In some specific embodiments, R ⁶ is methyl.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ⁶ is C _{1- 3} alkoxy. In some specific embodiments, R ⁶ is -OCH ₃ .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein a linker capable of being attached The reactive moiety or reactive moiety capable of being linked to the antibody is -Y-(CR ¹¹ R ¹² ) _p -NHR ¹³ , -Y-(CR ¹¹ R ¹² ) _p -C(O)OH, or -Y-(CR ¹¹ R ¹² ) _p -C(O)NHR ¹³ , where: Y is -O-, -CH ₂ -, -OCH ₂ CH ₂ -, or -OCH ₂ CH ₂ NR ¹⁴ -; R ¹¹ at each occurrence are independently H, halogen, C _1-3 alkyl, or C _1-3 haloalkyl; R ¹² at each occurrence is independently H, halogen, C _1-3 alkyl, or C _{1- 3} haloalkyl; R ¹³ is H; or R ¹¹ at each occurrence and R ¹² at each occurrence, together with the atom to which it is attached, form a ring; or R ¹¹ at each occurrence and R ¹³ form a ring; R ¹⁴ is H, halogen, C _1-3 alkyl, or C _1-3 haloalkyl; and p is 0-5.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein a linker capable of being attached The reactive moiety or reactive moiety capable of being linked to the antibody is -Y-(CR ¹¹ R ¹² ) _p -NHR ¹³ , -Y-(CR ¹¹ R ¹² ) _p -C(O)OR ¹³ , -Y-(CR ¹¹ R ¹² ) _p -C(O)NHR ¹³ , or -Y-(CR ¹¹ R ¹² ) _p -O-phenyl-C(O)-C _1-3 alkyl, wherein: Y is absent, - O-, -C(O)-, -C(O)O-, -CH ₂ -, -OCH ₂ CH ₂ -, -OCH ₂ CH ₂ O-, -C(O)NR ¹³ -, -OCH ₂ CH ₂ NR ¹³ (C)O-, -OCH ₂ CH ₂ NR ¹³ C(O)CH ₂ CH ₂ CH ₂ C(O)NR ¹³ -, -OCH ₂ CH ₂ CH ₂ NR ¹³ C(O)CH ₂ CH ₂ CH ₂ C(O)NR ¹³ -, or -OCH ₂ CH ₂ NR ¹⁴ -; R ¹¹ at each occurrence is independently H, halogen, C _1-3 alkyl, or C _1-3 haloalkane radical, or R ¹⁵ ; R ¹² at each occurrence is independently H, halogen, C _1-3 alkyl or C _1-3 haloalkyl, or R ¹⁵ ; R ¹³ is H or C _1-3 alkane or R ¹¹ at each occurrence and R ¹² at each occurrence, together with the atoms to which it is attached, form a ring; or R ¹¹ at each occurrence and R ¹³ form a ring; R ¹⁴ is H, halogen, C _1-3 alkyl, or C _1-3 haloalkyl; R ¹⁵ is -C _0-3 alkyl-C(O)OR ¹³ ; and p is 0-5.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ⁷ is -Y- (CR ¹¹ R ¹² ) _p -NHR ¹³ . In some specific embodiments, Y is -O-. In other specific embodiments, Y is _-CH2- . _In yet other specific embodiments, Y is _-OCH2CH2- . In a further specific embodiment, Y is -OCH ₂ CH ₂ NR ¹⁴ -.

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ⁷ is -Y- (CR ¹¹ R ¹² ) _p -NHR ¹³ . In some embodiments, the Y series is absent. In some specific embodiments, Y is -O-. In other specific embodiments, Y is _-CH2- . _In yet other specific embodiments, Y is _-OCH2CH2- . In a further specific embodiment, Y is -OCH ₂ CH ₂ NR ¹⁴ -. In some embodiments, the Y series is absent. In some specific embodiments, Y is -C(O)-. In some specific embodiments, Y is -C(O)O-. _In some specific embodiments, Y is _-OCH2CH2O- . In some specific embodiments, Y is -C(O)NR ¹³ -. In some specific embodiments, Y is ^-OCH2CH2NR13 ₍ C) _O- . In some specific embodiments, ^{-OCH2CH2NR13C} ₍ O _{) CH2CH2CH2C (} ^O ) _NR13- . In some specific embodiments, ^{-OCH2CH2CH2NR13C} ₍ O _{) CH2CH2CH2C (} ^O _{) NR13-} .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ⁷ is -Y- (CR ¹¹ R ¹² ) _p -C(O)OR ¹³ . In some embodiments, the Y series is absent. In some specific embodiments, Y is -O-. In other specific embodiments, Y is _-CH2- . _In yet other specific embodiments, Y is _-OCH2CH2- . In a further specific embodiment, Y is -OCH ₂ CH ₂ NR ¹⁴ -. In some embodiments, the Y series is absent. In some specific embodiments, Y is -C(O)-. In some specific embodiments, Y is -C(O)O-. _In some specific embodiments, Y is _-OCH2CH2O- . In some specific embodiments, Y is -C(O)NR ¹³ -. In some specific embodiments, Y is ^-OCH2CH2NR13 ₍ C) _O- . In some specific embodiments, ^{-OCH2CH2NR13C} ₍ O _{) CH2CH2CH2C (} ^O ) _NR13- . In some specific embodiments, ^{-OCH2CH2CH2NR13C} ₍ O _{) CH2CH2CH2C (} ^O _{) NR13-} .

In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R ⁷ is -Y- (CR ¹¹ R ¹² ) _p -O-phenyl-C(O)-C _1-3 alkyl. In some embodiments, the Y series is absent. In some specific embodiments, Y is -O-. In other specific embodiments, Y is _-CH2- . _In yet other specific embodiments, Y is _-OCH2CH2- . In a further specific embodiment, Y is -OCH ₂ CH ₂ NR ¹⁴ -. In some embodiments, the Y series is absent. In some specific embodiments, Y is -C(O)-. In some specific embodiments, Y is -C(O)O-. _In some specific embodiments, Y is _-OCH2CH2O- . In some specific embodiments, Y is -C(O)NR ¹³ -. In some specific embodiments, Y is ^-OCH2CH2NR13 ₍ C) _O- . In some specific embodiments, ^{-OCH2CH2NR13C} ₍ O _{) CH2CH2CH2C (} ^O ) _NR13- . In some specific embodiments, ^{-OCH2CH2CH2NR13C} ₍ O _{) CH2CH2CH2C (} ^O _{) NR13-} .

、

、

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、

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、

、

、

、

、

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。 In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ^R is:

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。 In particular embodiments, provided compounds are of formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The structure of any one of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ^R is:

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N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.2

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.3

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.4

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氯苯胺    1.5

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲基苯胺    1.6

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲氧基苯胺    1.7

2-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苄腈    1.8

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺    1.9

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氯苯胺    1.10

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苄腈    1.11

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲醯胺    1.12

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.13

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3,4-二氟苯胺    1.14

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-(二甲基胺基)苄腈    1.15

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-(二甲基胺基)苄腈    1.16

N3-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-4-氟-N1,N1-二甲苯-1,3-二胺    1.17

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟-5-硝基苯胺    1.18

N-((5-(3-(4-胺基-3,3-二氟丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.19

2-氟-N-((4-(6-甲基吡啶-2-基)-5-(3-(2-(哌啶-4-基)乙氧基)喹啉-6-基)-1H-咪唑-2-基)甲基)苯胺    1.20

N-((5-(3-(2-(3,3-二氟哌啶-4-基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.21

N-((5-(3-(3-胺基丙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.22

N-((5-(3-(4-胺基丁氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.23

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.24

2-氟-N-((4-(6-甲基吡啶-2-基)-5-(2-甲基喹啉-6-基)-1H-咪唑-2-基)甲基)苯胺    1.25

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺    1.26

N-((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺    1.27

N-((5-(3-(2-(2-胺基乙氧基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺    1.28

N-((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.29

N-((5-(3-(2-(2-胺基乙氧基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.31

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.32

N-((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.33

N-((5-(3-(2-(2-胺基乙氧基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.34

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-2-醇    1.35

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺    1.36

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺    1.37

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺    1.38

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.39

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺    1.40

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺    1.41

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)-N-甲基喹啉-3-甲醯胺    1.42

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)-N,N-二甲基喹啉-3-甲醯胺    1.43

(S)-N-((5-(3-((1-胺基丙-2-基)氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.44

(R)-N-((5-(3-((1-胺基丙-2-基)氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.45

N-((5-(3-((1-胺基-2-甲基丙-2-基)氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.46

N-((5-(3-(四氫吖唉-3-基氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.47

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-(甲氧基甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.48

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-(三氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.49

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.50

N-((5-(3-(2-胺基乙基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.51

N-((5-(3-(胺基甲基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.52

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氟-6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.53

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(甲氧基甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.54

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.55

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(三氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.56

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(5-氟-6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.57

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.58

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.59

N-((5-(3-((1r,3r)-3-胺基環丁氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.60

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.61

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(三氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.62

N-((5-(3-(2-胺基乙基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.63

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(5-氟-6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.64

N-(2-胺基乙基)-6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-甲醯胺    1.65

N-(2-胺基乙基)-6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)-N-甲基喹啉-3-甲醯胺    1.66

2-胺基-1-(6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-基)乙-1-酮    1.67

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.68

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺    1.69

N-(2-胺基乙基)-6-(4-(6-(二氟甲基)吡啶-2-基)-2-(((2-氟苯基)胺基)甲基)-1H-咪唑-5-基)喹啉-3-甲醯胺    1.70

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-羧酸甲酯    1.71

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-羧酸    1.72

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-羧酸2-胺基乙酯    1.73

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.74

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.75

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺    1.76

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺    1.77

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺    1.78

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺    1.79

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺    1.80

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺    1.81

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺    1.82

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺    1.83

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺    1.84

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺    1.85

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,5-二氟苯胺    1.86

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3,4-二氟苯胺    1.87

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)-N-(2-羥乙基)喹啉-3-甲醯胺    1.88

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.89

2-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.90

2-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.91

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.92

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.93

4-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.94

4-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.95

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.96

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.97

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.98

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.99

4-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.100

4-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.101

2-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.102

2-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.103

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯    1.104

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.105

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸甲酯    1.106

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸    1.107

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸甲酯    1.108

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸    1.109

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯    1.110

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.111

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯    1.112

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.113

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸甲酯    1.114

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸    1.115

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸甲酯    1.116

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸    1.117

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯    1.118

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.119

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯    1.120

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.121

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸甲酯    1.122

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸    1.123

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸甲酯    1.124

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸    1.125

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯    1.126

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.127

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺    1.128

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.129

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯    1.130

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.131

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸甲酯    1.132

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸    1.133

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸甲酯    1.134

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸    1.135

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯    1.136

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.137

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.138

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.139

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲醯胺    1.140

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺    1.141

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺    1.142

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲醯胺    1.143

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲醯胺    1.144

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    1.145

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    1.146

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲醯胺    1.147

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺    1.148

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲醯胺    1.149

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲醯胺    1.150

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺    1.151

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.152

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.153

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.154

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯    1.155

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.156

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲醯胺    1.157

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺    1.158

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺    1.159

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲醯胺    1.160

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲醯胺    1.161

3-(((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.162

5-(((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.163

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.164

5-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.165

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    1.166

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    1.167

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴苯甲酸    1.168

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴苯甲酸    1.169

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2,6-二氟苯甲酸    1.170

(S)-3-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.171

O-(6-(2-(((2,3-二氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-基)-L-絲胺酸    1.172

(S)-3-(((5-(3-(3-胺基-3-羧丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.173

O-(6-(2-(((2,3-二氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-基)-L-高絲胺酸    1.174

(R)-3-(((5-(3-(3-胺基-2-甲基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.175

(S)-3-(((5-(3-(3-胺基-2-甲基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.176

(R)-3-(((5-(3-(3-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.177

(S)-3-(((5-(3-(3-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.178

2-氟-3-(((5-(3-(3-(甲基胺基)丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸    1.179

3-(((5-(3-(3-胺基-2,2-二氟丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.180

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    1.181

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    1.182

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴苯甲酸    1.183

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴苯甲酸    1.184

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.185

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.186

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺    1.187

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺    1.188

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(甲磺醯基)苯甲醯胺    1.189

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(異丙基磺醯基)苯甲醯胺    1.190

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(三級丁基磺醯基)苯甲醯胺    1.191

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(環丙基磺醯基)苯甲醯胺    1.192

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(甲磺醯基)苯甲醯胺    1.193

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(異丙基磺醯基)苯甲醯胺    1.194

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(三級丁基磺醯基)苯甲醯胺    1.195

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(環丙基磺醯基)苯甲醯胺    1.196

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺    1.197

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺    1.198

3-(((5-(3-(2-(4-(4-乙醯基苯氧基)丁醯胺基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯    1.199

3-(((5-(3-(2-(4-(4-乙醯基苯氧基)丁醯胺基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    1.200

2-羥乙基3-(((5-(3-(2-(4-(4-乙醯基苯氧基)丁醯胺基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸酯    1.201

N-(2-((6-(4-(6-(二氟甲基)吡啶-2-基)-2-(((2,3-二氟苯基)胺基)甲基)-1H-咪唑-5-基)喹啉-3-基)氧基)乙基)-5-肼基-5-側氧基戊醯胺    1.202

N-(3-((6-(2-(((2,3-二氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-基)氧基)丙基)-5-肼基-5-側氧基戊醯胺    2.1

2-((7-(2-(2-氟苯乙基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    2.2

2-((7-(2-(2-氟苄基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    2.3

2-((7-(4-(6-(二氟甲基)吡啶-2-基)-2-(2-氟苄基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    2.4

3-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸甲酯    2.5

3-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸    2.6

3-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸甲酯    2.7

3-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸    2.8

3-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸    2.9

3-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸甲酯    3.1

2-((7-(2-((2-氟苯氧基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    3.2

3-((7-(2-((2-氟苯氧基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)丙-1-胺    3.3

4-((7-(2-((2-氟苯氧基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)丁-1-胺    4.1

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-5-氟吡啶-2-胺    4.2

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)嘧啶-4-胺    4.3

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟吡啶-4-胺    4.4

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲基嘧啶-4-胺    4.5

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-5-氟吡啶-3-胺    4.6

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)嘧啶-5-胺    4.7

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟吡啶-3-胺    4.8

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-4-甲基嘧啶-5-胺    4.9

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯并[d][1,3]二氧呃-5-胺    4.10

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-5-氟吡啶-2-胺    4.11

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟吡啶-3-胺    4.12

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟吡啶-2-胺    4.13

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3,4-二氟吡啶-2-胺    4.14

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲氧基嘧啶-4-胺    4.15

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲氧基嘧啶-5-胺    5.1

2-((7-(2-(三級丁基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    5.2

2-((7-(2-(三級丁基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    6.1

2-((7-(2-(2-(5-氟吡啶-2-基)乙基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    6.2

2-((7-(2-((5-氟吡啶-2-基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    6.3

2-((7-(2-(2-(2-氟吡啶-3-基)乙基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    6.4

2-((7-(2-((2-氟吡啶-3-基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺    7.1

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.2

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.3

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.4

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.5

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.6

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.7

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.8

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.9

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    7.10

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    7.11

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    7.12

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸    7.13

(S)-3-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.14

(S)-5-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.15

(S)-3-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    7.16

(S)-5-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 Formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV') , (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), and (VI) representative compounds, as applicable, include The compounds listed in Table 1 below, and their pharmaceutically acceptable salts. To this end, representative compounds are identified herein by their respective "compound number," sometimes abbreviated as "compound number,""compoundnumber," or "number." Table 1 Representative ALK5 inhibitor compounds Compound number structure name 1.1

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Fluoroaniline 1.2

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-fluoroaniline 1.3

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Fluoroaniline 1.4

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Chloroaniline 1.5

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-methylaniline 1.6

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Methoxyaniline 1.7

2-(((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzonitrile 1.8

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3-Fluoroaniline 1.9

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3-Chloroaniline 1.10

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzonitrile 1.11

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzamide 1.12

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,3-difluoroaniline 1.13

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3,4-difluoroaniline 1.14

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-5-(dimethylamino)benzonitrile 1.15

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-4-(dimethylamino)benzonitrile 1.16

N3-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-4-Fluoro-N1,N1-xylene-1,3-diamine 1.17

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Fluoro-5-nitroaniline 1.18

N-((5-(3-(4-Amino-3,3-difluorobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole -2-yl)methyl)-2-fluoroaniline 1.19

2-Fluoro-N-((4-(6-methylpyridin-2-yl)-5-(3-(2-(piperidin-4-yl)ethoxy)quinolin-6-yl)- 1H-imidazol-2-yl)methyl)aniline 1.20

N-((5-(3-(2-(3,3-difluoropiperidin-4-yl)ethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl )-1H-imidazol-2-yl)methyl)-2-fluoroaniline 1.21

N-((5-(3-(3-aminopropoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-fluoroaniline 1.22

N-((5-(3-(4-Aminobutoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-fluoroaniline 1.23

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoroaniline 1.24

2-Fluoro-N-((4-(6-methylpyridin-2-yl)-5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline 1.25

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3-Fluoroaniline 1.26

N-((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3-Fluoroaniline 1.27

N-((5-(3-(2-(2-aminoethoxy)ethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole -2-yl)methyl)-3-fluoroaniline 1.28

N-((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Fluoroaniline 1.29

N-((5-(3-(2-(2-aminoethoxy)ethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole -2-yl)methyl)-2-fluoroaniline 1.31

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,3-difluoroaniline 1.32

N-((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,3-difluoroaniline 1.33

N-((5-(3-(2-(2-aminoethoxy)ethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole -2-yl)methyl)-2,3-difluoroaniline 1.34

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinolin-2-ol 1.35

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base)-2,4-difluoroaniline 1.36

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base)-3,5-difluoroaniline 1.37

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-3-fluoroaniline 1.38

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base)-2,3-difluoroaniline 1.39

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,4-difluoroaniline 1.40

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3,5-difluoroaniline 1.41

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)-N-methylquinoline -3-Carboxamide 1.42

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)-N,N-dimethyl quinoline-3-carboxamide 1.43

(S)-N-((5-(3-((1-aminopropan-2-yl)oxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl) -1H-imidazol-2-yl)methyl)-2-fluoroaniline 1.44

(R)-N-((5-(3-((1-aminopropan-2-yl)oxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl) -1H-imidazol-2-yl)methyl)-2-fluoroaniline 1.45

N-((5-(3-((1-amino-2-methylpropan-2-yl)oxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl) )-1H-imidazol-2-yl)methyl)-2-fluoroaniline 1.46

N-((5-(3-(Tetrahydroazera-3-yloxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2- yl)methyl)-2-fluoroaniline 1.47

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-(methoxymethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,3-difluoroaniline 1.48

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline 1.49

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2, 3-Difluoroaniline 1.50

N-((5-(3-(2-aminoethyl)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,3-difluoroaniline 1.51

N-((5-(3-(Aminomethyl)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)- 2,3-Difluoroaniline 1.52

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(3-fluoro-6-methylpyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline 1.53

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(methoxymethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,3-difluoroaniline 1.54

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2, 3-Difluoroaniline 1.55

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline 1.56

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline 1.57

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2 ,3-Difluoroaniline 1.58

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methan base)-2,3-difluoroaniline 1.59

N-((5-(3-((1r,3r)-3-aminocyclobutoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H- Imidazol-2-yl)methyl)-2-fluoroaniline 1.60

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,3-difluoroaniline 1.61

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoroaniline 1.62

N-((5-(3-(2-aminoethyl)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Fluoroaniline 1.63

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoroaniline 1.64

N-(2-Aminoethyl)-6-(2-(((2-fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 5-yl)quinoline-3-carboxamide 1.65

N-(2-Aminoethyl)-6-(2-(((2-fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 5-yl)-N-methylquinoline-3-carboxamide 1.66

2-Amino-1-(6-(2-(((2-fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl )quinolin-3-yl)ethan-1-one 1.67

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoroaniline 1.68

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3-fluoroaniline 1.69

N-(2-Aminoethyl)-6-(4-(6-(difluoromethyl)pyridin-2-yl)-2-(((2-fluorophenyl)amino)methyl)- 1H-imidazol-5-yl)quinoline-3-carboxamide 1.70

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-3-carboxylic acid methyl ester 1.71

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-3-carboxylic acid 1.72

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-3-carboxylic acid 2-Aminoethyl ester 1.73

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2- Fluoroaniline 1.74

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2 -Fluoroaniline 1.75

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2 ,4-Difluoroaniline 1.76

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-3 -Fluoroaniline 1.77

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-3 ,5-Difluoroaniline 1.78

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2, 4-Difluoroaniline 1.79

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-3- Fluoroaniline 1.80

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-3, 5-Difluoroaniline 1.81

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,4-difluoroaniline 1.82

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3,5-difluoroaniline 1.83

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methan base)-2,4-difluoroaniline 1.84

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methan base)-3,5-difluoroaniline 1.85

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,5-difluoroaniline 1.86

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3,4-difluoroaniline 1.87

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)-N-(2-hydroxyl) Ethyl)quinoline-3-carboxamide 1.88

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)-2-fluoroaniline 1.89

2-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)methyl benzoate 1.90

2-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzoic acid 1.91

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)methyl benzoate 1.92

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzoic acid 1.93

4-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)methyl benzoate 1.94

4-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzoic acid 1.95

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)methyl benzoate 1.96

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)benzoic acid 1.97

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)methyl benzoate 1.98

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzoic acid 1.99

4-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)methyl benzoate 1.100

4-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzoic acid 1.101

2-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)methyl benzoate 1.102

2-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzoic acid 1.103

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid methyl ester 1.104

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid 1.105

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-4-fluorobenzoic acid methyl ester 1.106

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-4-fluorobenzoic acid 1.107

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-5-fluorobenzoic acid methyl ester 1.108

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-5-fluorobenzoic acid 1.109

5-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid methyl ester 1.110

5-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid 1.111

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan Methyl)amino)-2-fluorobenzoate 1.112

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid 1.113

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan Methyl)amino)-4-fluorobenzoate 1.114

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-4-fluorobenzoic acid 1.115

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan Methyl)amino)-5-fluorobenzoate 1.116

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-5-fluorobenzoic acid 1.117

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan Methyl)amino)-2-fluorobenzoate 1.118

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid 1.119

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid methyl ester 1.120

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid 1.121

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-4-fluorobenzoic acid methyl ester 1.122

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-4-fluorobenzoic acid 1.123

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-5-fluorobenzoic acid methyl ester 1.124

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-5-fluorobenzoic acid 1.125

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid methyl ester 1.126

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid 1.127

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2- yl)methyl)-2-fluoroaniline 1.128

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline 1.129

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid methyl ester 1.130

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid 1.131

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-4-fluorobenzoic acid methyl ester 1.132

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-4-fluorobenzoic acid 1.133

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-5-fluorobenzoic acid methyl ester 1.134

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-5-fluorobenzoic acid 1.135

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid methyl ester 1.136

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid 1.137

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)methyl benzoate 1.138

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)benzoic acid 1.139

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzamide 1.140

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzamide 1.141

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzamide 1.142

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-5-fluorobenzamide 1.143

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-4-fluorobenzamide 1.144

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-chlorobenzoic acid 1.145

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-chlorobenzoic acid 1.146

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzamide 1.147

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzamide 1.148

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-4-fluorobenzamide 1.149

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-5-fluorobenzamide 1.150

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzamide 1.151

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)-2,3-difluoroaniline 1.152

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)methyl benzoate 1.153

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzoic acid 1.154

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)- 1H-imidazol-2-yl)methyl)amino)methyl benzoate 1.155

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)- 1H-imidazol-2-yl)methyl)amino)benzoic acid 1.156

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)benzamide 1.157

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzamide 1.158

5-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzamide 1.159

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-5-fluorobenzamide 1.160

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-4-fluorobenzamide 1.161

3-(((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid 1.162

5-(((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid 1.163

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid 1.164

5-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid 1.165

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan (yl)amino)-2-chlorobenzoic acid 1.166

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan (yl)amino)-2-chlorobenzoic acid 1.167

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-bromobenzoic acid 1.168

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-bromobenzoic acid 1.169

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2,6-difluorobenzoic acid 1.170

(S)-3-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H -Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid 1.171

O-(6-(2-(((2,3-Difluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline olin-3-yl)-L-serine 1.172

(S)-3-(((5-(3-(3-amino-3-carboxypropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H -Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid 1.173

O-(6-(2-(((2,3-Difluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline olin-3-yl)-L-homoserine 1.174

(R)-3-(((5-(3-(3-amino-2-methylpropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)- 1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid 1.175

(S)-3-(((5-(3-(3-amino-2-methylpropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)- 1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid 1.176

(R)-3-(((5-(3-(3-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid 1.177

(S)-3-(((5-(3-(3-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid 1.178

2-Fluoro-3-(((5-(3-(3-(methylamino)propoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H -Imidazol-2-yl)methyl)amino)benzoic acid 1.179

3-(((5-(3-(3-Amino-2,2-difluoropropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H- Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid 1.180

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-chlorobenzoic acid 1.181

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-chlorobenzoic acid 1.182

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromobenzoic acid 1.183

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromobenzoic acid 1.184

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid 1.185

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid 1.186

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methan yl)-3-fluoroaniline 1.187

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,3-difluoroaniline 1.188

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromo-N-(methylsulfonyl)benzylamide 1.189

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromo-N-(isopropylsulfonyl)benzamide 1.190

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromo-N-(tertiarybutylsulfonyl)benzamide 1.191

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromo-N-(cyclopropylsulfonyl)benzamide 1.192

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-2-bromo-N-(methylsulfonyl)benzylamide 1.193

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-2-bromo-N-(isopropylsulfonyl)benzylamide 1.194

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-2-bromo-N-(tertiary butylsulfonyl)benzylamide 1.195

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-2-bromo-N-(cyclopropylsulfonyl)benzylamide 1.196

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)-2,4-difluoroaniline 1.197

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)-3,5-difluoroaniline 1.198

3-(((5-(3-(2-(4-(4-Acetylphenoxy)butamido)ethoxy)quinolin-6-yl)-4-(6-methyl Pyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid methyl ester 1.199

3-(((5-(3-(2-(4-(4-Acetylphenoxy)butamido)ethoxy)quinolin-6-yl)-4-(6-methyl Pyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid 1.200

2-Hydroxyethyl 3-(((5-(3-(2-(4-(4-acetylphenoxy)butyramido)ethoxy)quinolin-6-yl)-4- (6-Methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoate 1.201

N-(2-((6-(4-(6-(difluoromethyl)pyridin-2-yl)-2-(((2,3-difluorophenyl)amino)methyl)-1H -Imidazol-5-yl)quinolin-3-yl)oxy)ethyl)-5-hydrazino-5-pendoxalylamine 1.202

N-(3-((6-(2-(((2,3-difluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazole-5 -yl)quinolin-3-yl)oxy)propyl)-5-hydrazino-5-side oxypentanamide 2.1

2-((7-(2-(2-Fluorophenethyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-2-yl)oxy ) ethyl-1-amine 2.2

2-((7-(2-(2-Fluorobenzyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-2-yl)oxy) Ethan-1-amine 2.3

2-((7-(4-(6-(difluoromethyl)pyridin-2-yl)-2-(2-fluorobenzyl)-1H-imidazol-5-yl)quinoline-2-yl )oxy)ethan-1-amine 2.4

3-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base) methyl benzoate 2.5

3-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base) benzoic acid 2.6

3-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)methyl benzoate 2.7

3-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)benzoic acid 2.8

3-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)benzoic acid 2.9

3-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -Imidazol-2-yl)methyl)benzoic acid methyl ester 3.1

2-((7-(2-((2-Fluorophenoxy)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-2- yl)oxy)ethan-1-amine 3.2

3-((7-(2-((2-Fluorophenoxy)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-2- yl)oxy)propan-1-amine 3.3

4-((7-(2-((2-Fluorophenoxy)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-2- yl)oxy)butan-1-amine 4.1

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-5-fluoropyridin-2-amine 4.2

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)pyrimidin-4-amine 4.3

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-3-fluoropyridin-4-amine 4.4

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-methylpyrimidin-4-amine 4.5

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-5-fluoropyridin-3-amine 4.6

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)pyrimidin-5-amine 4.7

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-fluoropyridin-3-amine 4.8

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-4-methylpyrimidin-5-amine 4.9

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)benzo[d][1,3]diox-5-amine 4.10

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-5-fluoropyridin-2-amine 4.11

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoropyridin-3-amine 4.12

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3-fluoropyridin-2-amine 4.13

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3,4-difluoropyridin-2-amine 4.14

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-methoxypyrimidin-4-amine 4.15

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-methoxypyrimidin-5-amine 5.1

2-((7-(2-(tertiarybutyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-2-yl)oxy)ethyl -1-amine 5.2

2-((7-(2-(tertiarybutyl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazol-5-yl)quinoline-2-yl) oxy)ethan-1-amine 6.1

2-((7-(2-(2-(5-fluoropyridin-2-yl)ethyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quine olin-2-yl)oxy)ethan-1-amine 6.2

2-((7-(2-((5-fluoropyridin-2-yl)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline- 2-yl)oxy)ethan-1-amine 6.3

2-((7-(2-(2-(2-fluoropyridin-3-yl)ethyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quine olin-2-yl)oxy)ethan-1-amine 6.4

2-((7-(2-((2-fluoropyridin-3-yl)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline- 2-yl)oxy)ethan-1-amine 7.1

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid 7.2

3-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amine yl)-2-fluorobenzoic acid 7.3

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid 7.4

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amine yl)-2-fluorobenzoic acid 7.5

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid 7.6

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amino )-2-fluorobenzoic acid 7.7

5-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid 7.8

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amino )-2-fluorobenzoic acid 7.9

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amino )-2-chlorobenzoic acid 7.10

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amino )-2-chlorobenzoic acid 7.11

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)methan (yl)amino)-2-chlorobenzoic acid 7.12

5-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)methan (yl)amino)-2-chlorobenzoic acid 7.13

(S)-3-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid 7.14

(S)-5-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid 7.15

(S)-3-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H -Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid 7.16

(S)-5-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H -Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid

The compounds, salts, and conjugates of the present invention are useful in the treatment and/or prevention of, for example, vaccination, cancer, autoimmune disease, inflammation, fibrosis, sepsis, allergy, asthma, transplant rejection, graft-versus-host disease , immunodeficiency, and infectious diseases.

In certain embodiments, the compounds, salts, and conjugates have utility in cancer treatment as single agents or as combination therapies. In certain embodiments, the compounds, salts, and conjugates have utility as single-agent immunomodulators, vaccine adjuvants, and in combination with conventional cancer therapy. In certain embodiments, the compounds and salts are incorporated into conjugates, which can be used, for example, to potentiate an immune response. In certain embodiments, the present invention provides conjugates comprising a compound or salt described herein and an antibody construct.

In some aspects, the _IC50 value of the ALK5 inhibitor in an ALK5 enzyme inhibition assay is between 0.1 nM and 1000 nM, between 0.1 nM and 100 nM, or between 0.1 nM and 80 nM. Exemplary ALK5 enzyme inhibition assays are shown in Section B of the Examples herein.

In some aspects, the _IC50 value of the ALK5 inhibitor in the TGF-βR1 reporter assay is between 0.1 nM and 1000 nM, between 0.1 nM and 100 nM, between 0.1 nM and 80 nM, or Between 0.1 nM and 10 nM. Exemplary TGF-betaRl reporter assays are shown in Section B of the Examples herein.

In some aspects, the _IC50 value of the ALK5 inhibitor in an ALK5 enzyme inhibition assay is between 0.1 nM and 1000 nM, between 0.1 nM and 100 nM, or between 0.1 nM and 80 nM and _IC50 values for ALK5 inhibitors in the TGF-βR1 reporter assay were between 0.1 nM and 1000 nM, between 0.1 nM and 100 nM, between 0.1 nM and 80 nM, or between 0.1 nM and 10 nM between nM. Linkers vs Linkers - Payloads

The compounds and salts described herein can be bound to linkers (eg, peptide linkers). In certain embodiments, the linker is also attached to the antibody, antibody construct, or target moiety, and may be referred to as an antibody conjugate, antibody construct conjugate, or target moiety conjugate, respectively, or may be referred to as Simply referred to as the conjugate. The linker of the conjugate may not affect the binding of the active portion of the conjugate (eg, an antigen-binding domain, Fc region or domain, target-binding domain, antibody, target portion, or analog thereof) to the target, It can be a homologous binding partner (eg, an antigen). The conjugate may contain multiple linkers, each with one or more linked compounds. Multiple linkers can be the same linker or different linkers contained on a single conjugate or separate conjugates.

As understood by those skilled in the art, a linker binds one or more ALK5 inhibitors to an antibody or an antibody or antigen-binding fragment thereof by forming a covalent bond to the compound at one position and to the antibody or antigen-binding fragment thereof at another position. Its antigen-binding fragments are linked. Covalent linkages can be formed by reaction between functional groups on the linker and functional groups on the ALK5 inhibitor and the antibody or antigen-binding fragment thereof. The expression "linker" as used herein may include (i) a linker in unlinked form, which may include a functional group capable of covalently linking the linker to an ALK5 inhibitor and capable of covalently linking the linker to an antibody or its a functional group of an antigen-binding fragment; (ii) a partially linked form of a linker, which may include a functional group capable of covalently linking the linker to the antibody or antigen-binding fragment thereof and which may be covalently linked to an ALK5 inhibitor compound, or and vice versa; and (iii) a fully linked form of a linker that can be covalently linked to the ALK5 inhibitor compound and the antibody or antigen-binding fragment thereof. In some specific embodiments, the functional group on the linker and the covalent linkage formed between the linker and the antibody or its antigen-binding fragment can be specifically represented as Rx and Rx' , respectively.

Linkers can be short, flexible, rigid, cleavable, non-cleavable, hydrophilic or hydrophobic. Linkers may comprise segments with different properties, such as flexible segments and rigid segments. Linkers may be chemically stable to the extracellular environment, eg, in the bloodstream, or may include labile or selectively stable linkages. Linkers can include linkages designed to be specifically or non-specifically cleaved and/or sacrificed or otherwise cleaved within a cell. Cleavable linkers may be sensitive to enzymes. Cleavable linkers can be cleaved by enzymes such as proteases.

Cleavable linkers may include valine-citrulline (Val-Cit) peptides, valine-alanine (Val-Ala) peptides, phenylalanine-lysine (Phe-Lys), or other Peptides, such as peptides that form recognition and cleavage sites for proteases. The peptide-containing linker may contain a pentafluorophenyl group. The peptide-containing linker may include a succinimide or maleimide group. The peptide-containing linker may include a p-aminobenzoic acid (PABA) group. The peptide-containing linker may include an aminobenzyloxycarbonyl (PABC) group. The peptide-containing linker may include a PABA or PABC group and a pentafluorophenyl group. The peptide-containing linker may include a PABA or PABC group and a succinimidyl group. The peptide-containing linker may include a PABA or PABC group and a maleimide group.

Non-cleavable linkers are generally protease-insensitive and insensitive to intracellular processes. The non-cleavable linker can include a maleimide group. The non-cleavable linker can include a succinimidyl group. The non-cleavable linker can be a maleimido-alkyl-C(O)-linker. The non-cleavable linker can be a maleiminohexyl linker. The maleiminohexyl linker can be N- maleimidomethylcyclohexane-1-carboxylate. The maleiminohexyl linker may include a succinimidyl group. The maleiminohexyl linker may include a pentafluorophenyl group.

The linker can be a combination of maleimidohexanoyl and one or more polyethylene glycol molecules. The linker can be a maleimide-PEG4 linker. The linker may be a combination of a maleiminohexyl linker containing a succinimidyl group and one or more polyethylene glycol molecules. The linker can be a combination of a pentafluorophenyl-containing maleimidohexanoyl linker and one or more polyethylene glycol molecules. The linker may contain maleimide linked to a polyethylene glycol molecule, which may allow for more flexibility of the linker or may be used to extend the linker.

The linker may be a (maleiminohexyl)-(valine-alanine)-(p-aminobenzyloxycarbonyl) linker. The linker can be a (maleiminohexyl)-(valine-citrulline)-(p-aminobenzyloxycarbonyl) linker. The linker can be a (maleiminohexyl)-(phenylalanine-lysine)-(p-aminobenzyloxycarbonyl) linker. The linker may be a linker suitable for attachment to genetically engineered cysteine (THIOMAB). The THIOMAB linker may be a (maleimidohexanoyl)-(valine-citrulline)-(p-aminobenzyloxycarbonyl)-linker.

Linkers may also contain alkylene groups, alkenylene groups, alkynylene groups, polyethers, polyesters, polyamides, polyamino acids, peptides, polypeptides, cleavable peptides, and/or amine groups Fragment of benzyl-carbamate. The linker may contain maleimide at one end and N- hydroxysuccinimidyl ester at the other end. The linker may contain lysine with an N -terminal amine acetylated, as well as valine-citrulline, valine-alanine, or phenylalanine-lysine cleavage sites. A linker can be a linkage created by a microbial transglutaminase, where the linkage can be created between an amine-containing moiety and a moiety that has been genetically engineered to contain glutamic acid, causing the enzyme to move on the glutamic acid side Formation of a catalytic bond between the acyl group of the chain and the primary amine of the lysine chain. The linker may contain a reactive primary amine. The linker can be a sortase A linker. Sortase A linker The LPXTG recognition motif (SEQ ID NO: 49) can be fused to the N -terminal GGG motif using the sortase A enzyme to regenerate the original amide bond. Thus, the linker created will link the portion that binds to the LPXTG recognition motif (SEQ ID NO:49) with the portion that binds to the N -terminal GGG motif. The linker can be a linkage created between the reaction of an unnatural amino acid on one part and an oxime bond formed by modifying a keto group with an alkoxyamine on the other part. The moiety can be part of the conjugate. The moiety of the group can be part of an antibody. The moiety of the group can be part of an immunomodulatory compound such as an ALK5 inhibitor. The group moiety may be part of the binding domain. Linkers can be unsubstituted or substituted with, for example, substituents. Substituents may include, for example, hydroxyl, amino, nitro, cyano, azide, carboxyl, carboxaldehyde, imino, alkyl, alkenyl, alkynyl, alkoxy, alkenyl, alkenyloxy , amide group, and ester group.

In the conjugate, formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III ), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table 1 The compound or salt of any one is linked to the antibody through a linker (also referred to herein as L). L as used herein can be selected from any of the linker moieties discussed herein. The linker linking the compound or salt to the antibody construct of the conjugate can be short, long, hydrophobic, hydrophilic, flexible, or rigid, or can be a fragment each independently having one or more of the above properties The composition is such that the linker can include fragments with different properties. The linker can be multivalent, allowing it to covalently link more than one compound or salt to a single site on the antibody construct, or monovalent, allowing it to covalently link a single compound or salt to a single site on the antibody construct. site.

The linker can be multivalent, allowing it to covalently link more than one ALK5 compound to a single site on the antibody or antigen-binding fragment thereof, or monovalent, allowing it to covalently link a single ALK5 compound to the antibody or antigen-binding fragment thereof of a single point.

In formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV' ), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 In specific embodiments of the compound, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, the compound may further comprise a linker (L) , which produces a linker-payload. Linkers can be covalently bonded to formula (I'), (I''), (I), (II'), (II''), (II), (III'), ( III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or any position on a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof . For example, the linker can be bonded to ^R7 or ^R8 . In some embodiments, the linker is bonded to ^R7 . In further embodiments, the linker is bonded to formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI'') , (VI), or a compound of any one of Table 1, or a nitrogen atom of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof (eg amine) or oxygen atom (eg hydroxyl). The linker may contain a reactive moiety (eg, an electrophile) that can interact with an antibody, antibody construct, or reactive moiety of the target moiety (eg, lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamic acid, unnatural amino acid residues, or glutamic acid residues) react to form covalent bonds. In some specific embodiments, formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any of 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, can be covalently bonded to the antibody through a linker , antibody constructs, or target moieties.

In the conjugate, formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III ), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table 1 A compound of any one, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, is formed by a linker (also referred to herein as L) Linking to an antibody, antibody construct, or target moiety. L as used herein can be selected from any of the linker moieties discussed herein. The linker linking the compound or salt to the antibody, antibody construct, or target moiety of the conjugate can be short, long, hydrophobic, hydrophilic, flexible, or rigid, or can each independently have a or a plurality of fragments with the above properties, so that the linker can include fragments with different properties. Linkers can be multivalent, allowing them to covalently link more than one compound or salt to a single site on the antibody, antibody construct, or target moiety, or monovalent, allowing them to covalently link a single compound or salt to a single site on an antibody, antibody construct, or target moiety.

The linker (L) of the present invention may have about 10 to about 500 atoms in the linker, such as about 10 to about 400 atoms in the linker, such as about 10 to about 300 atoms in the linker. In certain embodiments, the linkers of the present invention have from about 30 to about 400 atoms, eg, from about 30 to about 300 atoms in the linker. The linker (L) of the present invention may have 10 to 500 atoms in the linker, eg 10 to 400 atoms in the linker, eg 10 to 300 atoms in the linker. In certain embodiments, the linkers of the invention have 30 to 400 atoms, eg, 30 to 300 atoms in the linker.

As understood by the skilled artisan, a linker can combine formula (I'), (I''), (I), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of the formulas (I'), (I''), (I), ( II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), ( V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, Racemates, hydrates, solvates, isotopes, or salts are linked to antibodies, antibody constructs, or targeting moieties and compounds to form conjugates. The expression "linker" as used herein is intended to include (i) linkers in unconjugated binding forms, including formulae (I'), (I'') capable of covalently linking the linker to the present invention , (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer thereof , functional groups of tautomers, racemates, hydrates, solvates, isotopes, or salts, and functional groups capable of covalently linking a linker to an antibody, antibody construct, or target moiety; (ii) a partially conjugated form of a linker comprising a functional group capable of covalently linking the linker to the antibody, antibody construct, or target moiety, and which is covalently linked to at least one of the formula (I' ), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV' '), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1, or formula (I' ), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV' '), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmacy thereof isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts of the above, or vice versa; and iii) linkers in fully conjugated forms, including those capable of Covalently linking the linker to formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or A compound of any of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and an antibody, antibody construct, or target part. Some specific embodiments are related. A specific example relates to the contact binding of a linker-compound described herein to a cell surface expressed on a tumor cell under conditions where the linker-compound is covalently bound to the antibody, antibody construct, or target moiety Conjugates formed by antibodies, antibody constructs, or targeting moieties of receptors or tumor-associated antigens. Further specific embodiments relate to constructs. One embodiment relates to a method of making a conjugate formed by contacting a linker-compound under conditions where the linker-compound is covalently bound to an antibody, antibody construct, or target moiety.

In certain specific embodiments, formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any of 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, described in Section B of the title "Compounds" The salts are covalently bonded to the linker (L) to form the linker-payload ((L-P)). The linker can be covalently bonded to any position of the compound if the valence permits. The linker can contain a reactive moiety (eg, an electrophile) that can interact with an antibody, antibody construct, or part of a target moiety (eg, lysine, serine, threonine, cysteine, tyramine) acid, aspartic acid, glutamic acid, unnatural amino acid residues, or glutamic acid residues) react to form covalent bonds. In some embodiments, the linker-payload (which comprises a compound or a salt of a compound in Section B of the heading "Compounds" herein and a linker (L)) is covalently linked to the antibody through the L linker, Antibody constructs, or target moieties. In certain embodiments, any of the compounds or salts described in Section B of the heading "Compounds" herein are covalently bonded to the linker (L). Linkers can be covalently bonded to any position if the valence permits. Linkers may contain reactive moieties (eg, electrophiles) that can interact with portions of antibody constructs (eg, lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamic acid, unnatural amino acid residues, or glutamic acid residues) react to form covalent bonds. In some embodiments, a compound or a salt of a compound in the heading "Compounds" section B herein is covalently linked to the antibody construct through a linker.

In certain embodiments, the linker-payload comprising an ALK5 inhibitor compound of the invention or a salt thereof and a linker (L) is covalently linked to the antibody through L. In a further embodiment, the linker-payload comprising an ALK5 inhibitor compound of the invention or a salt thereof and a linker (L) is covalently bonded to the antibody construct through L. In yet a further embodiment, the linker-payload comprising an ALK5 inhibitor compound of the invention or a salt thereof and a linker (L) is covalently bonded to the target moiety through L. In any of the foregoing embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III') '), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI ), or a compound of any one of Table 1, or a linker-payload of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof , L is a non-cleavable linker. Alternatively, in any of the foregoing embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), ( III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a linker of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof— Payload, L is a cleavable linker, eg, the linker can be cleaved by lysosomal enzymes. In any of the foregoing embodiments, the antibody, antibody construct, or targeting moiety can specifically bind to a tumor antigen. In any of the foregoing embodiments, the antibody, antibody construct, or target portion may further comprise a second antigen or target binding domain.

In some embodiments, the ALK5 inhibitor compounds of the invention are covalently linked to an antibody, antibody construct, or targeting moiety. In specific embodiments, the ALK5 inhibitor compounds of the invention are covalently linked to an antibody. In certain embodiments, the ALK5 inhibitor compounds of the invention are covalently linked to antibody constructs. In certain other embodiments, the compound is covalently linked to the target moiety. In any of the foregoing embodiments, the antibody, antibody construct, or targeting moiety can specifically bind to a tumor antigen. In any of the foregoing embodiments, the antibody, antibody construct, or target portion may further comprise a second antigen or target binding domain.

。 本方法致使高度負載共軛物（DAR高達20），同時維持良好的物理化學性質。此方法可搭配ALK5化合物使用，如下列流程圖所示，其中藥物’意指ALK5化合物。 Exemplary multivalent linkers that can be used to link compounds of the invention to antibody constructs are described herein. For example, Fleximer ^® linker technology has the potential to give high-DAR conjugates good physicochemical properties. As shown below, Fleximer ^® linker technology is based on the incorporation of drug molecules into a cosolvent polyacetal backbone via a series of ester linkages:

. This method results in highly loaded conjugates (DAR up to 20) while maintaining good physicochemical properties. This method can be used with ALK5 compounds, as shown in the following scheme, where drug' means ALK5 compounds.

To use the Fleximer ^® linker technology described in the scheme above, an aliphatic alcohol can be present or introduced into an ALK5 compound. Subsequently, the alcohol moiety was linked to the alanine moiety, followed by synthetic incorporation into the ^Fleximer® linker. In vitro liposomal processing of the conjugate releases the parent alcohol-containing drug.

，其表示連接點，例如，化學或功能部分與化合物的連接點，連接子與本發明化合物的連接點，或連接子與抗體、抗體構築體、或標靶部分的連接點。 In some embodiments, a moiety, construct, or conjugate described herein includes the notation

, which represents a point of attachment, eg, a chemical or functional moiety to a compound, a linker to a compound of the invention, or a linker to an antibody, antibody construct, or target moiety.

By way of example and not limitation, in addition to any other description herein, some cleavable and non-cleavable linkers that may be included in the conjugate are described below.

Sulfonamide linkers can be used to link many of the compounds of the invention to antibody constructs. Sulfonamide linkers are as described herein and in US Patent Publication No. 2019/0038765, the linkers of which are incorporated herein by reference.

Cleavable linkers can be cleaved in vitro, in vivo, or both. Cleavable linkers can include chemically or enzymatically labile or degradable linkages. Cleavable linkers can rely on intracellular processes to release compounds of formula (I), such as reduction reactions in the cytoplasm, exposure to acidic conditions in the lysosome, or cleavage by specific intracellular proteases or other enzymes. A cleavable linker can incorporate one or more chemical bonds that are chemically or enzymatically cleavable, while the remainder of the linker can be non-cleavable.

。 In some embodiments, L is a linker comprising a reactive moiety. In some specific embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a linker-payload of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof,- The L series is represented by the following formula:

.

， 其中每一R ³⁰係獨立地選自於任意地經取代之C ₁-C ₆烷基與任意地經取代之苯基，且RX為反應性部分。RX可包含離去基。RX可為馬來醯亞胺。L可進一步共價鍵接至抗體構築體。在一些具體實施例中，-L-係以下式表示：

， 其中RX ^*為一鍵、琥珀醯亞胺部分、或水解之琥珀醯亞胺部分，其鍵接至抗體構築體殘基，其中RX*上之

代表與抗體構築體之殘基的連接點；且每一R ³⁰係獨立地選自於任意地經取代之C ₁-C ₆烷基與任意地經取代之苯基。 In some specific embodiments, -L is represented by the following formula:

, wherein each R ³⁰ is independently selected from optionally substituted C ₁ -C ₆ alkyl and optionally substituted phenyl, and RX is a reactive moiety. RX may contain a leaving group. RX can be maleimide. L can be further covalently bonded to the antibody construct. In some specific embodiments, -L- is represented by the formula:

, where RX ^* is a bond, a succinimidyl moiety, or a hydrolyzed succinimidyl moiety, which is bonded to an antibody construct residue, where the above RX*

represents the point of attachment to the residue of the antibody construct; and each R ³⁰ is independently selected from optionally substituted C ₁ -C ₆ alkyl and optionally substituted phenyl.

In some specific embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and a linker of linker L- Payload, L contains methylene carbamate units.

In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), Or the compound of any one of Table 1, or its pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt and linker L-RX ^* Linker-Payload (LP), LP is part of the conjugate, and RX ^* comprises a hydrolyzed succinimidyl moiety that is linked to a cysteine residue of the antibody, antibody construct, or target moiety . In any of the foregoing embodiments, the antibody, antibody construct, or targeting moiety comprises an antigen binding domain that can specifically bind to ASGR1 or ASGR2. In any of the foregoing embodiments, the antibody, antibody construct, or targeting moiety comprises an antigen binding domain that specifically binds to ASGR1. In any of the foregoing embodiments, the antibody, antibody construct, or targeting moiety comprises an antigen binding domain that specifically binds to ASGR2.

In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), Or the compound of any one of Table 1, or its pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt and linker L-RX ^* Linker-Payload (LP), LP is part of the conjugate, and RX ^* comprises a hydrolyzed succinamide moiety that is linked to a cysteine residue of the antibody, antibody construct, or target moiety . In any of the foregoing embodiments, the antibody, antibody construct, or targeting moiety comprises an antigen-binding domain that specifically binds to an antigen selected from the group consisting of ASGR1, ASGR2, mesothelin (MSLN), HER2, CEA, TROP2, EPHA2, p-Cadherin, UPK1B, FOLH1, LYPD3, and PVRL4 (connexin-4). The antibody, antibody construct, or target moiety can specifically bind to ASGR1, ASGR2, MSLN, HER2, TROP2, or EPHA2.

By way of example and not limitation, in addition to any other description herein, some cleavable and non-cleavable linkers that may be included in the conjugate are described below.

Linkers may contain chemically labile groups such as hydrazone and/or disulfide groups. Linkers containing chemically labile groups can take advantage of the different properties between plasma and some cytoplasmic compartments. Can promote formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The intracellular conditions for the release of the compound, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof to the hydrazone-containing linker may be intracellular The acidic environment of the body and lysosome, and the disulfide-containing linker can be reduced in the cytoplasm, which can contain high concentrations of thiols (such as glutathione). Plasma stability of linkers containing chemically labile groups can be increased by introducing steric hindrance using substituents adjacent to the chemically labile group.

Acid-labile groups such as hydrazones remain intact during systemic circulation in a blood-neutral pH environment (pH 7.3-7.5) and once the antibody conjugate is internalized into the weakly acidic endosome of the cell (pH 5.0 -6.5) and lysosome (pH 4.5-5.0), the compound of the present invention can be hydrolyzed and released. This pH-dependent release mechanism can be associated with non-specific release of the drug. To increase the stability of the hydrazone group of the linker, the linker can be altered by chemical modification (eg, substitution reactions) to achieve more efficient release in the lysosome with minimal loss in circulation.

及

， 其中M係選自於C ₁-C ₆烷基、芳基、及-O-C ₁-C ₆烷基。 In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt of the linker-payload and linking Sub-L, -L contains a hydrazone moiety. For example, L can be selected from:

and

, wherein M is selected from C ₁ -C ₆ alkyl, aryl, and -OC ₁ -C ₆ alkyl.

。 In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt of the linker-payload and linking Subs L,-L react with the compound to form a hydrazone moiety. For example, a compound may contain a hydrazine moiety and L may contain a ketone or aldehyde moiety, which react to form a hydrazone moiety. For example, L can be:

.

(CIa)

(CIb)

(CIc) 其中D為式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物或鹽類且Ab為抗體構築體，且n代表鍵接至抗體構築體之化合物鍵接連接子（LP）的數量。在特定連接子中，如連接子（Ia），該連接子可包含兩個可切割之基團、雙硫鍵、及腙部分。針對此類連接子，未經修飾之游離化合物的有效釋放可需要酸性pH或雙硫鍵還原與酸性pH。具有單一腙切割位點的連接子（如（Ib）與（Ic））可能有效。 Hydrazone-containing linkers may contain additional cleavage sites, such as additional acid-labile cleavage sites and/or enzyme-labile cleavage sites. Conjugates containing exemplary hydrazone-containing linkers can include, for example, the following structures:

(CIa)

(CIb)

(CIc) wherein D is formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III ), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table 1 A compound or salt of any one and Ab is an antibody construct, and n represents the number of compound-linked linkers (LPs) linked to the antibody construct. In certain linkers, such as linker (Ia), the linker may comprise two cleavable groups, a disulfide bond, and a hydrazone moiety. For such linkers, acidic pH or disulfide bond reduction and acidic pH may be required for efficient release of the unmodified free compound. Linkers with a single hydrazone cleavage site (eg (Ib) and (Ic)) may be effective.

Other acid labile groups that can be included in the linker include cis -acityl-containing linkers. Cis aconityl chemistry can use a carboxylic acid juxtaposed to an amide linkage to accelerate amide hydrolysis under acidic conditions.

Cleavable linkers may also include disulfide groups. Disulfide bonds remain thermodynamically stable at physiological pH and can be engineered to release formulae (I'), (I''), (I), (II'), (II''), (II), ( III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), ( VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof class; when internalized inside a cell, where the cytoplasm can provide a significantly more reducing environment than the extracellular environment. In the cytoplasm, cleavage of disulfide bonds requires the presence of a cytoplasmic thiol cofactor, such as (reduced) glutathione (GSH), so that disulfide-containing linkers are reasonably stable in circulation, selecting Sexual release formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 compound, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof. The intracellular enzyme protein disulfide isomerase or similar enzymes capable of cleaving disulfide bonds may also contribute to the preferential cleavage of intracellular disulfide bonds. GSH can be present in cells at concentrations ranging from 0.5-10 mM, compared to significantly lower concentrations of GSH or cysteine (the most abundant low molecular weight thiol) in the circulation, around 5 µM. Tumor cells, where irregular blood flow can lead to hypoxia, can lead to enhanced reductase activity and thus even higher glutathione concentrations. The in vivo stability of disulfide-containing linkers can be enhanced by chemical modification of the linker, eg, the use of steric hindrance adjacent to the disulfide bond.

(CIIa)

(CIIb)

(CIIc) 其中D為式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類，且Ab為抗體、抗體構築體、或標靶部分，n代表鍵接至抗體、抗體構築體、或標靶部分之化合物鍵接連接子（L）的數量且R在每次出現時係獨立地選自於例如氫或烷基。增加雙硫鍵附近的空間位阻可增加連接子的穩定性。當一或多個R基團係選自於低級烷基（如甲基）時，諸如(CIIa)與(CIIc)等結構可顯示體內穩定性的增加。 Contains formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV' ), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 Compounds, or conjugates of pharmaceutically acceptable isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts thereof, and conjugates including exemplary disulfide-containing linkers can be Includes the following structures:

(CIIa)

(CIIb)

(CIIc) wherein D is formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III ), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table 1 A compound of any one, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and Ab is an antibody, an antibody construct, or Target moiety, n represents the number of compound linkages (L) bonded to the antibody, antibody construct, or target moiety and R at each occurrence is independently selected from, for example, hydrogen or alkyl. Increasing the steric hindrance near the disulfide bond increases the stability of the linker. Structures such as (CIIa) and (CIIc) may exhibit increased in vivo stability when one or more R groups are selected from lower alkyl groups (eg, methyl).

Another type of linker that can be used is a linker that can be specifically cleaved by an enzyme. For example, linkers can be cleaved using lysosomal enzymes. Such linkers may be peptide-based, or may include peptide regions, which may serve as substrates for enzymes. Peptide-based linkers are more stable in the plasma and extracellular environment than chemically labile linkers.

Peptide bonds may have good serum stability due to the very low activity of lysosomal proteolytic enzymes in blood due to endogenous inhibitors and the more unfavorable high pH compared to lysosomes. Formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV') , (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1 , or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof from an antibody, antibody construct, or target moiety conjugate Occurs due to the action of lysosomal proteases such as cellular autolysin and cytoplasmin. In certain tumor tissues, these proteases can be present at high levels. The linker can be cleaved using lysosomal enzymes. The lysosomal enzyme can be, for example, cellular autolysin B, beta-glucuronidase, or beta-galactosidase.

Cleavable peptides can be selected from tetrapeptides (such as Gly-Phe-Leu-Gly (SEQ ID NO: 235), Ala-Leu-Ala-Leu (SEQ ID NO: 236)) or dipeptides (such as Val-Cit, Val-Ala, and Phe-Lys). Dipeptides may have lower hydrophobicity than long-chain peptides.

A number of dipeptide-based cleavable linkers can be used with antibodies, antibody constructs, or targeting moiety constructs to form formulas (I'), (I''), (I) as described herein , (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V') , (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer thereof conjugates of compounds, racemates, hydrates, solvates, isotopes, or salts.

Enzymatically cleavable linkers may include self-sacrificial spacers to spatially separate formula (I'), (I''), (I), (II'), (II'' from the enzyme cleavage site ), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V) , (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, Solvates, isotopes, or salts. Formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV') , (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1 , or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof. Direct attachment of a peptide linker can result in formula (I'), ( I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable compound thereof Isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts, or formula (I'), (I''), (I), (II'), ( II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, Proteolytic release of amino acid adducts such as hydrates, solvates, isotopes, or salts, impairing their activity. The use of a self-sacrificial spacer allows the elimination of fully activated, chemically unmodified formulae (I'), (I''), (I), (II'), (II'' upon hydrolysis of the amide bond ), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V) , (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, Solvates, isotopes, or salts.

A self-sacrificing spacer can be a bifunctional p-aminobenzyl alcohol (PABA) group, which can be linked to the peptide through an amine group to form an amide bond, and formulas (I'), (I') '), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV ), (V'), (V''), (V), (VI'), (VI''), (VI), or the amine-containing compound of any one of Table 1, or a pharmaceutically acceptable compound thereof Isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts can be attached to the benzyl hydroxy group of the linker through a carbamate function (to give p-amidobenzyl carbamate, PABC). The resulting pro-compound can be activated upon protease-mediated cleavage, resulting in a 1,6-elimination reaction that releases formulae (I'), (I''), (I), (II'), (II ''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), ( V), (VI'), (VI''), (VI), or the unmodified compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate thereof Forms, hydrates, solvates, isotopes, or salts, carbon dioxide, and residues of linker groups.

其中D代表具有式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類結構的未經修飾藥物或有效負載。 The following scheme illustrates the fragmentation reaction of p-amidobenzylcarbamate and formulas (I'), (I''), (I), (II'), (II''), (II) , (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI') , (VI″), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or the release of salts:

wherein D represents the formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 A compound of one, or an unmodified drug or payload of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt structure thereof.

， 其中胜肽包含1至10個胺基酸，且

代表與化合物（有效負載）的連接點。 In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a linker-payload of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof,- The L series is represented by the following formula:

, wherein the peptide contains 1 to 10 amino acids, and

Represents the point of attachment to the compound (payload).

， 其中胜肽包含1至10個胺基酸且RX為反應性部分，且

代表與化合物（有效負載）的連接點。 In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a linker-payload of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof,- The L series is represented by the following formula:

, wherein the peptide comprises 1 to 10 amino acids and RX is the reactive moiety, and

Represents the point of attachment to the compound (payload).

， 其中胜肽包含1至10個胺基酸，L ⁴為胜肽之C端，且L ⁵係選自於一鍵、伸烷基、及雜伸烷基，其中L ⁵係任意地以一或多個獨立地選自於R ³²之基團取代，RX為反應性部分；且R ³²在每次出現時係獨立地選自於鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、-NO ₂；且C _1-10烷基、C _2-10烯基、及C _2-10炔基在每次出現時每一者係獨立地任意地以一或多個選自於下列之取代基取代：鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、及-NO ₂。反應性部分可選自於親電試劑，例如αβ-不飽和羰基（如馬來醯亞胺）及離去基。在一些具體實施例中，RX包含離去基。在特定具體實施例中，RX為馬來醯亞胺。 In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a linker-payload of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof,- The L series is represented by the following formula:

, wherein the peptide contains 1 to 10 amino acids, L ⁴ is the C-terminus of the peptide, and L ⁵ is selected from a bond, an alkylene group, and a heteroalkylene group, wherein L ⁵ is arbitrarily represented by a substituted with one or more groups independently selected from ^R32 , RX being the reactive moiety; and ^R32 at each occurrence is independently selected from halogen, -OH, -CN, -O-alkyl, - SH, =O, =S, -S(O)2OH, _-NH2 , _{-NO2 ;} and _C1-10 alkyl, _C2-10 alkenyl, and _C2-10 alkynyl at each occurrence each is independently optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O ) ₂ OH, -NH ₂ , and -NO ₂ . Reactive moieties can be selected from electrophiles such as αβ-unsaturated carbonyl groups (eg, maleimide) and leaving groups. In some embodiments, RX includes a leaving group. In certain specific embodiments, RX is maleimide.

， 其中抗體為抗體、RX ^*抗體構築體、或含有1至10個胺基酸的標靶部分胜肽、RX ^*為可與抗體上之部分反應的反應性部分、抗體構築體、或形成共軛物的標靶部分，且

代表與化合物（有效負載）的連接點。 In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a linker-payload of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, LP is part of the conjugate and -L is represented by the formula:

, wherein the antibody is an antibody, an RX ^* antibody construct, or a target moiety peptide containing 1 to 10 amino acids, and RX ^* is a reactive moiety that can react with a moiety on the antibody, an antibody construct, or forms a co- the target portion of the conjugate, and

Represents the point of attachment to the compound (payload).

， 其中胜肽包含1至10個胺基酸，L ⁴為胜肽之C端且L ⁵係選自於一鍵、伸烷基、及雜伸烷基，每一者係任意地以一或多個獨立地選自於R ¹²之基團取代；左邊的

代表與化合物（有效負載）的連接點，RX ^*為一鍵、琥珀醯亞胺部分、或水解之琥珀醯亞胺部分，其連接在抗體、抗體構築體、或標靶部分之殘基上右邊的

。 In a further embodiment, LP is part of a conjugate and -L- is represented by the formula:

, wherein the peptide comprises 1 to 10 amino acids, L ⁴ is the C-terminus of the peptide and L ⁵ is selected from a bond, an alkylene group, and a heteroalkylene group, each of which is optionally represented by one or A plurality of groups independently selected from R ¹² are substituted; the left

Represents the point of attachment to the compound (payload), RX ^* is a bond, a succinimidyl moiety, or a hydrolyzed succinimidyl moiety that is attached to the right of a residue in the antibody, antibody construct, or target moiety of

.

， 其中胜肽包含1至10個胺基酸，L ⁴代表胜肽之C端且L ⁵係選自於一鍵、伸烷基、及雜伸烷基，其中L ⁵係任意地以一或多個獨立地選自於R ³²之基團取代；RX ^*為一鍵、琥珀醯亞胺部分、或水解之琥珀醯亞胺部分，其鍵接至抗體、抗體構築體、或標靶部分之殘基，其中RX*上之

代表與抗體、抗體構築體、或標靶部分之殘基的連接點；且R ³²在每次出現時係獨立地選自於鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、-NO ₂；且C _1-10烷基、C _2-10烯基、及C _2-10炔基在每次出現時每一者係獨立地任意地以一或多個選自於下列之取代基取代：鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、及-NO ₂。在一些具體實施例中，L之胜肽包含Val-Cit或Val-Ala。 In some embodiments, LP is part of a conjugate and -L- is represented by the formula:

, wherein the peptide contains 1 to 10 amino acids, L ⁴ represents the C-terminus of the peptide and L ⁵ is selected from a bond, alkylene, and heteroalkyl, wherein L ⁵ is optionally one or A plurality of group substitutions independently selected from R ³² ; RX ^* is a bond, a succinimidyl moiety, or a hydrolyzed succinimidyl moiety that is bonded to the antibody, antibody construct, or one of the target moieties residues above RX*

represents the point of attachment to a residue of the antibody, antibody construct, or target moiety; and ^R at each occurrence is independently selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, -NH ₂ , -NO ₂ ; and C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl in each occurrence every One is independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, _-NH2 , and _-NO2 . In some embodiments, the L-peptide comprises Val-Cit or Val-Ala.

、

、

、或

。 In any of the foregoing embodiments, -L is:

,

,

,or

.

Heterocyclic variants of this self-sacrificing group can also be used.

The cleavable linker on the enzyme may be a β-glucuronic acid-based linker. Formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV') , (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1 , or pharmaceutically acceptable isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts thereof. Flexible release can be achieved by utilizing the lysosomal enzyme β-glucuronidase It is achieved by cleaving the β-glucuronide glycosidic bond. This enzyme is abundant in lysosomes and can be overexpressed in some tumor types, while extracellular enzyme activity may be low. β-glucuronic acid-based linkers can be used to circumvent formulae (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI'') , (VI), or a compound of any one of Table 1, or an antibody construct of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof The agglutination tendency of the conjugate is due to the hydrophilic nature of β-glucuronide. In some embodiments, a beta-glucuronic acid-based linker can link an antibody, antibody construct, or target moiety to formula (I'), (I''), (I), (II '), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V ''), (V), (VI'), (VI''), (VI), or the hydrophobic compound of any one of Table 1, or a pharmaceutically acceptable isomer or tautomer thereof , racemates, hydrates, solvates, isotopes, or salts.

其中Ab代表抗體、抗體構築體、或標靶部分。 The following flow diagrams illustrate formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III) , (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The release of any compound, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, derived from formula (I'), ( I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable compound thereof (D) of conjugates of isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts containing a β-glucuronic acid-based linker:

where Ab represents an antibody, antibody construct, or target moiety.

There are many cleavable β-glucuronic acid-based linkers suitable for linking drugs to the antibody, such as auristatin, camptothecin analogs, doxorubicin Analogs, CBI minor-groove binder, and psymberin. Those beta-glucuronic acid based linkers can be used in the conjugate. In some embodiments, the cleavable linker on the enzyme is a β-galactoside-based linker. β-Galactoside is abundantly present in lysosomes, while the activity of extracellular enzymes is very low.

In addition, formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The compounds, or pharmaceutically acceptable isomers, tautomers, racemates, hydrates, solvates, isotopes, or salts thereof, contain a phenolic group, which can be covalently bonded to the linkage through the phenolic oxygen son. One such linker relies on a method in which a diamino-ethane "Space Link" is used to combine with traditional "PABO-based self-sacrificing groups" to generate phenols.

Cleavable linkers can include non-cleavable moieties or fragments, and/or cleavable fragments or moieties can be included in other non-cleavable linkers, making them cleavable. By way of example only, polyethylene glycol (PEG) and related polymers can include cleavable groups in the polymer backbone. For example, a polyethylene glycol or polymeric linker can include one or more cleavable groups, such as disulfide bonds, hydrazones, or dipeptides.

Other cleavable linkages that can be included in the linker can include ester linkages through PEG carboxylic acids or activated PEG carboxylic acids with formula (I'), (I''), (I), (II '), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V ''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, exo Reaction formation of ethanol groups on racemates, hydrates, solvates, isotopes, or salts, wherein such ester groups can be hydrolyzed under physiological conditions to release formula (I'), (I''), (I ), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V' ), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer thereof Constructs, racemates, hydrates, solvates, isotopes, or salts. Hydrolytically cleavable linkages may include carbonate linkages; imine linkages due to the reaction of amines with aldehydes; phosphate linkages due to the reaction of ethanol with phosphate groups; acetal linkages due to the reaction of aldehydes with ethanol or orthoester linkages of the reaction product of formate and ethanol; and oligonucleotide linkages resulting from the reaction of a phosphamide group (including at the polymer end) with the 5' hydroxyl group of an oligonucleotide .

(CIIIa)

(CIIIb)

(CIIIc)

(CIIId) 或其鹽類，其中：「胜肽」代表可利用溶酶體酵素切割的胜肽（以N→C方向描繪，其中胜肽包括胺基與羧基「末端」）；T代表包含一或多個乙二醇單元或伸烷基鏈或其組合的聚合物；R ^a係選自於氫、烷基、磺酸酯、及甲基磺酸酯；R ^y為氫或C _1-4烷基-(O) _r-(C _1-4伸烷基) _s-G ¹或C _1-4烷基-(N)-[(C _1-4伸烷基)-G ¹] ₂；R ^z為C _1-4烷基-(O) _r-(C _1-4伸烷基) _s-G ²；G ¹為-SO ₃H、-CO ₂H、PEG 4-32、或糖部分；G ²為-SO ₃H、-CO ₂H、或PEG 4-32部分；r為0或1；s為0或1；p為0至5之整數；q為0或1；x為0或1；y為0或1；

代表連接子與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點；且*代表與連接子之其餘部分的連接點。 The linker may contain an enzymatically cleavable peptide, such as a linker of formula (CIIIa), (CIIIb), (CIIIc), or (CIIId):

(CIIIa)

(CIIIb)

(CIIIc)

(CIIId) or its salts, wherein: "peptide" represents a peptide that can be cleaved by lysosomal enzymes (depicted in the N→C direction, where the peptide includes an amine group and a carboxyl "terminal"); T represents a peptide containing a or a polymer of multiple ethylene glycol units or alkylene chains or combinations thereof; R ^a is selected from hydrogen, alkyl, sulfonate, and methylsulfonate; R ^y is hydrogen or C _1-4 Alkyl-(O) _r -(C _1-4 alkylene) _s -G ¹ or C _1-4 alkyl-(N)-[(C _1-4 alkylene)-G ¹ ] ₂ ; R ^z is C _1-4 alkyl-(O) _r -(C _1-4 alkylene) _s -G ² ; G ¹ is -SO ₃ H, -CO ₂ H, PEG 4-32, or a sugar moiety; G ² is -SO ₃ H, -CO ₂ H, or a PEG 4-32 moiety; r is 0 or 1; s is 0 or 1; p is an integer from 0 to 5; q is 0 or 1; 1; y is 0 or 1;

Represents a linker with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 A compound of one, or a point of attachment to a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; and * represents the remainder of the linker connection point.

In certain embodiments, peptides can be selected that contain natural amino acids, non-natural amino acids, or any combination thereof. In some embodiments, the peptide can be a tripeptide or a dipeptide. In certain embodiments, the dipeptide comprises an L-amino acid, such as Val-Cit; Cit-Val; Ala-Ala; Ala-Cit; Cit-Ala; Asn-Cit; Cit-Asn; Cit-Cit ;Val-Glu;Glu-Val;Ser-Cit;Cit-Ser;Lys-Cit;Cit-Lys;Asp-Cit;Cit-Asp;Ala-Val;Val-Ala;Phe-Lys;Lys-Phe;Val -Lys;Lys-Val;Ala-Lys;Lys-Ala;Phe-Cit;Cit-Phe;Leu-Cit;Cit-Leu;Ile-Cit;Cit-Ile;Phe-Arg;Arg-Phe;Cit-Trp ; and Trp-Cit, or a salt thereof.

(CIIIa.1)

(CIIIa.2)

(CIIIa.3)

(CIIIa.4)

(CIIIa.5)

(CIIIa.6)

(CIIIa.7)

(CIIIa.8)

(CIIIa.9)

(CIIIa.10) 其中

代表連接子(L)與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接位置。 Exemplary embodiments of linkers of structural formula (CIIIa) are depicted below (as depicted, linkers include reactive groups suitable for covalently linking linkers to antibodies, antibody constructs, or target moieties) :

(CIIIa.1)

(CIIIa.2)

(CIIIa.3)

(CIIIa.4)

(CIIIa.5)

(CIIIa.6)

(CIIIa.7)

(CIIIa.8)

(CIIIa.9)

(CIIIa.10) where

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or the attachment position of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

(CIIIb.1)

(CIIIb.2)

(CIIIb.3)

(CIIIb.4)

(CIIIb.5)

(CIIIb.6)

(CIIIb.7)

(CIIIb.8)

(CIIIb.9)

(CIIIb.10)

(CIIIb.11)

(CIIIb.12)

(CIIIb.13)

(CIIIb.14)

(CIIIb.15)

(CIIIb.16)

(CIIIb.17)

(CIIIb.18)

(CIIIb.19)

(CIIIb.20)

(CIIIb.21)

(CIIIb.22)

(CIIIc.1)

(CIIIc.2)

(CIIIc.3)

(CIIIc.4)

(CIIIc.5)

(CIIIc.6)

(CIIIc.7)

(CIIIc.8)

(CIIIc.9)

(CIIIc.10)

(CIIIc.11)

(CIIIc.12)

(CIIId.1)

(CIIId.2)

(CIIId.3)

(CIIId.4) 其中

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接位置。 Exemplary embodiments of linkers of structural formula (CIIIb), (CIIIc), or (CIIId) that can be included in the conjugate can include the linkers depicted below (as depicted, linkers include suitable linkers for Reactive groups covalently linked to antibody constructs):

(CIIIb.1)

(CIIIb.2)

(CIIIb.3)

(CIIIb.4)

(CIIIb.5)

(CIIIb.6)

(CIIIb.7)

(CIIIb.8)

(CIIIb.9)

(CIIIb.10)

(CIIIb.11)

(CIIIb.12)

(CIIIb.13)

(CIIIb.14)

(CIIIb.15)

(CIIIb.16)

(CIIIb.17)

(CIIIb.18)

(CIIIb.19)

(CIIIb.20)

(CIIIb.21)

(CIIIb.22)

(CIIIc.1)

(CIIIc.2)

(CIIIc.3)

(CIIIc.4)

(CIIIc.5)

(CIIIc.6)

(CIIIc.7)

(CIIIc.8)

(CIIIc.9)

(CIIIc.10)

(CIIIc.11)

(CIIIc.12)

(CIIId.1)

(CIIId.2)

(CIIId.3)

(CIIId.4) where

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The position of attachment of a compound, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

(CIVa)

(CIVb)

(CIVc)

(CIVd)

(CIVe) 或其鹽類，其中：q為0或1；r為0或1；X ¹為CH ₂、O、或NH；

代表連接子(L)與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點；且*代表與連接子之其餘部分的連接點。 Linkers may contain enzymatically cleavable sugar moieties, for example, linkers containing structural formula (CIVa), (CIVb), (CIVc), (CIVd), or (CIVe):

(CIVa)

(CIVb)

(CIVc)

(CIVd)

(CIVe) or a salt thereof, wherein: q is 0 or 1; r is 0 or 1; X ¹ is CH ₂ , O, or NH;

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt of the point of attachment; and * represents a linker connection point for the rest.

(CIVa.1)

(CIVa.2)

(CIVa.3)

(CIVa.4)

(CIVa.5)

(CIVa.6)

(CIVa.7)

(CIVa.8)

(CIVa.9)

(CIVa.10)

(CIVa.11)

(CIVa.12) 其中

代表連接子(L)與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點。 As described herein, can be included in formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or A compound of any of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt of an antibody construct conjugate thereof Exemplary embodiments of linkers of structural formula (CIVa) can include the following depicted linkers (as depicted, linkers include groups suitable for covalent linkage of linkers to antibody constructs):

(CIVa.1)

(CIVa.2)

(CIVa.3)

(CIVa.4)

(CIVa.5)

(CIVa.6)

(CIVa.7)

(CIVa.8)

(CIVa.9)

(CIVa.10)

(CIVa.11)

(CIVa.12) where

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or the point of attachment of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

(CIVb.1)

(CIVb.2)

(CIVb.3)

(CIVb.4)

(CIVb.5)

(CIVb.6)

(CIVb.7)

(CIVb.8)

(CIVb.9)

(CIVb.10) 其中

代表連接子(L)與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點。 Exemplary embodiments of linkers of structural formula (CIVb) that can be included in the conjugate include the linkers depicted below (as depicted, the linkers include those suitable for covalent linkage of the linker to the antibody construct. group):

(CIVb.1)

(CIVb.2)

(CIVb.3)

(CIVb.4)

(CIVb.5)

(CIVb.6)

(CIVb.7)

(CIVb.8)

(CIVb.9)

(CIVb.10) where

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or the point of attachment of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

(CIVc.1)

(CIVc.2)

(CIVc.3)

(CIVc.4)

(CIVc.5)

(CIVc.6)

(CIVc.7)

(CIVc.8)

(CIVc.9)

(CIVc.10)

(CIVc.11) 其中

代表連接子(L)與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點。 Exemplary embodiments of linkers of structural formula (CIVc) that can be included in the conjugate include the linkers depicted below (as depicted, the linkers include those suitable for covalent linkage of the linker to the antibody construct. group):

(CIVc.1)

(CIVc.2)

(CIVc.3)

(CIVc.4)

(CIVc.5)

(CIVc.6)

(CIVc.7)

(CIVc.8)

(CIVc.9)

(CIVc.10)

(CIVc.11) where

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or the point of attachment of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

(CIVd.1)

(CIVd.2)

(CIVd.3)

(CIVd.4)

(CIVd.5)

(CIVd.6) 其中

代表連接子(L)與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點。 Exemplary embodiments of linkers of structural formula (CIVd) that can be included in the conjugate include the linkers depicted below (as depicted, the linkers include those suitable for covalent linkage of the linker to the antibody construct. group):

(CIVd.1)

(CIVd.2)

(CIVd.3)

(CIVd.4)

(CIVd.5)

(CIVd.6) where

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or the point of attachment of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

(CIVe.1)

(CIVe.2) 其中

代表連接子(L)與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點。 Exemplary embodiments of linkers of structural formula (CIVe) that can be included in the conjugate include the linkers depicted below (as depicted, the linkers include those suitable for covalent linkage of the linker to the antibody construct. group):

(CIVe.1)

(CIVe.2) where

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or the point of attachment of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

Although cleavable linkers may provide certain advantages, linkers containing conjugates need not be cleavable. For non-cleavable linkers, the release of the payload compound may not depend on the different properties between plasma and some cytoplasmic compartments. Through antigen-mediated endocytosis, the conjugate releases the payload compound upon internalization and is delivered to the lysosomal compartment, where the antibody, antibody construct, or target moiety is accessible for intracellular proteolytic degradation Degraded to the amino acid level. This process releases payload compound derivatives (metabolites containing non-cleavable linker-heterocyclic compound conjugates) via payload compounds, linkers, and amino acid residues or linkers Covalently linked residues are formed. Payload compound derivatives of conjugates with non-cleavable linkers can be more hydrophilic and less membrane permeable than conjugates with cleavable linkers, which can lead to bystander effects Fewer and less non-specific toxicity. Conjugates with non-cleavable linkers are more stable in cycling than conjugates with cleavable linkers. The non-cleavable linker can include an alkylene chain, or can be polymerizable (eg, based on polyolefin-based glycol polymers, amide polymers), or can include alkylene chains, polyolefin-based glycols, and /or fragments of amide polymers. The linker may contain polyethylene glycol fragments having 1 to 6 ethylene glycol units.

(CVa)

(CVb)

(CVc)

(CVd)

(CVe) 或其鹽類，其中：R ^a係選自於氫、烷基、磺酸酯、及甲基磺酸酯；R ^x為包括能共價鍵聯連接子與抗體構築體之官能基的反應性部分；且

代表連接子(L)與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點。 The linker may be non-cleavable in vivo, eg, containing formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), ( VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof and linker L Linker - Payload; -L is represented by the following formula:

(CVa)

(CVb)

(CVc)

(CVd)

(CVe) or its salts, wherein: R ^a is selected from hydrogen, alkyl, sulfonate, and methylsulfonate; R ^x is a functional group including a covalently linked linker and an antibody construct the reactive portion of ; and

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or the point of attachment of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

， 其中n = 0-9且

代表與化合物（有效負載）的連接點。 In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof and a linker of linker L- Payload; -L is represented by the following formula:

, where n = 0-9 and

Represents the point of attachment to the compound (payload).

， 其中RX包含反應性部分（如馬來醯亞胺或離去基），n = 0-9，且

代表與化合物（有效負載）的連接點。 In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof and a linker of linker L- Payload; -L is represented by the following formula:

, where RX contains a reactive moiety (such as maleimide or a leaving group), n = 0-9, and

Represents the point of attachment to the compound (payload).

， RX ^*為連接在抗體、抗體構築體、或標靶部分之殘基右邊上之

之一鍵、琥珀醯亞胺部分、或水解之琥珀醯亞胺部分，左邊上之

代表與化合物（有效負載）的連接點，且n = 0-9。 In some embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, linker L, and antibody, An antibody construct, or a conjugate of a target moiety; -L- is represented by the following formula:

, RX ^* is a residue attached to the right of the antibody, antibody construct, or target moiety

A bond, succinimide moiety, or hydrolyzed succinimide moiety, top left

represents the point of attachment to the compound (payload) and n = 0-9.

代表連接子（L）與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點：

(CVa.1)

(CVc.1)

(CVc.2)

(CVd.1)

(CVd.2)

(CVd.3)

(CVd.4)

(CVe.1) Exemplary embodiments of linkers of structural formula (CVa)-(Ve) that can be included in the conjugate include the linkers depicted below (as depicted, linkers include those suitable for use in linkers and antibody constructs) valence-linked groups, and

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or a point of attachment of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof:

(CVa.1)

(CVc.1)

(CVc.2)

(CVd.1)

(CVd.2)

(CVd.3)

(CVd.4)

(CVe.1)

Linking groups used to link the linker to the antibody, antibody construct, or target moiety can be electrophilic in nature and include, for example, maleimide groups, activated disulfide bonds, activated esters (eg NHS esters and HOBt esters), haloformates, acid halides, alkyl, and benzyl halides (eg haloacetamides). Also used with the ALK5 inhibitor compounds of the present invention are emerging technologies related to "self-stabilizing" maleimides and "bridging disulfide bonds". Examples of linker-based cysteines are provided in PCT Patent Application Publication No. WO 2020/092385, the linkers of which are incorporated herein by reference.

。 Maleimide groups are commonly used in the preparation of conjugates due to their specificity in reacting with thiol groups such as cysteine groups of antibodies, antibody constructs, or targeting moieties. The reaction between a thiol group of an antibody, antibody construct, or target moiety and a drug with a linker (linker-load) involves a maleimide group according to the following scheme:

.

。 The reverse reaction of the elimination of the sulfur-substituted succinimide may also occur. This reverse reaction is not required because the maleimide group may subsequently react with another available thiol group, such as in other proteins with available cysteine in vivo. Accordingly, the reverse reaction can destroy the specificity of the conjugate. One way to prevent the reverse reaction is to incorporate basic groups into the linking groups shown in the scheme above. Without wishing to be bound by theory, the presence of basic groups may increase the nucleophilicity of nearby water molecules to facilitate ring-opening hydrolysis of the succinimidyl group. The hydrolyzed form of the linking group is resistant to deconjugation in the presence of plasma proteins. So-called "self-stabilizing" linkers provide conjugates with improved stability. A representative flowchart is shown below:

.

。 The hydrolysis reaction shown in the above scheme may occur at the carbonyl group of the succinimidyl group. From this, two possible isomers can be produced, as shown below:

.

The rate of hydrolysis of sulfur-substituted succinimidyl groups can be adjusted by modifying the identity of the bases and the distance between the bases and the maleimide groups, and by, for example, improving the specificity and stability of the conjugates properties to optimize conjugate delivery to the target.

A base suitable for inclusion in a linker (eg, any L with a maleimide group) can facilitate the antibody, antibody construct, or target prior to conjugation to the antibody, antibody construct, or target moiety. Hydrolysis of nearby succinimidyl groups formed upon conjugation of the target moiety to the linker. Bases can include, for example, amines (such as -N(R ²⁶ )(R ²⁷ ), where R ²⁶ and R ²⁷ are independently selected from H and C _1-6 alkyl), nitrogen-containing heterocycles (such as 3 to 12 membered heterocycles including one or more nitrogen atoms and optionally one or more double bonds), amidines, guanidines, and carbocyclic or heterocycles substituted with one or more amine groups (such as 3- to 12-membered aryl Aromatic or non-aromatic rings, which optionally include heteroatoms (such as nitrogen atoms) and are substituted with one or more amines of the type -N(R ²⁶ )(R ²⁷ ), wherein R ²⁶ and R ²⁷ are independently selected from in H or C _1-6 alkyl). The base unit can be separated from the maleimide group by, for example, an alkylene chain of the form -( _CH2 ) _m- , where m is an integer from 0 to 10. The alkylene chain can be optionally substituted with other functional groups described herein.

Linkers (L) with maleimide groups may include electron withdrawing groups such as -C(O)R, =O, -CN, -NO ₂ , -CX ₃ , -X, -C(O )OR, _-C (O)NR2, _-C (O)R, _-C (O)X, _-SO2R , _-SO2OR , _-SO2NHR , -SO2NR2, _{-PO3R 2} , -P(O)(CH ₃ )NHR, -NO, -NR ₃ ⁺ , -CR=CR ₂ , and -C≡CR, wherein each R is independently selected from H and C _1-6 alkanes and each X is independently selected from F, Br, Cl, and I. Self-stabilizing linkers may also include aryl (eg, phenyl) or heteroaryl (eg, pyridine) groups optionally substituted with electron withdrawing groups such as those described herein.

Examples of self-stabilizing linkers are provided, for example, in US Patent Application Publication No. US 2013/0309256, the linkers of which are incorporated herein by reference. It will be appreciated that self-stabilizing linkers suitable for conjugation to the compounds of the present invention can be equivalently described as unsubstituted linkers including maleimide, sulfur substituted linkers including succinimide, or Hydrolyzed, ring-opened sulfur substituted linkers including succinimide.

、

、

、及

。 In some specific embodiments, for formulas (I'), (I''), (I), (II'), (II''), (II), (III'), (III'') , (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof and a linker of linker L- Payload; -L contains the self-stabilizing part. For example, L can be selected from:

,

,

,and

.

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點。 In the flow diagrams provided above, the structure at the bottom may mean (maleimido)-DPR-Val-Cit-PAB, where DPR means diaminopropionic acid, Val means valine, and Cit means refers to citrulline, and PAB means p-aminobenzylcarbonyl.

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The point of attachment of a compound, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

。 A method for bridging a pair of sulfhydryl groups derived from a reduction reaction of the original hinge disulfide bond has been disclosed and is described in the following scheme. The advantage of this method is that homogeneous conjugates can be synthesized by complete reduction of IgG (4 pairs of sulfhydryl groups from interchain disulfide bonds, where DAR can range from 1 to 8) and subsequent reaction with 4 equivalents of alkylating agent. Conjugates containing "bridged disulfide bonds" also claim increased stability.

.

。 Likewise, as shown below, maleimide derivatives capable of bridging a pair of sulfhydryl groups were developed.

.

(CVIa)

(CVIb)

(CVIc) 或其鹽類，其中：R ^q為H或-O-(CH ₂CH ₂O) ₁₁-CH ₃；x為0或1；y為0或1；G ²為-CH ₂CH ₂CH ₂SO ₃H或-CH ₂CH ₂O-(CH ₂CH ₂O) ₁₁-CH ₃；R ^w為-O-CH ₂CH ₂SO ₃H或-NH(CO)-CH ₂CH ₂O-(CH ₂CH ₂O) ₁₂-CH ₃；且*代表與連接子之其餘部分的連接點。 The linker (L) of the present invention may contain the following structural formula (CVIa), (CVIb), or (CVIc):

(CVIa)

(CVIb)

(CVIc) or its salts, wherein: R ^q is H or -O-(CH ₂ CH ₂ O) ₁₁ -CH ₃ ; x is 0 or 1; y is 0 or 1; G ² is -CH ₂ CH ₂ CH ₂ SO ₃ H or -CH ₂ CH ₂ O-(CH ₂ CH ₂ O) ₁₁ -CH ₃ ; R ^w is -O-CH ₂ CH ₂ SO ₃ H or -NH(CO)-CH ₂ CH ₂ O -( _CH2CH2O ) ₁₂ - _{CH3 ;} and * represents the point of attachment to the rest of the linker.

(CVIa.1)

(CVIa.2)

(CVIa.3)

(CVIa.4)

(CVIb.1)

(CVIb.2)

(CVIb.3)

(CVIb.4)

(CVIb.5)

(CVIb.6)

(CVIb.7) 其中

代表連接子（L）與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點。 Exemplary embodiments of linkers of structural formulae (CVIa) and (CVIb), which may be included in the linker-load and conjugate structures of the present invention, include the linkers depicted below (as depicted, linkers Including groups suitable for covalent linkage of linkers to antibody constructs):

(CVIa.1)

(CVIa.2)

(CVIa.3)

(CVIa.4)

(CVIb.1)

(CVIb.2)

(CVIb.3)

(CVIb.4)

(CVIb.5)

(CVIb.6)

(CVIb.7) where

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or the point of attachment of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

(CVIc.1)

(CVIc.2)

(CVIc.3)

(CVIc.4)

(CVIc.5)

(CVIc.6) 其中

代表連接子（L）與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的連接點。 Exemplary embodiments of linkers of structural formula (CVIc), which can be included in the linker-payload and conjugate structures of the invention, include the linkers depicted below (as depicted, linkers include The covalently linked group of the linker to the antibody construct):

(CVIc.1)

(CVIc.2)

(CVIc.3)

(CVIc.4)

(CVIc.5)

(CVIc.6) where

Represents linker (L) with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), ( III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or Table A compound of any one of 1, or the point of attachment of a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

L2

L3

L4

L5

L6

L7

L8

L9

L10

L11

其中

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物或鹽類的氮連接；L ⁴代表胜肽之C端且L ⁵係選自於一鍵、伸烷基、及雜伸烷基，其中L ⁵係任意地以一或多個獨立地選自於R ³⁰之基團取代，且R ³⁰在每次出現時係獨立地選自於鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、-NO ₂；且C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、及C ₂-C ₁₀炔基在每次出現時每一者係獨立地任意地以一或多個選自於下列之取代基取代：鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、及-NO ₂；且RX代表反應性部分。反應性部分可選自於例如親電試劑（如α

-不飽和羰基，例如馬來醯亞胺）及離去基。舉例而言，-L可以下表3所述之化學式表示： 表3 化合物名稱 結構式 L12

L13

L14

L15

L16

L17

L18

L19

L20

L21

L22

L23

L24

L25

L26

其中

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物或鹽類的氮連接，且L ⁴代表胜肽之C端且L ⁵係選自於一鍵、伸烷基、及雜伸烷基，其中L ⁵係任意地以一或多個獨立地選自於R ³⁰之基團取代，且R ³⁰在每次出現時係獨立地選自於鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-NH ₂、-NO ₂；且C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、及C ₂-C ₁₀炔基在每次出現時每一者係獨立地任意地以一或多個選自於下列之取代基取代：鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-NH ₂、及-NO ₂。 The following paragraphs describe some exemplary linkers (L). In some specific embodiments, for formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or A compound of any of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the linker is with the nitrogen of the compound A cysteine residue linked and covalently attached to the antibody or target moiety, -L is represented by the formula described in Table 2 below: Table 2 Compound name Structural formula L1

L2

L3

L4

L5

L6

L7

L8

L9

L10

L11

in

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The nitrogen linkage of the compound or salt; L4 represents the C ^- terminus of the peptide and ^L5 is selected from a bond, alkylene, and heteroalkylene, wherein ^L5 is optionally one or more independently A group selected from R ³⁰ is substituted, and R ³⁰ at each occurrence is independently selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S( O) ₂ OH, -NH ₂ , -NO ₂ ; and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl at each occurrence are each independently any is substituted with one or more substituents selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O ₎ 2OH, _-NH2 , and _-NO2 ; and RX represents the reactive moiety. Reactive moieties can be selected from, for example, electrophiles such as alpha

- Unsaturated carbonyl groups such as maleimide) and leaving groups. For example, -L can be represented by the formula described in Table 3 below: Table 3 Compound name Structural formula L12

L13

L14

L15

L16

L17

L18

L19

L20

L21

L22

L23

L24

L25

L26

in

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The nitrogen of the compound or salt is attached, and L4 represents the C ^- terminus of the peptide and ^L5 is selected from a bond, alkylene, and heteroalkylene, wherein ^L5 is optionally one or more independent is substituted with a group selected from ^R30 , and ^R30 at each occurrence is independently selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -NH ₂ , -NO ₂ ; and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl at each occurrence each independently optionally selected from one or more Substituted from the following substituents: halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, _-NH2 , and _-NO2 .

L28

L29

L30

L31

L32

L33

L34

L35

L36

L37

其中RX ^*為一鍵、琥珀醯亞胺部分、或水解之琥珀醯亞胺部分鍵接至抗體構築體之半胱胺酸殘基，其中RX*上之

代表與此殘基的連接點；當存在L ⁴時，代表胜肽之C端，且L ⁵係選自於一鍵、伸烷基、及雜伸烷基，其中L ⁵係任意地以一或多個獨立地選自於R ³⁰之基團取代；且當存在R ³⁰時，在每次出現時係獨立地選自於鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、-NO ₂；且C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、及C ₂-C ₁₀炔基在每次出現時每一者係獨立地任意地以一或多個選自於下列之取代基取代：鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、及-NO ₂。特別較佳之胜肽為val-ala或val-cit。 When conjugated to a cysteine residue of an antibody or target moiety, such linkers can be represented, for example, by the formula described in Table 4 below: Table 4 Compound name Structural formula L27

L28

L29

L30

L31

L32

L33

L34

L35

L36

L37

where RX ^* is a bond, a succinimidyl moiety, or a hydrolyzed succinimidyl moiety bonded to a cysteine residue of the antibody construct, where on RX*

represents the point of attachment to this residue; when L4 is present, represents the C ^- terminus of the peptide, and ^L5 is selected from a bond, alkylene, and heteroalkylene, wherein ^L5 is optionally an or more groups independently selected from R ³⁰ substituted; and when R ³⁰ is present, at each occurrence is independently selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, -NH ₂ , -NO ₂ ; and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl in each Each appears independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S ( O) ₂ OH, -NH ₂ , and -NO ₂ . Particularly preferred peptides are val-ala or val-cit.

L39

其中

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的氮連接，且RX代表反應性部分。 In some specific embodiments, for formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or A compound of any of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the linker is attached to the formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or a compound of any one of Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof nitrogen-linked, and the conjugation link is isolated from the antibody or other target moiety The amino acid residue, -L is represented by the formula described in Table 5 below: Table 5 Compound name Structural formula L38

L39

in

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 A compound of , or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof is nitrogen attached, and RX represents a reactive moiety.

L41

Reactive moieties can be selected from, for example, leaving groups. For example, -L can be represented by the formula described in Table 6 below: Table 6 Compound name Structural formula L40

L41

代表與此殘基的連接點： 表7 化合物名稱 結構式 L42

L43

When conjugated to a lysine residue of an antibody or other targeting moiety, such linkers may be represented, for example, by the formula described in Table 7 below, wherein RX ^* is a lysine residue of the antibody construct or targeting moiety Bonding to the nitrogen of the radical, where RX* is above

Represents the point of attachment to this residue: Table 7 Compound name Structural formula L42

L43

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物，或其藥學上可接受之異構體、互變異構物、外消旋體、水合物、溶劑化物、同位素、或鹽類的氮連接。 As stated,

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 A compound, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, is nitrogen-linked.

As known to those skilled in the art, the linker selected for a particular conjugate can be influenced by a number of factors, including association with the antibody, antibody construct, or targeting moiety such as lysine, cysteine, or other amines base acid residues), the structural constraints of the pharmacophore, and the lipophilicity of the drug. For a specific antibody, antibody construct, or target moiety/drug combination, the specific linker chosen for the conjugate should seek to balance these various factors.

For example, cytotoxic conjugates have been observed to kill bystander antigen-negative cells present in the vicinity of antigen-positive tumor cells. The bystander effect mechanism of cytotoxic conjugates suggests that metabolites formed during intracellular processing of the conjugates may play a role. Neutral cytotoxic metabolites produced by the metabolism of the conjugate in antigen-positive cells play a role in bystander cell killing, while preventing charged metabolites from diffusing across the membrane into the medium or from Cells are killed via the bystander effect. In some embodiments, the linker is selected to attenuate bystander effects caused by cellular metabolites of the conjugate. In a further embodiment, the linker is selected to increase bystander effect.

The nature of the linker or linker-payload can also affect the agglutination of the conjugate under conditions of use and/or storage. The conjugates reported in the literature contain about 3-4 drug molecules per antibody molecule. Attempts to achieve higher drug-to-antibody ratios ("DAR") often fail due to agglutination of the conjugate, especially if both the drug and the linker are hydrophobic. In many cases a DAR higher than 3-4 may be beneficial as a means of increasing potency. In cases where the payload compound is more hydrophobic in nature, it may be desirable to choose a relatively hydrophilic linker as a means of reducing conjugate agglutination, especially if a DAR greater than 3-4 is desired. Thus, in some embodiments, incorporation of the linker into the chemical moiety may reduce agglutination of the conjugate during storage and/or use. Linkers can incorporate polar or hydrophilic groups, such as charged groups or groups that are charged at physiological pH, to reduce agglutination of the conjugate. For example, linkers can incorporate charged groups (such as salts), or deprotonated groups (such as carboxylates), or protonated groups (such as amines) at physiological pH.

In preferred embodiments, the agglutination of the conjugate during storage or use is less than about 40%, as determined by particle size sieve chromatography (SEC). In particular embodiments, the agglutination of the conjugate during storage or use is less than about 35%, such as less than about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, or even lower, as determined by particle size sieve chromatography (SEC). In preferred embodiments, the conjugate is less than 40% agglutinated during storage or use, as determined by particle size sieve chromatography (SEC). In certain embodiments, the agglutination of the conjugate during storage or use is less than 35%, such as less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, or even less, As determined by particle size sieve chromatography (SEC).

L44

L45

L46

L47

L48

L49

L50

L51

L52

L53

L54 其中

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物或鹽類的氮連接；L ⁴代表胜肽之C端且L ⁵係選自於一鍵、伸烷基、及雜伸烷基，其中L ⁵係任意地以一或多個獨立地選自於R ³⁰之基團取代，且R ³⁰在每次出現時係獨立地選自於鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、-NO ₂；且C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、及C ₂-C ₁₀炔基在每次出現時每一者係獨立地任意地以一或多個選自於下列之取代基取代：鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、及-NO ₂；且RX代表反應性部分。反應性部分可選自於例如親電試劑（如α

-不飽和羰基，例如馬來醯亞胺）及離去基。舉例而言，-L ³可以下表9所述之化學式表示： 表9

L55

L56

L57

L58

L59

L60

L61

L62

L63

L64

L65

L66

L67

L68

L69 其中

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物或鹽類的氮連接，且L ⁴代表胜肽之C端且L ⁵係選自於一鍵、伸烷基、及雜伸烷基，其中L ⁵係任意地以一或多個獨立地選自於R ³⁰之基團取代，且R ³⁰在每次出現時係獨立地選自於鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、-NO ₂；且C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、及C ₂-C ₁₀炔基在每次出現時每一者係獨立地任意地以一或多個選自於下列之取代基取代：鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、及-NO ₂。 The following paragraphs illustrate some exemplary linkers (L). In some specific embodiments, for formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or The compound or salt of any one of Table 1, wherein the linker is attached to the nitrogen of the compound and is conjugated to a cysteine residue of the antibody or target moiety, and -L is represented by the formula described in Table 8 below: Table 8

L44

L45

L46

L47

L48

L49

L50

L51

L52

L53

L54 in

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The nitrogen linkage of the compound or salt; L4 represents the C ^- terminus of the peptide and ^L5 is selected from a bond, alkylene, and heteroalkylene, wherein ^L5 is optionally one or more independently A group selected from R ³⁰ is substituted, and R ³⁰ at each occurrence is independently selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S( O) ₂ OH, -NH ₂ , -NO ₂ ; and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl at each occurrence are each independently any is substituted with one or more substituents selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O ₎ 2OH, _-NH2 , and _-NO2 ; and RX represents the reactive moiety. Reactive moieties can be selected from, for example, electrophiles such as alpha

- Unsaturated carbonyl groups such as maleimide) and leaving groups. For example, -L ³ can be represented by the chemical formula described in Table 9 below: Table 9

L55

L56

L57

L58

L59

L60

L61

L62

L63

L64

L65

L66

L67

L68

L69 in

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The nitrogen of the compound or salt is attached, and L4 represents the C ^- terminus of the peptide and ^L5 is selected from a bond, alkylene, and heteroalkylene, wherein ^L5 is optionally one or more independent is substituted with a group selected from ^R30 , and ^R30 at each occurrence is independently selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S (O) ₂ OH, -NH ₂ , -NO ₂ ; and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl at each occurrence each independently Optionally substituted with one or more substituents selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O ₎ 2OH, _-NH2 , and -NO ₂ .

L71

L72

L73

L74

L75

L76

L77

L78

L79

L80

L81

其中RX ^*為與抗體構築體之半胱胺酸殘基鍵接之一鍵、琥珀醯亞胺部分、或水解之琥珀醯亞胺部分，其中RX*上之

代表與此殘基的連接點；當存在L ⁴時，代表胜肽之C端，且L ⁵係選自於一鍵、伸烷基、及雜伸烷基，其中L ⁵係任意地以一或多個獨立地選自於R ³⁰之基團取代；且當存在R ³⁰時，在每次出現時係獨立地選自於鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、-NO ₂；且C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、及C ₂-C ₁₀炔基在每次出現時每一者係獨立地任意地以一或多個選自於下列之取代基取代：鹵素、-OH、-CN、-O-烷基、-SH、=O、=S、-S(O) ₂OH、-NH ₂、及-NO ₂。特別較佳之胜肽為val-ala或val-cit。 When conjugated to a cysteine residue of an antibody or target moiety, such linkers can be represented, for example, by the formula described in Table 10 below: Table 10 Compound name Structural formula L70

L71

L72

L73

L74

L75

L76

L77

L78

L79

L80

L81

wherein RX ^* is a bond, a succinimidyl moiety, or a hydrolyzed succinimidyl moiety to a cysteine residue of the antibody construct, wherein the above RX*

represents the point of attachment to this residue; when L4 is present, represents the C ^- terminus of the peptide, and ^L5 is selected from a bond, alkylene, and heteroalkylene, wherein ^L5 is optionally an or more groups independently selected from R ³⁰ substituted; and when R ³⁰ is present, at each occurrence is independently selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, -NH ₂ , -NO ₂ ; and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl in each Each appears independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S ( O) ₂ OH, -NH ₂ , and -NO ₂ . Particularly preferred peptides are val-ala or val-cit.

L83

其中

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物或鹽類的氮連接，且RX代表反應性部分。 In some specific embodiments, for formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or The compound or salt of any one of Table 1, wherein the linker is attached to formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or the nitrogen of any of the compounds or salts of Table 1, and conjugated to a lysine residue of the antibody or other targeting moiety, ^-L3 is the following table The chemical formula described in 11 represents: Table 11 Compound name Structural formula L82

L83

in

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 The nitrogen of the compound or salt is attached, and RX represents the reactive moiety.

L85

Reactive moieties can be selected from, for example, leaving groups. For example, -L ³ can be represented by the formula described in Table 12 below: Table 12 Compound name Structural formula L84

L85

代表與此殘基的連接點： 表13

L86

L87 When conjugated to a lysine residue of an antibody or other targeting moiety, such linkers can be represented, for example, by the formula described in Table 13 below, wherein RX ^* is a lysine residue associated with the antibody construct or targeting moiety Bonding to the nitrogen of the residue where RX* is above

Represents the point of attachment to this residue: Table 13

L86

L87

代表與式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之化合物或鹽類的氮連接。在示例性具體實施例中，本文所述之連接子，包括前述段落中之該等，係通過式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、(VI)、或表1之任一者之結構中所述之二級非環胺的氮連接至本發明化合物。在示例性具體實施例中，本文所述之連接子，包括前述段落中之該等，係在氮原子與本發明之化合物連接。 As stated,

Represents with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV '), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), (VI), or any of Table 1 the nitrogen linkage of the compound or salt. In exemplary embodiments, the linkers described herein, including those in the preceding paragraphs, are by formula (I'), (I''), (I), (II'), (II'' ), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V) , (VI'), (VI''), (VI), or the nitrogen of the secondary acyclic amine described in the structure of any of Table 1 is attached to the compound of the invention. In exemplary embodiments, the linkers described herein, including those in the preceding paragraphs, are attached to the compounds of the invention at the nitrogen atom.

As known to those skilled in the art, the linker selected for a particular conjugate can be influenced by a number of factors including, but not limited to, interaction with antibody constructs such as lysine, cysteine, or other amino acids residues), the structural constraints of the pharmacophore of the drug, and the lipophilicity of the drug. For a specific antibody construct/drug combination, the specific linker chosen for the conjugate should seek to balance these different factors.

The nature of the linker or linker-compound can also affect the agglutination of the conjugate under conditions of use and/or storage. Typically, the conjugates reported in the literature contain no more than 3-4 drug molecules per antibody molecule. Attempts to achieve higher drug-to-antibody ratios ("DAR") often fail due to agglutination of the conjugate, especially if both the drug and the linker are hydrophobic. In many cases a DAR higher than 3-4 may be beneficial as a means of increasing potency. In cases where the payload compound is more hydrophobic in nature, it may be desirable to choose a relatively hydrophilic linker as a means of reducing conjugate agglutination, especially if a DAR greater than 3-4 is desired. Thus, in certain embodiments, incorporation of the linker into the chemical moiety may reduce agglutination of the conjugate during storage and/or use. Linkers can incorporate polar or hydrophilic groups, such as charged groups or groups that are charged at physiological pH, to reduce agglutination of the conjugate. For example, linkers can incorporate charged groups (such as salts), or deprotonated groups (such as carboxylates), or protonated groups (such as amines) at physiological pH.

In certain embodiments, the conjugate is less than about 40% agglutinated during storage or use, as determined by particle size sieve chromatography (SEC). In particular embodiments, the agglutination of the conjugate during storage or use is less than 35%, such as less than about 30%, such as less than about 25%, such as less than about 20%, such as less than about 15%, such as less than about 10% %, eg, less than about 5%, eg, less than about 4%, or even lower, as determined by particle size sieve chromatography (SEC). In certain embodiments, the conjugate is less than 40% agglutinated during storage or use, as determined by particle size sieve chromatography (SEC). In particular embodiments, the agglutination of the conjugate during storage or use is less than 35%, such as less than 30%, such as less than 25%, such as less than 20%, such as less than 15%, such as less than 10%, such as less than 5% %, eg, less than 4%, or even lower, as determined by particle size sieve chromatography (SEC).

1202.5 [M+H]+    [1.8-CIIIb.3]

1009.5 [M+H]+    [1.3-CIIIb.2]

1095.5 [M+H]+    [1.4-CIIIb.2]

1111.5 [M+H]+    [1.5-CIIIb.2]

1091.5 [M+H]+    [1.7-CIIIb.2]

1102.5 [M+H]+    [1.8-CIIIb.2]

1095.5 [M+H]+    [1.9-CIIIb.2]

1111.5 [M+H]+    [1.10-CIIIb.2]

1102.5 [M+H]+    [1.17-CIIIb.2]

1139.5 [M+H]+    [1.19-CIIIb.2]

1135.6 [M+H]+    [1.8-CIIIb.20]

1066.5 [M+H]+    [1.8-CIIIb.21]

1114.5 [M+H]+    [1.8-CIIIc.8]

1229.6 [M+H]+    [1.12-CIIIc.8]

1247.6 [M+H]+    [1.13-CIIIc.8]

1247.6 [M+H]+    [1.18-CIIIc.8]

1265.6 [M+H]+    [1.21-CIIIc.8]

1216.6 [M+H]+    [1.22-CIIIc.8]

1230.6 [M+H]+    [1.25-CIIIc.8]

1201.5 [M+H]+    [1.27-CIIIc.8]

1245.6 [M+H]+    [1.1-CIIIc.8]

1201.5 [M+H]+    [3.1-CIIIc.8]

1203.5 [M+H]+    [3.2-CIIIc.8]

1217.5 [M+H]+    [3.3-CIIIc.8]

1231.6 [M+H]+    [1.35-CIIIc.8]

1220.5 [M+H]+    [1.36-CIIIc.8]

1220.5 [M+H]+    [1.37-CIIIc.8]

1202.5 [M+H]+    [1.38-CIIIc.8]

1220.5 [M+H]+    [1.44-CIIIc.8]

1216.6 [M+H]+    [1.47-CIIIc.8]

1277.4 [M+H]+    [2.2-CIIIc.8]

1187.5 [M+H]+    [1.59-CIIIc.8]

1228.6 [M+H]+    [1.8-CIIIc.9]

1143.5 [M+H]+    [1.8-CIIIa.9]

1214.6 [M+H]+    [1.8-CIIIb.22]

1224.6 [M+H]+    [1.12--CIIIb.22]

1242.6 [M+H]+    [1.13-CIIIb.22]

1242.6 [M+H]+    [1.38--CIIIb.22]

1215.5 [M+H]+    [1.38-CIIIa.10]

1420.6 [M+H]+    [1.1-CIIIc.10]

1330.6 [M+H]+    [1.31-CIIIc.10]

1348.6 [M+H]+    [5.1-CIIIc.10]

1264.6 [M+H]+    [1.64-CIIIc.‌10]

1357.6 [M+H]+    [1.100-CIIIc.8]

1227.5 [M+H]+    [1.102-CIIIc.8]

1227.5 [M+H]+    [1.112-CIIIc.8]

1244.5 [M+H]+    [1.114-CIIIc.8]

1245.5 [M+H]+    [1.116-CIIIc.8]

1245.5 [M+H]+    [1.118-CIIIc.8]

1245.5 [M+H]+    [1.120-CIIIc.8]

1282.5 [M+H]+    [1.126-CIIIc.8]

   1282.5 [M+H]+    [1.130-CIIIc.8]

1281.5 [M+H]+    [1.131-CIIIc.8]

   1295.5 [M+H]+    [1.132-CIIIc.8]

1281.5 [M+H]+    [1.134-CIIIc.8]

1281.5 [M+H]+    [1.136-CIIIc.8]

1281.5 [M+H]+    [1.138-CIIIc.8]

1263.5 [M+H]+    [1.145-CIIIc.8]

1298.5 [M+H]+    [1.153-CIIIc.8]

1228.5 [M+H]+    [1.155-CIIIc.8]

1264.5 [M+H]+    [1.163-CIIIc.8]

1273.6 [M+H]+    [1.164-CIIIc.8]

1273.6 [M+H]+    [1.165-CIIIc.8]

1261.5 [M+H]+    [1.166-CIIIc.8]

1261.5 [M+H]+    [1.167-CIIIc.8]

1305.4 [M+H]+    [1.168-CIIIc.8]

1305.4 [M+H]+    [1.169-CIIIc.8]

1263.5 [M+H]+    [1.170-CIIIc.8]

1289.5 [M+H]+    [1.171-CIIIc.8]

1263.5 [M+H]+    [1.172-CIIIc.8]

1303.5 [M+H]+    [1.173-CIIIc.8]

1277.5 [M+H]+    [1.174-CIIIc.8]

1273.6 [M+H]+    [1.175-CIIIc.8]

1273.6 [M+H]+    [1.176-CIIIc.8]

1273.6 [M+H]+    [1.177-CIIIc.8]

1273.6 [M+H]+    [1.178-CIIIc.8]

1273.6 [M+H]+    [1.180-CIIIc.8]

1262.5 [M+H]+    [1.181-CIIIc.8]

1262.5 [M+H]+    [1.182-CIIIc.8]

1306.4 [M+H]+    [1.183-CIIIc.8]

1306.4 [M+H]+    [1.184-CIIIc.8]

1246.5 [M+H]+    [1.185-CIIIc.8]

1246.5 [M+H]+    [1.188-CIIIc.8]

1383.4 [M+H]+    [1.189-CIIIc.8]

1411.4 [M+H]+    [1.190-CIIIc.8]

1425.5 [M+H]+    [1.191-CIIIc.8]

1409.4 [M+H]+    [1.192-CIIIc.8]

1382.4 [M+H]+    [1.193-CIIIc.8]

1410.4 [M+H]+    [1.194-CIIIc.8]

1424.5 [M+H]+    [1.195-CIIIc.8]

1408.5 [M+H]+    [1.8-CIIIc.10]

1358.7 [M+H]+    [1.2-CIIIc.10]

1331.6 [M+H]+    [1.23-CIIIc.10]

1331.5 [M+H]+    [1.1-CIIIc.10]

1330.5 [M+H]+    [1.54-CIIIc.10]

1334.4 [M+H]+    [1.56-CIIIc.10]

1366.5 [M+H]+    [1.57-CIIIc.10]

1335.5 [M+H]+    [2.2-CIIIc.10]

1316.5 [M+H]+    [1.60-CIIIc.10]

1385.5 [M+H]+    [1.67-CIIIc.10]

1367.5 [M+H]+    [1.68-CIIIc.10]

1367.5 [M+H]+    [4.10-CIIIc.10]

1368.5 [M+H]+    [2.3-CIIIc.10]

1352.5 [M+H]+    [1.72-CIIIc.10]

1358.5 [M+H]+    [1.85-CIIIc.10]

1385.5 [M+H]+    [1.86-CIIIc.10]

1385.5 [M+H]+    [4.12-CIIIc.10]

1368.6 [M+H]+    [1.89-CIIIc.10]

1407.6 [M+H]+    [1.90-CIIIc.10]

1393.6 [M+H]+    [1.91-CIIIc.10]

1407.6 [M+H]+    [1.92-CIIIc.10]

1393.6 [M+H]+    [1.93-CIIIc.10]

1407.6 [M+H]+    [1.94-CIIIc.10]

1393.6 [M+H]+    [2.4-CIIIc.10]

1356.6 [M+H]+    [1.95-CIIIc.10]

1371.6 [M+H]+    [1.96-CIIIc.10]

1357.6 [M+H]+    [1.98-CIIIc.10]

1356.6 [M+H]+    [1.99-CIIIc.10]

1370.6 [M+H]+    [1.103-CIIIc.10]

1389.6 [M+H]+    [1.104-CIIIc.10]

1375.6 [M+H]+    [1.105-CIIIc.10]

1389.6 [M+H]+    [1.106-CIIIc.10]

1375.6 [M+H]+    [1.108-CIIIc.10]

1375.6 [M+H]+    [1.109-CIIIc.10]

1389.6 [M+H]+    [1.110-CIIIc.10]

1375.6 [M+H]+    [1.113-CIIIc.10]

1388.6 [M+H]+    [1.115-CIIIc.10]

1388.6 [M+H]+    [1.122-CIIIc.10]

1411.5 [M+H]+    [1.140-CIIIc.10]

1410.5 [M+H]+    [1.143-CIIIc.10]

1410.5 [M+H]+    [1.147-CIIIc.10]

1373.6 [M+H]+    [1.148-CIIIc.10]

1373.6 [M+H]+    [1.150-CIIIc.10]

1373.6 [M+H]+    [1.157-CIIIc.10]

1374.6 [M+H]+    [1.32-CIIIc.11]

1477.2 [M+H]+    [1.91-CIIIc.11]

1536.6 [M+H]+    [1.92-CIIIc.11]

1522.6 [M+H]+    [1.32-CIIIc.12]

1606.6 [M+H]+    [1.201-CIc.1]

947 [M+H]+    [7.1-CIIIc.8]

1283.5 [M+H]+    [7.2-CIIIc.8]

1249.5 [M+H]+    [7.3-CIIIc.8]

1283.4 [M+H]+       [7.4-CIIIc.8]

1249.5 [M+H]+    [7.5-CIIIc.8]

1282.4 [M+H]+    [7.6-CIIIc.8]

1248.5 [M+H]+    [7.7-CIIIc.8]

1282.4 [M+H]+    [7.8-CIIIc.8]

1248.5 [M+H]+ 抗體、抗體構築體、及標靶部分 Exemplary linker-compounds of the invention include those described in Table 14, and salts thereof (including pharmaceutically acceptable salts thereof). Table 14 Linkers - Compounds Compound number structure Mass spectrum, m/z [1.2-CIIIa.1]

1202.5 [M+H]+ [1.8-CIIIb.3]

1009.5 [M+H]+ [1.3-CIIIb.2]

1095.5 [M+H]+ [1.4-CIIIb.2]

1111.5 [M+H]+ [1.5-CIIIb.2]

1091.5 [M+H]+ [1.7-CIIIb.2]

1102.5 [M+H]+ [1.8-CIIIb.2]

1095.5 [M+H]+ [1.9-CIIIb.2]

1111.5 [M+H]+ [1.10-CIIIb.2]

1102.5 [M+H]+ [1.17-CIIIb.2]

1139.5 [M+H]+ [1.19-CIIIb.2]

1135.6 [M+H]+ [1.8-CIIIb.20]

1066.5 [M+H]+ [1.8-CIIIb.21]

1114.5 [M+H]+ [1.8-CIIIc.8]

1229.6 [M+H]+ [1.12-CIIIc.8]

1247.6 [M+H]+ [1.13-CIIIc.8]

1247.6 [M+H]+ [1.18-CIIIc.8]

1265.6 [M+H]+ [1.21-CIIIc.8]

1216.6 [M+H]+ [1.22-CIIIc.8]

1230.6 [M+H]+ [1.25-CIIIc.8]

1201.5 [M+H]+ [1.27-CIIIc.8]

1245.6 [M+H]+ [1.1-CIIIc.8]

1201.5 [M+H]+ [3.1-CIIIc.8]

1203.5 [M+H]+ [3.2-CIIIc.8]

1217.5 [M+H]+ [3.3-CIIIc.8]

1231.6 [M+H]+ [1.35-CIIIc.8]

1220.5 [M+H]+ [1.36-CIIIc.8]

1220.5 [M+H]+ [1.37-CIIIc.8]

1202.5 [M+H]+ [1.38-CIIIc.8]

1220.5 [M+H]+ [1.44-CIIIc.8]

1216.6 [M+H]+ [1.47-CIIIc.8]

1277.4 [M+H]+ [2.2-CIIIc.8]

1187.5 [M+H]+ [1.59-CIIIc.8]

1228.6 [M+H]+ [1.8-CIIIc.9]

1143.5 [M+H]+ [1.8-CIIIa.9]

1214.6 [M+H]+ [1.8-CIIIb.22]

1224.6 [M+H]+ [1.12--CIIIb.22]

1242.6 [M+H]+ [1.13-CIIIb.22]

1242.6 [M+H]+ [1.38--CIIIb.22]

1215.5 [M+H]+ [1.38-CIIIa.10]

1420.6 [M+H]+ [1.1-CIIIc.10]

1330.6 [M+H]+ [1.31-CIIIc.10]

1348.6 [M+H]+ [5.1-CIIIc.10]

1264.6 [M+H]+ [1.64-CIIIc.‌10]

1357.6 [M+H]+ [1.100-CIIIc.8]

1227.5 [M+H]+ [1.102-CIIIc.8]

1227.5 [M+H]+ [1.112-CIIIc.8]

1244.5 [M+H]+ [1.114-CIIIc.8]

1245.5 [M+H]+ [1.116-CIIIc.8]

1245.5 [M+H]+ [1.118-CIIIc.8]

1245.5 [M+H]+ [1.120-CIIIc.8]

1282.5 [M+H]+ [1.126-CIIIc.8]

1282.5 [M+H]+ [1.130-CIIIc.8]

1281.5 [M+H]+ [1.131-CIIIc.8]

1295.5 [M+H]+ [1.132-CIIIc.8]

1281.5 [M+H]+ [1.134-CIIIc.8]

1281.5 [M+H]+ [1.136-CIIIc.8]

1281.5 [M+H]+ [1.138-CIIIc.8]

1263.5 [M+H]+ [1.145-CIIIc.8]

1298.5 [M+H]+ [1.153-CIIIc.8]

1228.5 [M+H]+ [1.155-CIIIc.8]

1264.5 [M+H]+ [1.163-CIIIc.8]

1273.6 [M+H]+ [1.164-CIIIc.8]

1273.6 [M+H]+ [1.165-CIIIc.8]

1261.5 [M+H]+ [1.166-CIIIc.8]

1261.5 [M+H]+ [1.167-CIIIc.8]

1305.4 [M+H]+ [1.168-CIIIc.8]

1305.4 [M+H]+ [1.169-CIIIc.8]

1263.5 [M+H]+ [1.170-CIIIc.8]

1289.5 [M+H]+ [1.171-CIIIc.8]

1263.5 [M+H]+ [1.172-CIIIc.8]

1303.5 [M+H]+ [1.173-CIIIc.8]

1277.5 [M+H]+ [1.174-CIIIc.8]

1273.6 [M+H]+ [1.175-CIIIc.8]

1273.6 [M+H]+ [1.176-CIIIc.8]

1273.6 [M+H]+ [1.177-CIIIc.8]

1273.6 [M+H]+ [1.178-CIIIc.8]

1273.6 [M+H]+ [1.180-CIIIc.8]

1262.5 [M+H]+ [1.181-CIIIc.8]

1262.5 [M+H]+ [1.182-CIIIc.8]

1306.4 [M+H]+ [1.183-CIIIc.8]

1306.4 [M+H]+ [1.184-CIIIc.8]

1246.5 [M+H]+ [1.185-CIIIc.8]

1246.5 [M+H]+ [1.188-CIIIc.8]

1383.4 [M+H]+ [1.189-CIIIc.8]

1411.4 [M+H]+ [1.190-CIIIc.8]

1425.5 [M+H]+ [1.191-CIIIc.8]

1409.4 [M+H]+ [1.192-CIIIc.8]

1382.4 [M+H]+ [1.193-CIIIc.8]

1410.4 [M+H]+ [1.194-CIIIc.8]

1424.5 [M+H]+ [1.195-CIIIc.8]

1408.5 [M+H]+ [1.8-CIIIc.10]

1358.7 [M+H]+ [1.2-CIIIc.10]

1331.6 [M+H]+ [1.23-CIIIc.10]

1331.5 [M+H]+ [1.1-CIIIc.10]

1330.5 [M+H]+ [1.54-CIIIc.10]

1334.4 [M+H]+ [1.56-CIIIc.10]

1366.5 [M+H]+ [1.57-CIIIc.10]

1335.5 [M+H]+ [2.2-CIIIc.10]

1316.5 [M+H]+ [1.60-CIIIc.10]

1385.5 [M+H]+ [1.67-CIIIc.10]

1367.5 [M+H]+ [1.68-CIIIc.10]

1367.5 [M+H]+ [4.10-CIIIc.10]

1368.5 [M+H]+ [2.3-CIIIc.10]

1352.5 [M+H]+ [1.72-CIIIc.10]

1358.5 [M+H]+ [1.85-CIIIc.10]

1385.5 [M+H]+ [1.86-CIIIc.10]

1385.5 [M+H]+ [4.12-CIIIc.10]

1368.6 [M+H]+ [1.89-CIIIc.10]

1407.6 [M+H]+ [1.90-CIIIc.10]

1393.6 [M+H]+ [1.91-CIIIc.10]

1407.6 [M+H]+ [1.92-CIIIc.10]

1393.6 [M+H]+ [1.93-CIIIc.10]

1407.6 [M+H]+ [1.94-CIIIc.10]

1393.6 [M+H]+ [2.4-CIIIc.10]

1356.6 [M+H]+ [1.95-CIIIc.10]

1371.6 [M+H]+ [1.96-CIIIc.10]

1357.6 [M+H]+ [1.98-CIIIc.10]

1356.6 [M+H]+ [1.99-CIIIc.10]

1370.6 [M+H]+ [1.103-CIIIc.10]

1389.6 [M+H]+ [1.104-CIIIc.10]

1375.6 [M+H]+ [1.105-CIIIc.10]

1389.6 [M+H]+ [1.106-CIIIc.10]

1375.6 [M+H]+ [1.108-CIIIc.10]

1375.6 [M+H]+ [1.109-CIIIc.10]

1389.6 [M+H]+ [1.110-CIIIc.10]

1375.6 [M+H]+ [1.113-CIIIc.10]

1388.6 [M+H]+ [1.115-CIIIc.10]

1388.6 [M+H]+ [1.122-CIIIc.10]

1411.5 [M+H]+ [1.140-CIIIc.10]

1410.5 [M+H]+ [1.143-CIIIc.10]

1410.5 [M+H]+ [1.147-CIIIc.10]

1373.6 [M+H]+ [1.148-CIIIc.10]

1373.6 [M+H]+ [1.150-CIIIc.10]

1373.6 [M+H]+ [1.157-CIIIc.10]

1374.6 [M+H]+ [1.32-CIIIc.11]

1477.2 [M+H]+ [1.91-CIIIc.11]

1536.6 [M+H]+ [1.92-CIIIc.11]

1522.6 [M+H]+ [1.32-CIIIc.12]

1606.6 [M+H]+ [1.201-CIc.1]

947 [M+H]+ [7.1-CIIIc.8]

1283.5 [M+H]+ [7.2-CIIIc.8]

1249.5 [M+H]+ [7.3-CIIIc.8]

1283.4 [M+H]+ [7.4-CIIIc.8]

1249.5 [M+H]+ [7.5-CIIIc.8]

1282.4 [M+H]+ [7.6-CIIIc.8]

1248.5 [M+H]+ [7.7-CIIIc.8]

1282.4 [M+H]+ [7.8-CIIIc.8]

1248.5 [M+H]+ Antibodies, antibody constructs, and target moieties

Disclosed herein are antibodies, antibody constructs, and target moieties that can be individually combined with the ALK5 inhibitor compounds disclosed herein alone. In certain embodiments, the ALK5 inhibitor compounds of the invention are conjugated directly or via a linker to an antibody, antibody construct, or target moiety to form a conjugate.

Unless explicitly defined otherwise herein, terms as understood by those skilled in the art of antibody technology have the meanings acquired in the art. An intact antibody comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and an antigen-binding fragment or portion of an intact antibody (which includes the antigen-binding domain) has or retains a binding target molecular capabilities. Monoclonal antibodies or antigen-binding portions thereof may be non-human, chimeric, humanized, or human, preferably humanized or human. Immunoglobulin structure and function is reviewed, for example, in Greenfield et al., Ed., Antibodies: A Laboratory Manual, Second Edition, Chapter 2 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2014).

For example, the terms "VL" and "VH" mean the variable binding regions derived from the light and heavy chains of an antibody, respectively. Variable binding regions are composed of discrete, well-defined subregions called "complementarity determining regions" (CDRs) and "framework regions" (FRs). The word "CL" means "immunoglobulin light chain constant region" or "light chain constant region", ie, the constant region derived from the light chain of an antibody. The word "CH" B means "immunoglobulin heavy chain constant region" or "heavy chain constant region", which can be further divided into CH1, CH2, and CH3 (IgA, IgD, IgG), or CH1 according to the antibody isotype , CH2, CH3, and CH4 domains (IgE, IgM).

The antigen binding domain of an antibody may comprise one or more light chain (LC) CDRs and one or more heavy chain (HC) CDRs. For example, the antigen binding domain of an antibody can comprise one or more of the following: light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), or light chain complementarity determining region 3 (LC CDR3 ). Another exemplary antigen binding domain may comprise one or more of the following: heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), or heavy chain complementarity determining region 3 (HC CDR3). As an additional example, the antigen binding domain of an antibody may comprise one or more of the following: LC CDRl, LC CDR2, LC CDR3, HC CDRl, HC CDR2, and HC CDR3. In some embodiments, the antigen binding domain of the antibody includes all six CDRs (ie, LC CDRl, LC CDR2, LC CDR3, HC CDRl, HC CDR2, and HC CDR3).

An antibody, antibody construct, or target portion of the invention can comprise an antibody light chain variable region having at least one, about two, about three, about four, about five, about six, about seven , about eight, about nine, or about ten modified (eg, insertions, deletions, mutations) amino acid sequences, provided that the modifications are not within the light chain CDRs. An antibody, antibody construct, or target portion of the invention may comprise an antibody light chain variable region having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 modifications (eg, insertions, deletion, mutation) amino acid sequence, provided that the modification is not within the light chain CDRs. In certain specific embodiments, the light chain variable region amino acid sequence does not have more than about 25, about 20, about 15, about 10, about 9 amino acid sequences of the light chain variable region relative to the native or native light chain variable region amino acid sequence , about 8, about 7, about 6, about 5, about 4, about 3, about 2, or 1 modification, provided that the modification is not within the light chain CDRs. In particular embodiments, the light chain variable region amino acid sequence does not have more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 modification, provided that the modification is not within the light chain CDRs. The antibody can comprise a heavy chain variable region having at least one, two, about three, about four, about five, about six, about seven, about eight, about nine, or about ten modifications (eg insertion, deletion, mutation) amino acid sequence, provided that the modification is not within the heavy chain CDRs. The antibody may comprise a heavy chain variable region having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 modified (eg, insertion, deletion, mutation) amino acid sequences, provided that This modification is not within the heavy chain CDRs. In certain specific embodiments, the heavy chain variable region amino acid sequence does not have more than about 25, about 20, about 15, about 10, about 9 amino acid sequences relative to the native or native heavy chain variable region amino acid sequence , about 8, about 7, about 6, about 5, about 4, about 3, 2, or 1 modification, provided that the modification is not within the heavy chain CDRs. In certain specific embodiments, the heavy chain variable region amino acid sequence does not have more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 modification, provided that the modification is not within the heavy chain CDRs.

As used herein, a "Fab" (antigen-binding fragment) is a fragment or portion of an antibody that binds to an antigen and includes the variable region, and the CH1 of the heavy chain is linked to the light chain via a disulfide bond between the chains. Antibody constructs or targeting moieties may comprise antigen-binding fragments derived from antibodies. Antibody-derived antigen-binding fragments may include (i) antigen-binding fragments (Fab), which are monovalent fragments containing VL, VH, CL, and CH1 domains, optionally all or part (including at least one Cys residue) The hinge region (Fab') of ; (ii) an F(ab')2 fragment, which is a bivalent fragment containing two Fab fragments linked at the hinge region by disulfide bridges; (iii) a single domain antibody (sdAb ) or Nanobodies, which comprise a single monomeric variable antibody domain; or (iv) Fv fragments, which comprise the VL and VH domains of one arm of the antibody. Although the two domains of the Fv fragment, VL and VH, can be encoded by different genes, they can be linked by synthetic linkers to make a single protein chain in which the VL and VH domains are paired to form a monovalent molecule, called Single-chain variable fragment (scFv).

The antigen-binding domain of the antibody construct or target moiety can be selected from any antigen-binding domain, including those derived from monoclonal antibodies, polyclonal antibodies, recombinant antibodies, or functional fragments thereof, e.g., heavy chain variable Domain (VH) and light chain variable domain (VL), or DARPin, affimer, avimer, knottin, monomer, affinity clamp clamp), ectodomain, ecto-receptor domain, receptor, interleukin, ligand, immune interleukin, T cell receptor, or recombinant T cell receptor. The antibody construct or target moiety can be one of a single chain antibody, anticalin, centyrin, affibody, knottin, diabody, DARPin, or peptibody form. In certain embodiments, the antibody construct or target moiety is an antibody.

Antibodies can be of any class, such as IgA, IgD, IgE, IgG, and IgM. Several of these classes can be further subdivided into isotypes, such as IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant regions (Fc) corresponding to the different classes of immunoglobulins can be alpha, delta, epsilon, gamma, or mu. The light chain can be one of kappa (κ) or lamuda (λ), based on the amino acid sequence of the constant domain.

Antibody constructs or targeting moieties may contain, for example, two, three, four, five, six, seven, eight, nine, ten, or more antigen binding domains. An antibody construct or targeting moiety may contain two antigen-binding domains, wherein each antigen-binding domain recognizes the same antigen. An antibody construct or targeting moiety may contain two antigen-binding domains, wherein each antigen-binding domain recognizes a different antigen. In certain embodiments, the antibody construct or targeting moiety may comprise an Fc fusion protein. In further embodiments, the antibody construct or target moiety may comprise an antibody.

In any of the foregoing embodiments, the antigen binding domain specifically binds to a tumor antigen, such as ASGR1, ASGR2, LRRC15, mesothelin (MSLN), HER2, CEA, TROP2, EPHA2, p-cadherin, UPK1B, FOLH1, LYPD3, and PVRL4 (connexin-4). Antigen binding domains can specifically bind to molecules on antigen presenting cells (APCs).

Further exemplary antibodies or antigen-binding domains thereof can specifically bind to: CTLA4 protein (cytotoxic T lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), which is a protein receptor that serves as an immune check point and down-regulate the immune response. CTLA4 is constitutively expressed in Tregs but is only upregulated in conventional T cells after activation. CTLA4 acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. The monoclonal antibody Ipilimamab has been developed to target CTLA4; programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), which are cells that act as cell surface receptors Surface receptors that play an important role in downregulating the immune system and promoting self-tolerance by inhibiting T-cell inflammatory activity. PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pre-B cells. PD-1 is an immune checkpoint that promotes apoptosis of antigen-specific T cells in lymph nodes (programmed cell death) while reducing the apoptosis of regulatory T cells (anti-inflammatory, suppressor T cells) through dual mechanisms. Prevent autoimmunity. Human IgG4 anti-PD-1 monoclonal antibody Opdivo® (nivolumab) and humanized antibody Keytruda® (pembrolizumab) have been developed to target PD-1. Antibodies pidilizumab (CT-011, Cure Tech) and BMS-936559 are in clinical development; PD-L1 (planned death ligand 1), also known as CD274 (cluster of differentiation 274). PD-L1 is a 40 kDa type 1 transmembrane protein that is postulated to play a major role in suppressing the immune system during specific events such as pregnancy, tissue allografts, autoimmune diseases, and other disease states such as hepatitis . Binding of PD-L1 to PD-1 or B7.1 transmits an inhibitory signal that reduces the proliferation of CD8+ T cells in lymph nodes, and PD-1 supplementation can also control the apoptosis of foreign antigen-specific T cells in lymph nodes. accumulation, which is further mediated by decreased regulation of the Bcl-2 gene. Monoclonal antibodies atezolizumab, durvalumab, avelumab, and MDX-1106 have been developed to target PD-L1; TNFR2 (tumor necrosis factor receptor 2), Also known as TNFRSF1B (tumor necrosis factor receptor superfamily 1B) and CD120b, it is a single-channel type I membrane protein and a member of the TNFR superfamily that contains four cysteine-rich domain (CRD) repeats. member. In addition to the full-length membrane-anchored form, soluble TNFR2 can also be generated by two distinct mechanisms: (1) shedding by proteolytic processes of the full-membrane-anchored form, and (2) selection from the extracellular domain encoding TNFR2 Translation of sexual splicing information. TNFR2 is a receptor with high affinity for TNF-alpha and about 5-fold lower affinity for the homotrimeric lymphotoxin-alpha. Mouse monoclonal antibodies against TNFR2 described by SEQ ID NO: 237 to SEQ ID NO: 263 and SEQ ID NO: 264 to SEQ ID NO: 272 have been developed, and by SEQ ID NO: 273 and SEQ ID NO: 272 : 274 described anti-TNFR2 antibodies to target TNFR2; OX40, also known as TNFRSF4 (tumor necrosis factor receptor superfamily, member 4), unlike CD28, is not constitutively active on resting naive T cells TNFR-superfamily member of expressed receptors. OX40 is a secondary costimulatory immune checkpoint molecule that is expressed 24 to 72 hours after activation; its ligand OX40L is also not expressed on quiescent antigen-presenting cells, but after their activation. OX40 expression is dependent on full activation of T cells; in the absence of CD28, OX40 expression is delayed and levels are reduced four-fold. The monoclonal antibody pegalizumab (Vonlerolizumab) has been developed to target OX40; CD27 is a member of the tumor necrosis factor receptor superfamily. The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is necessary for the generation and long-term maintenance of T cell immunity. It binds to the ligand CD70 and plays a key role in regulating B cell activation and immunoglobulin synthesis. This receptor transduces signals that lead to the activation of NF-κB and MAPK8/JNK. The aptamer proteins TRAF2 and TRAF5 have been shown to mediate the signaling process of this receptor. CD27-binding protein (SIVA) is a pro-apoptotic protein that binds to this receptor and is thought to play an important role in apoptosis induced by this receptor. The monoclonal antibody varilumab has been developed to target CD27; IL2RA encodes CD25, also known as IL2RA (interleukin-2 receptor alpha chain), which is present in activated T cells, activated B cells , a type I transmembrane protein on some thymocytes, myeloid precursors, and oligodendrocytes. IL2RA is expressed in most B-cell neoplasms, some acute non-lymphocytic leukemias, neuroblastoma, mastocytosis, and tumor-infiltrating lymphocytes. It acts as a receptor for HTLV-1 and is therefore expressed on neoplastic cells in adult T-cell lymphoma/leukemia. Its soluble form, called sIL-2R, may be elevated in these diseases and is occasionally used to track disease progression. Humanized monoclonal antibody Zinbryta ^® (Daclizumab) has been developed to target CD25; TNFRSF18 encodes GITR (glucocorticoid-induced TNFR-related protein), also known as TNFRSF18 (tumor necrosis factor receptor) superfamily member 18) and AITR (activation-inducible TNFR family receptor), a protein that is a member of the tumor necrosis factor receptor (TNF-R) superfamily. GITR (glucocorticoid-induced tumor necrosis factor receptor) is a surface receptor molecule that has been shown to be involved in suppressing the suppressive activity of T regulatory cells and prolonging the survival of T effector cells. Anti-GITR antibodies described by SEQ ID NO: 275 to SEQ ID NO: 280 and SEQ ID NO: 281 to SEQ ID NO: 282, and antibody TRX518 have been developed to target GITR; LAG-3 (lymphocyte activation gene) 3) Encoding cell surface molecules that have multiple biological effects on T cell function. LAG-3 is an immune checkpoint receptor. The LAG3 protein belonging to the immunoglobulin (Ig) superfamily comprises a type I transmembrane protein of 503 amino acids with four extracellular Ig-like domains (designated D1 to D4). LAG-3 is expressed on activated T cells, natural killer cells, B cells, and plasmacytoid dendritic cells. Anti-LAG-3 antibodies described by SEQ ID NO: 283 to SEQ ID NO: 288 and SEQ ID NO: 289 to SEQ ID NO: 290 have been developed to target LAG-3; GARP (glycoprotein A repeat main body) ) is a transmembrane protein containing a leucine-rich repeat that is present on the surface of stimulated Treg clones but not on Th clones. Anti-GARP antibodies described by SEQ ID NO: 291 to SEQ ID NO: 300 have been developed to target GARP; 4-1BB is a type 2 transmembrane carbohydrate that belongs to the TNF superfamily and is expressed on activated T lymphocytes protein. 4-1BB can be expressed by activated T cells. 4-1BB expression can be found on dendritic cells, B cells, follicular dendritic cells, natural killer cells, granulocytes, and vascular wall cells at the site of inflammation. Anti-4-1BB antibodies described by SEQ ID NO: 301 to SEQ ID NO: 306 and SEQ ID NO: 307 to SEQ ID NO: 312 have been developed to target 4-1BB; ICOS (Inducible T Cell Costimulatory Molecule ) are CD28 superfamily costimulatory molecules expressed on activated T cells. The protein encoded by this gene belongs to the CD28 and CTLA-4 cell surface receptor families. ICOS forms homodimers and plays an important role in the regulation of cell-cell signaling, immune responses, and cell proliferation. Anti-ICOS antibodies described by SEQ ID NO: 313 to SEQ ID NO: 316 have been developed to target ICOS; CD70 is expressed on highly activated lymphocytes, such as T-cell and B-cell lymphomas. CD70 is a cytokine belonging to the tumor necrosis factor (TNF) ligand family. This interleukin is a ligand for TNFRSF27/CD27. It is a surface antigen on activated but not resting T and B lymphocytes. CD70 induces the proliferation of costimulatory T cells, enhances the generation of cytolytic T cells, and contributes to T cell activation. This interleukin has also been reported to play a role in regulating B cell activation, the cytotoxic function of natural killer cells, and immunoglobulin synthesis. The monoclonal antibody Vorsetuzumab has been developed to target CD70; PDGFRβ (β-platelet-derived growth factor receptor) is a typical receptor tyrosine kinase, which is bound by extracellular ligands A transmembrane protein composed of domains, transmembrane domains, and intracellular tyrosine kinase domains. The molecular weight of the mature glycated PDGFRβ protein is about 180 kDA. The monoclonal antibody Rinucumab has been developed to target PDGFRβ; CD73 (cluster of differentiation 73), termed extracellular-5'-nucleotidase (extracellular-5'-NT, EC 3.1. 3.5), a glycosylphosphatidylinositol (GPI)-linked 70-kDa cell surface enzyme found in most tissues. CD73 is commonly used to convert AMP to adenosine. Extracellular-5-nucleotidase (5-ribonucleotide phosphohydrolase; EC 3.1.3.5) catalyzes the nucleoside conversion of purine 5 mononucleotides at neutral pH, preferably with AMP. This enzyme consists of a dimer of two identical 70-kD subunits bound to the outer surface of the plasma membrane via glycosylphosphatidylinositol linkages. This enzyme is used as a marker of lymphocyte differentiation. The monoclonal antibody Oleclumab and the anti-CD73 antibodies described in SEQ ID NO: 317 to SEQ ID NO: 318 have been developed to target CD73; CD38 (cluster of differentiation 38), also known as loop ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes, and natural killer cells. CD38 also plays a role in cell adhesion, signal transduction, and calcium signaling. Loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral changes including social amnesia that may be associated with autism. CD38 protein is a marker of cell activation. It is associated with HIV infection, leukemia, myeloma, solid tumors, Type II diabetes, and bone metabolism as well as several genetically determined conditions. CD38 produces an enzyme that regulates the release of oxytocin in the central nervous system. The monoclonal antibody Daratumumab has been developed to target CD38; integrin αvβ3 is a type of integrin, which is the receptor for vitronectin. Integrin αvβ3 consists of two components, integrin αV and integrin β3 (CD61), and is expressed by platelets. Integrin αvβ3 is a receptor for phagocytosis by macrophages or dendritic cells. Monoclonal antibodies Etaracizumab and Intetumumab have been developed to target integrin αvβ3; integrin αvβ8 (VN receptor) was identified as a potential negative regulator of cell growth. The cytoplasmic domain of β8 is sequence distinct and lacks all amino acid homology of the highly homologous cytoplasmic domain with the other αv-related integrin β subunits (β1, β3, β5, and β6). The β8 cytoplasmic domains are functionally distinct. αvβ8 has a restricted distribution and is highly expressed in non-proliferating cell types. Anti-integrin αvβ8 antibodies have been developed to target integrin αvβ8 as described in SEQ ID NO: 319 to SEQ ID NO: 320; CD248 encodes endosialin. Endosialin is a member of a novel C-type lectin transmembrane receptor family "group XIV" that plays a role not only in cell-cell adhesion but also in host defense. Endosialin has been implicated in angiogenesis in the embryo, in the uterus, and in tumor development and growth. The monoclonal antibody Ontuxizumab has been developed to target endosialin; FAP (Fibroblast Activation Protein Alpha) is a 170kDa melanoma membrane-bound gelatinase and is encoded by the FAP gene in humans protein. The protein encoded by this gene is a homodimeric integral membrane gelatinase belonging to the serine protease family. It is selectively expressed in reactive stromal fibroblasts of epithelial carcinomas, granulation tissue of healing wounds, and malignant cells of osteosarcoma and soft tissue sarcoma. This protein is now thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis. The anti-FAP antibodies described in SEQ ID NO: 321 to SEQ ID NO: 338 have been developed to target FAP; the integrin αv subunit and the five integrin β subunits β1, β3, β5, β6, or β8 One joins to form five different αVβ heterodimers. Integrin αVβ heterodimers on the cell surface interact with cell adhesion proteins such as collagen, fibrinogen, fibronectin, and vitronectin. These interactions play an important role in cell adhesion or migration, especially in tumor metastasis. The monoclonal antibody intetumumab and anti-intetum αv antibodies have been developed as described in SEQ ID NO: 339 to SEQ ID NO: 342 to target integrin αv; Heterotropic integrin, which is a receptor for the extracellular matrix (ECM) proteins fibronectin, vitronectin, tenascin, and latency-associated peptide (LAP) of TGF-β. Integrin αvβ6 is not expressed in healthy adult epithelium, but is upregulated during wound healing and in cancer. Integrin αvβ6 has been shown to regulate invasion, inhibit apoptosis, regulate expression of matrix metalloproteinases (MMPs) and activate TGF-β1. Anti-integrin αvβ6 antibodies have been developed as described in SEQ ID NO: 343 to SEQ ID NO: 350 to target integrin αvβ6; or ASGR1, also known as sialoglycoprotein receptor 1, is a sialic acid Major subunit of glycoprotein receptors. Sialylglycoprotein receptors are hetero-oligomeric proteins composed of major and minor subunits and are highly expressed on the surface of hepatocytes, several human cancer cell lines, and liver cancer. Sialylglycoprotein receptors mediate endocytosis of plasma glycoproteins in which terminal sialic acid residues of complex carbohydrate moieties are removed. The receptor recognizes terminal galactose and N-acetylgalactosamine units. After ligand binding to the receptor, the resulting complex is internalized and transported to the sorting organelle, where the receptor is separated from the ligand. Subsequently, the receptors return to the cell membrane surface. Sialylglycoprotein receptors promote liver infection by multiple viruses, including hepatitis B. ASGR1 includes mammalian ASGR1 proteins, such as mice, rats, rabbits, guinea pigs, pigs, sheep, dogs, non-human primates, and humans. In some specific embodiments, ASGR1 means an alternative splice variant. In some embodiments, ASGR1 is human ASGR1 having the amino acid sequence described in Accession No. NP_001184145.1 or NP_001662.1.

"Fc region constant domain portion" or "Fc region portion" as used herein means a heavy chain constant segment derived from an Fc fragment ("crystallizable fragment" region or Fc region) of an antibody, which may include one or more a constant domain such as CH2, CH3, CH4, or any combination thereof. In certain embodiments, the Fc region portion includes the CH2 and CH3 domains of an IgG, IgA, or IgD antibody, and any combination thereof, or the CH3 and CH4 domains of an IgM or IgE antibody, and any combination thereof.

By context, the Fc region is responsible for the effector functions of immunoglobulins such as ADCC (antibody-dependent cell-mediated cytotoxicity), ADCP (antibody-dependent cellular phagocytosis), CDC (complement-dependent cytotoxicity), and complement fixation, Binding to Fc receptors (eg CD16, CD32, FcRn), longer in vivo half-life relative to polypeptides lacking the Fc region, protein A binding, and possibly placental transfer (see Capon et al., Nature 337: 525, 1989).

Fc regions or domains can interact with different types of FcRs. Different types of FcRs can include, for example, FcyRI, FcyRIIA, FcyRIIB, FcyRIIIA, FcyRIIIB, FcaRI, FcyR, FceRI, FcyRII, and FcRn. FcRs can be located on the membrane of specific immune cells including, for example, B lymphocytes, natural killer cells, macrophages, neutrophils, follicular dendritic cells, eosinophils, basophils, platelets, and Mast cells. Once the FcR binds to the Fc domain, the FcR can initiate functions including, for example, clearance of antigen-antibody complexes by receptor-mediated endocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated Directed phagocytosis (ADCP), and ligand-triggered signal transport across the plasma membrane, which can lead to changes in secretion, exocytosis, and cellular metabolism. FcRs transmit signals when they are aggregated by antibodies and multivalent antigens on the cell surface. Agglutination of FcRs with immunoreceptor tyrosine-dominated activation motifs (ITAMs) can sequentially activate SRC family tyrosine kinases and SYK family tyrosine kinases. ITAM contains a twice-repeated YxxL sequence flanked by seven variable residues. SRC and SYK kinase can jointly activate the pathway to link transduction signals.

In some embodiments, an Fc region or domain may exhibit reduced binding affinity for one or more Fc receptors. In some embodiments, the Fc region or domain can exhibit reduced binding affinity for one or more Fcγ receptors. In some embodiments, the Fc region or domain may exhibit reduced binding affinity for the FcRn receptor. In some embodiments, the Fc region or domain can exhibit reduced binding affinity for Fcγ to the FcRn receptor. In some embodiments, the Fc domain is an Fc null domain or region. As used herein, "Fc null" means a domain that exhibits weak or no binding to any Fcγ receptor. In some embodiments, the Fc null domain or region exhibits at least about a 1000-fold reduction in binding affinity (eg, increased Kd) for an Fcγ receptor. As used herein, "Fc null" means a domain that exhibits weak or no binding to any Fcγ receptor. In some embodiments, the Fc null domain or region exhibits at least a 1000-fold reduction in binding affinity (eg, increased Kd) for an Fcγ receptor.

The Fc region or domain may have one or more, two or more, three or more, or four or more, or up to five amino acid substitutions that reduce binding of the Fc region or domain to an Fc receptor . In some specific embodiments, the Fc region or domain exhibits reduced binding to FcyRI (CD64), FcyRIIA (CD32), FcyRIIIA (CD16a), FcyRIIIB (CD16b), or any combination thereof. To reduce the binding affinity of an Fc region or domain for an Fc receptor, the Fc region or domain may contain one or more amino acid substitutions that have the effect of reducing the affinity of the Fc domain or domain for an Fc receptor. In particular embodiments, the Fc region or domain is IgGl and one or more substitutions in the Fc region or domain comprise any one or more of the IgGl heavy chain mutations, which correspond to E233P of the EU index of Kabat numbering , L234V, L234A, L235A, L235E, ∆G236, G237A, E318A, K320A, K322A, A327G, A330S, or P331S.

In some embodiments, the Fc region or domain may comprise an IgGl isotype sequence modified from a wild-type IgGl sequence. Modifications may include substitutions at more than one amino acid residue, for example at 5 different amino acid residues, including L235V/F243L/R292P/Y300L/P396L (IgG1VLPLL) according to the EU index by Kabat numbering. Modifications may include substitutions at more than one amino acid residue, eg at 2 different amino acid residues, including S239D/I332E (IgGlDE) according to the EU index by Kabat numbering. Modifications may include substitutions at more than one amino acid residue, eg at 3 different amino acid residues, including S298A/E333A/K334A (IgGlAAA) according to the EU index by Kabat numbering.

In some embodiments, the antibody constructs or targeting moieties of the invention comprise an Fc region, which may contain an Fc domain, wherein the Fc domain is found within the Fc region that interacts with Fc receptors. The Fc domains of the antibody constructs may interact with Fc receptors (FcRs) found on immune cells. The Fc domain can also mediate interactions between effector molecules and cells, thereby activating the immune system. The Fc region can be derived from an IgG, IgA, or IgD antibody isotype, and can comprise two identical protein fragments derived from the second and third constant domains of the antibody heavy chain. Among Fc domains or regions derived from IgG antibody isotypes, the Fc domains or regions may contain highly conserved N-glycosylation sites that may be essential for FcR-mediated downstream effects. The Fc domain or region can be derived from an IgM or IgE antibody isotype, wherein the Fc domain or region can comprise three heavy chain constant domains. An antibody or Fc domain can be modified to obtain or improve at least one constant region-mediated biological effector function, such as increased FcγR interaction, relative to an unmodified antibody or Fc domain. For example, according to the methods described herein, antibody constant regions can be generated that have binding to FcyRIIA, FcyRIIB, and/or FcyRIIIA with greater affinity than the corresponding wild-type constant regions. According to the methods described herein, Fc domains can be generated that have binding to FcyRIIA, FcyRIIB, and/or FcyRIIIA with greater affinity than the corresponding wild-type Fc domains.

In certain embodiments, the Fc region or domain of an antibody, antibody construct, or targeting moiety of the invention will be capable of mediating one or more of these effector functions, or will lack one or more or all of them Activity, or having one or more effector activities compared to an unmodified Fc region or domain, is increased by, for example, one or more mutations.

In addition, antibodies have a hinge sequence, usually located between the Fab and Fc regions (although the lower portion of the hinge may include the amine-terminal portion of the Fc region). By background, the immunoglobulin hinge acts as a flexible spacer, allowing the Fab moiety to move freely in space. In contrast to constant regions, hinges are structurally diverse, with sequence and length varying between classes of immunoglobulins and even within subclasses. For example, the human IgG1 hinge region has free flexibility that allows the Fab fragment to rotate about its axis of symmetry and move within a sphere centered on the first of the two inter-heavy chain disulfide bridges. In contrast, human IgG2 hinges are relatively short and contain rigid polyproline duplexes stabilized by four inter-heavy chain disulfide bridges, which limit flexibility. The human IgG3 hinge differs from other subclasses by its unique extended hinge region (about four times as long as the IgG1 hinge), which contains 62 amino acids (including 21 proline and 11 cysteine) ), forming a non-flexible polyproline duplex and providing greater flexibility due to the relative distance of the Fab fragment from the Fc fragment. The human IgG4 hinge is shorter than that of IgG1, but the length is the same as that of IgG2, and its flexibility is between IgG1 and IgG2.

In one aspect, antibodies (eg, isolated monoclonal antibodies) that specifically bind to ASGR1 are provided, also referred to as anti-ASGR1 antibodies or antigen-binding fragments thereof.

In various embodiments, the antibody or antigen-binding fragment thereof comprises two light chain polypeptides (light chain) and two heavy chain polypeptides (heavy chain) covalently bound together by disulfide bonds.

Heavy chains typically comprise a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region generally comprises three domains, CH1, CH2, and CH3. Non-limiting exemplary heavy chain constant regions include human IgGl, human IgG2, human IgG3, and human IgG4 constant regions. In some specific embodiments, the antibodies provided herein contain an IgGl constant region. Exemplary heavy chain constant regions include human IgG1 heavy chain constant region (SEQ ID NO:230), human IgG1 null heavy chain constant region (SEQ ID NO:231), mouse IgG2a heavy chain constant region (SEQ ID NO:233) , and the rat IgG2b heavy chain constant region (SEQ ID NO: 235).

Light chains typically comprise a light chain variable region (VL) and a light chain constant region. Non-limiting exemplary light chain constant regions include kappa and lambda constant regions. A non-limiting exemplary human kappa constant region is set forth in SEQ ID NO:232. Another exemplary light chain constant region is the mouse kappa constant region, set forth in SEQ ID NO:234. Another exemplary light chain constant region is the rat kappa constant region, set forth in SEQ ID NO:236.

The constant domains provide the general framework of the antibody and may not be directly involved in binding the antibody to the antigen, but may be involved in various effector functions, such as in antibody-dependent cellular cytotoxicity (ADCC), ADCP (antibody-dependent cellular phagocytosis) ), CDC (complement-dependent cytotoxicity) and complement fixation, binding to Fc receptors (eg CD16, CD32, FcRn), longer in vivo half-life relative to polypeptides lacking the Fc region, protein A binding, and possibly even Placental transfer (see Capon et al ., Nature 337 :525, 1989). As used herein, "Fc region constant domain protein" or "Fc region portion" means the heavy chain constant segment of an antibody Fc fragment ("crystallizable fragment" region or Fc region), which may include one or more constant structures domain, such as CH2, CH3, CH4, or any combination thereof. In certain embodiments, the Fc region portion includes the CH2 and CH3 domains of an IgG, IgA, or IgD antibody, and any combination thereof, or the CH3 and CH4 domains of an IgM or IgE antibody, and any combination thereof.

Fc regions or domains can interact with different types of FcRs. Different types of FcRs can include, for example, FcyRI, FcyRIIA, FcyRIIB, FcyRIIIA, FcyRIIIB, FcaRI, FcyR, FceRI, FcyRII, and FcRn. FcRs can be located on the membranes of specific immune cells including, for example, B lymphocytes, natural killer cells, macrophages, neutrophils, follicular dendritic cells, eosinophils, basophils, platelets, and Mast cells. Once the FcR binds to the Fc domain, the FcR can initiate functions including, for example, clearance of antigen-antibody complexes by receptor-mediated endocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated Directed phagocytosis (ADCP), trogocytosis, trogoptosis, and ligand-triggered signal transmission across the plasma membrane can lead to changes in secretion, exocytosis, and cellular metabolism. FcRs transmit signals when they are aggregated by antibodies and multivalent antigens on the cell surface. Agglutination of FcRs with immunoreceptor tyrosine-dominated activation motifs (ITAMs) can sequentially activate SRC family tyrosine kinases and SYK family tyrosine kinases. ITAM contains a twice-repeated YxxL sequence flanked by seven variable residues. SRC and SYK kinase can jointly activate the pathway to link transduction signals.

In some embodiments, an Fc region or domain may exhibit reduced binding affinity for one or more Fc receptors. In some embodiments, the Fc region or domain can exhibit reduced binding affinity for one or more Fcγ receptors. In some embodiments, the Fc region or domain may exhibit reduced binding affinity for the FcRn receptor. In some embodiments, the Fc region or domain can exhibit reduced binding affinity for Fcγ to the FcRn receptor. In some specific embodiments, the Fc domain is an Fc null domain or region. As used herein, "Fc null" means a domain that exhibits weak or no binding to any Fcγ receptor. In some embodiments, the Fc null domain or region exhibits at least about a 1000-fold reduction in binding affinity (eg, increased Kd) for an Fcγ receptor. In some embodiments, the Fc null domain or region exhibits at least a 1000-fold reduction in binding affinity (eg, increased Kd) for an Fcγ receptor.

The Fc region or domain may have one or more, two or more, three or more, or four or more, or up to five amino acid substitutions that reduce binding of the Fc region or domain to an Fc receptor . In some specific embodiments, the Fc region or domain exhibits reduced binding to FcyRI (CD64), FcyRIIA (CD32), FcyRIIIA (CD16a), FcyRIIIB (CD16b), or any combination thereof. To reduce the binding affinity of an Fc region or domain for an Fc receptor, the Fc region or domain may contain one or more amino acid substitutions that have the effect of reducing the affinity of the Fc domain or domain for an Fc receptor. In certain embodiments, the Fc region or domain is IgGl and one or more of the substitutions in the Fc region or domain comprise any one or more of the IgGl heavy chain mutations, which correspond to E233P of the EU index of Kabat numbering , L234V, L234A, L235A, L235E, ∆G236, G237A, E318A, K320A, K322A, A327G, A330S, or P331S.

In some embodiments, the Fc region or domain may comprise an IgGl isotype sequence modified from a wild-type IgGl sequence. Modifications may include substitutions at more than one amino acid residue, for example at 5 different amino acid residues, including L235V/F243L/R292P/Y300L/P396L (IgG1VLPLL) according to the EU index by Kabat numbering. Modifications may include substitutions at more than one amino acid residue, eg at 2 different amino acid residues, including S239D/I332E (IgGlDE) according to the EU index by Kabat numbering. Modifications may include substitutions at more than one amino acid residue, eg at 3 different amino acid residues, including S298A/E333A/K334A (IgGlAAA) according to the EU index by Kabat numbering. Non-limiting exemplary human IgGl heavy chain constant regions are set forth in SEQ ID NOS: 230 and 231. In certain other specific embodiments, the antibodies provided herein comprise a mouse IgG2a heavy chain constant region as set forth in SEQ ID NO:233. In yet other specific embodiments, the antibodies provided herein comprise a rat IgG2b heavy chain constant region, as set forth in SEQ ID NO:235.

An antibody or Fc domain can be modified to obtain or improve at least one constant region-mediated biological effector function, such as increased FcγR interaction, relative to an unmodified antibody or Fc domain. In certain embodiments, the modification increases CD32b binding (and supports transport in PBMC assays) according to the EU index by Kabat numbering, including substitutions at S267L and E329F (IgG1LF, also known as SELF double mutant). For example, according to the methods described herein, antibody constant regions can be generated that have binding to FcyRIIA, FcyRIIB, and/or FcyRIIIA with greater affinity than the corresponding wild-type constant regions. According to the methods described herein, Fc domains can be generated that have binding to FcyRIIA, FcyRIIB, and/or FcyRIIIA with greater affinity than the corresponding wild-type Fc domains.

In certain embodiments, the Fc regions or domains found in the anti-ASGR1 antibodies of the invention will be capable of mediating one or more of these effector functions, or will lack one or more or all of these activities, or Having one or more effector activities compared to an unmodified Fc region or domain is increased by, eg, one or more mutations.

The antigen-recognition region of the antibody variable domain usually contains six complementarity determining regions (CDRs), or hypervariable regions, which are located in the heavy chain variable region and light chain variable region framework at the N-terminus of the two heavy chains and the two light chains. Inside.

In some embodiments, the antigen binding domain comprises light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), light chain complementarity determining region 3 (LCDR3), heavy chain complementarity determining region 1 (HCDR1 ), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the antibody may be a heavy chain only antibody, in which case the antigen binding domain comprises HCDRl, HCDR2, and HCDR3, and the antibody lacks a light chain.

In some specific embodiments, the anti-ASGR1 antibody or antigen-binding fragment thereof comprises: One heavy chain CDR1 (VH-CDR1) containing the amino acid sequence of SEQ ID NO: 1, one VH-CDR2 containing the amino acid sequence selected from any one of SEQ ID NOS: 6-8, one containing VH-CDR3 of the amino acid sequence of SEQ ID NO: 13; and a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 18, a light chain CDR1 containing the amino acid sequence of SEQ ID NOS: 23-25 VL-CDR2 of the amino acid sequence of any one, and a VL-CDR3 of the amino acid sequence of SEQ ID NO: 33; One VH-CDR1 containing the amino acid sequence of SEQ ID NO:2, one VH-CDR2 containing the amino acid sequence of SEQ ID NO:9, one VH-CDR3 containing the amino acid sequence of SEQ ID NO:14 and a VL-CDR1 containing the amino acid sequence of SEQ ID NO: 19, a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26 or SEQ ID NO: 27, and a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 34 The VL-CDR3 of the amino acid sequence; One VH-CDR1 containing the amino acid sequence of SEQ ID NO:5, one VH-CDR2 containing the amino acid sequence of SEQ ID NO:12, one VH-CDR3 containing the amino acid sequence of SEQ ID NO:17 and a VL-CDR1 containing the amino acid sequence of SEQ ID NO: 22, a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 32, and a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 37 VL-CDR3; One VH-CDR1 containing the amino acid sequence of SEQ ID NO:3, one VH-CDR2 containing the amino acid sequence of SEQ ID NO:10, one VH-CDR3 containing the amino acid sequence of SEQ ID NO:15 and a VL-CDR1 containing the amino acid sequence of SEQ ID NO: 20, a VL-CDR2 containing an amino acid sequence selected from any one of SEQ ID NOS: 28-30, and a VL-CDR2 containing the amino acid sequence of SEQ ID NOS: 28-30 VL-CDR3 of the amino acid sequence of NO: 35; or One VH-CDR1 containing the amino acid sequence of SEQ ID NO:4, one VH-CDR2 containing the amino acid sequence of SEQ ID NO:11, one VH-CDR3 containing the amino acid sequence of SEQ ID NO:16 and a VL-CDR1 containing the amino acid sequence of SEQ ID NO:21, a VL-CDR2 containing the amino acid sequence of SEQ ID NO:31, and a VL-CDR2 containing the amino acid sequence of SEQ ID NO:36 VL-CDR3.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR1 (VH-CDR1 ) comprising the amino acid sequence of SEQ ID NO:1, an amine comprising any one of SEQ ID NO:8 VH-CDR2 of amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 13; and VL comprising a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 18, a VH-CDR1 containing A VL-CDR2 selected from the amino acid sequence of any one of SEQ ID NO:23, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:33.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR1 (VH-CDR1 ) comprising the amino acid sequence of SEQ ID NO:1, an amine comprising any one of SEQ ID NO:6 VH-CDR2 of amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 13; and VL comprising a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 18, a VH-CDR1 containing A VL-CDR2 selected from the amino acid sequence of any one of SEQ ID NO:23, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:33.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:2, an amine comprising any one of SEQ ID NO:9 VH-CDR2 of amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 14; and VL comprising a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 19, a VH-CDR1 containing A VL-CDR2 selected from the amino acid sequence of any one of SEQ ID NO:26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:34.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR1 (VH-CDR1 ) comprising the amino acid sequence of SEQ ID NO:1, an amine comprising any one of SEQ ID NO:6 VH-CDR2 of amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 13; and VL comprising a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 18, a VH-CDR1 containing A VL-CDR2 selected from the amino acid sequence of any one of SEQ ID NO:24, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:33.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR1 (VH-CDR1 ) comprising the amino acid sequence of SEQ ID NO:1, an amine comprising any one of SEQ ID NO:8 VH-CDR2 of amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 13; and VL comprising a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 18, a VH-CDR1 containing A VL-CDR2 selected from the amino acid sequence of any one of SEQ ID NO:24, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:33.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:2, an amine comprising any one of SEQ ID NO:9 VH-CDR2 of amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 14; and VL comprising a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 19, a VH-CDR1 containing A VL-CDR2 selected from the amino acid sequence of any one of SEQ ID NO:27, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:34.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, A heavy chain variable region (VH) of an amino acid sequence of 97%, 98%, or 99% identity, and a heavy chain variable region (VH) containing at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 126 , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the VH-CDRs (i.e. SEQ ID NOS: 1, 6, and 13) and the amino acid sequences of the VL-CDRs (ie, SEQ ID NOS: 18, 23, and 33) were unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92% of an amino acid sequence selected from any one of SEQ ID NOS: 43-88 and 352-357 , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain variable region (VH) of amino acid sequences, and one containing and selected from SEQ ID NOS: The amino acid sequence of any one of 131-133 and 358-363 has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity The amino acid sequence of the light chain variable region (VL), provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

In certain embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, A heavy chain variable region (VH) of an amino acid sequence of 97%, 98%, or 99% identity, and a heavy chain variable region (VH) containing at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 361 , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the amines of VH-CDRs and VL-CDRs The amino acid sequence was unchanged. In further embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96% of the amino acid sequence of SEQ ID NO:353 , 97%, 98%, or 99% identical heavy chain variable region (VH) of the amino acid sequence, and one containing at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 361 %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the VH-CDRs and VL-CDRs are identical The amino acid sequence was unchanged.

In certain embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, A heavy chain variable region (VH) of an amino acid sequence that is 97%, 98%, or 99% identical, and a heavy chain variable region (VH) that contains at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 362 , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the amines of VH-CDRs and VL-CDRs The amino acid sequence was unchanged. In further embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96% of the amino acid sequence of SEQ ID NO:353 , 97%, 98%, or 99% identical heavy chain variable region (VH) of the amino acid sequence, and a heavy chain variable region (VH) containing at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 362 %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the VH-CDRs and VL-CDRs are identical The amino acid sequence was unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, 94%, 95%, 90%, 91%, 92%, 93%, 94%, 95%, A heavy chain with an amino acid sequence of 96%, 97%, 98%, or 99% identity, and a heavy chain containing at least 90%, 91%, 92%, 93% with the amino acid sequence of SEQ ID NO: 127 , 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence light chain, provided that VH-CDRs (i.e. SEQ ID NOS: 2, 9, and 14) and VL - The amino acid sequences of the CDRs (ie SEQ ID NOS: 19, 26, and 34) are unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, 90%, 91%, 92%, 93%, A heavy chain variable region (VH) of an amino acid sequence of 94%, 95%, 96%, 97%, 98%, or 99% identity, and one containing and selected from SEQ ID NOS: 134-137 The amino acid sequence of any one has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity of the amino acid sequence of the light chain Variable region (VL), provided that the amino acid sequences of VH-CDRs and VL-CDRs are unchanged.

In certain embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, The heavy chain variable region (VH) of the amino acid sequence of 97%, 98%, or 99% identity, and one containing at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 134 , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the amines of VH-CDRs and VL-CDRs The amino acid sequence was unchanged. In further embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96% of the amino acid sequence of SEQ ID NO:89 , 97%, 98%, or 99% identical heavy chain variable region (VH) of the amino acid sequence, and one containing at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 136 %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the VH-CDRs and VL-CDRs are identical The amino acid sequence was unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, A heavy chain variable region (VH) of an amino acid sequence of 97%, 98%, or 99% identity, and a heavy chain variable region (VH) containing at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 130 , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the VH-CDRs (i.e. SEQ ID NOS: 5, 12, and 17) and the amino acid sequences of the VL-CDRs (ie, SEQ ID NOS: 22, 32, and 37) were unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, 90%, 91%, 92%, 93%, A heavy chain variable region (VH) of an amino acid sequence of 94%, 95%, 96%, 97%, 98%, or 99% identity, and a variable region (VH) containing an amino acid sequence selected from the group consisting of SEQ ID NOS: 143-149 The amino acid sequence of any one has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity of the amino acid sequence of the light chain Variable region (VL), provided that the amino acid sequences of VH-CDRs and VL-CDRs are unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, The heavy chain variable region (VH) of the amino acid sequence of 97%, 98%, or 99% identity, and one containing at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 128 , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the VH-CDRs (i.e. SEQ ID NOS: 3, 10, and 15) and the amino acid sequences of the VL-CDRs (ie, SEQ ID NOS: 20, 28, and 35) were unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, 90%, 91%, 92%, 93%, A heavy chain variable region (VH) of an amino acid sequence of 94%, 95%, 96%, 97%, 98%, or 99% identity, and one containing and selected from SEQ ID NOS: 138-141 The amino acid sequence of any one has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity of the amino acid sequence of the light chain Variable region (VL), provided that the amino acid sequences of VH-CDRs and VL-CDRs are unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, The heavy chain variable region (VH) of the amino acid sequence of 97%, 98%, or 99% identity, and one containing at least 90%, 91%, 92% with the amino acid sequence of SEQ ID NO: 129 , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the VH-CDRs (i.e. SEQ ID NOS: 4, 11, and 16) and the amino acid sequences of the VL-CDRs (ie, SEQ ID NOS: 21, 31, and 36) were unchanged.

In some embodiments, an antibody or antigen-binding fragment thereof can be identified by its heavy and/or light chain CDRs using any of the following methods: Kabat, Chothia, AbM, Contact, IMGT, and/or Aho. In some embodiments, antibodies or antigen-binding fragments thereof can be identified by the CDRs provided in Tables 32-36. In some embodiments, anti-ASGR1 antibodies or antigen-binding fragments thereof can be identified by the CDRs provided in Tables 32-36. In some embodiments, anti-ASGR1 antibodies or antigen-binding fragments thereof can be identified by the CDRs provided in Table 32. In some embodiments, anti-ASGR1 antibodies or antigen-binding fragments thereof can be identified by the CDRs provided in Table 33. In some embodiments, anti-ASGR1 antibodies or antigen-binding fragments thereof can be identified by the CDRs provided in Table 34. In some embodiments, anti-ASGR1 antibodies or antigen-binding fragments thereof can be identified by the CDRs provided in Table 35. In some embodiments, anti-ASGR1 antibodies or antigen-binding fragments thereof can be identified by the CDRs provided in Table 36. Table 32. hzG2D anti- ASGR1 CDRs Antibody CDR Identification Kabat Chothia AbM Contact IMGT VH CDR1 GYYMH (SEQ ID NO: 1) GYSFTGY (SEQ ID NO: 515) GYSFTGYYMH (SEQ ID NO: 516) TGYYMH (SEQ ID NO: 517) GYSFTGYY (SEQ ID NO: 518) VH CDR2 RINPNNGATNYNQNFKD (SEQ ID NO: 6; G2D) RINPNQGATNYNQNFKD (SEQ ID NO: 7; G2.1D) RINPNNAATNYNQNFKD (SEQ ID NO: 8; G2.2D) NPNNAA (SEQ ID NO: 519) RINPNNAATN (SEQ ID NO: 520) WMGRINPNNAATN (SEQ ID NO: 521) INPNNAAT (SEQ ID NO: 522) VH CDR3 VNFYY (SEQ ID NO: 13) VNFYY (SEQ ID NO: 13) VNFYY (SEQ ID NO: 13) TSVNFY (SEQ ID NO: 523) TSVNFYY (SEQ ID NO: 524) VL CDR1 KASQVINSYLS (SEQ ID NO: 18) KASQVINSYLS (SEQ ID NO: 18) KASQVINSYLS (SEQ ID NO: 18) NSYLSWF (SEQ ID NO: 525) QVINSY (SEQ ID NO: 526) VL CDR2 RANTLVD (SEQ ID NO: 23; G2D) RANTLVD (SEQ ID NO: 23) RANTLVD (SEQ ID NO: 23) SLIYRANTLV (SEQ ID NO: 527) RA RANTLVS (SEQ ID NO: 24; G2.1D) RANTLVE (SEQ ID NO: 25; G2.2D) VL CDR3 LQYAEFPYT (SEQ ID NO: 33) LQYAEFPYT (SEQ ID NO: 33) LQYAEFPYT (SEQ ID NO: 33) LQYAEFPY (SEQ ID NO: 528) LQYAEFPYT (SEQ ID NO: 33) Table 33. hzK2E anti- ASGR1 CDRs Antibody CDR Identification Kabat Chothia AbM Contact IMGT VH CDR1 SYTMH (SEQ ID NO: 2) GYTFTSY (SEQ ID NO: 529) GYTFTSYTMH (SEQ ID NO: 530) TSYTMH (SEQ ID NO: 531) GYTFTSYT (SEQ ID NO: 532) VH CDR2 YISPSSGYTEYNQKFKD (SEQ ID NO: 9) SPSSGY (SEQ ID NO: 533) YISPSSGYTE (SEQ ID NO:534) WMGYISPSSGYTE (SEQ ID NO:535) ISPSSGYT (SEQ ID NO:536) VH CDR3 KFDY (SEQ ID NO: 14) KFDY (SEQ ID NO: 14) KFDY (SEQ ID NO: 14) ARKFD (SEQ ID NO: 537) ARKFDY (SEQ ID NO: 538) VL CDR1 KASQDINSYLS (SEQ ID NO: 19) KASQDINSYLS (SEQ ID NO: 19) KASQDINSYLS (SEQ ID NO: 19) NSYLSWF (SEQ ID NO: 525) QDINSY (SEQ ID NO: 539) VL CDR2 RANRLVD (SEQ ID NO: 26) RANRLVD (SEQ ID NO: 26) RANRLVD (SEQ ID NO: 26) SLIYRANRLV (SEQ ID NO: 540) RA VL CDR3 LQYDEFPFT (SEQ ID NO: 34) LQYDEFPFT (SEQ ID NO: 34) FGQGTKLEIKRTV (SEQ ID NO: 541) LQYDEFPF (SEQ ID NO: 542) LQYDEFPFT (SEQ ID NO: 34) Table 34. hzL4L anti- ASGR1 CDRs Antibody CDR Identification Kabat Chothia AbM Contact IMGT VH CDR1 SDYAWN (SEQ ID NO: 3) GGSISSDY (SEQ ID NO: 543) GGSISSDYAWN (SEQ ID NO: 544) SSDYAWN (SEQ ID NO: 545) GGSISSDYA (SEQ ID NO: 546) VH CDR2 YISYSGSTRYNPSLKS (SEQ ID NO: 10) SYSGS (SEQ ID NO: 557) YISYSGSTR (SEQ ID NO: 558) WIGYISYSGSTR (SEQ ID NO: 559) ISYSGST (SEQ ID NO: 560) VH CDR3 RYRYDEGYGMDY (SEQ ID NO: 15) RYRYDEGYGMDY (SEQ ID NO: 15) RYRYDEGYGMDY (SEQ ID NO: 15) ARRYRYDEGYGMD (SEQ ID NO: 561) ARRYRYDEGYGMDY (SEQ ID NO: 562) VL CDR1 RASENIYSNLA (SEQ ID NO: 20) RASENIYSNLA (SEQ ID NO: 20) RASENIYSNLA (SEQ ID NO: 20) YSNLAWY (SEQ ID NO: 563) ENIYSN (SEQ ID NO: 564) VL CDR2 AATNLAD (SEQ ID NO: 28) AATNLAD (SEQ ID NO: 28) AATNLAD (SEQ ID NO: 28) LLIYAATNLA (SEQ ID NO: 565) AA VL CDR3 QHFWGTPPWT (SEQ ID NO: 35) QHFWGTPPWT (SEQ ID NO: 35) QHFWGTPPWT (SEQ ID NO: 35) QHFWGTPPW (SEQ ID NO: 566) QHFWGTPPWT (SEQ ID NO: 35) Table 35. hzJ4F anti- ASGR1 CDRs Antibody CDR Identification Kabat Chothia AbM Contact IMGT VH CDR1 SYWIN (SEQ ID NO: 5) GYTFTSY (SEQ ID NO: 529) GYTFTSYWIN (SEQ ID NO: 567) TSYWIN (SEQ ID NO: 568) GYTFTSYW (SEQ ID NO: 569) VH CDR2 RIVPGSGSTYYNEMFKD (SEQ ID NO: 12) VPGSGS (SEQ ID NO: 570) RIVPGSGSTY (SEQ ID NO: 571) WMGRIVPGSGSTY (SEQ ID NO: 572) IVPGSGST (SEQ ID NO: 573) VH CDR3 KPNFDV (SEQ ID NO: 17) KPNFDV (SEQ ID NO: 17) KPNFDV (SEQ ID NO: 17) ARKPNFD (SEQ ID NO: 574) ARKPNFDV (SEQ ID NO: 575) VL CDR1 KASQNVGTNVA (SEQ ID NO: 22) KASQNVGTNVA (SEQ ID NO: 22) KASQNVGTNVA (SEQ ID NO: 22) GTNVAWY (SEQ ID NO: 576) QNVGTN (SEQ ID NO: 577) VL CDR2 SASYRFS (SEQ ID NO: 32) SASYRFS (SEQ ID NO: 32) SASYRFS (SEQ ID NO: 32) AVIYSASYRF (SEQ ID NO: 578) SA VL CDR3 QQYNSYPLT (SEQ ID NO: 37) QQYNSYPLT (SEQ ID NO: 37) QQYNSYPLT (SEQ ID NO: 37) QQYNSYPL (SEQ ID NO: 579) QQYNSYPLT (SEQ ID NO: 37) Table 36. hzH8K anti- ASGR1 CDRs Antibody CDR Identification Kabat Chothia AbM Contact IMGT VH CDR1 SDYAWN (SEQ ID NO: 4) GGSISSDY (SEQ ID NO: 543) GGSISSDYAWN (SEQ ID NO: 544) SSDYAWN (SEQ ID NO: 545) GGSISSDYA (SEQ ID NO: 546) VH CDR2 YRSYRGSTSYNPSLKS (SEQ ID NO: 11) SYRGS (SEQ ID NO: 547) YRSYRGSTS (SEQ ID NO: 548) WIGYRSYRGSTS (SEQ ID NO: 549) RSYRGST (SEQ ID NO: 550) VH CDR3 RGYYGSSSHWYFDV (SEQ ID NO: 16) RGYYGSSSHWYFDV (SEQ ID NO: 16) RGYYGSSSHWYFDV (SEQ ID NO: 16) ARRGYYGSSSHWYFD (SEQ ID NO:551) ARRGYYGSSSHWYFDV (SEQ ID NO:552) VL CDR1 RASENIYSYLA (SEQ ID NO: 21) RASENIYSYLA (SEQ ID NO: 21) RASENIYSYLA (SEQ ID NO: 21) YSYLAWY (SEQ ID NO: 553) ENIYSY (SEQ ID NO: 554) VL CDR2 NAKTLAE (SEQ ID NO: 31) NAKTLAE (SEQ ID NO: 31) NAKTLAE (SEQ ID NO: 31) LLIYNAKTLA (SEQ ID NO: 555) NA VL CDR3 QHHYGTPLT (SEQ ID NO: 36) QHHYGTPLT (SEQ ID NO: 36) QHHYGTPLT (SEQ ID NO: 36) QHHYGTPL (SEQ ID NO: 556) QHHYGTPLT (SEQ ID NO: 36)

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, 90%, 91%, 92%, 93%, A heavy chain variable region (VH) of an amino acid sequence of 94%, 95%, 96%, 97%, 98%, or 99% identity, and one containing the amino acid sequence of SEQ ID NO: 142 having The light chain variable region (VL) of an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical, provided that The amino acid sequences of VH-CDRs and VL-CDRs were unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:38 and a light chain comprising the amino acid sequence of SEQ ID NO:126 chain variable region (VL).

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising an amino acid sequence selected from any of SEQ ID NOS: 43-88 and 352-357 and a VH comprising an amino acid sequence selected from SEQ ID NOS: 43-88 and 352-357 : VL of the amino acid sequence of any of 131-133 and 358-363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:44 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:46 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:50 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:52 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:54 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:58 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:60 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:61 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:62 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:72 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:74 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:75 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:76 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:77 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:78 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:79 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:80 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:81 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:82 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:83 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:84 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:85 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:86 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:88 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:352 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:353 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:354 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:355 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:356 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:357 and a VL comprising the amino acid sequence of SEQ ID NO:131.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:44 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:46 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:50 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:52 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:54 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:58 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:60 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:61 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:62 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:72 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:74 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:75 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:76 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:77 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:78 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:79 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:80 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:81 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:82 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:83 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:84 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:85 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:86 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:88 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:352 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:353 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:354 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:355 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:356 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:357 and a VL comprising the amino acid sequence of SEQ ID NO:132.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:44 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:46 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:50 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:52 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:54 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:58 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:60 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:61 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:62 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:72 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:74 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:75 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:76 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:77 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:78 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:79 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:80 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:81 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:82 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:83 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:84 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:85 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:86 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:88 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:352 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:353 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:354 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:355 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:356 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:357 and a VL comprising the amino acid sequence of SEQ ID NO:133.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:44 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:46 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:50 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:52 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:54 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:58 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:60 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:61 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:62 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:72 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:74 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:75 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:76 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:77 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:78 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:79 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:80 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:81 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:82 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:83 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:84 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:85 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:86 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:88 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:352 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:353 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:354 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:355 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:356 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:357 and a VL comprising the amino acid sequence of SEQ ID NO:358.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:44 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:46 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:50 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:52 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:54 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:58 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:60 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:61 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:62 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:72 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:74 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:75 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:76 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:77 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:78 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:79 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:80 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:81 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:82 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:83 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:84 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:85 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:86 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:88 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:352 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:353 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:354 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:355 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:356 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:357 and a VL comprising the amino acid sequence of SEQ ID NO:359.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:44 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:46 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:50 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:52 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:54 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:58 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:60 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:61 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:62 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:72 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:74 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:75 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:76 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:77 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:78 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:79 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:80 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:81 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:82 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:83 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:84 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:85 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:86 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:88 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:352 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:353 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:354 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:355 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:356 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:357 and a VL comprising the amino acid sequence of SEQ ID NO:360.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:44 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:46 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:50 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:52 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:54 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:58 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:60 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:61 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:62 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:72 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:74 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:75 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:76 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:77 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:78 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:79 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:80 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:81 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:82 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:83 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:84 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:85 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:86 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:88 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:352 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:353 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:354 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:355 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:356 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:357 and a VL comprising the amino acid sequence of SEQ ID NO:361.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:44 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:46 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:50 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:52 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:54 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:58 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:60 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:61 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:62 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:72 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:74 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:75 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:76 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:77 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:78 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:79 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:80 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:81 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:82 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:83 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:84 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:85 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:86 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:88 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:352 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:353 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:354 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:355 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:356 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:357 and a VL comprising the amino acid sequence of SEQ ID NO:362.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:44 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:46 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:50 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:52 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:54 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:58 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:60 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:61 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:62 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:72 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:74 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:75 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:76 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:77 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:78 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:79 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:80 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:81 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:82 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:83 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:84 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:85 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:86 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:88 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:352 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:353 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:354 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:355 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:356 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:357 and a VL comprising the amino acid sequence of SEQ ID NO:363.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:39 and a VL comprising the amino acid sequence of SEQ ID NO:127.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising an amino acid sequence selected from any one of SEQ ID NOS:89-93, and a VH comprising an amino acid sequence selected from SEQ ID NOS:134- VL of the amino acid sequence of any one of 137.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:89 and a VL comprising the amino acid sequence of SEQ ID NO:134.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:90 and a VL comprising the amino acid sequence of SEQ ID NO:134.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:91 and a VL comprising the amino acid sequence of SEQ ID NO:134.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:92 and a VL comprising the amino acid sequence of SEQ ID NO:134.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:93 and a VL comprising the amino acid sequence of SEQ ID NO:134.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:89 and a VL comprising the amino acid sequence of SEQ ID NO:135.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:90 and a VL comprising the amino acid sequence of SEQ ID NO:135.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:91 and a VL comprising the amino acid sequence of SEQ ID NO:135.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:92 and a VL comprising the amino acid sequence of SEQ ID NO:135.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:93 and a VL comprising the amino acid sequence of SEQ ID NO:135.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:89 and a VL comprising the amino acid sequence of SEQ ID NO:136.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:90 and a VL comprising the amino acid sequence of SEQ ID NO:136.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:91 and a VL comprising the amino acid sequence of SEQ ID NO:136.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:92 and a VL comprising the amino acid sequence of SEQ ID NO:136.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:93 and a VL comprising the amino acid sequence of SEQ ID NO:136.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:89 and a VL comprising the amino acid sequence of SEQ ID NO:137.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:90 and a VL comprising the amino acid sequence of SEQ ID NO:137.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:91 and a VL comprising the amino acid sequence of SEQ ID NO:137.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:92 and a VL comprising the amino acid sequence of SEQ ID NO:137.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:93 and a VL comprising the amino acid sequence of SEQ ID NO:137.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:42 and a VL comprising the amino acid sequence of SEQ ID NO:130.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising an amino acid sequence selected from any of SEQ ID NOS: 113-125 and a VH comprising an amino acid sequence selected from SEQ ID NOS: 143-149 VL of any of the amino acid sequences.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:113 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:118 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:122 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:113 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:118 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:122 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:113 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:118 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:122 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:113 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:118 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:122 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:114 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:116 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:124 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:120 and a VL comprising the amino acid sequence of SEQ ID NO:146.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:113 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:118 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:114 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:116 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:124 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:120 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:113 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:118 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:114 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:116 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:124 and a VL comprising the amino acid sequence of SEQ ID NO:148. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:120 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:113 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:118 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:114 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:116 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:124 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:120 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:114 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:114 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:114 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:116 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:116 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:116 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:120 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:120 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:120 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:122 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:122 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:122 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL comprising the amino acid sequence of SEQ ID NO:147.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL comprising the amino acid sequence of SEQ ID NO:148.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL comprising the amino acid sequence of SEQ ID NO:149.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:124 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:124 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:124 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL comprising the amino acid sequence of SEQ ID NO:143.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL comprising the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL comprising the amino acid sequence of SEQ ID NO:145.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:40 and a VL comprising the amino acid sequence of SEQ ID NO:128.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising an amino acid sequence selected from any of SEQ ID NOS:94-102 and a VH comprising an amino acid sequence selected from SEQ ID NOS:138-141 VL of any of the amino acid sequences.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:94 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:95 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:96 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:97 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:98 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:99 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:100 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:101 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:102 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:96 and a VL comprising the amino acid sequence of SEQ ID NO:139.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:96 and a VL comprising the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:96 and a VL comprising the amino acid sequence of SEQ ID NO:141.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:98 and a VL comprising the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:100 and a VL comprising the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:94 and a VL comprising the amino acid sequence of SEQ ID NO:139.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:94 and a VL comprising the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:94 and a VL comprising the amino acid sequence of SEQ ID NO:141.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:95 and a VL comprising the amino acid sequence of SEQ ID NO:139.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:95 and a VL comprising the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:95 and a VL comprising the amino acid sequence of SEQ ID NO:141.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:97 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:97 and a VL comprising the amino acid sequence of SEQ ID NO:139.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:97 and a VL comprising the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:97 and a VL comprising the amino acid sequence of SEQ ID NO:141.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:98 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:98 and a VL comprising the amino acid sequence of SEQ ID NO:139.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:98 and a VL comprising the amino acid sequence of SEQ ID NO:141.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:99 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:99 and a VL comprising the amino acid sequence of SEQ ID NO:139.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:99 and a VL comprising the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:99 and a VL comprising the amino acid sequence of SEQ ID NO:141.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:100 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:100 and a VL comprising the amino acid sequence of SEQ ID NO:139.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:100 and a VL comprising the amino acid sequence of SEQ ID NO:141.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:101 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:101 and a VL comprising the amino acid sequence of SEQ ID NO:139.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:101 and a VL comprising the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:101 and a VL comprising the amino acid sequence of SEQ ID NO:141.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:102 and a VL comprising the amino acid sequence of SEQ ID NO:138.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:102 and a VL comprising the amino acid sequence of SEQ ID NO:139.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:102 and a VL comprising the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:102 and a VL comprising the amino acid sequence of SEQ ID NO:141.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:41 and a VL comprising the amino acid sequence of SEQ ID NO:129.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising an amino acid sequence selected from any one of SEQ ID NOS: 103-112 and an amino acid sequence comprising SEQ ID NO: 142 VL.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:103 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:104 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:105 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:106 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:107 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:108 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:109 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:110 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:111 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:112 and a VL comprising the amino acid sequence of SEQ ID NO:142.

In any of the foregoing embodiments, the VH may be linked to a heavy chain constant region, eg, the human IgGl constant region of SEQ ID NO: 230 or 231.

In any of the foregoing embodiments, the VL may be linked to a light chain constant region, such as the human kappa constant region of SEQ ID NO:232.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, Heavy chains of amino acid sequences of 97%, 98%, or 99% identity, and one containing at least 90%, 91%, 92%, 93%, 94% with the amino acid sequence of SEQ ID NO: 206 , 95%, 96%, 97%, 98%, or 99% identical amino acid sequences of light chains, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, 90%, 91%, 92%, 93%, A heavy chain of amino acid sequences of 94%, 95%, 96%, 97%, 98%, or 99% identity, and one containing an amine group selected from any one of SEQ ID NOS: 211-213 A light chain having an amino acid sequence of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity in the acid sequence, provided that the VH-CDRs The amino acid sequences of the VL-CDRs were unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, Heavy chains of amino acid sequences of 97%, 98%, or 99% identity, and one containing at least 90%, 91%, 92%, 93%, 94% with the amino acid sequence of SEQ ID NO: 207 , 95%, 96%, 97%, 98%, or 99% identical amino acid sequences of light chains, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, A heavy chain of amino acid sequences of 94%, 95%, 96%, 97%, 98%, or 99% identity, and one containing an amine group selected from any of SEQ ID NOS: 214-217 A light chain having an amino acid sequence of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity in the acid sequence, provided that the VH-CDRs The amino acid sequences of the VL-CDRs were unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, Heavy chains of amino acid sequences of 97%, 98%, or 99% identity, and a heavy chain that contains at least 90%, 91%, 92%, 93%, 94% with the amino acid sequence of SEQ ID NO: 210 , 95%, 96%, 97%, 98%, or 99% identical amino acid sequences of light chains, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, A heavy chain with an amino acid sequence of 97%, 98%, or 99% identity, and a heavy chain containing at least 90%, 91%, 92%, 93%, 94% with the amino acid sequence of SEQ ID NO: 208 , 95%, 96%, 97%, 98%, or 99% identical amino acid sequences of light chains, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, Heavy chains of amino acid sequences of 97%, 98%, or 99% identity, and a heavy chain containing at least 90%, 91%, 92%, 93%, 94% of the amino acid sequence of SEQ ID NO: 209 , 95%, 96%, 97%, 98%, or 99% identical amino acid sequences of light chains, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:150 and a light chain comprising the amino acid sequence of SEQ ID NO:206.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence selected from any of SEQ ID NOS: 155-200 and a heavy chain comprising an amino acid sequence selected from SEQ ID NOS: 211- The light chain of the amino acid sequence of any one of 213.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:151 and a light chain comprising the amino acid sequence of SEQ ID NO:207.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence selected from any one of SEQ ID NOS:201-205 and a heavy chain comprising an amino acid sequence selected from SEQ ID NOS:214- The light chain of the amino acid sequence of any one of 217.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:154, and a light chain comprising the amino acid sequence of SEQ ID NO:210.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:152 and a light chain comprising the amino acid sequence of SEQ ID NO:208.

In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:153 and a light chain comprising the amino acid sequence of SEQ ID NO:209.

In any of the foregoing embodiments, the anti-ASGRl antibody or antigen-binding fragment thereof is conjugated to a small molecule drug to form an antibody drug conjugate. In certain embodiments, the small molecule drug is a TGFBR1 inhibitor as disclosed herein, thereby forming a conjugate.

In some embodiments, the anti-LRRC15 antibody or antigen-binding fragment thereof comprises: a) a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 580, a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 580, VH-CDR2 of the amino acid sequence of 590-594, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 611, a light chain CDR1 (VL-CDR1 containing the amino acid sequence of SEQ ID NO: 625) ), a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 636, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 644; or b) an amino group containing SEQ ID NO: 581 The VH-CDR1 of the acid sequence, the VH-CDR2 containing the amino acid sequence selected from SEQ ID NO: 595-597, the VH-CDR3 containing the amino acid sequence of SEQ ID NO: 612, the VH-CDR3 containing the amino acid sequence of SEQ ID NO: 612 A light chain CDR1 (VL-CDR1) containing the amino acid sequence of NO: 626 or 627, a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 637, and a VL-CDR2 containing the amino acid sequence selected from SEQ ID NOs: 645-649 or c) a VH-CDR1 containing the amino acid sequence of SEQ ID NO:582, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:598, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:598, VH-CDR3 of the amino acid sequence of ID NO: 613 or 614, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 628, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 638 or d) a VH-CDR1 containing the amino acid sequence of SEQ ID NO:583, a VL-CDR1 containing the amino acid sequence of SEQ ID NO:599 - VH-CDR2 of the amino acid sequence of 602, a VH-CDR3 of the amino acid sequence of SEQ ID NO: 615, a light chain CDR1 of the amino acid sequence of SEQ ID NO: 629 (VL-CDR1) , a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 639, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 651; or e) an amino acid containing SEQ ID NO: 580 Sequence VH-CDR1, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 603, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 616, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 616 The light chain CDR1 (VL-CDR1) of the amino acid sequence of NO:625, a VL-CDR2 containing the amino acid sequence of SEQ ID NO:636, and a VL containing the amino acid sequence of SEQ ID NO:644 -CDR3; or f) a VH-CDR1 containing the amino acid sequence of SEQ ID NO:581, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:595, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:621 VH-CDR3 of the amino acid sequence, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 626, a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 637, and a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 626 or g) a VH-CDR1 containing the amino acid sequence of SEQ ID NO: 581; a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 605 , a VH-CDR3 containing the amino acid sequence of SEQ ID NO:618, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO:631, an amino group containing SEQ ID NO:640 VL-CDR2 of the amino acid sequence, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 653; or h) a VH-CDR1 containing the amino acid sequence of SEQ ID NO: 584, a VH-CDR1 containing the amino acid sequence of SEQ ID NO: 584 VH-CDR2 of the amino acid sequence of: 604, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 617, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 630 , a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 639, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 652; or i) an amino acid containing SEQ ID NO: 585 Sequence of VH-CDR1, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:606, a VH-CDR3 containing the amino acid sequence of SEQ ID NO:619, a VH-CDR3 containing the amino acid sequence of SEQ ID NO:632 The light chain CDR1 (VL-CDR1) of the amino acid sequence, a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 641, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 654; or j) A VH-CDR1 containing the amino acid sequence of SEQ ID NO: 586, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 607, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 620 VH-CDR3, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO:632, a VL-CDR2 containing the amino acid sequence of SEQ ID NO:641, and a VL-CDR2 containing the amino acid sequence of SEQ ID NO:641: VL-CDR3 of the amino acid sequence of 654; or k) a VH-CDR1 containing the amino acid sequence of SEQ ID NO: 587, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 608, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 608 VH-CDR3 of the amino acid sequence of SEQ ID NO:622, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO:633, a light chain CDR1 containing the amino acid sequence of SEQ ID NO:641 VL-CDR2, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:655; or 1) a VH-CDR1 containing the amino acid sequence of SEQ ID NO:588, a VH-CDR1 containing the amino acid sequence of SEQ ID NO:609 VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 623, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 634, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 634. VL-CDR2 containing the amino acid sequence of SEQ ID NO: 642, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 656; or m) a VH containing the amino acid sequence of SEQ ID NO: 589 -CDR1, a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 610, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 624, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 635 Light chain CDR1 (VL-CDR1), a VL-CDR2 containing the amino acid sequence of SEQ ID NO:643, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:657. Table 37 describe sequence SEQ ID NO F36, F32 VH CDR1 SFVIH 580 J48, J24, K611 VH CDR1 DYYIN 581 J66 VH CDR1 NYWIG 582 K713 VH CDR1 DYYMN 583 F65 VH CDR1 TYDIN 584 K412 VH CDR1 DHYME 585 K55 VH CDR1 DYYMD 586 K72 VH CDR1 YSWIH 587 K84 VH CDR1 SYWMH 588 14K VH CDR1 DYGMA 589 F36 VH CDR2v1-6 YIYNDGTKYNERFRG 590 F36 VH CDR2v6.1 YIYNEGTKYNERFRG 591 F36 VH CDR2v6.2 YIYNQGTKYNERFRG 592 F36 VH CDR2v6.3 YIYNSGTKYNERFRG 593 F36 VH CDR2v6.4 YIYNDATKYNERFRG 594 J48, K611 VH CDR2v1 WIYPGSGNTKYNEKFKG 595 J48 VH CDR2v2 WIYPGSGNTKYSQKFQG 596 J48 VH CDR2v3 WIYPGSGNTKYAQKFQG 597 J66 VH CDR2 DIYPRSGYTNYNEKFKG 598 K713 VH CDR2v1 RVSPSNGGTNYNQKFRG 599 K713 VH CDR2v2 RVSPSQGGTNYNQKFRG 600 K713 VH CDR2v3 RVSPSSGGTNYNQKFRG 601 K713 VH CDR2v4 RVSPSNAGTNYNQKFRG 602 F32 VH CDR2 YIYNDGTKYNEKFRG 603 F65 VH CDR2 WIFPGDVTTKYNEKFKG 604 J24 VH CDR2 WIYPGSGNSKYNEIFKD 605 K412 VH CDR2 SIYPNHGGTSYNQKFKG 606 K55 VH CDR2 DIHPNTGGNSNNQKFKG 607 K72 VH CDR2 EINPNNGFTNYNEKFKS 608 K84 VH CDR2 EINPGNGDTYYNEKFKS 609 14K VH CDR2 FISNLAYSIYYADTVTG 610 F36 VH CDR3 DYYFDY 611 J48 VH CDR3 WGYGAYFTY 612 J66 VH CDR3v1 SGGMYYFDY 613 J66 VH CDR3v2 SGGLYYFDY 614 K713 VH CDR3 RGAGYSYYAMDY 615 F32 VH CDR3 DFYFDY 616 F65 VH CDR3 AGYGYVRYSMDY 617 J24 VH CDR3 WDYGAYFPY 618 K412 VH CDR3 GYYGYDGFFDF 619 K55 VH CDR3 GYYGYDGFFDY 620 K611 VH CDR3 WGYGAWFAY 621 K72 VH CDR3 GAYYAMDY 622 K84 VH CDR3 WYDNYIDY 623 14K VH CDR3 HGYYGSSYDY 624 F36, F32 VL CDR1 RASESVDYYGISFMN 625 J48, K611 VL CDR1v1-v1.3 KASQNVGINVA 626 J48 VL CDR1v2 KASQKVGIKVA 627 J66 VL CDR1 KSSQSLLYSSNQKNYLA 628 K713 VL CDR1 RASESVDSYGNSLMY 629 F65 VL CDR1 RVSESVDSYGNSFMH 630 J24 VL CDR1 KASQNVGTNVA 631 K412, K55 VL CDR1 KSSQSLLYSNGKTYLN 632 K72 VL CDR1 KPSQSLLDSDGKTYLN 633 K84 VL CDR1 KASQDVNTAVA 634 14K VL CDR1 KSSQSLLNSDGKTYFN 635 F36, F32 VL CDR2 AASNQGS 636 J48, K611 VL CDR2v1-2 SASYRSS 637 J66 VL CDR2 WASTRES 638 K713, F65 VL CDR2 LASNLES 639 J24 VL CDR2 SASYRYS 640 K412, K55, K72 VL CDR2 LVSKLDS 641 K84 VL CDR2 WASSRHT 642 14K VL CDR2 QVSKLDP 643 F36, F32 VL CDR3 QQSKEVPYT 644 J48, K611 VL CDR3v1 QQYNSFPYT 645 J48 VL CDR3v1.1 QQYSSFPYT 646 J48 VL CDR3v1.2 QQYQSFPYT 647 J48 VL CDR3v1.3 QQYNAFPYT 648 J48 VL CDR3v2 QQYKSFPYT 649 J66 VL CDR3 QQYYYYPLT 650 K713 VL CDR3 QQNNEDPLT 651 F65 VL CDR3 QQNNEDPWT 652 J24 VL CDR3 HQYNSFPYT 653 K412, K55 VL CDR3 VQGTHFPYT 654 K72 VL CDR3 WQGTHFPRT 655 K84 VL CDR3 HQYSTSPYT 656 14K VL CDR3 LQGTYFPHT 657 F36 VH QVQLQQSGPELVKPGASVKMSCKASGYTFTSFVIHWVKQMPGQGLEWISYIYNDGTKYNERFRGRATLTSDKSSSTAYMELNSLTSEDSAVYYCARDYYFDYWGQGTTLTVSS 683 J48 VH QVQLQQSGPELVRPGASVKISCKASGYTFTDYYINWVKQRPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTAYMQFSSLTSEDSAVYFCARWGYGAYFTYWGQGTLVTVSS 684 J66 VH QVQMKESGTELVRPGTSVKMSCKAAGYTFTNYWIGWVKQRPGHGPEWIGDIYPRSGYTNYNEKFKGKATLTADTSSSTAYMQLSSLTSEDSTIYFCARSGGMYYFDYWGQGTTLTVSS 685 K713 VH EVQLQQSGPELVKPGASVKMSCKASGYTFTDYYMNWVKQSHGKSLEWIGRVSPSNGGTNYNQKFRGKATLTVDKSLSTAYMQLNSLTSEDSAVYYCARRGAGYSYYAMDYWGQGTSVTVSS 686 F32 VH EVQLQQSGPELVKPGASVKMSCKASGYTFTSFVIHWVKQMPGQGLEWIAYIYNDGTKYNEKFRGRATLTSDKSSSTAYMELNSLTSEDSAVYYCARDFYFDYWGQGTTLTVSS 687 F65 VH QLQQSGAELVKPGASVKLSCKASGYTFTTYDINWVRQRPEQGLEWIGWIFPGDVTTKYNEKFKGKATLTTDKSSSTAYMHLSRLTSEDSAVYFCARAGYGYVRYSMDYWGQGTSVTVSS 688 J24 VH QVQMKESGPELARPGASVKISCKASGYTFTDYYINWVKQRPGQGLEWIGWIYPGSGNSKYNEIFKDKATLTVDTSSSTAYMQLSSLTSEDSAVYFCTKWDYGAYFPYWGQGTLVTVSS 689 K412 VH QVQLQQSGPELVKPGDSVKMSCKASGYTFTDHYMEWVKQSHGKSLEWIGSIYPNHGGTSYNQKFKGKATLTVDKSSNTAYMELHSLTSEDSAVYYCARGYYGYDGFFDFWGQGTTLTVSS 690 K55 VH QVQLQQSGPELVKPGDSVKMSCEASGYTFTDYYMDWVKQSHGKSPEWIGDIHPNTGGNSNNQKFKGKATLTVDKSSGTAYMELHSVTSEDSAVYYCARGYYGYDGFFDYWGQGTTLTVSS 691 K611 VH QVQLQQSGPELVRPGASVKISCKASGYTFTDYYINWVKQRPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTTYMQLSSLTSEDSAVYFCTKWGYGAWFAYWGQGTLVTVSS 692 K72 VH EVQLQQSGAELVKPGASVRLSCKASGYTFTYSWIHWMKQRPGQGLEWIGEINPNNGFTNYNEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYCTIGAYYAMDYWGQGTSVTVSS 693 K84 VH EVQLQQSGTKLVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPGNGDTYYNEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYSTIWYDNYIDYWGQGTTLTVSS 694 14K VH EVKLVESGGGLVKPGGSRKLSCAASGFTFSDYGMAWVRQAPGKGPEWVAFISNLAYSIYYADTVTGRFTISRENAKNTLYLEMSSLRSEDTAMYYCARHGYYGSSYDYWGQGTTLTVSS 695 hzF36 VHv1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWISYIYNDGTKYNERFRGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 696 hzF36 VHv2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWISYIYNDGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 697 hzF36 VHv3 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 698 hzF36 VHv4 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRATLTRDTSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 699 hzF36 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRVTMTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 700 hzF36 VHv6 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 701 hzF36 VHv6.1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNEGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 702 hzF36 VHv6.2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNQGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 703 hzF36 VHv6.3 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNSGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 704 hzF36 VHv6.4 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDATKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSS 705 hzJ48 VHv1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQRLEWMGWIYPGSGNTKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSS 706 hzJ48 VHv1.1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSS 707 hzJ48 VHv1.2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYNEKFKGRVTMTVDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSS 708 hzJ48 VHv2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQRLEWMGWIYPGSGNTKYSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSS 709 hzJ48 VHv3 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSS 710 hzJ48 VHv3.1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYAQKFQGRVTMTVDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSS 711 hzJ66 VHv1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSS 712 hzJ66 VHv1.1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGRVTMTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSS 713 hzJ66 VHv1.2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGKATMTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSS 714 hzJ66 VHv1.3 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGKATLTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSS 715 hzJ66 VHv1.4 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQRPGQGLEWIGDIYPRSGYTNYNEKFKGKATLTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSS 716 hzJ66 VHv2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLYYFDYWGQGTTVTVSS 717 hzK713 VHv1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSS 718 hzK713 VHv1.1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSS 719 hzK713 VHv1.2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGKATITVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSS 720 hzK713 VHv1.3 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGKATLTVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSS 721 hzK713 VHv1.4 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVKQAPGQRLEWIGRVSPSNGGTNYNQKFRGKATLTVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSS 722 hzK713 VHv2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSQGGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSS 723 hzK713 VHv3 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSSGGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSS 724 hzK713 VHv4 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNAGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSS 725 F36 VL, F32 VL DIVLTQSPASLAVSLGQRATISCRASESVDYYGISFMNWFQQKPGQPPKLLIYAASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDTAMYFCQQSKEVPYTFGGGTRLEIK 726 J48 VL, K611 VL DIVMTQSQKFMSTSVGDRVSVTCKASQNVGINVAWYQQKPGQSPKALIYSASYRSSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSFPYTFGGGTKLEIK 727 J66 VL DIVMTQSPSSLAVSVGEKVTMSCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYYYPLTFGAGTKLELK 728 K713 VL DIVMTQSTASLAVSLGQRATISCRASESVDSYGNSLMYWYQQKPGQTPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAAIYYCQQNNEDPLTFGAGTKLELK 729 F65 VL DIVMTQSPASLAVSLGQRATISCRVSESVDSYGNSFMHWYRQKPGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAATYYCQQNNEDPWTFGGGTKLEIK 730 J24 VL DIVMTQSQKFMSTSVGDRVNVTCKASQNVGTNVAWYQQKPGQSPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTVSNVQSEDLTEYFCHQYNSFPYTFGGGTRLEIK 731 K412 VL, K55 VL DIVMTQSTLTLSVTLGQPASISCKSSQSLLYSNGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCVQGTHFPYTFGGGTRLEIK 732 K72 VL DIVLTQTPLTLSVTIGQPASISCKPSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPRTFGGGTKLEIK 733 K84 VL DIVMTQSHKFMSTSVGDRVSITCKASQDVNTAVAWYQQKPGQSPKQLIYWASSRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCHQYSTSPYTFGGGTRLEIK 734 14K VL DIVMTQSPLSLSVTIGQPASISCKSSQSLLNSDGKTYFNWLHQRPGQSPKRLIFQVSKLDPGIPDRFSGSGSETDFTLKISRVETEDLGVYYCLQGTYFPHTFGGGTRLEIK 735 hzF36, hzF32 VLv1 DIVMTQSPDSLAVSLGERATINCRASESVDYYGISFMNWYQQKPGQPPKLLIYAASNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEVPYTFGGGTKVEIK 736 hzF36, hzF32 VLv1.1 DIVLTQSPDSLAVSLGERATINCRASESVDYYGISFMNWYQQKPGQPPKLLIYAASNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEVPYTFGGGTKVEIK 737 hzJ48 VLv1 DIQMTQSPSSLSASVGDRVTITCKASQNVGINVAWYQQKPGKAPKLLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSFPYTFGGGTKVEIK 738 hzJ48 VLv1.1 DIQMTQSPSSLSASVGDRVTITCKASQNVGINVAWYQQKPGKAPKLLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSSFPYTFGGGTKVEIK 739 hzJ48 VLv1.2 DIQMTQSPSSLSASVGDRVTITCKASQNVGINVAWYQQKPGKAPKLLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYQSFPYTFGGGTKVEIK 740 hzJ48 VLv1.3 DIQMTQSPSSLSASVGDRVTITCKASQNVGINVAWYQQKPGKAPKLLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNAFPYTFGGGTKVEIK 741 hzJ48 VLv2 DIQMTQSPSSLSASVGDRVTITCKASQKVGIKVAWFQQKPGKAPKSLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYKSFPYTFGGGTKVEIK 742 hzJ66 VLv1 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYYYPLTFGGGTKVEIK 743 hzJ66 VLv1.1 DIVMTQSPDSLAVSLGERATISCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYYYPLTFGGGTKVEIK 744 hzK713 VLv1 DIVMTQSPDSLAVSLGERATINCRASESVDSYGNSLMYWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEDPLTFGGGTKVEIK 745 hzK713 VLv1.1 DIVMTQSPDSLAVSLGERATINCRASESVDSYGNSLMYWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSRTDFTLTISSLQAEDVAVYYCQQNNEDPLTFGGGTKVEIK 746 IgG1 HC ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 747 IgG1 null HC ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 748 κLC RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 749 F36 heavy chain (VH-IgG1) QVQLQQSGPELVKPGASVKMSCKASGYTFTSFVIHWVKQMPGQGLEWISYIYNDGTKYNERFRGRATLTSDKSSSTAYMELNSLTSEDSAVYYCARDYYFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 750 J48 heavy chain (VH-IgG1) QVQLQQSGPELVRPGASVKISCKASGYTFTDYYINWVKQRPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTAYMQFSSLTSEDSAVYFCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 751 J66 heavy chain (VH-IgG1) QVQMKESGTELVRPGTSVKMSCKAAGYTFTNYWIGWVKQRPGHGPEWIGDIYPRSGYTNYNEKFKGKATLTADTSSSTAYMQLSSLTSEDSTIYFCARSGGMYYFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 752 K713 heavy chain (VH-IgG1) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYYMNWVKQSHGKSLEWIGRVSPSNGGTNYNQKFRGKATLTVDKSLSTAYMQLNSLTSEDSAVYYCARRGAGYSYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 753 F32 heavy chain (VH-IgG1) EVQLQQSGPELVKPGASVKMSCKASGYTFTSFVIHWVKQMPGQGLEWIAYIYNDGTKYNEKFRGRATLTSDKSSSTAYMELNSLTSEDSAVYYCARDFYFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 754 F65 heavy chain (VH-IgG1) QLQQSGAELVKPGASVKLSCKASGYTFTTYDINWVRQRPEQGLEWIGWIFPGDVTTKYNEKFKGKATLTTDKSSSTAYMHLSRLTSEDSAVYFCARAGYGYVRYSMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 755 J24 heavy chain (VH-IgG1) QVQMKESGPELARPGASVKISCKASGYTFTDYYINWVKQRPGQGLEWIGWIYPGSGNSKYNEIFKDKATLTVDTSSSTAYMQLSSLTSEDSAVYFCTKWDYGAYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 756 K412 heavy chain (VH-IgG1) QVQLQQSGPELVKPGDSVKMSCKASGYTFTDHYMEWVKQSHGKSLEWIGSIYPNHGGTSYNQKFKGKATLTVDKSSNTAYMELHSLTSEDSAVYYCARGYYGYDGFFDFWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 757 K55 heavy chain (VH-IgG1) QVQLQQSGPELVKPGDSVKMSCEASGYTFTDYYMDWVKQSHGKSPEWIGDIHPNTGGNSNNQKFKGKATLTVDKSSGTAYMELHSVTSEDSAVYYCARGYYGYDGFFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 758 K611 heavy chain (VH-IgG1) QVQLQQSGPELVRPGASVKISCKASGYTFTDYYINWVKQRPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTTYMQLSSLTSEDSAVYFCTKWGYGAWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 759 K72 heavy chain (VH-IgG1) EVQLQQSGAELVKPGASVRLSCKASGYTFTYSWIHWMKQRPGQGLEWIGEINPNNGFTNYNEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYCTIGAYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 760 K84 heavy chain (VH-IgG1) EVQLQQSGTKLVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPGNGDTYYNEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYSTIWYDNYIDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 761 14K heavy chain (VH-IgG1) EVKLVESGGGLVKPGGSRKLSCAASGFTFSDYGMAWVRQAPGKGPEWVAFISNLAYSIYYADTVTGRFTISRENAKNTLYLEMSSLRSEDTAMYYCARHGYYGSSYDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 762 hzF36 heavy chain (VHv1-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWISYIYNDGTKYNERFRGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 763 hzF36 heavy chain (VHv2-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWISYIYNDGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 764 hzF36 heavy chain (VHv3-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 765 hzF36 heavy chain (VHv4-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRATLTRDTSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 766 hzF36 heavy chain (VHv5-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRVTMTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 767 hzF36 heavy chain (VHv6-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 768 hzF36 heavy chain (VHv6.1-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNEGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 769 hzF36 heavy chain (VHv6.2-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNQGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 770 hzF36 heavy chain (VHv6.3-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNSGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 771 hzF36 heavy chain (VHv6.4-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDATKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 772 hzJ48 heavy chain (VHv1-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQRLEWMGWIYPGSGNTKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 773 hzJ48 heavy chain (VHv1.1-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 774 hzJ48 heavy chain (VHv1.2-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYNEKFKGRVTMTVDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 775 hzJ48 heavy chain (VHv2-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQRLEWMGWIYPGSGNTKYSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 776 hzJ48 heavy chain (VHv3-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 777 hzJ48 heavy chain (VHv3.1-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYAQKFQGRVTMTVDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 778 hzJ66 heavy chain (VHv1-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 779 hzJ66 heavy chain (VHv1.1-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGRVTMTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 780 hzJ66 heavy chain (VHv1.2-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGKATMTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 781 hzJ66 heavy chain (VHv1.3-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGKATLTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 782 hzJ66 heavy chain (VHv1.4-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQRPGQGLEWIGDIYPRSGYTNYNEKFKGKATLTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 783 hzJ66 heavy chain (VHv2-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 784 hzK713 heavy chain (VHv1-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 785 hzK713 heavy chain (VHv1.1-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 786 hzK713 heavy chain (VHv1.2-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGKATITVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 787 hzK713 heavy chain (VHv1.3-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGKATLTVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 788 hzK713 heavy chain (VHv1.4-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVKQAPGQRLEWIGRVSPSNGGTNYNQKFRGKATLTVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 789 hzK713 heavy chain (VHv2-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSQGGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 790 hzK713 heavy chain (VHv3-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSSGGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 791 hzK713 heavy chain (VHv4-IgG1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNAGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 792 F36 heavy chain (VH-IgG1 null) QVQLQQSGPELVKPGASVKMSCKASGYTFTSFVIHWVKQMPGQGLEWISYIYNDGTKYNERFRGRATLTSDKSSSTAYMELNSLTSEDSAVYYCARDYYFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 793 J48 heavy chain (VH-IgG1 null) QVQLQQSGPELVRPGASVKISCKASGYTFTDYYINWVKQRPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTAYMQFSSLTSEDSAVYFCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 794 J66 heavy chain (VH-IgG1 null) QVQMKESGTELVRPGTSVKMSCKAAGYTFTNYWIGWVKQRPGHGPEWIGDIYPRSGYTNYNEKFKGKATLTADTSSSTAYMQLSSLTSEDSTIYFCARSGGMYYFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 795 K713 heavy chain (VH-IgG1 null) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYYMNWVKQSHGKSLEWIGRVSPSNGGTNYNQKFRGKATLTVDKSLSTAYMQLNSLTSEDSAVYYCARRGAGYSYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 796 F32 heavy chain (VH-IgG1 null) EVQLQQSGPELVKPGASVKMSCKASGYTFTSFVIHWVKQMPGQGLEWIAYIYNDGTKYNEKFRGRATLTSDKSSSTAYMELNSLTSEDSAVYYCARDFYFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 797 F65 heavy chain (VH-IgG1 null) QLQQSGAELVKPGASVKLSCKASGYTFTTYDINWVRQRPEQGLEWIGWIFPGDVTTKYNEKFKGKATLTTDKSSSTAYMHLSRLTSEDSAVYFCARAGYGYVRYSMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 798 J24 heavy chain (VH-IgG1 null) QVQMKESGPELARPGASVKISCKASGYTFTDYYINWVKQRPGQGLEWIGWIYPGSGNSKYNEIFKDKATLTVDTSSSTAYMQLSSLTSEDSAVYFCTKWDYGAYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 799 K412 heavy chain (VH-IgG1 null) QVQLQQSGPELVKPGDSVKMSCKASGYTFTDHYMEWVKQSHGKSLEWIGSIYPNHGGTSYNQKFKGKATLTVDKSSNTAYMELHSLTSEDSAVYYCARGYYGYDGFFDFWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 800 K55 heavy chain (VH-IgG1 null) QVQLQQSGPELVKPGDSVKMSCEASGYTFTDYYMDWVKQSHGKSPEWIGDIHPNTGGNSNNQKFKGKATLTVDKSSGTAYMELHSVTSEDSAVYYCARGYYGYDGFFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 801 K611 heavy chain (VH-IgG1 null) QVQLQQSGPELVRPGASVKISCKASGYTFTDYYINWVKQRPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTTYMQLSSLTSEDSAVYFCTKWGYGAWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 802 K72 heavy chain (VH-IgG1 null) EVQLQQSGAELVKPGASVRLSCKASGYTFTYSWIHWMKQRPGQGLEWIGEINPNNGFTNYNEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYCTIGAYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 803 K84 heavy chain (VH-IgG1 null) EVQLQQSGTKLVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPGNGDTYYNEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYSTIWYDNYIDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 804 14K heavy chain (VH-IgG1 null) EVKLVESGGGLVKPGGSRKLSCAASGFTFSDYGMAWVRQAPGKGPEWVAFISNLAYSIYYADTVTGRFTISRENAKNTLYLEMSSLRSEDTAMYYCARHGYYGSSYDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 805 hzF36 heavy chain (VHv1-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWISYIYNDGTKYNERFRGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 806 hzF36 heavy chain (VHv2-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWISYIYNDGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 807 hzF36 heavy chain (VHv3-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 808 hzF36 heavy chain (VHv4-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRATLTRDTSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 809 hzF36 heavy chain (VHv5-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRVTMTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 810 hzF36 heavy chain (VHv6-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 811 hzF36 heavy chain (VHv6.1-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNEGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 812 hzF36 heavy chain (VHv6.2-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNQGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 813 hzF36 heavy chain (VHv6.3-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNSGTKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 814 hzF36 heavy chain (VHv6.4-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSFVIHWVRQAPGQGLEWMGYIYNDATKYNERFRGRATLTSDKSTSTVYMELSSLRSEDTAVYYCARDYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 815 hzJ48 heavy chain (VHv1-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQRLEWMGWIYPGSGNTKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 816 hzJ48 heavy chain (VHv1.1-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 817 hzJ48 heavy chain (VHv1.2-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYNEKFKGRVTMTVDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 818 hzJ48 heavy chain (VHv2-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQRLEWMGWIYPGSGNTKYSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 819 hzJ48 heavy chain (VHv3-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 820 hzJ48 heavy chain (VHv3.1-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWIYPGSGNTKYAQKFQGRVTMTVDTSTSTVYMELSSLRSEDTAVYYCARWGYGAYFTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 821 hzJ66 heavy chain (VHv1-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 822 hzJ66 heavy chain (VHv1.1-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGRVTMTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 823 hzJ66 heavy chain (VHv1.2-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGKATMTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 824 hzJ66 heavy chain (VHv1.3-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGKATLTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 825 hzJ66 heavy chain (VHv1.4-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQRPGQGLEWIGDIYPRSGYTNYNEKFKGKATLTADTSTSTVYMELSSLRSEDTAVYYCARSGGMYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 826 hzJ66 heavy chain (VHv2-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPRSGYTNYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 827 hzK713 heavy chain (VHv1-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 828 hzK713 heavy chain (VHv1.1-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 829 hzK713 heavy chain (VHv1.2-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGKATITVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 830 hzK713 heavy chain (VHv1.3-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNGGTNYNQKFRGKATLTVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 831 hzK713 heavy chain (VHv1.4-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVKQAPGQRLEWIGRVSPSNGGTNYNQKFRGKATLTVDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 832 hzK713 heavy chain (VHv2-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSQGGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 833 hzK713 heavy chain (VHv3-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSSGGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 834 hzK713 heavy chain (VHv4-IgG1 null) QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMNWVRQAPGQRLEWMGRVSPSNAGTNYNQKFRGRVTITRDTSASTAYMELSSLRSEDTAVYYCARRGAGYSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 835 F36 light chain (VL-κ), F32 light chain (VL-κ) DIVLTQSPASLAVSLGQRATISCRASESVDYYGISFMNWFQQKPGQPPKLLIYAASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDTAMYFCQQSKEVPYTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 836 J48 light chain (VL-κ), K611 light chain (VL-κ) DIVMTQSQKFMSTSVGDRVSVTCKASQNVGINVAWYQQKPGQSPKALIYSASYRSSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSFPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 837 J66 light chain (VL-κ) DIVMTQSPSSLAVSVGEKVTMSCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYYYPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 838 K713 light chain (VL-κ) DIVMTQSTASLAVSLGQRATISCRASESVDSYGNSLMYWYQQKPGQTPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAAIYYCQQNNEDPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 839 F65 light chain (VL-κ) DIVMTQSPASLAVSLGQRATISCRVSESVDSYGNSFMHWYRQKPGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAATYYCQQNNEDPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 840 J24 light chain (VL-κ) DIVMTQSQKFMSTSVGDRVNVTCKASQNVGTNVAWYQQKPGQSPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTVSNVQSEDLTEYFCHQYNSFPYTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 841 K412 light chain (VL-κ), K55 light chain (VL-κ) DIVMTQSTLTLSVTLGQPASISCKSSQSLLYSNGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCVQGTHFPYTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 842 K72 light chain (VL-κ) DIVLTQTPLTLSVTIGQPASISCKPSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPRTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 843 K84 light chain (VL-κ) DIVMTQSHKFMSTSVGDRVSITCKASQDVNTAVAWYQQKPGQSPKQLIYWASSRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCHQYSTSPYTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 844 14K light chain (VL-κ) DIVMTQSPLSLSVTIGQPASISCKSSQSLLNSDGKTYFNWLHQRPGQSPKRLIFQVSKLDPGIPDRFSGSGSETDFTLKISRVETEDLGVYYCLQGTYFPHTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 845 hzF36, hzF32 light chain (VLv1-κ) DIVMTQSPDSLAVSLGERATINCRASESVDYYGISFMNWYQQKPGQPPKLLIYAASNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 846 hzF36, hzF32 light chain (VLv1.1-κ) DIVLTQSPDSLAVSLGERATINCRASESVDYYGISFMNWYQQKPGQPPKLLIYAASNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 847 hzJ48 light chain (VLv1-κ) DIQMTQSPSSLSASVGDRVTITCKASQNVGINVAWYQQKPGKAPKLLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 848 hzJ48 light chain (VLv1.1-κ) DIQMTQSPSSLSASVGDRVTITCKASQNVGINVAWYQQKPGKAPKLLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSSFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 849 hzJ48 light chain (VLv1.2-κ) DIQMTQSPSSLSASVGDRVTITCKASQNVGINVAWYQQKPGKAPKLLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYQSFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 850 hzJ48 light chain (VLv1.3-κ) DIQMTQSPSSLSASVGDRVTITCKASQNVGINVAWYQQKPGKAPKLLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNAFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 851 hzJ48 light chain (VLv2-κ) DIQMTQSPSSLSASVGDRVTITCKASQKVGIKVAWFQQKPGKAPKSLIYSASYRSSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYKSFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 852 hzJ66 light chain (VLv1-κ) DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYYYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 853 hzJ66 light chain (VLv1.1-κ) DIVMTQSPDSLAVSLGERATISCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYYYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 854 hzK713 light chain (VLv1-κ) DIVMTQSPDSLAVSLGERATINCRASESVDSYGNSLMYWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEDPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 855 hzK713 light chain (VLv1.1-κ) DIVMTQSPDSLAVSLGERATINCRASESVDSYGNSLMYWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSRTDFTLTISSLQAEDVAVYYCQQNNEDPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 856

In some embodiments, the anti-MSLN antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) having the amino acid sequence of the heavy chain variable region CDRs set forth in SEQ ID NO:658 and a light chain variable region comprising CDRs having the amino acid sequence of the light chain variable region CDRs described in SEQ ID NO:659. In some such aspects, the antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) having the amino acid sequence of the heavy chain variable region CDRs set forth in SEQ ID NO:660. In other such aspects, the antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) having the amino acid sequences of the heavy chain variable region CDRs set forth in SEQ ID NO:661. CDRs can be determined, for example, by Kabat. For example, in specific embodiments in which the CDRs are determined by Kabat, CDR1 of the heavy chain is SEQ ID NO:662, CDR2 of the heavy chain is SEQ ID NO:663 or SEQ ID NO:664, and CDR3 of the heavy chain is SEQ ID NO:664 ID NO:665, CDR1 of the light chain is SEQ ID NO:666, CDR2 of the light chain is SEQ ID NO:667, and CDR3 of the light chain is SEQ ID NO:668. In some aspects, an antibody comprising a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:663 is more stable than an antibody comprising a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:664.

In some aspects, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:658. In some aspects, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:661. In some aspects, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:669. In some aspects, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:670. In some aspects, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:671. In some aspects, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:672. In some aspects, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:673. In some aspects, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:674. In some aspects, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:660.

In some aspects, the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:659. In some aspects, the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:675. In some aspects, the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:676. In some aspects, the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:677. In some aspects, the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:678. In some aspects, the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:679.

Antibodies of the invention may comprise any combination of heavy chain variable regions and light chain variable regions described herein. For example, the antibody can comprise a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID Nos: 658, 661, 669, 670, 671, 672, 673, 674, or 660, and a heavy chain variable region comprising SEQ ID Nos: the light chain variable region of the amino acid sequence described in 659, 675, 676, 677, 678, or 679. For example, in exemplary embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:658 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:659 or SEQ ID NO:679 The light chain variable region of the amino acid sequence of SEQ ID NO:674; a heavy chain variable region containing the amino acid sequence of SEQ ID NO:674 and a light chain containing the amino acid sequence of SEQ ID NO:675 variable region; a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 660 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 675; or a light chain variable region containing SEQ ID NO: 675 The heavy chain variable region of the amino acid sequence set forth in ID NO:660 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:679.

In exemplary embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:680 or SEQ ID NO:681 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:682 Sequence of the light chain variable region.

In some embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:859, a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:860 VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 861, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 862, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 862 VL-CDR2 containing the amino acid sequence of SEQ ID NO:863, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:864. In some such embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, 94%, 95%, 96% of the amino acid sequence of SEQ ID NO: 865 %, 97%, 98%, or 99% identical heavy chain variable region (VH) of the amino acid sequence, and one containing the amino acid sequence of SEQ ID NO: 866 with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that the VH-CDRs (i.e. SEQ ID NOS: 859-861) and the amino acid sequences of the VL-CDRs (ie, SEQ ID NOS: 862, 863, and 864) were unchanged. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, 94%, 95%, 90%, 91%, 92%, 93%, 94%, 95%, A heavy chain with an amino acid sequence of 96%, 97%, 98%, or 99% identity, and a heavy chain containing at least 90%, 91%, 92%, 93% with the amino acid sequence of SEQ ID NO: 868 , 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences of light chains, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

In some embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof comprises a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:859, an amine comprising SEQ ID NO:860 The VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 861, a light chain CDR1 containing the amino acid sequence selected from SEQ ID NOS: 862, 869, or 870 ( VL-CDR1), a VL-CDR2 containing the amino acid sequence of SEQ ID NO:863, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:864. In some such embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising at least 90%, 91%, 92%, 93%, 94%, 95%, 96% of the amino acid sequence of SEQ ID NO: 871 %, 97%, 98%, or 99% identical heavy chain variable region (VH) of amino acid sequences, and one containing at least 90 amino acid sequences selected from the group consisting of SEQ ID NOS: 872-877 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the light chain variable region (VL) of the amino acid sequence, provided that VH- The amino acid sequences of the CDRs and VL-CDRs were unchanged. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, Heavy chains of amino acid sequences of 97%, 98%, or 99% identity, and an amino acid sequence selected from the group consisting of SEQ ID NOS: 879-884 having at least 90%, 91%, 92%, 93% %, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences of light chains, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

In some embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:859, a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:860 VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 861, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 862, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 862 VL-CDR2 containing the amino acid sequence of SEQ ID NO:863, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:864. In some such embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 871, (b) a heavy chain variable region (VH) comprising SEQ ID NO: 871 : the light chain variable region (VL) of the amino acid sequence of 872, or both (a) and (b).

In some embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:859, a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:860 VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 861, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 862, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 862 VL-CDR2 containing the amino acid sequence of SEQ ID NO:863, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:864. In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:871, (b) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:873 The amino acid sequence of the light chain variable region (VL), or both (a) and (b).

In some embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:859, a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:860 VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 861, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 869, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 869 VL-CDR2 containing the amino acid sequence of SEQ ID NO:863, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:864. In some such embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 871, (b) a heavy chain variable region (VH) comprising SEQ ID NO: 871 : the light chain variable region (VL) of the amino acid sequence of 874, or both (a) and (b).

In some embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:859, a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:860 The VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 861, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 870, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 870 VL-CDR2 containing the amino acid sequence of SEQ ID NO:863, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:864. In some such embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 871, (b) a heavy chain variable region (VH) comprising SEQ ID NO: 871 : the light chain variable region (VL) of the amino acid sequence of 875, or both (a) and (b).

In some embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:859, a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:860 The VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 861, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 870, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 870 VL-CDR2 containing the amino acid sequence of SEQ ID NO:863, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:864. In some such embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 871, (b) a heavy chain variable region (VH) comprising SEQ ID NO: 871 : the light chain variable region (VL) of the amino acid sequence of 876, or both (a) and (b).

In some embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:859, a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:860 VH-CDR2 of the amino acid sequence, a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 861, a light chain CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 869, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 869 VL-CDR2 containing the amino acid sequence of SEQ ID NO:863, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:864. In some such embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 871, (b) a heavy chain variable region (VH) comprising SEQ ID NO: 871 : the light chain variable region (VL) of the amino acid sequence of 877, or both (a) and (b).

In some embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 865, and a heavy chain variable region (VH) comprising SEQ ID NO: 865 The light chain variable region (VL) of the amino acid sequence of NO: 866; or (b) a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 871, and a heavy chain variable region (VH) containing the amino acid sequence selected from Light chain variable region (VL) of the amino acid sequences of SEQ ID NOs: 872-877.

In some such embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:871 and an amino acid sequence comprising SEQ ID NO:872 The light chain variable region (VL).

In some such embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:871 and an amino acid sequence comprising SEQ ID NO:873 The light chain variable region (VL).

In some such embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:871 and an amino acid sequence comprising SEQ ID NO:874 The light chain variable region (VL).

In some such embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:871 and an amino acid sequence comprising SEQ ID NO:875 The light chain variable region (VL).

In some such embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:871 and an amino acid sequence comprising SEQ ID NO:876 The light chain variable region (VL).

In some such embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:871 and an amino acid sequence comprising SEQ ID NO:877 The light chain variable region (VL).

In some embodiments, the anti-conjugin-4 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:867, and a light chain comprising the amino acid sequence of SEQ ID NO:868 or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 878, and a light chain comprising the amino acid sequence selected from SEQ ID NOS: 879-884.

In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:878 and a light chain comprising the amino acid sequence of SEQ ID NO:879.

In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:878 and a light chain comprising the amino acid sequence of SEQ ID NO:880.

In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:878 and a light chain comprising the amino acid sequence of SEQ ID NO:881.

In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:878 and a light chain comprising the amino acid sequence of SEQ ID NO:882.

In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:878 and a light chain comprising the amino acid sequence of SEQ ID NO:883.

In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:878 and a light chain comprising the amino acid sequence of SEQ ID NO:884. In any of the foregoing embodiments, the anti-conjugin-4 antibody or antigen-binding fragment thereof is conjugated to a small molecule drug to form an antibody-drug conjugate. Anti-conjugin-4 antibodies or antigen-binding fragments thereof may be chimeric or humanized. A chimeric or humanized form of a non-human (eg, murine) antibody may be an intact (full-length) chimeric immunoglobulin, immunoglobulin chain, or antigen-binding fragment thereof (eg, Fv, Fab, Fab', F(ab') ₂ , or other target-binding subdomains), which may contain sequences of non-human immunoglobulins. In general, a humanized antibody or antigen-binding fragment thereof may comprise substantially all of at least one and usually two variable domains, wherein all or substantially all of the CDR regions correspond to the non-human immunoglobulins And all or substantially all framework (FR) regions are such human immunoglobulin sequences. Humanized antibodies may also comprise at least a portion of an immunoglobulin constant region (Fc), typically the Fc domain of human immunoglobulin sequences.

The anti-conjugin-4 antibody or antigen-binding fragment thereof of the present invention can be a human antibody. As used herein, "human antibody" may include antibodies having, for example, the amino acid sequence of human immunoglobulins and includes antibodies isolated from human immunoglobulin libraries or from transgenic animals for one or more human immunoglobulins , and it usually does not express endogenous immunoglobulins. Human antibodies can be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins but express human immunoglobulin genes. Using a guided selection approach, fully human antibodies recognizing selected epitopes can be generated. In this method, selected non-human monoclonal antibodies (eg, mouse antibodies) are used to guide the selection of fully human antibodies that recognize the same epitope.

The anti-conjugin-4 antibodies or antigen-binding fragments thereof described herein can be bispecific antibodies or dual variable domain antibodies (DVDs). Bispecific and DVD antibodies are monoclonal (often human or humanized) antibodies with binding specificities for at least two different antigens, one of which is connexin-4.

The anti-conjugin-4 antibodies or antigen-binding fragments thereof described herein can be derivatized or otherwise modified. For example, derivatized antibodies can be subjected to glycosylation, acetylation, pegylation, phosphorylation, amination, derivatization with known protecting/blocking groups, proteolytic cleavage, or analogs thereof retouch. Antibody CDRs

Congxin-4 antibody CDR sequences can be determined by one or more methods, including Kabat, Chothia, AbM, Contact, IMGT, and AHo (see Table A below). Unless otherwise stated herein, CDR sequences were determined according to the Kabat method. Reference variable region or CDR numbering such as Kabat, amino acid position numbering such as Kabat, CDR sequences determined according to the Kabat method, and variations thereof, mean the heavy chain variable region or light of Kabat et al. for compiling antibodies. Numbering System for Chain Variable Regions ((1991) Sequences of Proteins of Immunological Interest , Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to shortening or insertions of the FRs or CDRs of the variable domains. For example, a heavy chain variable domain can include a single amino acid insertion after residue 52 (residue 52a according to Kabat) and three inserted residues after residue 82 (as according to Kabat residues 82a, 82b, and 82c, etc.). For a given antibody, the Kabat numbering of residues can be determined by aligning the homologous regions of the antibody sequences with the "standard" Kabat numbering sequences. When referring to residues in a variable domain, the Kabat numbering system is generally used (roughly residues 1-107 for the light chain and 1-113 for the heavy chain) (eg, Kabat et al., supra).

When referring to residues in the constant region of an immunoglobulin heavy chain, the "EU numbering system" or "EU index" is generally used (as reported by Kabat et al., supra). "EU index, such as Kabat" means the residue numbering of a human IgGi EU antibody.

Other numbering systems have been described, for example by AbM (Oxford Molecular's AbM antibody modeling software (see, e.g., Antibody Engineering Vol. 2 (Kontermann and Dithel eds., 2d ed. 2010)), Chothia (see, Chothia and Lesk, 1987 , J. Mol. Biol. 196:901-17), Contact, IMGT (ImMunoGeneTics (IMGT) Information System® (see, Lafranc et al., 2003, Dev. Comp. Immunol. 27(1):55-77) ), and AHon (see, Honegger and Plückthun, 2001, J. Mol. Biol. 309: 657-70) and other methods, and are well known to those of ordinary skill in the art.

In a specific embodiment, the anti-conjunctin-4 antibody of the invention comprises (a) a heavy chain variable region (VH) comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 859 , a VH-CDR2 containing the amino acid sequence of SEQ ID NO: 860, and a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 861; and (b) a light chain variable region (VL), which comprising a CDR1 (VL-CDR1) comprising an amino acid sequence selected from any one of SEQ ID NOS: 862, 869, or 870, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 863, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:864.

In a further embodiment, the anti-conjugin-4 antibody of the present invention comprises (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 885, a CDR1 comprising the amino acid sequence of SEQ ID NO: 885, a VH-CDR2 of the amino acid sequence of: 886, and a VH-CDR3 containing the amino acid sequence of SEQ ID NO: 887; and (b) VL, comprising an amino acid sequence of SEQ ID NO: 888 CDR1 (VL-CDR1), a VL-CDR2 containing the amino acid sequence of SEQ ID NO:889, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:890.

In yet a further embodiment, the anti-conjugin-4 antibody of the present invention comprises (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 891, a CDR1 comprising the amino acid sequence of SEQ ID NO: 891, a VH-CDR2 of the amino acid sequence of NO:892, and a VH-CDR3 containing the amino acid sequence of SEQ ID NO:893; and (b) VL, comprising an amino acid of SEQ ID NO:894 Sequence CDR1 (VL-CDR1), a VL-CDR2 containing the amino acid sequence of SEQ ID NO:895, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:896.

In yet a further embodiment, the anti-conjugin-4 antibody of the present invention comprises (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 897, a CDR1 comprising the amino acid sequence of SEQ ID NO: 897, a VH-CDR2 of the amino acid sequence of NO:898, and a VH-CDR3 of the amino acid sequence of SEQ ID NO:899; and (b) VL, comprising an amino acid of SEQ ID NO:900 Sequence CDR1 (VL-CDR1), a VL-CDR2 containing the amino acid sequence of SEQ ID NO:901, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:902.

In yet a further embodiment, the anti-conjugin-4 antibody of the present invention comprises (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 903, a CDR1 comprising the amino acid sequence of SEQ ID NO: 903, a VH-CDR2 of the amino acid sequence of NO:904, and a VH-CDR3 containing the amino acid sequence of SEQ ID NO:905; and (b) VL, comprising an amino acid of SEQ ID NO:906 Sequence CDR1 (VL-CDR1), a VL-CDR2 containing the amino acid sequence of SEQ ID NO:907, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:908.

In yet a further embodiment, the anti-conjugin-4 antibody of the present invention comprises (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 909, a CDR1 comprising the amino acid sequence of SEQ ID NO: 909, a VH-CDR2 of the amino acid sequence of NO:910, and a VH-CDR3 containing the amino acid sequence of SEQ ID NO:911; and (b) VL, comprising an amino acid of SEQ ID NO:912 Sequence CDR1 (VL-CDR1), a VL-CDR2 containing the amino acid sequence of SEQ ID NO:913, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:914. Table 38. Anti-junction 4 CDRs Antibody CDR Identification Kabat Chothia Abm Contact IMGT AHo D6C VH CDR1 NYDMS (SEQ ID NO: 859) GFTFSNY (SEQ ID NO: 885) GFTFSNYDMS (SEQ ID NO: 891) SNYDMS (SEQ ID NO: 897) GFTFSNYD (SEQ ID NO: 903) SGFTFSNYDM (SEQ ID NO: 909) D6C VH CDR2 TISSGGSYTYYVDSVKG (SEQ ID NO: 860) SSGGSY (SEQ ID NO: 886) TISSGGSYTY (SEQ ID NO: 892) WVATISSGGSYTY (SEQ ID NO: 898) ISSGGSYT (SEQ ID NO: 904) SSGGSYTYYVDSVKGRF (SEQ ID NO: 910) D6C VH CDR3 QELGSYYAMDY (SEQ ID NO: 861) QELGSYYAMDY (SEQ ID NO: 887) QELGSYYAMDY (SEQ ID NO: 893) ARQELGSYYAMD (SEQ ID NO: 899) ARQELGSYYAMDY (SEQ ID NO: 905) ELGSYYAMDY (SEQ ID NO: 911) D6.2C and D6.5C VL CDR1 RSSQSIVHSNANTYLE (SEQ ID NO: 869) RSSQSIVHSNGNTYLE (SEQ ID NO: 888) RSSQSIVHSNGNTYLE (SEQ ID NO: 894) VHSNGNTYLEWY (SEQ ID NO: 900) QSIVHSNGNTY (SEQ ID NO: 906) SSQSIVHSNGNTY (SEQ ID NO: 912) D6C VL CDR2 KVSNRFS (SEQ ID NO: 863) KVSNRFS (SEQ ID NO: 889) KVSNRFS (SEQ ID NO: 895) LLIYKVSNRF (SEQ ID NO: 901) KVS (SEQ ID NO: 907) KVSNRFSGVPDR (SEQ ID NO: 913) D6C VL CDR3 FQGSHVPYT (SEQ ID NO: 864) FQGSHVPYT (SEQ ID NO: 890) FQGSHVPYT (SEQ ID NO: 896) FQGSHVPY (SEQ ID NO: 902) FQGSHVPYT (SEQ ID NO: 908) GSHVPYTF (SEQ ID NO: 914)

Antibodies or antigen-binding fragments thereof can be chimeric or humanized. A chimeric or humanized form of a non-human (eg, murine) antibody may be an intact (full-length) chimeric immunoglobulin, immunoglobulin chain, or antigen-binding fragment thereof (eg, Fv, Fab, Fab', F(ab') ₂ , or other target binding subdomains), which may contain sequences derived from non-human immunoglobulins. In general, a humanized antibody or antigen-binding fragment thereof may comprise substantially all of at least one and usually two variable domains, wherein all or substantially all of the CDR regions correspond to the non-human immunoglobulins And all or substantially all framework (FR) regions are such human immunoglobulin sequences. Humanized antibodies may also comprise at least a portion of an immunoglobulin constant region (Fc), typically the Fc domain of human immunoglobulin sequences.

The antibodies or antigen-binding fragments thereof described herein can be human antibodies. As used herein, "human antibody" may include antibodies having, for example, the amino acid sequence of human immunoglobulins and includes antibodies isolated from human immunoglobulin libraries or from transgenic animals for one or more human immunoglobulins , and it usually does not express endogenous immunoglobulins. Human antibodies can be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins but express human immunoglobulin genes. Using a guided selection approach, fully human antibodies recognizing selected epitopes can be generated. In this method, selected non-human monoclonal antibodies (eg, mouse antibodies) are used to guide the selection of fully human antibodies that recognize the same epitope.

The antibodies or antigen-binding fragments thereof described herein can be bispecific antibodies or dual variable domain antibodies (DVDs). Bispecific and DVD antibodies are monoclonal (often human or humanized) antibodies with binding specificities for at least two different antigens, one of which is ASGR1.

The anti-antibodies or antigen-binding fragments thereof described herein may be derivatized or otherwise modified. For example, derivatized antibodies can be subjected to glycosylation, acetylation, pegylation, phosphorylation, amination, derivatization with known protecting/blocking groups, proteolytic cleavage, or analogs thereof retouch.

The antibody, antibody construct, or target moiety can be a derivatized antibody. For example, derivatized antibodies can be glycated, acetylated, pegylated, phosphorylated, aminated, derivatized with known protecting/blocking groups, proteolytically cleaved, linked to cellular ligands body or other proteins. Conjugate

In any of the foregoing embodiments, antibodies, antibody constructs, or targeting moieties can be used to generate conjugates with ALK5 inhibitor compounds of the invention as described herein.

In some embodiments, the ALK5 inhibitor compounds of the invention are directly covalently linked to an antibody, antibody construct, or target moiety. In specific embodiments, the ALK5 inhibitor compounds of the invention are covalently linked directly to the antibody. In certain embodiments, the ALK5 inhibitor compounds of the invention are covalently linked directly to the antibody construct. In certain other embodiments, the compound is covalently linked directly to the target moiety. In any of the foregoing embodiments, the antibody, antibody construct, or targeting moiety can specifically bind to a tumor antigen. In any of the foregoing embodiments, the antibody, antibody construct, or target portion may further comprise a second antigen or target binding domain.

The conjugates described herein can include linkers, such as peptide linkers. The linker of the conjugate may not affect the active portion of the conjugate (e.g., including antigen binding domains, Fc domains, target binding domains, antibodies, formula (I'), (I''), (I) , (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V') , (V''), (V), (VI'), (VI''), or (VI) ALK5 inhibitor compounds, or pharmaceutically acceptable isomers, racemates, hydrates thereof , solvate, isotope, or active moiety of a salt, or analog thereof) to a target, which may be a cognate binding partner (eg, an antigen). Linkers can form linkages between different parts of a conjugate (eg, between an antibody construct and a compound of the invention). In a specific embodiment, the conjugate comprises a plurality of linkers. In a specific embodiment, wherein the conjugate comprises multiple linkers, the linkers may be the same linker or different linkers.

The linker or linker-payload can be linked to the antibody, antibody construct, or target moiety through a bond between the antibody, antibody construct, or target moiety and the linker or linker-payload, respectively. The linker or linker-payload can be linked to the anti-tumor antigen antibody, antibody construct, or target moiety through a bond between the anti-tumor antigen antibody construct and the linker or linker-payload. The linker or linker-payload can be bonded to the end of the amino acid sequence of the antibody, antibody construct, or target moiety, or can be bonded to the side chain modification of the antibody, antibody construct, or target moiety, For example, lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamic acid, glutamic acid, or side chains of unnatural amino acid residues. The linker or linker-payload can be linked to the amino acid sequence terminus of the Fc region or domain of the antibody, antibody construct, or target moiety, or can be linked to the antibody, antibody construct, or target moiety Side chain modifications of the Fc region, such as lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamic acid, glutamic acid, or unnatural amino groups side chains of acid residues.

The linker or linker-payload can be linked to the antibody, antibody construct, or target moiety at one or more hinge cysteines. The linker or linker-payload can be linked to the antibody, antibody construct, or target moiety at one or more light chain constant domain lysines. The linker or linker-payload can be linked to the antibody, antibody construct, or target moiety at the genetically engineered cysteine of the light chain. The linker or linker-payload can be linked to the antibody, antibody construct, or target moiety at one or more Fc region or domain lysine or cysteine. The linker or linker-payload can be linked to the antibody, antibody construct, or target moiety at a light chain glutamic acid (eg, genetically engineered glutamic acid). The linker or linker-payload can be linked to the antibody, antibody construct, or target moiety at a heavy chain glutamic acid (eg, genetically engineered glutamic acid). The linker or linker-payload can be linked to the antibody construct at the unnatural amino acid of the genetically engineered light or heavy chain. Amino acids can be genetically engineered into the amino acid sequence of an antibody, antibody construct, target moiety (eg, a linker or linker-payload of a conjugate). Genetically engineered amino acids can be added to sequences of existing amino acids. Genetically engineered amino acids can be used to replace one or more existing amino acids in an amino acid sequence.

The linker or linker-payload can be bound to the antibody, antibody construct, or target moiety via sulfhydryl conjugation on the antibody, antibody construct, or target moiety. The linker or linker-payload can be conjugated to the antibody, antibody construct, or target moiety via a primary amine conjugation on the antibody, antibody construct, or target moiety. The linker or linker-payload can be conjugated to the antibody, antibody construct, or target moiety via conjugation to an antibody, antibody construct, or a residue of a non-natural amino acid on the target moiety (eg, a ketone moiety).

In certain embodiments, when one or more linkers or linker-payloads (eg, linked to formula (I'), (I''), (I), (II'), (II'' ), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V) , (VI'), (VI''), or a compound of (VI), or a linker of a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof) When covalently linked to an antibody, antibody construct, or target moiety, the Fc region or domain of the antibody, antibody construct, or target moiety will bind to an Fc receptor. In further embodiments, when one or more linkers or linker-payloads (eg, linked to formula (I'), (I''), (I), (II'), (II' '), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V ), (VI'), (VI''), or (VI), or a linker of a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof ) is covalently linked to an antibody, antibody construct, or target moiety, and the antigen-binding domain of the antibody, antibody construct, or target moiety will be approximately the same as the unmodified antibody, antibody construct, or target moiety The same affinity specifically binds its antigen.

In certain embodiments, the linker or linker-payload (eg, bonded to formula (I'), (I''), (I), (II'), (II''), (II) , (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI') , (VI″), or a compound of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt of the linker) can be linked to a linker selected from the group consisting of Amino acid residues in the following IgG Fc domains: 221, 222, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 280, 281, 283, 285, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302, 305, 313, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 396, 428, or any subset thereof, wherein the amino acid residues in the Fc domain are numbered according to Kabat's EU Index.

In certain embodiments, the linker or linker-payload (eg, bonded to formula (I'), (I''), (I), (II'), (II''), (II) , (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI') , (VI″), or a compound of (VI), or a linker of a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof) is not linked to the Amino acid residues from the following IgG Fc domains: 221, 222, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243 , 244, 245, 246, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 280, 281 , 283, 285, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302, 305, 313, 317, 318, 320, 322, 323, 324, 325 , 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 396, 428, or any subset thereof, wherein the amino acid residues in the Fc domain are numbered according to, for example, Kabat the EU index.

， 其中A'為抗體、抗體構築體、或標靶部分；L為連接子；D為式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、或(VI)之ALK5抑制劑化合物，或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類；且z為1至20。在特定具體實施例中，z為1至約10，例如1至約9，例如1至約8，例如2至約8，例如1至約6，例如1至約3，或例如約3至約5。在特定具體實施例中，z為約4。在特定具體實施例中，z為1至10，例如1至9，例如1至8，例如2至8，例如1至6，例如1至3，或例如3至5。在特定具體實施例中，z為4。 In a further specific embodiment, the conjugate of the present invention is represented by the following formula:

, wherein A' is an antibody, an antibody construct, or a target moiety; L is a linker; D is a formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), ( An ALK5 inhibitor compound of VI'), (VI''), or (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof; and z 1 to 20. In certain specific embodiments, z is 1 to about 10, such as 1 to about 9, such as 1 to about 8, such as 2 to about 8, such as 1 to about 6, such as 1 to about 3, or such as about 3 to about 5. In certain specific embodiments, z is about 4. In certain specific embodiments, z is 1 to 10, such as 1 to 9, such as 1 to 8, such as 2 to 8, such as 1 to 6, such as 1 to 3, or such as 3 to 5. In certain specific embodiments, z is 4.

， 其中A'為抗體、抗體構築體、或標靶部分，D為式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、或(VI)之化合物，或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類；L為連接子；且z為1至8；其中抗體、抗體構築體、或標靶部分之Fc結構域為Fc無效結構域。 In specific embodiments, the present invention provides conjugates of the formula:

, wherein A' is an antibody, an antibody construct, or a target moiety, and D is a formula (I'), (I''), (I), (II'), (II''), (II), ( III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), ( VI''), or a compound of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof; L is a linker; and z is 1 to 8; wherein the Fc domain of the antibody, antibody construct, or target portion is an Fc null domain.

In any of the foregoing embodiments, the antibody, antibody construct, or target portion of the conjugate of the invention comprises an antigen binding domain that can specifically bind to a tumor antigen. In any of the foregoing embodiments, the antibody, antibody construct, or target portion of the conjugate of the invention comprises an antigen binding domain that specifically binds to ASGR1 or ASGR2. In any of the foregoing embodiments, the antibody, antibody construct, or target portion of the conjugate of the invention comprises an antigen binding domain that specifically binds to ASGR1.

In any of the foregoing embodiments, the antibody, antibody construct, or target portion of the conjugate of the invention comprises an antigen binding domain that can specifically bind to a tumor antigen. In any of the foregoing embodiments, the antibody, antibody construct, or target portion of the conjugate of the invention comprises an antigen binding domain that specifically binds to an antigen selected from the group consisting of: ASGR1, ASGR2, LRRC15, Corticosteroids (MSLN), HER2, CEA, TROP2, EPHA2, p-cadherin, UPK1B, FOLH1, LYPD3, and PVRL4 (conjunctive-4). In any of the foregoing embodiments, the antigen binding domain of the conjugates of the invention can specifically bind to ASGR1, ASGR2, LRRC15, MSLN, HER2, TROP2, or EPHA2.

In certain embodiments, the conjugates of the invention comprise antibodies, antibody constructs, or target moieties having an antigen binding domain and an IgG Fc domain, wherein the antigen binding domain binds to a first antigen in the presence of the compound The _Kd is less than about 100 nM and no greater than about 100-fold the _Kd for binding of the antigen binding domain to the first antigen in the absence of the compound. In a further embodiment, the antibody, antibody construct, or target moiety contained in the conjugate of the present invention has a _Kd between the IgG Fc domain and the Fc receptor in the presence of the compound that is no greater than that of IgG in the absence of the compound About 100 times the _Kd of the Fc domain and the Fc receptor. In certain specific embodiments, the first antigen is expressed on an immune cell.

In some embodiments, the first antigen is selected from ASGR1 (sialoglycoprotein receptor 1), ASGR2 (sialoglycoprotein receptor 2), mesothelin (MSLN), HER2, carcinoembryonic antigen (CEA) ), TROP2, EPHA2, UPK1B, p-cadherin, FOLH1, LYPD3, CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD40, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC, HLD-DR, TAG-72, EpCAM, MUC1, Folic Acid Binding Protein, A33, G250, Prostate Specific Membrane Antigen (PSMA), Ferritin, GD2, GD3, GM2, ^Ley , CA -125, CA19-9, epidermal growth factor, p185HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein, tenascin, metalloproteinase, endosialin, vascular endothelium Growth factors, avB3, WT1, LMP2, HPV E6 E7, Her-2/neu, MAGE A3, p53 non-mutant, NY-ESO-1, MelanA/MART1, Ras mutant, gp100, p53 mutant, PR1, bcr -abl, tyrosinase, survivin, PSA, hTERT, sarcoma translocation breakpoint protein, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B1, Polysialic acid, MYCN, RhoC, TRP-2, Fucosyl GM1, PSCA, MAGE Al, sLe (animal), CYP1B1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic Anhydrase IX, PAX5, OY-TESL sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, TRAIL1, MUC16, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, MUC15, CA6, NAPI2B, CLDN6, CLDN16, CLDN18.2, CLorf186, RON, LY6E, FRA, DLL, PTK7, STRA6, TMPRSS3, TMPRSS4, TMEM238, VTCN1, LIV1, ROR1, or Fos-associated antigen 1. In a further embodiment, the first antigen is selected from ASGR1, ASGR2, LRRC15, mesothelin (MSLN), HER2, CEA, TROP2, EPHA2, p-cadherin, UPK1B, FOLH1, LYPD3, and PVRL4 (Conjugin-4). In still further embodiments, the antigen binding domain specifically binds to ASGR1, ASGR2, LRRC15, mesothelin (MSLN), HER2, CEA, TROP2, EPHA2, p-cadherin, UPK1B, FOLH1, LYPD3, and PVRL4 (conjuxin-4). In certain specific embodiments, the first antigen is ASGR1, ASGR2, LRRC15, MSLN, HER2, TROP2, or EPHA2. In specific embodiments, the first antigen is ASGR1 or ASGR2. In certain specific embodiments, the first antigen is ASGR1.

In certain embodiments, the conjugates of the invention comprise antibodies, antibody constructs, or target moieties, which are human antibodies or humanized antibodies or portions thereof, eg, humanized ASGR1, ASGR2, LRRC15, mesothelial (MSLN), HER2, CEA, TROP2, EPHA2, p-Cadherin, UPK1B, FOLH1, LYPD3, or PVRL4 (adhesin-4) antibodies.

Conjugates of the invention containing antibodies, antibody constructs, or targeting moieties may include antibodies with modifications at at least one amino acid residue, provided that the CDRs are unsubstituted (unless otherwise specified). Modifications can be substitutions, additions, mutations, deletions, or the like. Antibody modifications may be insertion of unnatural amino acids, provided that the CDRs do not have insertion of unnatural amino acids (unless otherwise specified). Nucleic Acids, Vectors, and Host Cells

The present invention provides isolated nucleic acids encoding the anti-ASGR1 antibodies or antigen-binding fragments thereof described herein. In some embodiments, nucleic acids encoding anti-ASGR1 antibodies or antigen-binding fragments thereof are codon-optimized to enhance or maximize expression in specific cell types (eg, Scholten et al ., Clin. Immunol. 119 :135 -145, 2006). A "codon-optimized" polynucleotide as used herein is a heterologous polypeptide having codons modified with silent mutations corresponding to the abundance of tRNA levels in the host cell.

In some embodiments, the nucleic acid molecule encodes an anti-ASGR1 antibody or antigen-binding fragment thereof disclosed herein (eg, antibody heavy and light chains, or antibody binding domains comprising _VH and _VL binding regions), wherein two or more The individual strands or regions are separated using cleavage sites. In some embodiments, the cleavage site is a self-cleaving amino acid sequence comprising a sequence derived from porcine rotavirus-1 (P2A), equine rhinitis A virus (E2A), Thosea asigna virus (T2A) ), foot-and-mouth disease virus (F2A), or a 2A peptide of any combination thereof (see, e.g., Kim et al ., PLOS One 6:e18556, 2011, wherein the 2A nucleic acid sequence and amino acid sequence are incorporated herein in their entirety as references).

In another aspect, an expression construct is provided comprising a nucleic acid encoding an anti-ASGRl antibody or antigen-binding fragment thereof as described herein. In some embodiments, the nucleic acid may be operably linked to an expression control sequence. As used herein, "expression construct" means a DNA construct containing a nucleic acid molecule operably linked to suitable control sequences capable of affecting the expression of the nucleic acid molecule in a suitable host. The expression construct can be present in a vector (eg, bacterial vector, viral vector) or can be integrated into a genome. The term "operably linked" means the association of two or more nucleic acids on a single polynucleotide fragment such that the function of one is affected by the other. For example, when a promoter is operably linked to a coding sequence, it can affect the expression of the coding sequence (ie, the coding sequence is under the transcriptional control of the promoter). The term "expression control sequence" (also referred to as regulatory sequence) means a nucleic acid sequence that affects the expression and processing of a coding sequence to which it is operably linked. For example, expression control sequences can include transcription initiation sequences, termination sequences, promoter sequences, and enhancer sequences; efficient RNA processing signals, such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNAs; enhance translation efficiency (i.e., the Kozak consensus sequence); sequences that enhance protein stability; and possibly sequences that enhance protein secretion.

In some embodiments, a nucleic acid or expression construct encoding an anti-ASGRl antibody or antigen-binding fragment thereof is present in a vector. A "vector" is a nucleic acid molecule capable of carrying another nucleic acid. A vector can be, for example, a plastid, a cosmid, a virus, an RNA vector, or a linear or circular DNA or RNA molecule, which can include chromosomal, non-chromosomal, semi-synthetic, or synthetic nucleic acids. Exemplary vectors are those capable of replicating autonomously (episomal vectors) or expressing the nucleic acid to which they are linked (expression vectors). Exemplary viral vectors include retroviruses, adenoviruses, parvoviruses (such as adeno-associated virus), coronaviruses, negative-strand RNA viruses such as orthomyxoviruses (such as influenza virus), baculoviruses (such as rabies and vesicular stomatitis virus) ), paramyxoviruses (such as measles and Sendai virus), positive-strand RNA viruses such as picornaviruses and alphaviruses, and double-stranded DNA viruses including adenoviruses, herpesviruses (such as herpes simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), and poxviruses (eg, vaccinia, fowlpox, and canarypox). Other viruses include, for example, Norwalk virus, togavirus, flaviviruses, reoviruses, papovavirus, hepadnavirus, and hepatitis virus. Examples of retroviruses include avian leukemia sarcoma, mammalian type C, type B virus, type D virus, HTLV-BLV group, lentivirus, foamy virus (Coffin, J. M., Retroviridae: The viruses and their replication, In Fundamental Virology, Third Edition, B. N. Fields et al., Eds., Lippincott-Raven Publishers, Philadelphia, 1996). In some specific embodiments, the vector is a plastid. In some other specific embodiments, the vector is a viral vector. In some embodiments, the viral vector is a lentiviral vector or a gamma-retroviral vector.

In yet another aspect, the present invention provides an isolated host cell comprising a nucleic acid, expression construct, or vector as described herein encoding an anti-ASGRl antibody or antigen-binding fragment thereof. The term "host" as used herein means a cell or microorganism that has been genetically modified with a heterologous or exogenous nucleic acid molecule targeted to produce a polypeptide of interest (eg, an anti-ASGR1 antibody or antigen-binding fragment thereof). In certain embodiments, the host cell can optionally have or be engineered to encompass other genetic modifications that provide desired or unrelated biosynthesis of a heterologous or exogenous protein (eg, comprising a detectable label) nature. More than one heterologous or exogenous nucleic acid molecule can be introduced into a host as separate nucleic acid molecules, as a plurality of individually controlled genes, as polycis-trans nucleic acid molecules, as a single nucleic acid molecule encoding a fusion protein, or any combination thereof in cells. When two or more exogenous nucleic acid molecules are introduced into a host cell, it is to be understood that two or more exogenous nucleic acid molecules may be introduced as a single nucleic acid molecule (eg, on a single vector), on different vectors, on Introduction into the host chromosome at a single site or multiple sites. Reference to the amount of heterologous nucleic acid molecule or protein activity means that the number of encoding nucleic acid molecules or the amount of protein activity is introduced into the host cell, not the number of different nucleic acid molecules. Bioconjugation method

， 其中A'為抗體構築體，且L-D包含式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、或(VI)之化合物，或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，以及連接子，其包含以抗體構築體接觸每一L-D，其中z為1至8。 In some aspects, the present invention provides a method of making an antibody conjugate of the formula

, wherein A' is an antibody construct, and LD comprises formulae (I'), (I''), (I), (II'), (II''), (II), (III'), (III ''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), or The compound of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a linker, comprising contacting each LD with an antibody construct, wherein z is 1 to 8.

， 其中A'為抗體構築體，且L為連接子，且D為式(I’)、(I’’)、(I)、(II’)、(II’’)、(II)、(III’)、(III’’)、(III)、(IV’)、(IV’’)、(IV)、(V’)、(V’’)、(V)、(VI’)、(VI’’)、或(VI)之化合物，或其藥學上可接受之異構體、外消旋體、水合物、溶劑化物、同位素、或鹽類，其包含以抗體構築體接觸L，以形成A'-（L） _z，且隨後以D接觸A'-（L） _z，其中z為1至8。 In some aspects, the present invention provides a method of making an antibody conjugate of the formula

, wherein A' is an antibody construct, and L is a linker, and D is of formula (I'), (I''), (I), (II'), (II''), (II), ( III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), ( VI''), or a compound of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, comprising contacting L with an antibody construct to A'-(L) _z is formed, and then A'-(L) _z is contacted with D, where z is 1-8.

In some embodiments, the conjugate comprises an antibody, antibody construct, or target moiety, wherein the antibody, antibody construct, or target moiety comprises an antigen binding domain that specifically binds to an antigen selected from the group consisting of : ASGR1, ASGR2, LRRC15, mesothelin (MSLN), HER2, CEA, TROP2, EPHA2, p-cadherin, UPK1B, FOLH1, LYPD3, and PVRL4 (conjugin-4). In some embodiments, the antibody, antibody construct, or target moiety specifically binds to ASGR1, ASGR2, LRRC15, MSLN, HER2, TROP2, EPHA2, ASGR1, or ASGR2. In some embodiments, the antibody, antibody construct, or target moiety specifically binds to ASGR1. The method of preparing the conjugate can further comprise purifying the conjugate. Scheme A: Lysine-based bioconjugation reaction

The antibody construct can be conjugated to the linker via a lysine-based bioconjugation reaction. The antibody construct can be exchanged into a suitable buffer, such as phosphate, borate, PBS, histidine, Tris-acetate, at a concentration of about 2 mg/mL to about 10 mg/mL. Appropriate equivalents of the constructs of the compounds of the invention and the linkers, linker-payloads described herein can be added in solution with stirring. Depending on the physical properties of the linker-payload, a co-solvent may be introduced prior to addition of the linker-payload to facilitate solubility. The reaction can be stirred at room temperature for 2 hours to about 12 hours, depending on the observed reactivity. The progress of the reaction can be monitored by LC-MS. Once the reaction is complete, the remaining linker-payload can be removed by suitable methods and the antibody conjugate can be exchanged into the desired formulation buffer. Lysine-linked conjugates can be synthesized starting from an antibody (mAb) and a linker-payload (eg, 10 equiv.), as shown in Scheme A below (conjugate is an antibody conjugate). The monomer content and drug-antibody construct ratio (molar ratio) can be determined using the methods described herein. Scheme B: Cysteine-based bioconjugation reaction

The antibody construct can be conjugated to the linker via a cysteine-based bioconjugation reaction. The antibody construct can be exchanged into a suitable buffer, such as phosphate, borate, PBS, histidine, Tris-acetate, at a concentration of about 2 mg/mL to about 10 mg/mL, and appropriate equivalents of Reducing agents such as dithiothreitol or gins(2-carboxyethyl)phosphine. The resulting solution can be stirred at an appropriate time and temperature to achieve the desired reduction reaction. The constructs and linkers of the compounds of the invention can be added in solution with stirring. Depending on the physical properties of the linker-payload, a co-solvent may be introduced prior to addition of the linker-payload to facilitate solubility. The reaction can be stirred at room temperature for about 1 hour to about 12 hours, depending on the observed reactivity. The progress of the reaction can be monitored by chromatography-mass spectrometry (LC-MS). Once the reaction is complete, the remaining free linker-payload can be removed by suitable methods and the antibody conjugate can be exchanged into the desired formulation buffer. Such cysteine-based conjugates can be synthesized starting with an antibody (mAb) and a linker-payload (eg, 7 equiv.) using the conditions described in Scheme B (the conjugate is an antibody conjugate). ). The monomer content and drug-antibody ratio can be determined using the methods described herein. pharmaceutical composition

In a specific embodiment, the present invention provides a pharmaceutical composition comprising an ALK5 inhibitor compound of the present invention or a conjugate thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, an ALK5 inhibitor compound of the invention or a conjugate thereof can be mixed with a carrier, or diluted by a carrier, or enclosed in a carrier, which can be an ampule, capsule, sachet, paper, or other container. When the ALK5 inhibitor compounds of the present invention or their conjugates are mixed with a carrier, or when the carrier is used as a diluent, the carrier can be a solid, semi-solid, or liquid material, which can serve as a vehicle, vehicle for the active compound agent, or medium. The ALK5 inhibitor compounds of the invention or their conjugates can be adsorbed on, for example, a particulate solid carrier contained in a sachet. Some examples of suitable carriers include water, saline solutions, alcohols, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar , cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides Esters and diglycerides, pentabutyritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose, and polyvinylpyrrolidone. Likewise, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in admixture with a wax.

The term "pharmaceutically acceptable carrier" as used herein means any ingredient other than the disclosed compound or its conjugate, or a pharmaceutically acceptable isomer, racemate, hydrate, or solvate thereof , isotopes, or salts such as a carrier capable of suspending or dissolving the active compound and possess the properties of being non-toxic and non-inflammatory to the subject or patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents agents or coatings, flavors, fragrances, slip agents (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. Exemplary excipients include butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (disalt base), calcium stearate, croscarmellose, crospovidone, citric acid, crosspolymer Vidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methyl Cellulose, Methylparaben, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinylpyrrolidone, Povidone, Pregelatinized Starch, Propylparaben, Retinyl Palmitate, Shellac, Dimethicone Silicon oxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

The term "pharmaceutical composition" as used herein means a composition comprising one or more of the ALK5 inhibitor compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvent thereof Compounds, isotopes, or salts, or conjugates thereof, formulated with a pharmaceutically acceptable carrier, excipient, or diluent, which may also include one or more other additives, and manufactured with approval from a governmental regulatory agency or sold as part of a regimen for the treatment of diseases (eg, cancer) in mammals (eg, humans). In certain embodiments, the compositions of the present invention comprise conjugates comprising between covalently linked antibodies, antibody constructs, or target moieties and formulae (I'), (I''), (I ), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V' ), (V''), (V), (VI'), (VI''), or (VI) ALK5 inhibitor compounds, or pharmaceutically acceptable isomers, racemates, hydrated compound, solvate, isotope, or salt; and a linker between a pharmaceutically acceptable carrier, excipient, or diluent. In a further specific embodiment, the composition of the present invention comprises formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV'), (IV''), (IV), (V'), (V''), (V), (VI'), (VI'') , or the ALK5 inhibitor compound of (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof; and a pharmaceutically acceptable carrier, excipient , or thinner. Pharmaceutical compositions can be formulated, for example, for subcutaneous administration; oral administration in unit dosage forms (eg, tablets, capsules, caplets, softgels, or syrups); topical administration (eg, creams, gels) , lotion, or ointment); intravenous administration (eg, sterile particulate-free embolic solutions and solvent systems suitable for intravenous use); or in any other formulation described herein. Routine procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States, published in 2013 States Pharmacopeia: The National Formulary (USP 36 NF31).

The formulations can be mixed with adjuvants that do not adversely react with the ALK5 inhibitor compounds of the invention or their conjugates. Such additives may include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffers and/or coloring substances, preservatives, sweetening agents, or flavoring agents. If desired, the composition can also be sterilized.

In any of the foregoing embodiments, the conjugate or composition thereof comprises an ALK5 inhibitor covalently linked to the antibody. In particular embodiments, each antibody of the antibody conjugate comprises 1 to about 20 ALK5 inhibitors, preferably in the range of 1 to about 8, 3 to about 5, or 1 to about 3. In particular embodiments, each antibody of the antibody conjugate comprises 1 to 20 ALK5 inhibitors, preferably in the range of 1 to 8, 3 to 5, or 1 to 3. In further embodiments, the conjugate average DAR of the antibody conjugate composition ranges from about 2 to about 8, about 1 to about 3, or about 3 to about 5. In further embodiments, the conjugate average DAR of the antibody conjugate composition ranges from 2 to 8, 1 to 3, or 3 to 5. In other specific embodiments, the antibody conjugates of the composition have an average DAR ranging from 1 to about 10, 1 to about 9, 1 to about 8, 1 to about 6, 1 to about 3, about 2 to about 8, about 2 to about 6, about 2.5 to about 5.5, about 2.5 to about 4.5, about 2 to about 4, about 3.5 to about 5.5, about 3 to about 5, about 3.5 to about 4.5, or about 3 to about 4. In other specific embodiments, the antibody conjugates of the composition have an average DAR ranging from 1 to 10, 1 to 9, 1 to 8, 1 to 6, 1 to 3, 2 to 8, 2 to 6, 2.5 to 5.5, 2.5 to 4.5, 2 to 4, 3.5 to 5.5, 3 to 5, 3.5 to 4.5, or 3 to 4. In certain embodiments, the conjugates of the composition have an average DAR of about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7. About 7.5, or about 8. In certain embodiments, the conjugates of the composition have an average DAR of 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8.

The route of administration can be any route that effectively delivers the ALK5 inhibitor compounds, ALK5 inhibitor conjugates, or compositions thereof of the invention to the appropriate or desired site of action, such as parenteral (including intravenous, subcutaneous, intramuscular, etc.) ), subepidermal, intradermal, transdermal, oral, intranasal, transpulmonary, or buccal. In certain specific embodiments, the route of administration is subcutaneous. In further embodiments, the route of administration is intravenous.

The dosage form may be administered once a day, or more than once a day, eg, two or three times a day. Alternatively, the dosage form may be administered less frequently than once a day, eg, every other day or once a week, if deemed feasible by the prescribing physician or the drug's prescribing information. Dosage regimens include, for example, titrating the dose to the extent necessary or useful for the indication being treated, thereby adapting the patient's body to the treatment, to minimize or avoid undesired side effects associated with the treatment, and/or to maximize the benefits of the treatment. Therapeutic effects of compounds. Other dosage forms include delayed or controlled release forms. Suitable dosage regimens and/or forms include, for example, those listed in the latest edition of the Physicians' Desk Reference, which is incorporated herein by reference.

In other embodiments, methods of making compositions of the compounds or conjugates described herein are provided, comprising formulating the compounds or conjugates of the invention with a pharmaceutically acceptable carrier, excipient, or diluent . In some embodiments, a pharmaceutically acceptable carrier, excipient, or diluent is suitable for parenteral administration (eg, subcutaneous or intravenous). In other specific embodiments, the method further comprises the step of lyophilizing the composition to form a lyophilized formulation. therapeutic application

The compositions, conjugates, and methods of the present invention are applicable to a plurality of different subjects, including, but not limited to, mammals, humans, non-human mammals, domestic animals (eg, laboratory animals, household pets, or livestock) ), non-domesticated animals (such as wild animals), dogs, cats, rodents, mice, hamsters, cows, birds, chickens, fish, pigs, horses, goats, sheep, rabbits, and any combination thereof. In some specific embodiments, the subject is a non-human primate (NHP). In some specific embodiments, the subject is a human.

The compositions, conjugates, and methods can be used as therapeutic agents, eg, can be administered to a subject in need thereof. The therapeutic utility of the present invention can be achieved by a subject by reducing, inhibiting, alleviating, or eliminating a disease state, including but not limited to its symptoms. Therapeutic utility in a subject suffering from a disease or disorder or prone to or beginning to suffer from a disease or disorder may be achieved by reducing, inhibiting, preventing, alleviating, or eliminating the disorder or disorder, or a pre-disorder or pre-disease state and obtained.

In practicing the methods described herein, therapeutically effective amounts of the compositions and conjugates can be administered to a subject in need thereof, typically for the treatment and/or prevention of a disorder or progression thereof. A pharmaceutical composition can affect a subject's physiology, such as the immune system, inflammatory response, or other physiological effects. A therapeutically effective amount may vary depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound used, and other factors.

Treating and/or treating means successfully treating or ameliorating any indication of a disease or condition. Treatment can include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or can include reducing the frequency of symptoms of a disease, defect, disorder, or adverse condition, etc., experienced by a patient. Treatment can be used herein to mean a method of treatment or amelioration that results in some level of a disease or condition, and a range of outcomes can be considered against that goal, including, but not limited to, complete prevention of the condition.

Preventing, preventing, etc. means preventing a disease or condition, such as tumor formation, in a patient. For example, if an individual at risk of developing a tumor or other form of cancer is treated with the methods of the invention and does not later develop the tumor or other form of cancer, the disease is prevented in that individual for at least a period of time. Prevention can also mean preventing the recurrence of a disease or condition in a patient who has previously been treated for the disease or condition, eg, by preventing recurrence.

A therapeutically effective amount (also referred to as an effective amount) can be a composition (such as a conjugate or compound) or its active ingredient that is sufficient to provide a beneficial effect to the individual to whom the composition is administered, or otherwise reduce a detrimental, non-beneficial event amount. A therapeutically effective dose can be one administered to produce one or more desired or desirable (eg, beneficial) effects, one or more times over a given period of time. The exact dosage may depend on the purpose of treatment and can be determined by one of skill in the art using known techniques and the teachings provided herein.

Conjugates useful in therapy can be formulated and determined in a manner consistent with good medical practice taking into account the disease or condition to be treated, the condition of the individual patient, the site of delivery of the composition, the method of administration, and other factors known to practitioners dose. Compositions can be prepared according to the preparation descriptions described herein.

Pharmaceutical compositions can be used in the methods described herein, and can be administered to a subject in need thereof using techniques known to those of ordinary skill in the art that may be suitable as therapy for a disease or condition affecting the subject. One of ordinary skill in the art will appreciate that the amount, duration, and frequency of administration of a pharmaceutical composition to a subject in need depends on several factors including, for example, but not limited to, the subject's health, the patient's the specific disease or condition of the patient, the grade or level of the specific disease or condition of the patient, the additional treatment the subject is receiving or has received, etc.

The methods and compositions can be used for administration to a subject in need. In general, administration of the composition may include a route of administration, non-limiting examples of routes of administration including intravenous, arterial, subcutaneous, subdural, intramuscular, intracranial, intrasternal, intratumoral, or intraperitoneal. In addition, the pharmaceutical composition can be administered to a subject by additional routes of administration, such as by inhalation, oral, dermal, intranasal, or intrathecal administration.

The compositions and conjugates of the present invention can be administered to a subject in need in a first administration and one or more additional administrations. One or more additional administrations may be administered to a subject in need minutes, hours, days, weeks, or months after the first administration. Any of the additional doses may be administered less than 21 days, or less than 14 days, less than 10 days, less than 7 days, less than 4 days, or less than 1 day after the first dose. Subjects in need. The one or more administrations may occur more than once per day, more than once per week, or more than once per month. Administration can be weekly, biweekly (every two weeks), every three weeks, monthly, or bimonthly.

The compositions, conjugates, and methods provided herein can be used to treat a plurality of diseases, conditions, prevent a disease or condition in a subject, or have other therapeutic applications in a subject in need thereof. In general, the compositions, conjugates, and methods provided herein can be used to treat proliferative conditions, including but not limited to neoplasms, cancers, tumors, and the like. The compositions, conjugates, and methods provided herein can be used to specifically target TGFβ1, TGFβR1, TGFβR2, or a combination thereof. The compositions and methods provided herein can be used to inhibit TGFβ1, TGFβR1, TGFβR2, or a combination thereof. In one embodiment, the compounds of the present invention activate or enhance an immune response. In another embodiment, the conjugates of the present invention activate or enhance immune responses.

Conditions, such as cancer, can be associated with the expression of molecules on cancer cells. Typically, molecules expressed by cancer cells may contain extracellular moieties that are recognized by the antibody construct in the conjugate. Molecules expressed by cancer cells can be tumor antigens. The antibody construct of the conjugate can recognize tumor antigens.

In certain embodiments, the antigen binding domain specifically binds to an antigen that is associated with the pathogenicity of T cells, B cells, astrocytes, endothelial cells, tumor cells, APCs, fibroblasts, fibroblasts, or fibrosis Antigens on sex-associated cells are at least 80% identical. In certain embodiments, the antigen binding domain specifically binds to an antigen with at least 80% identity to the antigen on T cells, APCs, and/or B cells. In certain embodiments, the antigen binding domain can specifically bind to an antigen with at least 80% identity to an antigen selected from the group consisting of: CLTA4, PD-1, OX40, LAG-3, GITR , GARP, CD25, CD27, PD-L1, TNFR2, ICOS, 41BB, CD70, CD73, CD38, or VTCN1. In certain embodiments, the antigen binding domain specifically binds to an antigen that is associated with an antigen on astrocytes, endothelial cells, fibroblasts, fibroblasts, or cells associated with the pathogenicity of fibrosis or cancer At least 80% consistency. In certain embodiments, the antigen binding domain can specifically bind to an antigen with at least 80% identity to an antigen selected from the group consisting of PDGFRβ, integrin αvβ1, integrin αvβ3, integrin αvβ6 , integrin αvβ8, endosialin, FAP, ADAM12, LRRC15, MMP14, PDPN, CDH11, and F2RL2. In certain embodiments, the antigen binding domain can specifically bind to an antigen with at least 80% identity to an antigen selected from the group consisting of: FAP, ADAM12, LRRC15, MMP14, PDPN, CDH11, and F2RL2. In certain specific embodiments, the antigen binding domain specifically binds to an antigen that is at least 80% identical to the antigen on the tumor cell, the tumor antigen. In certain embodiments, the antigen binding domain specifically binds to an antigen with at least 80% identity to an antigen selected from the group consisting of: ASGR1, ASGR2, LRRC15, MUC16, UPK1B, VTCN1, TMPRSS3, TMEM238, Clorf186, TMPRSS4, CLDN6, CLDN8, STRA6, MSLN, or CD73.

In certain embodiments, the antigen binding domain specifically binds to T cells, B cells, astrocytes, endothelial cells, tumor cells, APCs, fibroblasts, fibroblasts, or one of the pathogenic associations of fibrosis antigens on cells. In certain embodiments, the antigen binding domain specifically binds to an antigen on T cells, APCs, and/or B cells. In certain embodiments, the antigen binding domain can specifically bind to an antigen selected from the group consisting of: CLTA4, PD-1, OX40, LAG-3, GITR, GARP, CD25, CD27, PD-L1 , TNFR2, ICOS, 41BB, CD70, CD73, CD38, or VTCN1. In certain embodiments, the antigen binding domain specifically binds to an antigen on astrocytes, endothelial cells, fibroblasts, fibroblasts, or cells associated with the pathogenicity of fibrosis or cancer. In certain embodiments, the antigen binding domain can specifically bind to an antigen selected from the group consisting of PDGFRβ, integrin αvβ1, integrin αvβ3, integrin αvβ6, integrin αvβ8, endosialin, FAP, ADAM12, LRRC15, MMP14, PDPN, CDH11, and F2RL2. In certain embodiments, the antigen binding domain can specifically bind to an antigen selected from the group consisting of FAP, ADAM12, LRRC15, MMP14, PDPN, CDH11, and F2RL2. In certain specific embodiments, the antigen binding domain specifically binds to an antigen on a tumor cell, a tumor antigen. In certain embodiments, the antigen binding domain specifically binds to an antigen selected from the group consisting of MUC16, UPK1B, VTCN1, TMPRSS3, TMEM238, Clorf186, TMPRSS4, CLDN6, CLDN8, STRA6, MSLN, or CD73 .

In addition, such antigens may be derived from specific conditions and/or families of conditions including, but not limited to, cancers such as brain cancer, skin cancer, lymphoma, sarcoma, lung cancer, liver cancer, leukemia, uterine cancer, breast cancer, ovarian cancer , cervical cancer, bladder cancer, kidney cancer, angiosarcoma, bone cancer, blood cancer, testicular cancer, prostate cancer, stomach cancer, bowel cancer, pancreatic cancer, and other types of cancer, as well as precancerous conditions such as hyperplasia.

Non-limiting examples of cancers may include acute lymphoblastic leukemia (ALL); acute myeloid leukemia; adrenocortical carcinoma; childhood cerebellar or cerebral astrocytoma; basal cell carcinoma; bladder cancer; bone tumor, osteosarcoma/malignant fibrous histiocytes tumor; brain cancer; brain tumors such as cerebellar astrocytoma, glioblastoma, ependymoma, medulloblastoma, visual pathway and hypothalamic gliomas; brain stem gliomas; breast cancer; bronchial adenomas/types Carcinoma; Burkitt's lymphoma; Cerebellar Astrocytoma; Cervical Cancer; Cholangiocarcinoma; Chondrosarcoma; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Chronic Myeloproliferative Disorders; Colon Cancer; Cutaneous T cell lymphoma; endometrial cancer; ependymoma; esophageal cancer; eye cancers such as intraocular melanoma and retinoblastoma; gallbladder cancer; glioma; hairy cell leukemia; head and neck cancer; heart cancer; hepatocellular ( liver) cancer; Hodgkin lymphoma; hypopharyngeal cancer; pancreatic islet cell carcinoma (endocrine pancreas); Kaposi sarcoma; kidney cancer (renal cell carcinoma); Acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia; lip and mouth cancer; liposarcoma; lung cancer, such as non-small cell lung cancer and small cell lung cancer; lymphoma, such as AIDS-related lymphoma , Burkitt lymphoma; cutaneous T-cell lymphoma, Hodgkin and non-Hodgkin lymphoma, macroglobulinemia, malignant fibrous histiocytoma/osteosarcoma of bone; melanoma; Merkel cell carcinoma ( Merkel cell cancer); mesothelioma; multiple myeloma/plasma cell neoplasms; mycosis fungoides; myelodysplastic syndromes; myelodysplastic/myeloproliferative disorders; chronic myeloproliferative disorders; nasal cavity and paranasal sinuses carcinoma; nasopharyngeal carcinoma; neuroblastoma; oligodendroglioma; or oropharyngeal carcinoma; osteosarcoma/malignant fibrous histiocytoma of bone; ovarian carcinoma; pancreatic carcinoma; parathyroid carcinoma; pharyngeal carcinoma; pheochromocytoma tumor; pituitary adenoma; plasmacytoma; pleuropulmonary blastoma; prostate cancer; rectal cancer; renal cell carcinoma (kidney cancer); transitional cell carcinoma of the renal pelvis and ureter; rhabdomyosarcoma; salivary gland cancer; Ewing sarcoma family tumors; Kaposi's sarcoma; soft tissue sarcoma; uterine sarcoma; Sézary syndrome; skin cancer (non-melanoma); skin cancer; small bowel cancer; soft tissue sarcoma; squamous cell carcinoma; squamous cervical carcinoma with occult progenitors primary, metastatic; gastric cancer; testicular cancer; laryngeal cancer; thymoma and thymic cancer; thymoma; thyroid cancer; childhood thyroid cancer; uterine cancer; vaginal cancer; Waldenström macroglobulinemia); Wilmstumor; and any combination thereof.

Non-limiting examples of fibrosis or fibrotic diseases include adhesive capsulitis, arterial stiffness, articular fibrosis, atrial fibrosis, cirrhosis, Crohn's disease, collagen fibroma, cystic fibrosis, ligaments Desmoid-type fibromatosis, Dupuytren's contracture, elastic fibroma, endomyocardial fibrosis, fibroma of tendon sheath, glial scar, idiopathic pulmonary fibrosis, keloid ( keloid), mediastinal fibrosis, myelofibrosis, cervical fibrosis, nephrogenic systemic fibrosis, old myocardial infarction, Peyronie's disease, pulmonary fibrosis, progressive massive fibrosis, Nonalcoholic steatohepatitis (also known as NASH), radiation-induced lung injury, retroperitoneal fibrosis, scarring, scleroderma/systemic sclerosis.

The present invention provides any of the therapeutic compounds or conjugates disclosed herein for use in the methods of treating the human or animal body by therapy. Treatment can be by any of the mechanisms disclosed herein, such as by stimulating the immune system. The present invention provides any of the therapeutic compounds or conjugates disclosed herein for use in stimulating the immune system, vaccination, or immunotherapy (including, for example, enhancing immune responses). The invention further provides methods for preventing or treating any of the conditions disclosed herein (eg, cancer, autoimmune disease, inflammation, sepsis, allergy, asthma, transplant rejection, graft-versus-host disease, immunodeficiency, or infectious disease (usually caused by an infectious pathogen)) of any of the therapeutic compounds or conjugates disclosed herein. In certain specific embodiments, the antigen binding domain specifically binds to an antigen on an infected cell. In some embodiments, the infected cells are hepatocytes. In some specific embodiments, the hepatocyte line is infected with hepatitis B virus (HBV). In some specific embodiments, the antigen binding domain specifically binds to ASGR1 or ASGR2. In some specific embodiments, the antigen binding domain specifically binds to ASGR1. In some specific embodiments, the antigen binding domain specifically binds to ASGR2.

The invention also provides any of the therapeutic compounds or conjugates disclosed herein for use in achieving any of the clinical outcomes disclosed herein for any of the conditions disclosed herein, such as reduction of tumor cells in vivo. The invention also provides the use of any of the therapeutic compounds or conjugates disclosed herein for the manufacture of a medicament for the prevention or treatment of any of the disorders disclosed herein. General Synthesis Flow Diagram

The following synthetic flow diagrams are provided for illustrative purposes only and are not limiting. The following examples illustrate various methods of making the compounds described herein. It will be appreciated that those skilled in the art may manufacture these compounds by analogous methods or by combining other methods known to those skilled in the art. It will also be appreciated that those skilled in the art will be able to manufacture in a similar manner as described below by using appropriate starting materials and modifying synthetic routes as desired. In general, starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

Schemes 1A-1B show the general procedure used to prepare the purported Tankyrase inhibitor (payload). Flowcharts 2A-2B outline the procedure for attaching a linker to a payload. Flowcharts 3A-3B illustrate the general procedure for linking a linker-payload to an antibody. List of Abbreviations

Unless otherwise stated, as used above, the following abbreviations used throughout the description of the present invention should be understood to have the following meanings: ACN or MeCN Acetonitrile Bn Benzyl BOC or Boc Tertiary Butyl Carbamate CDI 1,1 '-Carbonyldiimidazole Cy Cyclohexyl DCE Dichloroethane (ClCH ₂ CH ₂ Cl ) DCM Dichloromethane (CH ₂ Cl ₂ ) DIPEA or DIEA Diisopropylethylamine DMAP 4--( N,N -Dimethyl amino)pyridine DMF dimethylformamide DMA N,N -dimethylacetamide DMSO dimethylsulfoxide equiv equiv Et ethyl EtOH ethanol EtOAc ethyl acetate h h HATU 1-[bis(dimethylene) amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxohexafluorophosphate HFIP 1,1,1,3,3,3-hexa Fluoropropan-2-ol HPLC High performance liquid chromatography LAH Lithium aluminum hydride LCMS Liquid chromatography-mass spectrometry mc-Val-Cit-PAB-PNP [4-[[(2S)-5-(aminocarbamoylamino)-2-[[(2S)-2-[6-( 2,5-Di-oxypyrrol-1-yl)hexylamino]-3-methylbutyryl]amino]pentyl]amino]phenyl]methyl(4-nitrophenyl) Carbonate Me Methyl MeOH Methanol MS Mass Spectrometry NMM N-Methyl Phosphonoline NMR Nuclear Magnetic Resonance PdCl ₂ (dppf) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd( OH) ₂ palladium hydroxide PMB p-methoxybenzyl rt room temperature TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Scheme I: Preparation of ALK5 inhibitor

In one method, compounds of formula (I) are prepared according to Scheme 1, wherein ^Q3 , ^Q4 , ^Q5 , and ^Q6 are CH. In particular, R ¹ substituted pyridine-2-carbaldehyde is reacted with aniline and diphenyl phosphite to give N,P-acetal (ii), which can be further substituted with R ⁷ , R ⁸ quinoline- Coupling of 6-carbaldehyde (i) followed by hydrolysis under acidic conditions yields the monoketone (iii). Monoketone (iii) can be oxidized to diketone (iv) with HBr in DMSO. Diketone (iv) can be condensed with aldehyde (v) in the presence of ammonium acetate to give imidazole (vi). The nitrogen substituted with the protecting group (PG) can then be deprotected under suitable conditions to yield compounds of formula (I). Example

The invention is further illustrated by the following examples. The following examples are non-limiting and represent only aspects of the invention. Solid and dashed wedges within the structures disclosed herein illustrate relative stereochemistry, absolute stereochemistry is described only when specifically illustrated or depicted. general method

All reagents for syntheses not described in the experimental section are commercially available, or are known compounds, or can be generated from known compounds by methods known to those skilled in the art.

Compounds and intermediates produced according to the methods of the present invention may require purification. The purification of organic compounds is known to those skilled in the art, and there may be several methods of purifying the same compounds. In some cases, purification may not be required. In some cases, compounds can be purified by crystallization. In some cases, impurities can be stirred out using a suitable solvent.

In some cases, compounds can be purified by chromatography, particularly flash column chromatography, using tailored or prepacked silica gel columns and elution agents such as solvent gradients (eg, heptane, diethyl ether, ethyl acetate, etc.) esters, acetonitrile, ethanol, and the like). In some cases, compounds can be purified by preparative HPLC using the methods described.

The purification methods described herein can provide compounds of the invention with sufficiently basic or acidic functionality in salt form, for example, where the compounds of the invention are sufficiently basic (trifluoroacetate or formate), or in When the compound of the present invention is sufficiently acidic (ammonium salt). Salts of this type can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent biological assays. It is to be understood that the particular form of a compound of the present invention that is isolated and as described herein is not necessarily the only form in which the compound can be used in biological assays to quantify a particular biological activity.

All starting materials and reagents were commercially available and used as received. Unless otherwise stated, ¹ H nuclear magnetic resonance (NMR) spectroscopy was performed with an instrument operating at 400 MHz using the solvent at approximately room temperature. In all cases, the NMR data were consistent with the proposed structure. Chemical shifts (δ) are characterized in parts per million using conventional abbreviations for designating major spikes: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd , doublet; dt, triplet; m, multiplet; br, broad. Preparative HPLC purification was performed by reverse phase HPLC using a gradient of ethyl acetate containing petroleum ether or an equivalent HPLC system.

合成流程圖

步驟 1 ：6-溴-3-羥基喹啉-4-羧酸（ 化合物 A1-b）之製備

Chemical names were generated using PerkinElmer Informatics, Inc's ChemDraw naming software (version 17.0.0.206). In some cases, the names generated by the naming software were replaced by generally accepted names of commercially available reagents. Example 1 Synthesis of intermediates (2-((6-(2-(6-methylpyridin-2-yl)-2-oxyethanoyl)quinolin-3-yl)oxy)ethyl ) Synthesis of tertiary butyl carbamate ( compound A1 )

Synthesis flow chart

Step 1 : Preparation of 6-bromo-3-hydroxyquinoline-4-carboxylic acid ( compound A1-b )

5-Bromoindoline-2,3-dione ( A1-a ) (20.3 g, 89.8 mmol, 1.0 equiv) was added to a solution containing KOH (40.3 g, 718 mmol, 8.0 equiv) under N at ₂₀ °C equiv.) in water (400 mL). The mixture was stirred at 50°C for 1.5 hours, then 3-bromo-2-pendoxopropionic acid (15.0 g, 89.8 mmol, 1.0 equiv) was added and stirred at 25°C for 90 hours. The reaction mixture was quenched with aqueous HCl (4 M) at 0 °C until pH = 4, the desired solid was precipitated and filtered to give 6-bromo-3-hydroxyquinoline-4-carboxylic acid ( A1-b ) (21.0 g, 78.3 mmol, 87.2% yield) as a brown solid.

¹ H NMR (DMSO- d ₆ , 400 MHz) δ8.69 (s, 1H), 8.54 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H) ). Step 2 : Preparation of 6-bromoquinolin-3-ol ( compound A1-c )

A solution of 6-bromo-3-hydroxyquinoline-4-carboxylic acid ( A1-b ) (15.0 g, 56.0 mmol, 1.0 equiv) in nitrobenzene (150 mL) was heated to 180 °C and then Stir at temperature for 6 hours. The reaction mixture was cooled to 0°C and methyl tert-butyl ether (300 mL) was added, the desired solid was precipitated and then filtered to give 6-bromoquinolin-3-ol ( A1-c ) (7.0 g, 31.2 mmol, 55.8% yield) as a brown solid.

¹ H NMR (DMSO- d ₆ , 400 MHz) δ8.57 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.53 (dd, J = 2.0, 9.2 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H). Step 3 : Preparation of N- [2-[(6-bromo-3-hydroquinoneyl)oxy]ethyl]carbamic acid tertiary butyl ester ( compound A1-d )

KI (741 mg, 4.46 mmol, 1.0 equiv) and K2CO3 ₍ 1.85 _g , 13.4 mmol, 3.0 equiv) were added to a mixture containing 6-bromoquinolin- ₃ -ol ( A1 -c ) (1.00 g, 4.46 mmol, 1.0 equiv) in a mixture of tert-butyl N-(2-bromoethyl)carbamate (5.00 g, 22.3 mmol, 5.0 equiv) in DMF (30 mL). The mixture was stirred at 45°C for 10 hours. Water (70 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (40 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether/ethyl acetate = 10/1, 1/1) to obtain N-[2 -[(6-Bromo-3-hydroquinoneyl)oxy]ethyl]carbamic acid tert-butyl ester ( A1-d ) (700 mg, 1.91 mmol, 42.7% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.60 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 2.4, 8.8 Hz, 1H), 7.05 (br t, J = 5.6 Hz, 1H), 4.08 (t, J = 5.6 Hz, 2H) , 3.34 (q, J = 5.6 Hz, 2H), 1.33 (s, 9H). Step 4 : Preparation of N- [2-[(6-carbamoyl-3-hydroquinoneyl)oxy]ethyl]carbamic acid tertiary butyl ester ( compound A1-e )

Under _N2 , Pd(dppf)Cl2 (357 _mg , 490 umol, 0.1 equiv), _Et3N (1.49 g, 14.7 mmol, 2.05 mL, 3.0 equiv), and _Et3SiH (11.4 g, 98.0 mmol) were mixed together , 15.7 mL, 20.0 equiv) was added to tertiary butyl ester containing N-[2-[(6-bromo-3-hydroquinoneyl)oxy]ethyl]carbamate ( A1-d ) (1.80 g, 4.90 mmol) , 1.0 equiv) in DMF (30 mL). The suspension was degassed in vacuo and flushed with CO several times. The mixture was stirred at 80°C under CO (50 psi) for 15 hours. Water (70 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether/ethyl acetate = 10/1, 1/1) to obtain N-[2 -[(6-Carboxylo-3-hydroquinoneyl)oxy]ethyl]carbamic acid tertiary butyl ester ( A1-e ) (800 mg, 2.53 mmol, 51.6% yield) as a yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ10.13 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 4.18-4.13 (m, 2H), 3.62-3.58 (m, 2H), 1.41 (s , 9H). Step 5 : N-[2-[[6-[2-(6-Methyl-2-pyridyl)-2-oxyethyl]-3-hydroquinonyl]oxy]ethyl]carbamic acid Preparation of Tertiary Butyl Ester ( Compound A1-f )

Cs ₂ CO ₃ (783 mg, 2.40 mmol, 1.0 equiv) was added to a solution containing N-[2-[(6-carbamoyl-3-hydroquinoneyl)oxy]ethane under N ₂ at 25°C tertiary butyl]carbamate ( A1-e ) (760 mg, 2.40 mmol, 1.0 equiv) and N-[diphenoxyphosphate-(6-methyl-2-pyridyl)methyl]aniline ( 1.03 g, 2.40 mmol, 1.0 equiv) in a mixture of THF (15 mL) and i-PrOH (5 mL), and then stirred at 25 °C for 2 h. The reaction mixture was quenched with aqueous HCl (4 M) at 0 °C until pH = 4, and then stirred for an additional 2 hours. Water (20 mL) was added and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether/ethyl acetate = 10/1, 1/1) to obtain N-[2 -[[6-[2-(6-Methyl-2-pyridyl)-2-oxyethyl]-3-hydroquinyl]oxy]ethyl]carbamic acid tertiary butyl ester ( A1- f ) (0.45 g, 1.07 mmol, 44.4% yield) as a yellow oil. Step 6 : N- [2-[[6-[2-(6-Methyl-2-pyridinyl)-2-oxyethanoyl]-3-hydroquinoneyl]oxy]ethyl]amine Preparation of tertiary butyl formate ( compound A1 )

Under N, Pd/C (518 mg, ₅ % purity, 0.2 equiv) was added to the side containing N-[2-[[6-[2-(6-methyl-2-pyridyl)-2- Oxyethyl]-3-hydroquinoneyl]oxy]ethyl]carbamic acid tert-butyl ester ( A1-f ) (450 mg, 1.07 mmol, 1.0 equiv) in MeCN (15 mL). The suspension was degassed in vacuo and flushed with O ₂ several times. The mixture was stirred at 80°C under O ₂ (15 psi) for 5 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give N-[2-[[6-[2-(6-methyl-2-pyridinyl)-2-oxyacetyl]-3-hydroquinone tert-butyl]oxy]ethyl]carbamate ( Compound A1 ) (390 mg, 896 umol, 83.9% yield) as a yellow oil.

合成流程圖

步驟 1 ： N-[2-(7-溴喹㗁啉-2-基)氧基乙基]胺甲酸三級丁酯（ 化合物 A2-b）之製備

¹ H NMR (CDCl ₃ , 400 MHz) δ8.75 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 8.15-8.07 (m, 2H), 8.02 (d, J = 7.6 Hz, 1H) ), 7.80 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 5.01 (s, 1H), 4.12 (t, J = 5.2 Hz, 2H), 3.59 (q, J = 5.2 Hz, 2H), 2.44 (s, 3H), 1.42 (s, 9H). (2-((7-(2-(6-Methylpyridin-2-yl)-2-oxyethanoyl)quinoline-2-yl)oxy)ethyl)carbamic acid tertiary butyl Synthesis of Esters ( Compound A2 )

Synthesis flow chart

Step 1 : Preparation of N- [2-(7-Bromoquinoline-2-yl)oxyethyl]carbamic acid tertiary butyl ester ( compound A2-b )

K ₂ CO ₃ (1.70 g, 12 mmol, 1.5 equiv) was added to a mixture containing 7-bromo-2-chloro-quinoline ( A2-a ) (2 g, 8.21 mmol, 1.0 equiv) and N-(2- tert-butyl hydroxyethyl)carbamate (1.99 g, 12 mmol, 1.9 mL, 1.5 equiv) in DMF (20 mL) and then stirred at 80 °C for 12 h. The reaction mixture was quenched by addition of _H2O (20 mL) at 20 °C, and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 4/1) to give compound N-[2-(7-bromoquinolin-2-yl)oxy tert-butyl ethyl]carbamate ( A2-b ) (2.5 g, 7 mmol, 82.66% yield) as a yellow solid.

¹ H NMR (CDCl ₃ , 400MHz) δ8.45 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 2.4, 8.8 Hz, 1H), 4.53 (t, J = 5.2 Hz, 2H), 3.65-3.60 (m, 2H), 1.44 (s, 9H). Step 2 : Preparation of tert-butyl N- [2-(7-carboxyquinacetin-2-yl)oxyethyl]carbamate ( compound A2-c )

_Et3N (2.06 g, 20.4 mmol, 2.83 mL, 3.0 equiv), _Et3SiH (15.8 g, 136 mmol, 21.7 mL, 20.0 equiv), and Pd(dppf)Cl2 (496 _mg , 678 umol, 0.1 equiv) to DMF containing tert-butyl N-[2-(7-bromoquinacetin-2-yl)oxyethyl]carbamate ( A2-b ) (2.5 g, 6.79 mmol, 1.0 equiv) (30 mL) solution, the suspension was degassed in vacuo and flushed with CO several times. The mixture was stirred at 80°C under CO (50 psi) for 20 hours. The reaction mixture was quenched by addition of _H2O (50 mL) at 20 °C, and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to give compound N-[2-(7-methylaminoquinoline-2-yl) )oxyethyl]carbamic acid tert-butyl ester ( A2-c ) (1 g, 3 mmol, 46.41% yield) as a yellow solid.

¹ H NMR (CDCl ₃ , 400MHz) δ10.22 (s, 1H), 8.59 (s, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 5.00 (s, 1H), 4.60 (t, J = 5.2 Hz, 2H), 3.68-3.62 (m, 2H), 1.46 (s, 9H). Step 3 : N- [2-[7-[2-(6-Methyl-2-pyridyl)-2-oxyethyl]quinoline-2-yl]oxyethyl]carbamic acid tris Preparation of grade butyl ester ( compound A2-d )

At 20°C, Cs ₂ CO ₃ (1.54 g, 4.73 mmol, 1.5 equiv) was added to a solution containing N-[2-(7-carboxyquinoxolin-2-yl)oxyethyl]carbamic acid Tertiary butyl ester ( A2-c ) (1 g, 3.15 mmol, 1.0 equiv) and N-[diphenoxyphosphate-(6-methyl-2-pyridyl)methyl]aniline (2.03 g, 4.73 mmol, 1.5 equiv) in THF (10 mL) and i-PrOH (4 mL), and then stirred at 35 °C for 6 h, the pH of the mixture was adjusted to pH ~3 with 2N HCl at 0 °C , and it was stirred for an additional 2 hours at 20°C. The reaction mixture was poured into H ₂ O (20 mL), and then the pH of the mixture was adjusted to ~8 by addition of aqueous NaHCO ₃ , extracted twice with EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give compound N-[2-[7-[2-(6-methyl-2 -Pyridinyl)-2-oxyethyl]quinoline-2-yl]oxyethyl]carbamic acid tert-butyl ester ( A2-d ) (1.5 g, crude) as a yellow solid.

¹ H NMR (MeOD, 400MHz) δ8.39 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.85-7.82 (m, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 1.2 Hz, 1H), 7.56 (dd, J = 1.6, 8.4 Hz, 1H), 7.45 (dd, J = 1.2, 7.2 Hz, 1H), 4.73 (s, 2H), 4.52 (t , J = 5.2 Hz, 2H), 3.53 (t, J = 5.2 Hz, 2H), 2.66 (s, 3H), 1.42 (s, 9H). Step 3 : N- [2-[7-[2-(6-Methyl-2-pyridyl)-2-oxyethanoyl]quinolin-2-yl]oxyethyl]carbamic acid Preparation of Tertiary Butyl Ester ( Compound A2 )

Pd/C (0.5 g, 10% purity) was added to the mixture containing N-[2-[7-[2-(6-methyl-2-pyridyl)-2-pendoxyloxyethyl at 20°C A solution of tert-butyl]quinoline-2-yl]oxyethyl]carbamate ( A2-d ) (1.5 g, 3.55 mmol, 1.0 equiv.) in MeCN (20 mL) was suspended under vacuum gas, and _flushed with O for several times. The mixture was stirred under _O2 (15 psi) at 80°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 2/1) to obtain compound N-[2-[7-[2-(6-methyl-2 -Pyridinyl)-2-oxyethanoyl]quinoline-2-yl]oxyethyl]carbamic acid tert-butyl ester ( Compound A2 ) (0.94 g, 2.15 mmol, 60.66% yield), For the yellow solid.

合成流程圖

步驟 1 ： N-(2-氟苯基)胺甲酸三級丁酯（ 化合物 1.1-b）之製備

¹ H NMR (CDCl ₃ , 400MHz) δ8.57 (s, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.21-8.18 (m, 1H), 8.17-8.13 (m, 1H), 8.06 ( d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 4.54 (t, J = 5.2 Hz, 2H), 3.61 (d, J = 5.2 Hz, 2H), 2.48 (s, 3H), 1.44 (s, 9H). Example 2: Synthesis of ALK5 inhibitor Example 2A: ALK5 inhibitor synthesis method A N -[[5-[3-(2-aminoethoxy)-6-hydroquinone]-4-(6- Synthesis of methyl-2-pyridyl) -1H -imidazol-2-yl]methyl]-2-fluoro-aniline (compound 1.1 )

Synthesis flow chart

Step 1 : Preparation of tert-butyl N- (2-fluorophenyl)carbamate ( compound 1.1-b )

Boc2O (73.6 _g , 337 mmol, 77.5 mL, 1.5 equiv) was added to THF (300 mL) containing 2-fluoroaniline ( 1.1-a ) ( 25 g, 225 mmol, 1.0 equiv) at 25°C ) solution and then stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure to give tert-butyl N-(2-fluorophenyl)carbamate ( 1.1-b ) (47 g, 223 mmol, 98.90% yield) as a colorless oil.

¹ H NMR (DMSO- d ₆ , 400MHz) δ 8.98 (s, 1H), 7.68-7.60 (m, 1H), 7.27-7.10 (m, 3H), 1.50 (s, 9H). Step 2 : Preparation of N -allyl-N-(2-fluorophenyl)carbamic acid tertiary butyl ester ( compound 1.1-c )

NaH (2.84 g, 71 mmol, 60% purity, 1.5 equiv) was slowly added to a solution containing tert-butyl N- (2-fluorophenyl)carbamate ( 1.1-b ) (10 g, 47 mmol, 1.0 equiv) in DMF (100 mL), the mixture was stirred at 0 °C for 10 min, then 3-bromoprop-1-ene (8.59 g, 71 mmol, 1.5 equiv) was added and added at 20 Stir at °C for 2 hours. The reaction mixture was poured into _H2O (100 mL) and extracted twice with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 9/1) to obtain compound N-allyl-N-(2-fluorophenyl)carbamic acid tris Grade butyl ester ( 1.1-c ) (10.3 g, 41 mmol, 86.58% yield) as a colorless liquid.

¹ H NMR (DMSO- d ₆ , 400 MHz) δ7.35-7.10 (m, 4H), 5.86-5.72 (m, 1H), 5.14-5.02 (m, 2H), 4.14 (d, J = 5.6 Hz, 2H), 1.38-1.31 (m, 9H). Step 3 : Preparation of N- (2-fluorophenyl)-N-(2-oxyethyl)carbamic acid tertiary butyl ester ( compound 1.1-d )

K ₂ OsO ₄ .2H ₂ O (453 mg ^, 1 mmol, 0.03 equiv) and NaIO ₄ (43.8 g, 205 mmol, 5.0 equiv) were added at 20°C to a mixture containing N-allyl-N-( tert-butyl 2-fluorophenyl)carbamate ( 1.1-c ) (10.3 g, 41.0 mmol, 1.0 equiv) in a mixture of THF (100 mL) and _H2O (100 mL) and then at 35°C under stirring for 5 hours. The reaction mixture was filtered, and the filtrate was poured into _H2O (100 mL) and extracted twice with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 9/1) to obtain compound N-(2-fluorophenyl)-N-(2-pendoxyloxy) Tertiary butyl ethyl)carbamate ( 1.1-d ) (4.26 g, 17 mmol, 41.04% yield) as a brown oil.

¹ H NMR (CDCl ₃ , 400 MHz) δ9.71 (s, 1H), 7.34-7.17 (m, 2H), 7.12 (d, J = 8.8 Hz, 2H), 4.28-4.16 (m, 2H), 1.40 (d, J = 6.4 Hz, 9H). Step 4 : N -[[5-[3-[2-(tertiary butoxycarbonylamino)ethoxy]-6-hydroquinone]-4-(6-methyl-2-pyridyl) Preparation of -1H-imidazol - 2-yl]methyl]-N-(2-fluorophenyl)carbamic acid tertiary butyl ester ( compound 1.1-e )

NH ₄ OAc (89 mg, 1.15 mmol, 5 equiv) was added to the compound containing N-[2-[[6-[2-(6-methyl-2-pyridyl)-2-pendant oxyethanoyl] -3-Hydroquinyl]oxy]ethyl]carbamic acid tertiary butyl ester ( A1 ) (100 mg, 223 umol, 1.0 equiv) with N-(2-fluorophenyl)-N-(2-oxygen tert-butylethyl)carbamate ( 1.1-d ) (87.0 mg, 344 umol, 1.5 equiv) in THF (5 mL) and then stirred at 35 °C for 12 h. The reaction mixture was quenched by addition of _H2O (10 mL) at 20 °C, and then extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to obtain compound N-[[5-[3-[2-(tertiary butoxy Carbonylamino)ethoxy]-6-hydroquinoneyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2-yl]methyl]-N-(2-fluorophenyl ) tertiary butyl carbamate ( 1.1-e ) (127 mg, 190 umol, 82.7% yield) as a white solid.

¹ H NMR (MeOD, 400MHz) δ8.59 (d, J = 2.8 Hz, 1H), 7.97 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J = 6.4 Hz, 1H), 7.20-7.11 (m, 4H), 6.95 (s, 1H), 4.94 (s, 2H), 4.19 (t, J = 5.2 Hz, 2H), 3.52 (q, J = 5.2 Hz, 2H), 2.50 (s, 3H), 1.44 (s, 18H). Step 5 : N -[[5-[3-(2-Aminoethoxy)-6-hydroquinoneyl]-4-(6-methyl-2-pyridyl) -1H -imidazole-2- Preparation of [methyl]methyl]-2-fluoro-aniline ( compound 1.1 )

HCl/EtOAc (4M, 5 mL) was added to the mixture containing N-[[5-[3-[2-(tertiary butoxycarbonylamino)ethoxy]-6-hydroquinone]-4-( 6-Methyl-2-pyridyl)-1H-imidazol-2-yl]methyl]-N-(2-fluorophenyl)carbamate (0.127 g, 189.91 umol, 1 equiv) in EtOAc (2 mL) of the mixture, and then stirred at 20°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to give N -[[5-[3-(2-aminoethoxy)-6-hydroquinone]-4-(6-methyl-2-pyridyl) -1H -imidazol-2-yl]methyl]-2-fluoro-aniline ( compound 1.1 ) (80.0 mg, 146 umol, 77.0% yield, 92.3% purity, HCl) as a yellow solid.

¹ H NMR (MeOD, 400 MHz) δ9.22 (d, J = 2.4 Hz, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.31 (d , J = 9.2 Hz, 1H), 8.16-8.02 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.10-7.00 (m, 2H) , 6.91-6.83 (m, 1H), 6.80-6.71 (m, 1H), 4.89 (s, 2H), 4.65 (t, J = 4.8 Hz, 2H), 3.54 (t, J = 4.4 Hz, 2H), 2.76 (s, 3H).

HPLC: 92.30% (220 nm), 95.72% (254 nm).

合成流程圖

步驟 1 ： N-[[5-[3-[2-(三級丁氧基羰基胺基)乙氧基]喹㗁啉-6-基]-4-(6-甲基-2-吡啶基)-1 H-咪唑-2-基]甲基]- N-(2-氟苯基)胺甲酸三級丁酯（ 化合物 1.2-a）之製備

MS (ESI): Calculated mass. m/z found to be 469.2 _[ M+H] ⁺ for _{C27H25FN6O 468.21} . N -[[5-[3-(2-Aminoethoxy)-6-hydroquinoneyl]-4-(6-methyl-2-pyridyl)-1 H -imidazol-2-yl]methyl Synthesis of base]-2-fluoro-aniline (compound 1.2 )

Synthesis flow chart

Step 1 : N -[[5-[3-[2-(tertiary butoxycarbonylamino)ethoxy]quinoline-6-yl]-4-(6-methyl-2-pyridyl )-1H-imidazol - 2-yl]methyl]-N-(2-fluorophenyl)carbamic acid tertiary butyl ester ( compound 1.2-a ) preparation

NH ₄ OAc (265 mg, 3.44 mmol, 5.0 equiv) was added to the mixture containing N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxyethanoyl]quino Tri-butyl quinoline-2-yl]oxyethyl]carbamate ( A2 ) (300 mg, 687 umol, 1.0 equiv) with N-(2-fluorophenyl)-N-(2-pendant oxy tert-butyl ethyl)carbamate ( 1.1-d ) (261 mg, 1.03 mmol, 1.5 equiv) in THF (5 mL) and then stirred at 35 °C for 12 h. The reaction mixture was quenched by addition of _H2O (10 mL) at 20 °C, and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to obtain compound N-[[5-[3-[2-(tertiary butoxy Carbonylamino)ethoxy]quinoline-6-yl]-4-(6-methyl-2-pyridyl) -1H -imidazol-2-yl]methyl]-N-(2-fluoro Tertiary butyl phenyl)carbamate ( 1.2-a ) (300 mg, 448 umol, 65.17% yield) as a yellow solid.

¹ H NMR (MeOD, 400MHz) δ8.44 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.34-7.28 (m, 3H), 7.21-7.13 (m, 3H), 4.95 (s, 2H), 4.51 (t, J = 5.2 Hz, 2H) ), 3.51 (t, J = 5.6 Hz, 2H), 2.51 (s, 3H), 1.41 (s, 18H). Step 2 : N -[[5-[3-[2-(tertiary butoxycarbonylamino)ethoxy]quinoline-6-yl]-4-(6-methyl-2-pyridyl )-1H-imidazol - 2-yl]methyl]-N-(2-fluorophenyl)carbamic acid tertiary butyl ester ( compound 1.2 ) preparation

HCl/EtOAc (4 M 10 mL) was added to the mixture containing N-[[5-[3-[2-(tertiary butoxycarbonylamino)ethoxy]quinoline-6-yl]-4- (6-Methyl-2-pyridyl)-1H-imidazol-2-yl]methyl]-N-(2-fluorophenyl)carbamic acid tert-butyl ester ( 1.2-a ) (300 mg, 448 umol, 1.0 equiv) in EtOAc (5 mL) and then stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The crude product was purified by reverse phase HPLC (column: YMC-Actus Triart C18 100 x 30mm x 5um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%-40%, 7 min) to give Compound N -[[5-[3-(2-aminoethoxy)quinoline-6-yl]-4-(6-methyl-2-pyridyl) -1H -imidazol-2-yl ]methyl]-2-fluoro-aniline ( compound 1.2 ) (101 mg, 164 umol, 36.64% yield, 4HCl) as a yellow solid.

¹ H NMR (MeOD, 400MHz) δ8.66 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.75 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.09-7.01 (m, 2H), 6.84 (t, J = 8.4 Hz, 1H), 6.79-6.73 (m, 1H), 4.86 (s, 2H), 4.78-4.74 (m, 2H), 3.48 (t, J = 4.8 Hz, 2H ), 2.74 (s, 3H).

HPLC: 96.99% (220 nm), 96.53% (254 nm). MS (ESI): Calculated mass. m/z found to be _470.1 [ _M +H] ⁺ for _C26H24FN7O 469.20.

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (DMSO-d6, 400 MHz) δ8.73 (d, J = 2.4 Hz, 1H), 8.16 (s, 1H), 8.09-7.94 (m, 4H), 7.88 (d, J = 2.4 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 2.0, 8.8 Hz, 1H), 7.32 (dd, J = 7.6, 15.6 Hz, 2H), 7.07 (dd, J = 7.6, 12.0 Hz, 1H), 7.02-6.95 (m, 1H), 6.95-6.88 (m, 1H), 6.69-6.59 (m, 1H), 4.77 (s, 2H), 4.15 (t, J = 6.4 Hz, 2H), 2.90-2.78 (m, 2H), 2.53 (s, 3H), 1.89-1.80 (m, 2H), 1.79-1.68 (m, 2H) MS: m/z = 497.3 [M+H]+ 1.4 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氯苯胺 1H NMR (DMSO-d6, 400MHz) δ8.75 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.05-7.92 (m, 3H), 7.88 (s, 1H), 7.77 (t, J= 8.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8.8 Hz, 2H), 7.21-7.15 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 4.84 (s, 2H), 4.18 (t, J = 6.4 Hz, 2H), 2.89-2.85 (m, 2H), 2.58 (s, 3H), 1.91-1.83 (m, 2H), 1.82-1.72 (m, 2H). MS: m/z = 513.2 [M+H]+ 1.5 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲基苯胺 1H NMR (DMSO-d6, 400MHz,) δ8.80 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.96 (s, 1H), 7.80-7.73 (m, 2H), 7.36 (t, J = 6.8 Hz, 2H), 7.03 (d, J = 4.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 7.6 Hz, 1H), 4.82 (s, 2H), 4.20 (t, J = 6.0 Hz, 2H), 2.88-2.85 (m, 2H), 2.54 (s, 3H), 2.23 (s, 3H), 1.93-1.83 (m, 2H), 1.83-1.73 (m, 2H). MS: m/z = 493.2 [M+H]+ 1.6 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲氧基苯胺 1H NMR (MeOD, 400MHz) δ9.16 (d, J = 2.4 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.48 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.12 (t, J = 8.0 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.23-7.17 (m, 1H), 7.16-7.10 (m, 2H), 7.00-6.95 (m, 1H), 4.84 (s, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.98 (s, 3H), 3.08 (t, J = 7.6 Hz, 2H), 2.81 (s, 3H), 2.08-2.01 (m, 2H), 1.99-1.91 (m, 2H). MS: m/z = 509.3 [M+H]+ 1.7 A

2-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苄腈 1H NMR (DMSO-d6, 400MHz) δ8.76 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.11-8.00 (m, 3H), 7.92 (d, J = 2.4 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.79 (t, J=7.2 Hz, 1H), 4.89 (s, 2H), 4.18 (t, J=6.0 Hz, 2H), 4.32-4.02 (m, 2H), 2.59 (s, 2H), 1.89-1.86 (m, 2H), 1.80-1.77 (m, 2H) MS: m/z = 504.3 [M+H]+ 1.8 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺 1H NMR (DMSO-d6, 400MHz) δ8.77 (d, J = 2.8 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.03 (s, 3H), 7.91 (d, J = 2.4 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.73 (dd, J = 1.6, 8.7 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.16 (q, J = 8.0 Hz, 1H), 6.58 (d, J = 8.8 Hz, 2H), 6.44 (t, J = 8.0 Hz, 1H), 4.74 (m, 1H), 4.19 (t, J = 6.0 Hz, 2H), 2.93-2.82 (m, 2H), 2.58 (s, 3H), 1.93-1.83 (m, 2H), 1.82-1.72 (m, 2H) MS: m/z = 497.3 [M+H]+ 1.9 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氯苯胺 1H NMR (DMSO-d6, 400MHz) δ8.81 (d, J = 2.8 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 8.8 Hz, 4H), 7.97 (d, J = 2.4 Hz, 1H), 7.84-7.72 (m, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.15 (t, J = 8.4 Hz, 1H), 6.82 (s, 1H), 6.75-6.63 (m, 2H), 4.76 (s, 2H), 4.20 (t, J = 6.4 Hz, 2H), 2.97-2.75 (m, 2H), 2.56 (s, 3H), 1.92-1.70 (m, 4H) MS: m/z = 513.2 [M+H]+ 1.10 A

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苄腈 1H NMR (DMSO-d6, 400MHz) δ8.78 (d, J = 2.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.13-8.00 (m, 4H), 7.93 (d, J = 2.4 Hz, 1H), 7.83-7.70 (m, 2H), 7.42-7.30 (m, 3H), 7.16 (s, 1H), 7.12-7.02 (m, 2H), 4.78 (s, 2H), 4.19 (t, J = 6.4 Hz, 2H), 2.89-2.86 (m, 2H), 2.57 (s, 3H), 1.90-1.83 (m, 2H), 1.82-1.70 (m, 2H) MS: m/z = 504.2 [M+H]+ 1.11 A

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲醯胺 1H NMR (DMSO-d6, 400MHz) δ8.74 (d, J = 2.8 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.30-7.13 (m, 4H), 6.87 (d, J = 7.6 Hz, 1H), 4.71 (s, 2H), 4.16 (t, J = 5.6 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.57 (s, 3H), 1.91-1.80 (m, 2H), 1.80-1.69 (m, 2H) MS: m/z = 522.3 [M+H]+ 1.12 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (DMSO-d6, 400MHz) δ8.74 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.01-7.96 (m, 3H), 7.87 (d, J = 2.8 Hz, 1H), 7.81-7.74 (m, 1H), 7.71 (dd, J = 1.6, 8.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.05-6.97 (m, 1H), 6.77-6.58 (m, 3H), 4.82 (s, 2H), 4.19 (t, J = 6.0 Hz, 2H), 2.92-2.81 (m, 2H), 2.62-2.57 (m, 3H), 1.92-1.84 (m, 2H), 1.82-1.71 (m, 2H) MS: m/z = 515.2 [M+H]+ 1.13 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3,4-二氟苯胺 1H NMR (DMSO-d6, 400MHz) δ8.75 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.06-8.03 (m, 3H), 7.88 (d, J = 2.5 Hz, 1H), 7.81-7.69 (m, 2H), 7.35 (dd, J = 7.6, 19.2 Hz, 2H), 7.24-7.16 (m, 1H), 6.88-6.80 (m, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.70 (s, 2H), 4.18 (t, J = 6.0 Hz, 2H), 2.89-2.85 (m, 2H), 2.57 (s, 3H), 1.86 (d, J = 7.6 Hz, 2H), 1.81-1.72 (m, 2H) MS: m/z = 515.2 [M+H]+ 1.14 A

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-(二甲基胺基)苄腈 1H NMR (MeOD-d4, 400MHz) δ = 8.69 (d, J = 2.8 Hz, 1H), 8.14-8.07 (m, 2H), 7.79-7.74 (m, 2H), 7.72-7.68 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.47-6.44 (m, 1H), 6.35 (s, 1H), 6.31 (J = 2.0 Hz, 1H), 4.74 (s, 2H), 4.23 (t, J = 5.6 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.94 (s, 6H), 2.68 (s, 3H), 2.02-1.89 (m, 4H) MS: m/z = 547.3 [M+H]+ 1.15 A

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-(二甲基胺基)苄腈 1H NMR (DMSO-d6, 400MHz) δ8.71 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 1.6, 8.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.15-7.07 (m, 3H), 4.75 (s, 2H), 4.15 (t, J = 6.0 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.67 (s, 6H), 2.59 (s, 3H), 1.90-1.81 (m, 2H), 1.79-1.70 (m, 2H) MS: m/z = 547.3 [M+H]+ 1.16 A

N3-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-4-氟-N1,N1-二甲苯-1,3-二胺 1H NMR (DMSO-d6, 400 MHz) δ 8.86 (d, J = 2.8 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.17-8.10 (m, 4H), 8.04 (d, J = 2.4 Hz, 1H), 7.88-7.77 (m, 2H), 7.66 (d, J = 6.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.26 (dd, J = 8.6, 11.2 Hz, 1H), 7.16-7.12 (m, 1H), 4.95 (s, 2H), 4.22 (t, J = 6.0 Hz, 2H), 3.15 (s, 6H), 2.91-2.84 (m, 2H), 2.52 (s, 3H), 1.91-1.84 (m, 2H), 1.83-1.72 (m, 2H) MS: m/z = 540.3 [M+H]+ 1.17 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟-5-硝基苯胺 1H NMR (DMSO-d6, 400 MHz) δ8.77 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.13-7.99 (m, 4H), 7.92 (d, J = 2.4 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.75-7.69 (m, 2H), 7.62-7.55 (m, 1H), 7.44-7.36 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 4.90 (s, 2H), 4.19 (t, J = 6.0 Hz, 2H), 2.89-2.84 (m, 2H), 2.59 (s, 3H), 1.93-1.83 (m, 2H), 1.83-1.71 (m, 2H) MS: m/z = 542.3 [M+H]+ 1.18 A

N-((5-(3-(4-胺基-3,3-二氟丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (MeOD, 400MHz) δ9.16 (d, J = 2.8 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.02 (dd, J = 2.0, 8.8 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.08-6.97 (m, 2H), 6.86-6.79 (m, 1H), 6.77-6.70 (m, 1H), 4.83 (s, 2H), 4.60 (t, J = 6.0 Hz, 2H), 3.70 (t, J = 16.0 Hz, 2H), 2.82-2.72 (m, 2H), 2.71 (s, 3H) MS: m/z = 533.2 [M+H]+ 1.19 A

2-氟-N-((4-(6-甲基吡啶-2-基)-5-(3-(2-(哌啶-4-基)乙氧基)喹啉-6-基)-1H-咪唑-2-基)甲基)苯胺 1H NMR (DMSO-d6, 400MHz) δ8.90-8.87 (m, 1H), 8.73 (d, J = 2.8 Hz, 1H), 8.70-8.66 (m, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.70 (dd, J = 1.6, 8.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 8.0, 12.2 Hz, 1H), 7.05-6.99 (m, 1H), 6.95-6.87 (m, 1H), 6.72-6.62 (m, 1H), 4.79 (s, 2H), 4.20 (t, J = 6.0 Hz, 2H), 3.24 (d, J = 12.0 Hz, 2H), 2.94-2.78 (m, 2H), 2.58 (s, 3H), 1.88 (d, J =13.6 Hz, 2H), 1.80-1.74 (m, 3H), 1.49-1.35 (m, 2H) MS: m/z = 537.2 [M+H]+ 1.20 A

N-((5-(3-(2-(3,3-二氟哌啶-4-基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (DMSO-d6, 400MHz) δ10.17-10.13 (m, 1H), 9.39-9.36 (m, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.20 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.82-7.69 (m, 2H), 7.35 (dd, J = 7.6, 20.0 Hz, 2H), 7.15-6.87 (m, 3H), 6.73-6.63 (m, 1H), 4.80 (s, 2H), 4.34-4.22 (m, 2H), 3.72-3.68 (m, 1H), 3.57-3.37 (m, 1H), 3.24 (d, J = 12.8 Hz, 1H), 3.05-3.01 (m, 1H), 2.57 (s, 3H), 2.28-2.11 (m, 2H), 1.80-1.75 (m, 1H), 1.71-1.52 (m, 1H), 1.28-1.19 (m, 1H) MS: m/z = 573.2 [M+H]+ 1.21 A

N-((5-(3-(3-胺基丙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (METHANOL-d4, 400MHz) δ = 8.60 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.72 (dd, J = 8.4 Hz, J = 2.0Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.09 - 7.01 (m, 2H), 6.87 - 6.81 (m, 1H), 6.79 - 6.72 (m, 1H), 4.86 (s, 2H), 4.62 (t, J = 6.0 Hz, 2H), 3.20 (t, J = 7.2 Hz, 2H), 2.74 (s, 3H), 2.29 - 2.19 (m, 2H) MS: m/z = 484.2 [M+H]+ 1.22 A

N-((5-(3-(4-胺基丁氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (METHANOL-d4, 400MHz) δ = 8.55 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.72 (dd, J = 2.0, 8.4 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.07 - 6.99 (m, 2H), 6.83 - 6.77 (m, 1H), 6.76 - 6.69 (m, 1H), 4.79 (s, 2H), 4.55 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H), 2.68 (s, 3H), 2.02 - 1.94 (m, 2H), 1.93 - 1.84 (m, 2H) MS: m/z = 498.2 [M+H]+ 1.23 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 MS: m/z = 469 [M+H] ⁺ 1.24 A

2-氟-N-((4-(6-甲基吡啶-2-基)-5-(2-甲基喹啉-6-基)-1H-咪唑-2-基)甲基)苯胺 1H NMR (MeOD, 400 MHz) δ9.03 (d, J = 8.4 Hz, 1H), 8.53 (s, 1H), 8.33-8.18 (m, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.53-7.32 (m, 2H), 7.09-6.95 (m, 2H), 6.87-6.66 (m, 2H), 4.80 (s, 2H), 3.05 (s, 3H), 2.67 (s, 3H) MS: m/z =424.1 [M+H]+ 1.25 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺 1H NMR (MeOD, 400MHz) δ9.17 (d, J = 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.49 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.09-7.93 (m, 2H), 7.64-7.47 (m, 2H), 7.24-7.08 (m, 1H), 6.59 (dd, J = 2.0, 8.4 Hz, 1H), 6.55-6.50 (m, 1H), 6.46 (dt, J = 2.4, 8.4 Hz, 1H), 4.80 (s, 2H), 4.63 (t, J = 4.8 Hz, 2H), 3.53 (t, J = 4.8 Hz, 2H), 2.73 (s, 3H) MS: m/z = 469.1 [M+H]+ 1.26 A

N-((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺 1H NMR (MeOD, 400MHz) δ9.18 (d, J = 2.8 Hz, 1H), 8.73 (d, J = 2.8 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.05 (dd, J = 1.6, 8.8 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.61-7.54 (m, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.22-7.11 (m, 1H), 6.59 (dd, J = 1.6, 8.0 Hz, 1H), 6.52 (td, J = 2.4, 11.6 Hz, 1H), 6.46 (dt, J = 2.0, 8.4 Hz, 1H), 4.79 (s, 2H), 4.50 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.72 (s, 3H), 2.31 (q, J = 6.4 Hz, 2H) MS: m/z = 483.2 [M+H]+ 1.27 A

N-((5-(3-(2-(2-胺基乙氧基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺 1H NMR (MeOD, 400MHz) δ9.23 (d, J = 2.4 Hz, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.20 (t, J = 8.0 Hz, 1H), 8.07 (dd, J = 1.6, 8.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.25-7.16 (m, A1H), 6.66 (dd, J = 2.0, 8.4 Hz, 1H), 6.60 (td, J = 2.4, 11.6 Hz, 1H), 6.52 (dt, J = 2.4, 8.4 Hz, 1H), 4.87 (s, 2H), 4.62-4.54 (m, 2H), 4.07-3.98 (m, 2H), 3.89-3.79 (m, 2H), 3.17 (t, J = 4.8 Hz, 2H), 2.80 (s, 3H) MS: m/z = 513.2 [M+H]+ 1.28 A

N-((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (MeOD, 400MHz) δ9.17 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.59-7.45 (m, 2H), 7.10-6.97 (m, 2H), 6.89-6.67 (m, 2H), 4.84 (s, 2H), 4.50 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.77-2.66 (m, 3H), 2.38-2.25 (m, 2H) MS: m/z = 483.2 [M+H]+ 1.29 A

N-((5-(3-(2-(2-胺基乙氧基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (MeOD, 400MHz) δ8.73 (d, J = 2.8 Hz, 1H), 8.17-8.05 (m, 2H), 7.83 (d, J = 2.4 Hz, 1H), 7.79-7.68 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.08-6.98 (m, 2H), 6.84-6.68 (m, 2H), 4.80 (s, 2H), 4.41-4.32 (m, 2H), 4.04-3.94 (m, 2H), 3.86-3.78 (m, 2H), 3.17 (t, J = 4.8 Hz, 2H), 2.68 (s, 3H) MS: m/z = 513.2 [M+H]+ 1.31 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (MeOD, 400MHz) δ9.23 (d, J = 2.4 Hz, 1H), 8.87 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.16-8.04 (m, 2H), 7.75-7.62 (m, 2H), 7.04-6.93 (m, 1H), 6.70-6.55 (m, 2H), 4.90 (s, 2H), 4.66 (t, J = 4.8 Hz, 2H), 3.54 (t, J = 4.8 Hz, 2H), 2.77 (s, 3H) MS: m/z = 487.1 [M+H]+ 1.32 A

N-((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (MeOD, 400MHz) δ9.20 (d, J = 2.8 Hz, 1H), 8.75 (d, J = 2.8 Hz, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.11-7.93 (m, 2H), 7.66-7.47 (m, 2H), 6.98 (ddt, J = 2.0, 6.0, 8.4 Hz, 1H), 6.69-6.52 (m, 2H), 4.86 (s, 2H), 4.51 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.73 (s, 3H), 2.32 (q, J = 6.4Hz, 2H) MS: m/z = 501.2 [M+H]+ 1.33 A

N-((5-(3-(2-(2-胺基乙氧基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (MeOD, 400MHz) δ8.71 (d, J = 2.8 Hz, 1H), 8.10 (dd, J = 3.6, 5.2 Hz, 2H), 7.81-7.74 (m, 2H), 7.70 (dd, J = 2.0, 8.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.05-6.95 (m, 1H), 6.64-6.54 (m, 2H), 4.80 (s, 2H), 4.38-4.33 (m, 2H), 4.02-3.97 (m, 2H), 3.86-3.78 (m, 2H), 3.18 (t, J = 5.2 Hz, 2H), 2.69 (s, 3H) MS: m/z = 531.2 [M+H]+ 1.34 A

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-2-醇 1H NMR (MeOD, 400MHz) δ7.98 (d, J = 9.4 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.67 (dd, J = 2.0, 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.09-6.96 (m, 2H), 6.81-6.64 (m, 3H), 4.79 (s, 2H), 2.68 (s, 3H) MS: m/z = 426.1 [M+H]+ 1.35 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺 1H NMR (MeOD, 400MHz) δ = 8.65 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.82-7.74 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 5.91-6.97 (m, 1H), 6.85-6.75 (m, 2H), 4.78-4.71 (m, 4H), 3.51-3.45 (m, 2H), 2.68 (s, 3H) MS: m/z = 488.1 [M+H]+ 1.36 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺 1H NMR (MeOD, 400MHz) δ8.66 (s, 1H), 8.20-8.07 (m, 2H), 7.97 (t, J = 8.4 Hz, 1H), 7.76 (dd, J = 2.2, 8.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.52-7.45 (m, 1H), 6.39-6.31 (m, 2H), 6.24 (m, 1H), 4.78-4.74 (m, 4H), 3.51-3.46 (m, 2H), 2.74 (s, 3H) MS: m/z = 488.2 [M+H]+ 1.37 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺 1H NMR (MeOD, 400 MHz) δ8.66 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.85-7.73 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.21-7.11 (m, 1H), 6.56-6.41 (m, 3H), 4.78-4.72 (m, 4H), 3.51-3.45 (m, 2H), 2.69 (s, 3H) MS: m/z =470.3 [M+H]+ 1.38 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (MeOD, 400 MHz) δ8.68-8.65 (m, 1H), 8.16-8.10 (m, 3H), 7.78-7.68 (m, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.05-6.95 (m, 1H), 6.70-6.57 (m, 2H), 4.91 (s, 2H), 4.81-4.73 (m, 2H), 3.53-3.46 (m, 2H), 2.78 (s, 3H) MS: m/z =488.3 [M+H]+ 1.39 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺 1H NMR (MeOD, 400 MHz) δ9.18 (d, J = 2.8 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.08-7.97 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.00-6.92 (m, 1H), 6.88-6.80 (m, 2H), 4.82 (s, 2H), 4.63 (t, J = 4.8 Hz, 2H), 3.54 (t, J = 4.8 Hz, 2H), 2.73 (s, 3H) MS: m/z =487.1 [M+H]+ 1.40 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺 1H NMR (MeOD, 400 MHz) δ9.09 (d, J = 2.8 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.02-7.89 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.40-6.28 (m, 2H), 6.27-6.17 (m, 1H), 4.75 (s, 2H), 4.59 (t, J = 4.8 Hz, 2H), 3.53 (t, J = 4.4 Hz, 2H), 2.72 (s, 3H) MS: m/z =487.2 [M+H]+ 1.41 A

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)-N-甲基喹啉-3-甲醯胺 1H NMR (MeOD, 400 MHz) δ9.33 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 2.0, 8.8 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.08-6.98 (m, 2H), 6.80 (t, J = 7.6 Hz, 1H), 6.76-6.69 (m, 1H), 4.80 (s, 2H), 3.00 (s, 3H), 2.68 (s, 3H) MS: m/z =467.2 [M+H]+ 1.42 A

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)-N,N-二甲基喹啉-3-甲醯胺 1H NMR (MeOD, 400 MHz) δ9.02 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.95 (dd, J = 2.0, 8.8 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.07-6.99 (m, 2H), 6.82-6.76 (m, 1H), 6.76-6.69 (m, 1H), 4.79 (s, 2H), 3.19 (s, 3H), 3.11 (s, 3H), 2.68 (s, 3H) MS: m/z =481.2 [M+H]+ 1.43 A

(R)-N-((5-(3-((1-胺基丙-2-基)氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (MeOD, 400 MHz) δ8.61 (s, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.10 (s, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.09-6.99 (m, 2H), 6.81 (t, J = 7.8 Hz, 1H), 6.73-6.75 (m, 1H), 5.63-5.65 (m, 1H), 4.82 (s, 2H), 3.43-3.35 (m, 2H), 2.70 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H) MS: m/z =484.2 [M+H]+ 1.44 A

(S)-N-((5-(3-((1-胺基丙-2-基)氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (MeOD, 400MHz) δ8.62 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.75 (dd, J = 1.6, 8.4 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.10-6.97 (m, 2H), 6.86-6.68 (m, 2H), 5.65-5.63 (m, 1H), 4.82 (s, 2H), 3.42-3.32 (m, 2H), 2.70 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H) MS: m/z = 484.2 [M+H]+ 1.45 A

N-((5-(3-((1-胺基-2-甲基丙-2-基)氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 MS: m/z = 497 [M+H] ⁺ 1.46 A

N-((5-(3-(四氫吖唉-3-基氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (MeOD, 400 MHz) δ8.68 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.81-7.71 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.08-6.97 (m, 2H), 6.85-6.77 (m, 1H), 6.76-6.66 (m, 1H), 5.76-5.62 (m, 1H), 4.76 (s, 2H), 4.64-4.59 (m, 2H), 4.34-4.30 (m, 2H), 2.65 (s, 3H) MS: m/z =482.2 [M+H]+ 1.47 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-(甲氧基甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (300 MHz, Methanol-d4) δ: 1.90-2.03 (m, 4H), 3.05-3.10 (m, 2H), 3.51 (s, 3H), 4.25-4.28 (m, 2H), 4.65 (s, 2H), 4.90-4.92 (m, 2H), 6.58-6.67 (m, 2H), 6.97-7.01 (m, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.73-7.79 (m, 2H), 7.90 (s, 1H), 8.13-8.19 (m, 2H), 8.77 (d, J = 2.7 Hz, 1H). MS m/z [M-H]-  (ESI)：543 1.48 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-(三氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (300 MHz, Methanol-d4) δ: 1.91-2.03 (m, 4H), 3.05-3.09 (m, 2H), 3.29-3.31 (m, 2H), 4.23-4.26 (m, 2H), 6.57-6.66 (m, 2H), 6.95-7.03 (m, 1H), 7.66-7.82 (m, 4H), 7.96-8.09 (m, 1H), 8.12-8.19 (m, 1H), 8.20 (s, 1H), 8.71 (d, J = 2.7 Hz, 1H). MS: m/z [M+H]+ (ESI)：569 1.49 A

N-((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (400 MHz, Methanol-d4) δ: 1.93-2.03 (m, 4H), 3.06-3.09 (m, 2H), 4.24-4.27 (m, 2H), 4.84 (s, 2H), 6.59-6.64 (m, 2H), 6.97-6.99 (m, 1H), 7.49-7.53 (m, 2H), 7.72-7.75 (m, 1H), 7.84-7.87 (m, 2H), 8.12-8.15 (m, 2H), 8.71-8.74 (m, 2H). MS: m/z [M+H]+ (ESI)：501 1.50 A

N-((5-(3-(2-胺基乙基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (300 MHz, Methanol-d4) δ: 2.64-2.70 (m, 3H), 3.47-3.61 (m, 4H), 4.83 (s, 2H), 6.57-6.65 (m, 2H), 6.93-7.03 (m, 1H), 7.37-7.47 (m, 2H), 7.80-7.85 (m, 1H), 7.92-7.95 (m, 1H), 8.22 (d, J = 5.7 Hz, 1H), 8.34 (s, 1H), 8.94 (s, 1H). MS: m/z [M+H]+ (ESI)：472 1.51 A

N-((5-(3-(胺基甲基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 MS: m/z = 457 [M+H] ⁺ 1.52 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氟-6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 MS: m/z = 504 [M+H] ⁺ 1.53 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(甲氧基甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 MS: m/z = 516 [M+H] ⁺ 1.54 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (300 MHz, Methanol-d4) δ: 3.49-3.53 (m, 2H), 4.46-4.49 (m, 2H), 4.86 (s, 2H), 6.56-6.65 (m, 2H), 6.95-7.01 (m, 1H), 7.50-7.54 (m, 2H), 7.76-7.79 (m, 1H), 7.85-7.94 (m, 2H), 8.14-8.19 (m, 2H), 8.72 (d, J = 5.1 Hz, 1H), 8.83 (d, J = 2.7 Hz, 1H). MS: m/z [M+H]+ (ESI)：473 1.55 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(三氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (300 MHz, Methanol-d4) δ: 3.48-3.54 (m, 2H), 4.41-4.44 (m, 2H), 4.64-4.78 (m, 1H), 4.80-4.88 (m, 1H), 6.57-6.65 (m, 2H), 6.94-7.00 (m, 1H), 7.64-7.67 (m, 1H), 7.80-7.83 (m, 3H), 7.91-8.00 (m, 1H), 8.12-8.20 (m, 1H), 8.21 (s, 1H), 8.79-8.80 (m, 1H). MS: m/z [M+H]+ (ESI)：541 1.56 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(5-氟-6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 1H NMR (300 MHz, Methanol-d4) δ: 2.60 (s, 3H), 3.50-3.56 (m, 2H), 4.43-4.47 (m, 2H), 4.78-4.88 (m, 2H), 6.58-6.68 (m, 2H), 6.97-7.04 (m, 1H), 7.25-7.29 (m, 1H), 7.42-7.48 (m, 1H), 7.74-7.77 (m, 1H), 7.86-7.87 (m, 1H), 8.13-8.15 (m, 2H), 8.79 (s, 1H). MS: m/z [M+H]+ (ESI)：505 1.57 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 MS: m/z = 473 [M+H] ⁺ 1.58 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 MS: m/z = 473 [M+H] ⁺ 1.59 A

N-((5-(3-((1r,3r)-3-胺基環丁氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 1H NMR (MeOD, 400 MHz) δ8.60 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.73 (dd, J = 2.0, 8.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.08-6.99 (m, 2H), 6.81 (t, J = 7.6 Hz, 1H), 6.77-6.70 (m, 1H), 5.67-5.58 (m, 1H), 4.82 (s, 2H), 4.10-4.01 (m, 1H), 2.76 (t, J = 6.4 Hz, 4H), 2.70 (s, 3H) MS: m/z =496.2 [M+H]+ 1.60 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 MS: m/z = 523 [M+H] ⁺ 1.61 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(三氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 MS: m/z = 620 [M+H] ⁺ 1.62 A

N-((5-(3-(2-胺基乙基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 MS: m/z = 453 [M+H] ⁺ 1.63 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(5-氟-6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 MS: m/z = 487 [M+H] ⁺ 1.64 A

N-(2-胺基乙基)-6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-甲醯胺 1H NMR (MeOD, 400 MHz) δ9.62 (d, J = 2.0 Hz, 1H), 9.48 (s, 1H), 8.60 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.09-6.97 (m, 2H), 6.85-6.78 (m, 1H), 6.77-6.67 (m, 1H), 4.83 (s, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.27 (t, J = 5.6 Hz, 2H), 2.70 (s, 3H) MS: m/z =496.2 [M+H]+ 1.65 A

N-(2-胺基乙基)-6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)-N-甲基喹啉-3-甲醯胺 1H NMR (MeOD, 400 MHz) δ9.08 (s, 1H), 8.58 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 2.0, 8.8 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.06-6.99 (m, 2H), 6.80 (t, J = 8.4 Hz, 1H), 6.76-6.66 (m, 1H), 4.79 (s, 2H), 3.95-3.86 (m, 2H), 3.28-3.32 (m, 2H), 3.14 (s, 3H), 2.67 (s, 3H) MS: m/z =510.2 [M+H]+ 1.66 A

2-胺基-1-(6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-基)乙-1-酮 MS: m/z = 466 [M+H] ⁺ 1.67 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 ¹H NMR (MeOD, 400MHz) δ8.63 (s, 1H), 8.17-8.07 (m, 2H), 7.94-7.87 (m, 1H), 7.82 (dd, J= 1.6, 8.4 Hz, 1H), 7.67 (d, J= 7.2 Hz, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.08-6.99 (m, 2H), 6.88-6.56 (m, 3H), 4.78 (s, 2H), 4.77-4.73 (m, 2H), 3.49-3.45 (m, 2H) MS: m/z = 506.2 [M+H] ⁺ 1.68 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺 ¹H NMR (MeOD, 400MHz) δ 8.68 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 8.14 (d, J= 1.6 Hz, 1H), 7.96-7.90 (m, 1H), 7.81 (dd, J= 2.0, 8.4 Hz, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.23-7.13 (m, 1H), 6.78 (t, J= 55.2 Hz, 1H), 6.57-6.43 (m, 3H), 4.84-4.84 (m, 2H), 4.78-4.73 (m, 2H), 3.51-3.45 (m, 2H) MS: m/z = 506.2 [M+H] ⁺ 1.69 A

N-(2-胺基乙基)-6-(4-(6-(二氟甲基)吡啶-2-基)-2-(((2-氟苯基)胺基)甲基)-1H-咪唑-5-基)喹啉-3-甲醯胺 ¹H NMR (MeOD, 400 MHz) δ9.50 (d, J= 1.6 Hz, 1H), 9.17 (s, 1H), 8.51 (s, 1H), 8.30 (d, J= 8.8 Hz, 1H), 8.14 (dd, J= 1.6, 8.8 Hz, 1H), 7.99-7.92 (m, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.12-6.99 (m, 2H), 6.92-6.60 (m, 3H), 4.91 (s, 2H), 3.77 (t, J= 6.0 Hz, 2H), 3.25 (t, J= 6.0 Hz, 2H) MS: m/z =532.1 [M+H] ⁺ 1.70 A

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-羧酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 9.67 (s, 1H), 9.60 (s, 1H), 8.66 (s, 1H), 8.43 (d, J= 8.8 Hz, 1H), 8.37-8.35 (m, 1H), 8.06 (t, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.08-7.08 (m, 2H), 6.87 (t, J= 8.0 Hz, 1H), 6.79-6.73 (m, 1H), 4.85 (s, 2H), 4.09 (s, 3H), 2.72 (s, 3H) MS: m/z =468.2 [M+H] ⁺ 1.71 A

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-羧酸 ¹H NMR (MeOD, 400 MHz) δ 9.33 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 8.02 (d, J= 9.2 Hz, 1H), 7.93 (dd, J= 1.6, 8.8 Hz, 1H), 7.61 (t, J= 7.6 Hz, 1H), 7.29 (d, J= 8.0 Hz, 1H), 7.17 (d, J= 8.0 Hz, 1H), 6.99-6.94 (m, 2H), 6.87-6.83 (m, 1H), 6.66-6.60 (m, 1H), 4.57 (s, 2H), 2.49 (s, 3H) MS: m/z =454.2 [M+H] ⁺ 1.72 A

2-胺基乙基 6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-羧酸酯 ¹H NMR (MeOD, 400MHz) δ 9.77 (s, 1H), 9.75 (s, 1H), 8.67 (s, 1H), 8.39 (d, J= 8.8 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 7.98 (t, J= 8.0 Hz, 1H), 7.58 (d, J= 7.6 Hz, 1H), 7.53 (d, J= 7.6 Hz, 1H), 7.08 - 6.99 (m, 2H), 6.81-6.87 (m, 1H), 6.77-6.71 (m, 1H), 4.85 (s, 2H), 4.73 (t, J= 4.8 Hz, 2H), 3.48 (t, J= 4.8 Hz, 2H), 2.72 (s, 3H) MS: m/z = 497.1 [M+H] ⁺ 1.73 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 ¹H NMR (MeOD, 400 MHz) δ 8.91 (d, J= 2.4 Hz, 1H), 8.71 (d, J= 5.6 Hz, 1H), 8.26 (s, 1H), 8.19 (d, J= 8.8 Hz, 1H), 8.14 (s, 1H), 7.90-7.81 (m, 2H), 7.54-7.47 (m, 2H), 7.08-6.98 (m, 2H), 6.80 (t, J= 7.6 Hz, 1H), 6.77-6.69 (m, 1H), 4.83 (s, 2H), 4.50 (t, J= 4.8 Hz, 2H), 3.50 (t, J= 4.8 Hz, 2H) MS: m/z =455.2 [M+H] ⁺ 1.74 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 ¹H NMR (MeOD, 400MHz) δ 8.69-8.67 (m, 1H), 8.63 (s, 1H), 8.13 (d, J= 8.4 Hz, 1H), 8.07 (d, J= 1.6 Hz, 1H), 7.83 (dt, J= 1.6, 7.6 Hz, 1H), 7.77 (dd, J= 2.0, 8.4 Hz, 1H), 7.52-7.45 (m, 2H), 7.06-6.98 (m, 2H), 6.84-6.77 (m, 1H), 6.68-6.74 (m, 1H), 4.77 (s, 2H), 4.76-4.73 (m, 2H), 7.42 (t, J= 4.8 Hz, 2H) MS: m/z = 456.1 [M+H] ⁺ 1.75 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺 MS m/z [M+H] ⁺(ESI)：474； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.47-3.50 (m, 2H), 4.76-4.78 (m, 4H), 6.78-6.86 (m, 2H), 6.92-6.97 (m, 1H), 7.48-7.53 (m, 2H), 7.77-7.88 (m, 2H), 8.12 (s, 1H), 8.15 (d, J= 8.4 Hz, 1H), 8.65 (s, 1H), 8.70 (d, J= 5.2 Hz, 1H)。 1.76 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺 MS m/z [M+H] ⁺(ESI)：456； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.48-3.50 (m, 2H), 4.75-4.78 (m, 4H), 6.43-6.56 (m, 3H), 7.14-7.20 (m, 1H), 7.51-7.54 (m, 2H), 7.78-7.80 (m, 1H), 7.84-7.89 (m, 1H), 8.10 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 8.72 (s, 1H), 8.73 (d, J= 1.6 Hz, 1H)。 1.77 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺 MS m/z [M+H] ⁺: 473 1.78 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺 MS m/z [M+H] ⁺ (ESI)：373； ¹H NMR (300 MHz, Methanol-d ₄) δ: 3.49-3.52 (m, 2H), 4.45-4.49 (m, 2H), 4.81 (s, 2H), 6.80-6.85 (m, 2H), 6.92-6.99 (m, 1H), 7.51-7.54 (m, 2H), 7.77-7.94 (m, 3H), 8.15-8.19 (m, 2H), 8.72-8.74 (m, 1H), 8.84 (s, 1H). 1.79 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺 MS m/z [M+H] ⁺ (ESI)：455； ¹H NMR (300 MHz, Methanol-d ₄) δ: 3.49-3.52 (m, 2H), 4.45-4.48 (m, 2H), 4.78 (s, 2H), 6.45-6.57 (m, 3H), 7.13-7.19 (m, 1H), 7.47-7.53 (m, 2H), 7.76-7.91 (m, 3H), 8.14-8.18 (m, 2H), 8.72-8.74 (m, 1H), 8.82 (s, 1H). 1.80 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺 MS m/z [M+H] ⁺ (ESI)：473； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.49-3.51 (m, 2H), 4.44-4.47 (m, 2H), 4.75 (s, 2H), 6.21-6.24 (m, 1H), 6.26-6.37 (m, 2H), 7.50-7.54 (m, 2H), 7.75-7.78 (m, 1H), 7.86-7.89 (m, 2H), 8.14-8.17 (m, 2H), 8.71-8.72 (m, 1H), 8.81 (s, 1H). 1.81 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺 ¹H NMR (MeOD, 400 MHz) δ8.68 (s, 1H), 8.19 (d, J= 8.4 Hz, 1H), 8.14 (d, J= 1.6 Hz, 1H), 7.97-7.90 (m, 1H), 7.81 (dd, J= 2.0, 8.4 Hz, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.02-6.57 (m, 4H), 4.87 (s, 2H), 4.78-4.72 (m, 2H), 3.48 (t, J= 4.8 Hz, 2H) MS: m/z =524.2 [M+H] ⁺ 1.82 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺 ¹H NMR (MeOD, 400 MHz) δ8.68 (s, 1H), 8.19 (d, J= 8.4 Hz, 1H), 8.14 (d, J= 1.6 Hz, 1H), 7.97-7.89 (m, 1H), 7.82 (dd, J= 2.0, 8.4 Hz, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.55 (d, J= 8.0 Hz, 1H), 6.93-6.62 (m, 1H), 6.38-6.31 (m, 2H), 6.31-6.23 (m, 1H), 4.80-4.73 (m, 4H), 3.48 (t, J= 4.8 Hz, 2H) MS: m/z =524.2 [M+H] ⁺ 1.83 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺 MS: m/z = 473 [M+H] ⁺ 1.84 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺 MS: m/z = 473 [M+H] ⁺ 1.85 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,5-二氟苯胺 ¹H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.13 (s, 1H), 8.12 (d, J= 6.8 Hz, 1H), 7.90 (t, J= 15.6 Hz, 1H), 7.82 (dd, J= 8.4, 12.0 Hz, 1H), 7.66 (d, J= 7.6 Hz, 1H), 7.60 (d, J= 7.8 Hz, 1H), 7.0-6.97 (m, 1H), 6.87-6.57 (m, 2H), 6.41-6.35 (m, 1H), 4.78-4.73 (m, 4H), 3.47 (t, J= 9.6 Hz, 1H) MS: m/z = 524.2 [M+H] ⁺ 1.86 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3,4-二氟苯胺 ¹H NMR (MeOD, 400 MHz) δ 8.62 (s, 1H), 8.13-8.09 (m, 2H), 7.89 (t, J= 15.6 Hz, 1H), 7.82 (dd, J= 2.0, 8.4 Hz, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.05 (q, J= 28.8 Hz, 1H), 6.92-6.58 (m, 2H), 6.49-6.46 (m, 1H), 4.75 (t, J= 10 Hz, 2H), 4.64 (s, 2H), 3.47 (t, J= 10.4 Hz, 2H) MS: m/z =524.2 [M+H] ⁺ 1.87 A

6-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)-N-(2-羥乙基)喹啉-3-甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 9.35 (d, J= 2.0 Hz, 1H), 8.83 (d, J= 1.6 Hz, 1H), 8.29 (d, J= 1.6 Hz, 1H), 8.21 (d, J= 8.8 Hz, 1H), 7.97 (dd, J= 2.0, 8.8 Hz, 1H), 7.78 (t, J= 8.0 Hz, 1H), 7.41 (d, J= 8.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.06-7.00 (m, 2H), 6.82-6.78 (m, 1H), 6.75-6.69 (m, 1H), 4.80 (s, 2H), 3.77 (t, J= 5.6 Hz, 2H), 3.59 (t, J= 5.6 Hz, 2H), 2.68 (s, 3H) MS: m/z =497.2 [M+H] ⁺ 1.88 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 ¹H NMR (MeOD, 400MHz) δ 8.89 (d, J= 2.8 Hz, 1H), 8.54 (d, J= 8.8 Hz, 1H), 8.19-8.09 (m, 2H), 8.04 (d, J= 8.0 Hz, 1H), 7.97-7.93 (m, 1H), 7.85 (d, J= 7.6 Hz, 1H), 7.02 (t, J= 7.6 Hz, 2H), 6.88-6.70 (m, 3H), 4.83 (s, 2H), 4.53 (t, J= 4.8 Hz, 2H), 3.53 (t, J= 4.8 Hz, 2H) MS: m/z = 506.1 [M+H] ⁺ 1.89 A

2-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 ¹H NMR (MeOD, 400MHz) δ 8.67 (s, 1H), 8.17 (d, J= 8.4 Hz, 1H), 8.12 (d, J= 1.6 Hz, 1H), 7.98 (d, J= 6.4 Hz, 1H), 7.92 (t, J= 8.0 Hz, 1H), 7.79 (dd, J= 2.0, 8.4 Hz, 1H), 7.73 (d, J= 7.6 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.45 (t, J= 7.6 Hz, 1H), 6.93-6.63 (m, 3H), 5.03 (s, 2H), 4.78-4.70 (m, 2H), 3.90 (s, 3H), 3.47 (s, 2H) MS: m/z = 546.2 [M+H] ⁺ 1.90 A

2-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.16-8.07 (m, 2H), 7.98 (dd, J= 1.6, 8.0 Hz, 1H), 7.90 (t, J= 8.0 Hz, 1H), 7.79 (dd, J= 1.6, 8.8 Hz, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.42 (t, J= 7.6 Hz, 1H), 6.88-6.56 (m, 3H), 4.91 (s, 2H), 4.75 (t, J= 5.2 Hz, 2H), 3.46 (t, J= 5.2 Hz, 2H) MS: m/z = 532.2 [M+H] ⁺ 1.91 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.17 (d, J= 8.4 Hz, 1H), 8.13 (d, J= 1.6 Hz, 1H), 7.92 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 2.0, 8.4 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.37 (d, J= 2.4 Hz, 1H), 7.31 (t, J= 8.0 Hz, 1H), 7.00 (dd, J= 1.6, 8.0 Hz, 1H), 6.76 (t, J= 54.8 Hz, 1H), 4.82-4.80 (m, 2H), 4.78-4.71 (m, 2H), 3.87 (s, 3H), 3.48 (t, J= 3.6 Hz, 2H) MS: m/z = 546.2[M+H] ⁺ 1.92 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.16-8.10 (m, 2H), 7.90 (t, J= 15.6 Hz, 1H), 7.82 (dd, J= 2.0, 8.4 Hz, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.59 (d, J= 7.6 Hz, 1H), 7.46-7.35 (m, 2H), 7.29 (t, J= 7.6 Hz, 1H), 6.98 (dd, J= 1.6, 8.4 Hz, 1H), 6.71 (t, J= 55.2 Hz, 1H), 4.78-4.72 (m, 4H), 3.47 (t, J= 10.0 Hz, 2H) MS: m/z = 532.2[M+H] ⁺ 1.93 A

4-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 ¹H NMR (MeOD, 400MHz) δ 8.68 (s, 1H), 8.21-8.12 (m, 2H), 7.94 (t, J= 8.0 Hz, 1H), 7.88 (d, J= 8.4 Hz, 2H), 7.81 (d, J= 8.0 Hz, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.56 (d, J= 7.6 Hz, 1H), 6.94-6.64 (m, 3H), 4.94 (s, 2H), 4.77 (t, J= 4.4 Hz, 2H), 3.83 (s, 3H), 3.45-3.51 (m, 2H) MS: m/z = 546.1 [M+H] ⁺ 1.94 A

4-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.62 (s, 1H), 8.13-8.11 (m, 2H), 7.94-7.85 (m, 3H), 7.81 (dd, J= 2.0, 8.4 Hz, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 6.88-6.56 (m, 3H), 4.79 (s, 2H), 4.77-4.72 (m, 2H), 3.47 ( t, J= 5.2 Hz, 2H) MS: m/z = 532.1 [M+H] ⁺ 1.95 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.18-8.07 (m, 3H), 7.77-7.68 (m, 2H), 7.63 (d, J= 8.0 Hz, 1H), 7.50-7.43 (m, 2H), 7.35 (t, J= 8.0 Hz, 1H), 7.16-7.08 (m, 1H), 4.87 (s, 2H), 4.77 (t, J= 10.0 Hz, 2H), 3.87 (s, 3H), 3.49 (t, J= 9.6 Hz, 2H), 2.78 (s, 3H) MS: m/z = 510.2[M+H] ⁺ 1.96 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.14 (d, J= 8.4 Hz, 1H), 8.08 (d, J= 1.6 Hz, 1H), 7.80-7.74 (m, 2H), 7.44-7.36 (m, 3H), 7.35-7.24 (m, 2H), 6.98 (dd, J= 2.4 Hz, 8.4 Hz, 1H), 4.79 (s, 2H), 4.77-4.72 (m, 2H), 3.52-3.43 (m, 2H), 2.67 (s, 3H) MS: m/z = 496.2[M+H] ⁺ 1.97 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：509； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.69 (s, 3H), 3.48-3.51 (m, 2H), 3.88-3.92 (m, 3H), 4.43-4.46 (m, 2H), 4.79 (s, 2H), 6.98-7.02 (m, 1H), 7.28-7.33 (m, 2H), 7.38-7.43 (m, 3H), 7.66-7.78 (m, 2H), 7.85-7.86 (m, 1H), 8.11-8.14 (m, 2H), 8.79 (s, 1H). 1.98 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 MS m/z [M+H] ⁺(ESI)：495； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.71 (s, 3H), 3.48-3.51 (m, 2H), 4.43-4.48 (m, 2H), 4.81 (s, 2H), 6.98-7.01 (m, 1H), 7.28-7.33 (m, 2H), 7.39-7.44 (m, 3H), 7.73-7.78 (m, 2H), 7.86-7.89 (m, 1H), 8.12-8.14 (m, 2H), 8.95 (s, 1H). 1.99 A

4-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：509； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.68 (s, 3H), 3.48-3.51 (m, 2H), 3.82-3.84 (m, 3H), 4.44 (t, J= 5.1 Hz, 2H), 4.78 (s, 2H), 6.76-6.80 (m, 2H), 7.30-7.40 (m, 2H), 7.72-7.89 (m, 5H), 8.09-8.15 (m, 2H), 8.80 (s, 1H)。 1.100 A

4-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 MS m/z [M+H] ⁺(ESI)：495； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.70 (s, 3H), 3.36-3.50 (m, 2H), 4.44 (t, J= 5.2 Hz, 2H), 4.82 (s, 2H), 6.76-6.79 (m, 2H), 7.32 (d, J= 8.0 Hz, 1H), 7.41 (d, J= 7.6 Hz, 1H), 7.73-7.78 (m, 2H), 7.80-7.89 (m, 3H), 8.11-8.13 (m, 2H), 8.78 (s, 1H).    1.101 A

2-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：509.15； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.70 (s, 3H), 3.33 (s, 2H), 3.49-3.51 (m, 2H), 3.91 (s, 3H), 4.44 (t, J= 4.8 Hz, 2H), 6.73-6.77 (m, 1H), 6.85 (d, J= 8.0 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.42-7.46 (m, 2H), 7.72-7.85 (m, 3H), 7.96-7.99 (m, 1H), 8.11-8.13 (m, 2H), 8.79 (s, 1H). 1.102 A

2-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 MS m/z [M+H] ⁺(ESI)：495.15； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.70 (s, 3H), 3.33 (s, 2H), 3.50 (t, J= 4.8 Hz, 2H), 4.45 (t, J= 4.8 Hz, 2H), 6.73-6.76 (m, 1H), 6.83 (d, J= 8.0 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.41-7.45 (m, 2H), 7.73-7.86 (m, 3H), 7.99-8.01 (m, 1H), 8.11-8.13 (m, 2H), 8.79 (s, 1H)。  1.103 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯 ¹H NMR (MeOD, 400MHz) δ 8.66 (s, 1H), 8.15 (d, J= 8.4 Hz, 1H), 8.11 (s, 1H), 7.92 (t, J= 7.6 Hz, 1H), 7.76 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 7.6 Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.24 (t, J= 7.6 Hz, 1H), 7.11 (t, J= 7.6 Hz, 1H), 7.04 (t, J= 7.6 Hz, 1H), 4.86 (s, 2H), 4.79-4.73 (m, 2H), 3.89 (s, 3H), 3.50-3.48 (m, 2H), 2.72 (s, 3H) MS: m/z = 528.2 [M+H] ⁺ 1.104 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.13 (d, J= 8.4 Hz, 1H), 8.08 (d, J= 1.6 Hz, 1H), 7.82-7.73 (m, 2H), 7.41 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.23 (t, J= 6.4 Hz, 1H), 7.08 (t, J= 8.0 Hz, 1H), 7.00 (t, J= 7.2 Hz, 1H), 4.80 (s, 2H), 4.78-4.72 (m, 2H), 3.52-3.42 (m, 2H), 2.67 (s, 3H) MS: m/z = 514.2 [M+H] ⁺ 1.105 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸甲酯 ¹H NMR (MeOD, 400MHz) δ 8.66 (s, 1H), 8.16 (d, J= 8.4 Hz, 1H), 8.11 (s, 1H), 7.91 (t, J= 8.0 Hz, 1H), 7.79-7.75 (m, 1H), 7.52 (d, J= 7.6 Hz, 1H), 7.45 (d, J= 7.2 Hz, 3H), 7.16 (dd, J= 8.8, 11.4 Hz, 1H), 4.86 (s, 2H), 4.79-4.73 (m, 2H), 3.85 (s, 3H), 3.50-3.48 (m, 2H), 2.72 (s, 3H) MS: m/z = 528.2 [M+H] ⁺ 1.106 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.64 (s, 1H), 8.14 (d, J= 8.4 Hz, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.85-7.74 (m, 2H), 7.49-7.40 (m, 3H), 7.37 (d, J= 8.0 Hz, 1H), 7.14 (dd, J= 9.2, 11.2 Hz, 1H), 4.83 (s, 2H), 4.78-4.71 (m, 2H), 3.51-3.44 (m, 2H), 2.69 (s, 3H) MS: m/z = 514.2 [M+H] ⁺ 1.107 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.16 (d, J= 8.4 Hz, 1H), 8.10 (d, J= 2.0 Hz, 1H), 7.87 (t, J= 8.0 Hz, 1H), 7.77 (dd, J= 2.0, 8.4 Hz, 1H), 7.48 (d, J= 7.6 Hz, 1H), 7.41 (d, J= 8.0 Hz, 1H), 7.24-7.20 (m, 1H), 7.07-7.01 (m, 1H), 6.73 (td, J= 2.4, 11.2 Hz, 1H), 4.78 (s, 2H), 4.77-4.74 (m, 2H), 3.87 (s, 3H), 3.48 (t, J= 4.8 Hz, 2H), 2.71 (s, 3H) MS: m/z = 528.2[M+H] ⁺ 1.108 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.16-8.04 (m, 2H), 7.86-7.71 (m, 2H), 7.37 (dd, J= 8.0, 14.8 Hz, 2H), 7.22 (s, 1H), 7.02 (d, J= 9.2 Hz, 1H), 6.76-6.65 (m, 1H), 4.78-4.69 (m, 4H), 3.50-3.44 (m, 2H), 2.66 (s, 3H) MS: m/z = 514.2[M+H] ⁺ 1.109 A

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.13 (d, J= 8.4 Hz, 1H), 8.08 (d, J= 1.6 Hz, 1H), 7.83-7.71 (m, 2H), 7.41 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 8.4 Hz, 1H), 7.22 (dd, J= 3.2, 5.6 Hz, 1H), 7.11-7.02 (m, 1H), 7.00-6.92 (m, 1H), 4.77-4.73 (m, 2H), 4.72 (s, 2H), 3.88 (s, 3H), 3.50-3.44 (m, 2H), 2.67 (s, 3H) MS: m/z = 528.2[M+H] ⁺ 1.110 A

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.14 (d, J= 8.4 Hz, 1H), 8.08 (d, J= 1.6 Hz, 1H), 7.81-7.72 (m, 2H), 7.41 (d, J= 7.6 Hz, 1H), 7.34 (d, J= 8.0 Hz, 1H), 7.23 (dd, J= 3.2, 5.6 Hz, 1H), 7.09-7.00 (m, 1H), 6.99-6.91 (m, 1H), 4.75 (d, J= 5.2Hz, 2H), 4.73 (s, 2H), 3.51-3.44 (m, 2H), 2.67 (s, 3H) MS: m/z = 514.2[M+H] ⁺ 1.111 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：527； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.69 (s, 3H), 3.49-3.51 (m, 2H), 3.91 (s, 3H), 4.44 (t, J= 4.8 Hz, 2H), 4.82 (s, 2H), 7.03-7.09 (m, 2H), 7.11-7.25 (m, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.41 (d, J= 7.6 Hz, 1H), 7.73-7.79 (m, 2H), 7.84-7.85 (m, 1H), 8.11-8.13 (m, 2H), 8.79 (s, 1H). 1.112 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：513.25； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.68 (s, 3H), 3.48 (t, J= 4.8 Hz, 2H), 4.43 (t, J= 4.8 Hz, 2H), 4.82 (s, 2H), 6.97-7.02 (m, 1H), 7.06-7.10 (m, 1H), 7.21-7.25 (m, 1H), 7.31 (d, J= 8.0 Hz, 1H), 7.41 (d, J= 7.6 Hz, 1H), 7.72-7.80 (m, 2H), 7.86-7.87 (m, 1H), 8.11-8.13 (m, 2H), 8.79 (s, 1H)。 1.113 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：527； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.71 (s, 3H), 3.48-3.51 (m, 2H), 3.86 (s, 3H), 4.44 (t, J= 4.8 Hz, 2H), 4.84 (s, 2H), 7.14-7.19 (m, 1H), 7.33-7.35 (m, 1H), 7.37-7.51 (m, 3H), 7.74-7.86 (m, 3H), 8.12-8.14 (m, 2H), 8.79 (s, 1H). 1.114 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：513.15； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.67 (s, 3H), 3.49 (t, J= 4.8 Hz, 2H), 4.43 (t, J= 4.8 Hz, 2H), 4.84 (s, 2H), 7.12-7.17 (m, 1H), 7.32 (d, J= 7.6 Hz, 1H), 7.38 (d, J= 7.6 Hz, 1H), 7.44-7.49 (m, 2H), 7.74-7.78 (m, 2H), 7.84 (s, 1H), 8.13-8.13 (m, 2H), 8.77 (s, 1H)。 1.115 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：527； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.70 (s, 3H), 3.48-3.51 (m, 2H), 3.88 (s, 3H), 4.44 (t, J= 4.5 Hz, 2H), 4.76 (s, 2H), 6.71-6.75 (m, 1H), 7.03-7.06 (m, 1H), 7.22 (s, 1H), 7.33 (d, J= 8.1 Hz, 1H), 7.42 (d, J= 7.8 Hz, 1H), 7.73-7.85 (m, 3H), 8.11-8.14 (m, 2H), 8.79 (s, 1H)。 1.116 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：513.15； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.69 (s, 3H), 3.55-3.57 (m, 2H), 4.44 (t, J= 5.1 Hz, 2H), 4.77 (s, 2H), 6.69-6.75 (m, 1H), 7.04-7.07 (m, 1H), 7.23-7.24 (m, 1H), 7.33 (d, J= 8.1 Hz, 1H), 7.41 (d, J= 7.8 Hz, 1H), 7.74-7.78 (m, 2H), 7.85-7.86 (m, 1H), 8.12-8.14 (m, 2H), 8.79 (s, 1H). 1.117 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：527.15； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.68 (s, 3H), 3.46-3.49 (m, 2H), 3.87 (s, 3H), 4.42 (t, J= 4.8 Hz, 2H), 4.74 (s, 2H), 6.95-6.99 (m, 1H), 7.03-7.09 (m, 1H), 7.19-7.22 (m, 1H), 7.29 (d, J= 8.1 Hz, 1H), 7.40 (d, J= 7.8 Hz, 1H), 7.72-7.78 (m, 2H), 7.85-7.86 (m, 1H), 8.11-8.14 (m, 2H), 8.79 (s, 1H). 1.118 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：513.25； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.64 (s, 3H), 3.45 (t, J= 4.5 Hz, 2H), 3.40 (t, J= 4.8 Hz, 2H), 4.71 (s, 2H), 6.91-7.05 (m, 2H), 7.18-7.21 (m, 1H), 7.26 (d, J= 7.8 Hz, 1H), 7.36 (d, J= 7.8 Hz, 1H), 7.69-7.74 (m, 2H), 7.84 (s, 1H), 8.08-8.10 (m, 2H), 8.76 (s, 1H)。 1.119 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.18-8.08 (m, 2H), 7.91 (t, J= 7.6 Hz, 1H), 7.81 (dd, J= 2.0, 8.4 Hz, 1H), 7.68 (d, J= 7.6 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.26-7.18 (s, 1H), 7.07 (d, J= 10.0 Hz, 1H), 7.06-6.54 (m, 2H), 4.83 (s, 2H), 4.79-4.71 (m, 2H), 3.89 (s, 3H), 3.50-3.45 (m, 2H) MS: m/z = 564.2.[M+H] ⁺ 1.120 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.17-8.08 (m, 2H), 7.91 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 2.0, 8.8 Hz, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.59 (d, J= 7.6 Hz, 1H), 7.26-7.20 (m, 1H), 7.12-7.06 (m, 1H), 7.05-6.98 (m, 1H), 6.89-6.53 (m, 1H), 4.82 (s, 2H), 4.77-4.73 (m, 2H), 3.50-3.44 (m, 2H) MS: m/z = 550.2[M+H] ⁺ 1.121 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.17-8.12 (m, 2H), 7.92 (t, J= 8.0 Hz, 1H), 7.86-7.77 (m, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.44 (d, J= 10.4 Hz, 2H), 7.15 (dd, J= 9.2, 11.2 Hz, 1H), 6.91-6.58 (m, 1H), 4.79-4.71 (m, 2H), 3.86 (s, 3H), 3.51-3.44 (m, 2H), 3.31 (d, J= 0.8 Hz, 2H) MS: m/z = 564.2 [M+H] ⁺ 1.122 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.65 (s, 1H), 8.18-8.11 (m, 2H), 7.92 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 2.0, 8.4 Hz, 1H), 7.70 (d, J= 7.6 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.49-7.40 (m, 2H), 7.15 (dd, J= 8.4, 11.2 Hz, 1H), 6.92-6.58 (m, 1H), 4.91-4.90 (m, 2H), 4.78-4.73 (m, 2H), 3.51-3.43 (m, 2H) MS: m/z = 550.2 [M+H] ⁺ 1.123 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.68 (s, 1H), 8.25-8.11 (m, 2H), 7.94 (t, J= 8.0 Hz, 1H), 7.82 (dd, J= 1.6, 8.4 Hz, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.21 (s, 1H), 7.07 (d, J= 8.8 Hz, 1H), 6.96-6.59 (m, 2H), 4.90 (s, 2H), 4.79-4.72 (m, 2H), 3.88 (s, 3H), 3.48 (t, J= 4.4 Hz, 2H) MS: m/z = 564.2[M+H] ⁺ 1.124 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.68 (s, 1H), 8.23-8.11 (m, 2H), 7.94 (t, J= 8.0 Hz, 1H), 7.82 (dd, J= 1.6, 8.4 Hz, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.21 (s, 1H), 7.07 (d, J= 9.2 Hz, 1H), 6.95-6.61 (m, 2H), 4.90 (s, 2H), 4.79-4.74 (m, 2H), 3.48 (t, J= 4.8 Hz, 2H) MS: m/z = 550.2[M+H] ⁺ 1.125 A

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.17-8.09 (m, 2H), 7.91 (t, J= 8.0 Hz, 1H), 7.82 (dd, J= 2.0, 8.4 Hz, 1H), 7.68 (d, J= 7.6 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.22 (dd, J= 3.2, 5.6 Hz, 1H), 7.09-7.02 (m, 1H), 7.01-6.94 (m, 1H), 6.88-6.56 (m, 1H), 4.77-4.73 (m, 4H), 3.88 (s, 3H), 3.51-3.44 (m, 2H) MS: m/z = 564.2 [M+H] ⁺ 1.126 A

   ¹H NMR (MeOD, 400MHz) δ 8.64 (s, 1H), 8.18-8.11 (m, 2H), 7.94-7.88 (m, 1H), 7.81 (dd, J= 2.0, 8.4 Hz, 1H), 7.70 (d, J= 7.6 Hz, 1H), 7.57 (d, J= 7.6 Hz, 1H), 7.23 (dd, J= 3.2, 5.6 Hz, 1H), 7.09-7.02 (m, 1H), 7.00-6.94 (m, 1H), 6.90-6.59 (m, 1H), 4.79 (s, 2H), 4.77-4.74 (m, 2H), 3.50-3.45 (m, 2H) MS: m/z = 550.2 [M+H] ⁺ 1.127 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟苯胺 MS m/z [M+H] ⁺(ESI)：505.20； ¹H NMR (300 MHz, Methanol-d ₄) δ: 3.48 (t, J= 4.8 Hz, 2H), 4.42 (t, J= 5.1 Hz, 2H), 4.74 (s, 2H), 6.52-6.72 (m, 2H), 6.79-6.89 (m, 1H), 7.01-7.04 (m, 2H), 7.55 (d, J= 7.8 Hz, 1H), 7.62 (d, J= 7.5 Hz, 1H), 7.74-7.89 (m, 3H), 8.06 (d, J= 8.7 Hz, 1H), 8.15 (s, 1H), 8.73 (s, 1H)。 1.128 A

N-((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 MS m/z [M+H] ⁺(ESI)：523.15； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.50 (t, J= 5.2 Hz, 2H), 4.44 (t, J= 4.8 Hz, 2H), 4.86 (s, 2H), 6.59-6.65 (m, 3H), 6.97-7.03 (m, 1H), 7.54 (d, J= 7.6 Hz, 1H), 7.71-7.78 (m, 1H), 7.80-7.85 (m, 1H), 7.86-7.93 (m, 2H), 8.13-8.19 (m, 2H), 8.79 (s, 1H). 1.129 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：563.20； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.48 (t, J= 4.8 Hz, 2H), 3.88 (s, 3H), 4.43 (t, J= 5.2 Hz, 2H), 4.84 (s, 2H), 6.74 (t, J= 55.2 Hz, 1H), 7.00-7.04 (m, 2H), 7.11-7.23 (m, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.66 (d, J= 7.6 Hz, 1H), 7.75-7.77 (m, 1H), 7.83-7.89 (m, 2H), 8.09 (d, J= 8.8 Hz, 1H), 8.17 (s, 1H), 8.76 (s, 1H)。 1.130 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：549.15； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.48-3.51 (m, 2H), 4.43-4.45 (m, 2H), 4.89 (s, 2H), 6.78 (t, J= 55.2 Hz, 1H), 7.00-7.04 (m, 1H), 7.09-7.13 (m, 1H), 7.24-7.28 (m, 1H), 7.53-7.55 (m, 1H), 7.69-7.71 (m, 1H), 7.77-7.80 (m, 1H), 7.86-7.93 (m, 2H), 8.13-8.15 (m, 1H), 8.19 (s, 1H), 8.79 (s, 1H). 1.131 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：563.20； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.48-3.51 (m, 2H), 3.86 (s, 3H), 4.42-4.45 (m, 2H), 4.88 (s, 2H), 6.77 (t, J= 55.2 Hz, 1H), 7.14-7.19 (m, 1H), 7.44-7.45 (m, 2H), 7.56 (d, J= 7.6 Hz, 1H), 7.69-7.79 (m, 1H), 7.81-7.89 (m, 3H), 8.12-8.14 (m, 1H), 8.20 (s, 1H), 8.78 (s, 1H)。 1.132 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：549.15； ¹H NMR (300 MHz, Methanol-d ₄) δ: 3.46-3.54 (m, 2H), 4.40-4.44 (m, 2H), 4.89 (s, 2H), 6.75 (t, J= 55.2 Hz, 1H), 7.11-7.18 (m, 1H), 7.42-7.48 (m, 2H), 7.52-7.55 (m, 1H), 7.67 (d, J= 7.8 Hz, 1H), 7.77-7.79 (m, 1H), 7.80-7.91 (m, 2H), 8.11 (d, J= 8.7 Hz, 1H), 8.18 (s, 1H), 8.77 (s, 1H). 1.133 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：563.15； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.48-3.51 (m, 2H), 3.88 (s, 3H), 4.44 (t, J= 5.2 Hz, 2H), 4.84 (s, 2H), 6.64-6.92 (m, 2H), 7.05-7.08 (m, 1H), 7.22-7.23 (m, 1H), 7.55 (d, J= 7.6 Hz, 1H), 7.70 (d, J= 7.6 Hz, 1H), 7.78-7.81 (m, 1H), 7.86-7.93 (m, 2H), 8.14 (d, J= 8.8 Hz, 1H), 8.20 (s, 1H), 8.80 (s, 1H)。 1.134 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：549.15； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.48-3.51 (m, 2H), 4.44 (t, J= 4.8 Hz, 2H), 4.87 (s, 2H), 6.65-6.93 (m, 2H), 7.06-7.09 (m, 1H), 7.21-7.22 (m, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.72 (d, J= 7.6 Hz, 1H), 7.78-7.81 (m, 1H), 7.87-7.93 (m, 2H), 8.15 (d, J= 8.8 Hz, 1H), 8.20 (s, 1H), 8.81 (s, 1H)。 1.135 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：563.20； ¹H NMR (300 MHz, Methanol-d ₄) δ: 3.48 (t, J= 4.8 Hz, 2H), 3.85 (s, 3H), 4.42 (t, J= 4.8 Hz, 2H), 4.65 (s, 2H), 6.68 (t, J= 55.2 Hz, 1H), 6.93-7.06 (m, 2H), 7.20-7.23 (m, 1H), 7.57-7.61 (m, 2H), 7.76-7.89 (m, 3H), 8.03-8.07 (m, 1H), 8.15 (s, 1H), 8.72 (s, 1H)。 1.136 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：549.15； ¹H NMR (300 MHz, Methanol-d ₄) δ: 3.46-3.54 (m, 2H), 4.40-4.44 (m, 2H), 4.73 (s, 2H), 6.73 (t, J= 55.2 Hz, 1H), 6.94-7.07 (m, 2H), 7.21-7.24 (m, 1H), 7.53-7.56 (m, 1H), 7.65 (d, J= 7.8 Hz, 1H), 7.76-7.91 (m, 3H), 8.08-8.11 (m, 1H), 8.17 (s, 1H), 8.75 (s, 1H). 1.137 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 MS m/z [M+H] ⁺(ESI)：545.15； ¹H NMR (400 MHz, Methanol-d ₄) δ: 3.48-3.51 (m, 2H), 3.88 (s, 3H), 4.44 (t, J= 4.8 Hz, 2H), 4.88 (s, 2H), 6.80 (t, J= 55.2 Hz, 1H), 6.99-7.02 (m, 1H), 7.30-7.38 (m, 2H), 7.43 (d, J= 7.6 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.72 (d, J= 7.6 Hz, 1H), 7.77-7.80 (m, 1H), 7.87-7.93 (m, 2H), 8.16 (d, J= 8.8 Hz, 1H), 8.20 (s, 1H), 8.81 (s, 1H)。 1.138 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 MS m/z [M+H] ⁺(ESI)：531.05； ¹H NMR (300 MHz, Methanol-d ₄) δ: 3.48-3.57 (m, 2H), 4.43-4.46 (m, 2H), 4.88 (s, 2H), 6.80 (t, J= 55.2 Hz, 1H), 6.99-7.02 (m, 1H), 7.29-7.44 (m, 2H), 7.45-7.46 (m, 1H), 7.52-7.54 (m, 1H), 7.72 (d, J= 7.5 Hz, 1H), 7.78 (d, J= 2.1 Hz, 1H), 7.81-7.94 (m, 2H), 8.15-8.21 (m, 2H), 8.82 (s, 1H). 1.139 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲醯胺 ¹H NMR (MeOD, 400MHz) δ 8.65 (s, 1H), 8.16-8.11 (m, 2H), 7.91 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 2.0, 8.4 Hz, 1H), 7.70 (d, J= 7.6 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.31-7.26 (m, 1H), 7.25-7.21 (m, 2H), 6.97-6.92 (m, 1H), 6.75 (t, J= 55.2 Hz, 1H), 4.83 (s, 2H), 4.77-4.73 (m, 2H), 3.49-3.44 (m, 2H) MS: m/z = 553.1 [M+H] ⁺ 1.140 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ8.63 (s, 1H), 8.13-8.10 (m, 2H), 7.90 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 2.0, 8.8 Hz, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.13-7.04 (m, 2H), 7.00-6.93 (m, 1H), 6.72 (t, J= 55.2 Hz, 1H),, 4.81 (s, 2H), 4.77-4.73 (m, 2H), 3.47 (t, J= 4.8 Hz, 2H) MS: m/z = 549.2.[M+H] ⁺ 1.141 A

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ8.65 (s, 1H), 8.17-8.12 (m, 2H), 7.91 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 2.0, 8.8 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.14 (dd, J= 3.2, 6.0 Hz, 1H), 7.08 (dd, J= 9.2, 10.8 Hz, 1H), 6.96-6.90 (m, 1H), 6.74 (t, J= 56.0 Hz, 1H), 4.78 (s, 2H), 4.77-4.73 (t, J= 4.8 Hz,  2H), 3.50-3.45 (t, J= 5.2 Hz, 2H) MS: m/z = 549.2.[M+H] ⁺ 1.142 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2- ¹H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.17-8.08 (m, 2H), 7.91 (t, J= 8.0 Hz, 1H), 7.82 (dd, J= 2.0, 8.8 Hz, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.59 (d, J= 7.6 Hz, 1H), 7.05 (d, J= 1.6 Hz, 1H), 6.96-6.90 (m, 1H), 6.88-6.57 (m, 2H), 4.81-4.70 (m, 4H), 3.47 (t, J= 4.8 Hz, 2H) MS: m/z = 549.2 [M+H] ⁺ 1.143 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲醯胺 ¹H NMR (MeOD, 400MHz) δ 8.64 (s, 1H), 8.20-8.10 (m, 2H), 7.91 (t, J= 8.0 Hz, 1H), 7.81 (dd, J=1.8, 8.8 Hz, 1H), 7.70 (d, J= 8.8 Hz, 1H), 7.57 (d, J= 7.6 Hz, 1H), 7.39-7.24 (m, 2H), 7.13 (dd, J= 8.4, 11.2 Hz, 1H), 6.75 (t, J= 55.2 Hz, 1H), 4.90 (s, 2H), 4.75 (t, J= 4.8 Hz, 2H), 3.47 (t, J= 4.8 Hz, 2H) MS: m/z = 549.2 [M+H] ⁺ 1.144 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.14-8.11 (m, 2H), 7.91 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 1.6 Hz, J= 8.4 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.25 (t, J= 8.0 Hz, 1H), 7.13 (dd, J= 1.2, 7.6 Hz, 1H), 6.94 (dd, J= 1.2, 8.0 Hz, 1H), 6.78 (t, J= 55.2 Hz, 1H), 4.87 (br s, 2H), 4.75  (t, J= 4.8 Hz, 2H), 3.47 (t, J= 4.8 Hz, 2H) MS: m/z = 566.1 [M+H] ⁺ 1.145 A

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400MHz) δ8.62 (s, 1H), 8.12 (dd, J= 3.2, 5.2 Hz, 2H), 7.96-7.87 (m, 1H), 7.81 (dd, J= 1.6, 8.8 Hz, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.27 (d, J= 8.8 Hz, 1H), 7.18 (d, J= 3.2 Hz, 1H), 6.89-6.55 (m, 2H), 4.76 (t, J= 5.2 Hz, 2H), 4.74 (s, 2H), 3.51-3.44 (m, 2H) MS: m/z = 566.2 [M+H] ⁺ 1.146 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲醯胺 MS m/z [M+H] ⁺(ESI)：494.25； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.67 (s, 3H), 3.46-3.53 (m, 2H), 4.41-4.44 (m, 2H), 4.79 (s, 2H), 6.92-6.96 (m, 1H), 7.20-7.31 (m, 4H), 7.33-7.39 (m, 1H), 7.71-7.79 (m, 2H), 7.84-7.85 (m, 1H), 8.09-8.12 (m, 2H), 8.78 (s, 1H)。 1.147 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺 MS m/z [M+H] ⁺(ESI)：512.20； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.69 (s, 3H), 3.49-3.51 (m, 2H), 4.45 (t, J= 4.4 Hz, 2H), 4.84 (s, 2H), 6.94-6.98 (m, 1H), 7.05-7.12 (m, 2H), 7.34 (d, J= 8.0 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.73-7.82 (m, 2H), 7.87-7.88 (m, 1H), 8.11-8.15 (m, 2H), 8.80 (s, 1H). 1.148 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲醯胺 MS m/z [M+H] ⁺(ESI)：512.20； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.68 (s, 3H), 3.48 (t, J= 4.8 Hz, 2H), 4.43 (t, J= 5.1 Hz, 2H), 4.84 (s, 2H), 7.08-7.15 (m, 1H), 7.23-7.46 (m, 4H), 7.72-7.74 (m, 2H), 7.85-7.86 (m, 1H), 8.10-8.14 (m, 2H), 8.78 (s, 1H)。 1.149 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲醯胺 MS m/z [M+H] ⁺(ESI)：512.10； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.70 (s, 3H), 3.48-3.51 (m, 2H), 4.44 (t, J= 5.2 Hz, 2H), 4.79 (s, 2H), 6.66-6.69 (m, 1H), 6.93-6.96 (m, 1H), 7.07 (s, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.42 (d, J= 7.6 Hz, 1H), 7.74-7.71 (m, 2H), 7.86 (s, 1H), 8.11-8.15 (m, 2H), 8.79 (s, 1H)。 1.150 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺 MS m/z [M+H] ⁺(ESI)：512.25； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.67 (s, 3H), 3.46-3.54 (m, 2H), 4.43 (t, J= 5.1 Hz, 2H), 4.75 (s, 2H), 6.89-6.94 (m, 1H), 7.03-7.16 (m, 2H), 7.29 (d, J= 7.8 Hz, 1H), 7.33-7.36 (m, 1H), 7.72-7.77 (m, 2H), 7.85 (s, 1H), 8.10-8.13 (m, 2H), 8.78 (s, 1H)。 1.151 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 ¹H NMR (MeOD, 400MHz) δ8.81 (d, J= 2.4 Hz, 1H), 8.43 (d, J= 8.8 Hz, 1H), 8.17 (d, J= 8.8 Hz, 1H), 8.12-8.02 (m, 2H), 7.84 (d, J= 2.4 Hz, 1H), 7.71 (d, J= 7.2 Hz, 1H), 7.00-6.87 (m, 1H), 6.78-6.50 (m, 3H), 4.73 (s, 2H), 4.48 (t, J= 4.8 Hz, 2H), 3.51 (t, J= 4.4 Hz, 2H) MS: m/z = 524.2 [M+H] ⁺ 1.152 A

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ  8.87 (d, J= 2.4 Hz, 1H), 8.61 (d, J= 8.8 Hz, 1H), 8.41 (d, J= 8.0 Hz, 1H), 8.37-8.30 (m, 2H), 8.04 (d, J= 2.4 Hz, 1H), 7.72 (d, J= 7.6 Hz, 1H), 7.42 (s, 1H), 7.31 (d, J= 7.6 Hz, 1H), 7.23 (t, J= 8.0 Hz, 1H), 7.01-6.98 (m, 1H), 4.64 (s, 2H), 4.53 (t, J= 4.4 Hz, 2H), 3.84 (s, 3H), 3.55 (t, J= 4.4 Hz, 2H), 3.04 (s, 3H) MS: m/z = 510.2 [M+H] ⁺ 1.153 A

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 ¹H NMR (MeOD, 400 MHz) δ  8.88 (d, J= 2.8 Hz, 1H), 8.60 (d, J= 8.8 Hz, 1H), 8.37 (d, J= 7.6 Hz, 1H), 8.33-8.27 (m, 2H), 8.04 (d, J= 2.4 Hz, 1H), 7.69 (d, J= 7.2 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.24 (t, J= 8.0 Hz, 1H), 7.00 (dd, J= 8.0 Hz, 1.6 Hz, 1H), 4.65 (s, 2H), 4.52 (t, J= 4.8 Hz, 2H), 3.55 (t, J= 4.8 Hz, 2H), 3.01 (s, 3H) MS: m/z = 496.2 [M+H] ⁺ 1.154 A

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ  8.83 (d, J= 2.8 Hz, 1H), 8.45 (d, J= 8.8 Hz, 1H), 8.15 (d, J= 8.8 Hz, 1H), 8.08-8.06 (m, 2H), 7.86 (d, J= 2.8 Hz, 1H), 7.75 (t, J= 8.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.27 (t, J= 8.0 Hz, 1H), 7.00 (dd, J= 8.0 Hz, 2.0 Hz, 1H), 6.78 (t, J= 55.2 Hz, 1H), 4.75 (s, 2H), 4.49 (t, J= 4.8 Hz, 2H), 3.85 (s, 3H), 3.51 (t, J= 4.8 Hz, 2H) MS: m/z = 546.2 [M+H] ⁺ 1.155 A

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 ¹H NMR (MeOD, 400 MHz) δ  8.83 (d, J= 2.8 Hz, 1H), 8.46 (d, J= 9.2 Hz, 1H), 8.14 (d, J= 8.8 Hz, 1H), 8.08-8.05 (m, 2H), 7.87 (d, J= 2.4 Hz, 1H), 7.78-7.75 (m, 1H), 7.41-7.37 (m, 2H), 7.27 (t, J= 8.0 Hz, 1H), 6.99 (dd, J= 8.0 Hz, 1.6 Hz, 1H), 6.80 (t, J= 55.2 Hz, 1H), 4.77 (s, 2H), 4.49 (t, J= 4.8 Hz, 2H), 3.52 (t, J= 4.8 Hz, 2H) MS: m/z = 532.2 [M+H] ⁺ 1.156 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲醯胺 ¹H NMR (MeOD, 400MHz) δ 8.64 (s, 1H), 8.14 (d, J= 8.8 Hz, 1H), 8.09 (d, J= 2.0 Hz, 1H), 7.80-7.71 (m, 2H), 7.40 (d, J= 7.6 Hz, 1H), 7.35-7.25 (m, 2H), 7.24-7.19 (m, 2H), 6.96-6.89 (m, 1H), 4.81-4.69 (m, 4H), 3.52-3.43 (m, 2H), 2.67 (s, 3H) MS: m/z = 495.2 [M+H] ⁺ 1.157 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.13 (d, J= 8.8 Hz, 1H), 8.07 (d, J= 1.6 Hz, 1H), 7.80 (s, 1H), 7.82-7.73 (m, 1H), 7.42 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.13-7.02 (m, 2H), 6.95 (dt, J= 2.4, 7.6 Hz, 1H), 4.81 (s, 2H), 4.74 (t, J= 5.2 Hz 2H), 3.52-3.43 (t, J= 4.8 Hz 2H), 2.68 (s, 3H) MS: m/z = 513.2[M+H] ⁺ 1.158 A

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.13 (d, J= 8.8 Hz, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.81-7.74 (m, 2H), 7.41 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.15 (dd, J= 3.2, 5.6 Hz, 1H), 7.06 (dd, J= 9.2, 10.8 Hz, 1H), 6.92 (td, J= 3.6, 8.8 Hz, 1H), 4.78-4.73 (m, 4H), 3.51-3.45 (m, 2H), 2.67 (s, 3H) MS: m/z = 513.2[M+H] ⁺ 1.159 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-5-氟苯甲醯胺 ¹H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.16-8.07 (m, 2H), 7.83-7.74 (m, 2H), 7.44-7.33 (m, 2H), 7.06 (s, 1H), 6.92 (d, J= 9.6 Hz, 1H), 6.66 (d, J= 10.8 Hz, 1H), 4.78-4.72 (m, 4H), 3.52-3.44 (m, 2H), 2.68 (s, 3H) MS: m/z = 513.2 [M+H] ⁺ 1.160 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-4-氟苯甲醯胺 ¹H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.18-8.06 (m, 2H), 7.84-7.74 (m, 2H), 7.41 (d, J= 7.6 Hz, 1H), 7.36 (d, J= 8.0 Hz, 2H), 7.29-7.22 (m, 1H), 7.12 (dd, J= 8.4, 11.2 Hz, 1H), 4.82 (s, 2H), 4.78-4.72 (m, 2H), 3.52-3.43 (m, 2H), 2.68 (s, 3H) MS: m/z = 513.2 [M+H] ⁺ 1.161 A

3-(((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：527.25； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.23-2.32 (m, 2H), 2.70 (s, 3H), 3.22-3.27 (m, 2H), 4.30-4.34 (m, 2H), 4.83 (s, 2H), 6.98-7.13 (m, 2H), 7.23-7.25 (m, 1H), 7.27-7.31 (m, 1H), 7.33-7.43 (m, 1H), 7.71-7.81 (m, 3H), 8.09-8.12 (m, 2H), 8.74 (s, 1H). 1.162 A

5-(((5-(3-(3-胺基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：527.15； ¹H NMR (300 MHz, Methanol-d ₄) δ: 2.25-2.29 (m, 2H), 2.69 (s, 3H), 3.19-3.29 (m, 2H), 4.28-4.32 (m, 2H), 4.73 (s, 2H), 6.92-6.98 (m, 1H), 7.01-7.08 (m, 1H), 7.21-7.24 (m, 1H), 7.27-7.39 (m, 2H), 7.69-7.79 (m, 3H), 8.08-8.10 (m, 2H), 8.71 (s, 1H). 1.163 A

3-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：541.25； ¹H NMR (400 MHz, Methanol-d ₄) δ: 1.77-1.93 (m, 4H), 2.58 (s, 3H), 2.93-2.98 (m, 2H), 4.10-4.14 (m, 2H), 4.71 (s, 2H), 6.87-7.00 (m, 2H), 7.10-7.22 (m, 3H), 7.60-7.69 (m, 3H), 7.96-7.99 (m, 2H), 8.57 (s, 1H). 1.164 A

5-(((5-(3-(4-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：541.20； ¹H NMR (400 MHz, Methanol-d ₄) δ: 1.93-2.05 (m, 4H), 2.68 (s, 3H), 3.05-3.09 (m, 2H), 4.22-4.25 (m, 2H), 4.75 (s, 2H), 6.96-6.99 (m, 1H), 7.04-7.08 (m, 1H), 7.23-7.24 (m, 1H), 7.25-7.29 (m, 1H), 7.31-7.40 (m, 1H), 7.73-7.78 (m, 3H), 8.09-8.14 (m, 2H), 8.69 (s, 1H). 1.165 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.78 (d, J= 2.8 Hz, 1H), 8.15-8.08 (m, 2H), 7.84 (d, J= 2.8 Hz, 1H), 7.79 (t, J= 8.0 Hz, 1H), 7.73 (dd, J= 2.0, 8.8 Hz, 1H), 7.41 (d, J= 7.6 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.23 (t, J= 8.0 Hz, 1H), 7.13 (dd, J= 1.2, 7.6 Hz, 1H), 6.93 (dd, J= 1.2, 8.0 Hz, 1H), 4.86 (s, 2H), 4.43 (t, J= 4.8 Hz, 2H), 3.48 (t, J= 4.8 Hz, 2H), 2.69 (s, 3H) MS: m/z = 529.2[M+H] ⁺ 1.166 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.78 (d, J= 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.85 (d, J= 2.4 Hz, 1H), 7.81-7.67 (m, 2H), 7.40 (d, J= 7.6 Hz, 1H), 7.28 (dd, J= 8.4, 12.4 Hz, 2H), 7.17 (d, J= 2.8 Hz, 1H), 6.85 (dd, J= 2.8, 8.8 Hz, 1H), 4.75 (s, 2H), 4.43 (t, J= 4.8 Hz, 2H), 3.48 (t, J= 4.4 Hz, 2H), 2.68 (s, 3H) MS: m/z = 529.2 [M+H] ⁺ 1.167 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.77 (d, J= 2.8 Hz, 1H), 8.15-8.08 (m, 2H), 7.84 (d, J= 2.8 Hz, 1H), 7.79 (t, J= 8.0 Hz, 1H), 7.73 (dd, J= 2.0, 8.8 Hz, 1H), 7.42 (d, J= 7.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.27 (t, J= 7.6 Hz, 1H), 7.05 (dd, J= 1.2, 7.6 Hz, 1H), 6.88 (dd, J= 1.2, 8.3 Hz, 1H), 4.86 (s, 2H), 4.42 (t, J= 4.8 Hz, 2H), 3.48 (t, J= 4.8 Hz, 2H), 2.69 (s, 3H) MS: m/z = 575.2[M+H] ⁺ 1.168 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.78 (d, J= 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.84 (d, J= 2.8 Hz, 1H), 7.80-7.70 (m, 2H), 7.44 (d, J= 8.8 Hz, 1H), 7.40 (d, J= 7.6 Hz, 1H), 7.30 (d, J= 8.0 Hz, 1H), 7.15 (d, J= 2.8 Hz, 1H), 6.78 (dd, J=3.2, 8.8 Hz, 1H), 4.75 (s, 2H), 4.42 (t, J= 4.8 Hz, 2H), 3.48 (t, J= 4.8 Hz, 2H), 2.68 (s, 3H) MS: m/z = 575.2[M+H] ⁺ 1.169 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2,6-二氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ  8.79 (d, J= 3.2 Hz, 1H), 8.14 (d, J= 1.6 Hz, 1H), 8.11 (d, J= 8.4 Hz, 1H), 7.88 (d, J= 2.8 Hz, 1H), 7.79 (t, J= 8.0 Hz, 1H), 7.74 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 7.41 (d, J= 7.6 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 6.93-6.88 (m, 2H), 4.79 (s, 2H), 4.45 (t, J= 4.8 Hz, 2H), 3.49 (t, J= 4.8 Hz, 2H), 2.68 (s, 3H) MS: m/z = 531.3 [M+H] ⁺ 1.170 A

(S)-3-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.76 (d, J= 2.8 Hz, 1H), 8.16-8.08 (m, 2H), 7.88 (d, J= 2.8 Hz, 1H), 7.82-7.69 (m, 2H), 7.40 (d, J= 7.6 Hz, 1H), 7.31 (d, J= 8.0 Hz, 1H), 7.27-7.18 (m, 1H), 7.08 (t, J= 8.0 Hz, 1H), 7.02-6.92 (m, 1H), 4.81 (s, 2H), 4.73-4.67 (m, 1H), 4.63-4.58 (m, 1H), 4.54 (dd, J= 3.2, 4.8 Hz, 1H), 2.68 (s, 3H) MS: m/z = 557.2[M+H] ⁺ 1.171 A

O-(6-(2-(((2,3-二氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-基)-L-絲胺酸 ¹H NMR (MeOD, 400 MHz) δ 8.65 (d, J= 2.8 Hz, 1H), 8.17-7.88 (m, 2H), 7.86-7.41 (m, 3H), 7.16 (d, J= 7.2 Hz, 2H), 6.98-6.82 (m, 1H), 6.64 (t, J= 7.6 Hz, 1H), 6.54-6.34 (m, 1H), 4.63-4.55 (m, 3H), 4.54-4.47 (m, 1H), 4.11-4.00 (m, 1H), 2.51 (s, 3H) MS: m/z = 531.2[M+H] ⁺ 1.172 A

(S)-3-(((5-(3-(3-胺基-3-羧丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.73 (d, J= 2.8 Hz, 1H), 8.16-8.04 (m, 2H), 7.84-7.68 (m, 3H), 7.40 (d, J= 7.6 Hz, 1H), 7.30 (d, J= 8.0 Hz, 1H), 7.24 (t, J= 6.4 Hz, 1H), 7.08 (t, J= 8.0 Hz, 1H), 7.03-6.96 (m, 1H), 4.82 (s, 2H), 4.46-4.34 (m, 2H), 4.28 (t, J= 6.4 Hz, 1H), 2.69 (s, 3H), 2.62-2.43 (m, 2H) MS: m/z = 571.2 [M+H] ⁺ 1.173 A

O-(6-(2-(((2,3-二氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-基)-L-高絲胺酸 ¹H NMR (400MHz, MeOD) δ 8.73 (d, J=2.8 Hz, 1H), 8.15-8.06 (m, 2H), 7.83-7.67 (m, 3H), 7.42-7.37 (m, 1H), 7.32-7.27 (m, 1H), 7.02-6.92 (m, 1H), 6.66-6.52 (m, 2H), 4.79 (s, 2H), 4.48-4.35 (m, 2H), 4.31-4.21 (m, 1H), 2.68 (s, 3H), 2.61-2.43 (m, 2H) MS: m/z = 545.2 [M+H] ⁺ 1.174 A

(R)-3-(((5-(3-(3-胺基-2-甲基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：541.25； ¹H NMR (300 MHz, Methanol-d ₄) δ: 1.19-1.22 (m, 3H), 2.40-2.50 (m, 1H), 2.66 (s, 3H), 3.04-3.06 (m, 1H), 3.19-3.21 (m, 1H), 4.09-4.12 (m, 1H), 4.20-4.22 (m, 1H), 4.78 (s, 2H), 6.99-7.07 (m, 2H), 7.22-7.28 (m, 1H), 7.30-7.38 (m, 2H), 7.68-7.77 (m, 3H), 8.06-8.09 (m, 2H), 8.72 (s, 1H)。 1.175 A

(S)-3-(((5-(3-(3-胺基-2-甲基丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：541.25； ¹H NMR (400 MHz, Methanol-d ₄) δ: 1.15-1.25 (m, 3H), 2.44-2.47 (m, 1H), 2.67 (s, 3H), 3.04-3.05 (m, 1H), 3.19-3.21 (m, 1H), 4.07-4.12 (m, 1H), 4.21-4.24 (m, 1H), 4.79 (s, 2H), 6.98-6.99 (m, 1H), 7.01-7.09 (m, 1H), 7.21-7.22 (m, 1H), 7.24-7.25 (m, 1H), 7.29-7.39 (m, 1H), 7.69-7.78 (m, 3H), 8.07-8.09 (m, 2H), 8.72 (s, 1H)。 1.176 A

(R)-3-(((5-(3-(3-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸    MS m/z [M+H] ⁺(ESI)：541.10； ¹H NMR (400 MHz, Methanol-d ₄) δ: 1.42-1.46 (m, 3H), 2.16-2.19 (m, 1H), 2.26-2.28 (m, 1H), 2.69 (s, 3H), 3.63-3.68 (m, 1H), 4.32-4.38 (m, 2H), 4.83 (s, 2H), 6.99-7.11 (m, 2H), 7.23-7.25 (m, 1H), 7.26-7.27 (m, 1H), 7.31-7.42 (m, 1H), 7.71-7.82 (m, 3H), 8.10-8.12 (m, 2H), 8.74 (s, 1H). 1.177 A

(S)-3-(((5-(3-(3-胺基丁氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺(ESI)：541.05； ¹H NMR (300 MHz, Methanol-d ₄) δ: 1.40-1.43 (m, 3H), 2.14-2.27 (m, 2H), 2.68 (s, 3H), 3.60-3.67 (m, 1H), 4.29-4.36 (m, 2H), 4.81 (s, 2H), 6.99-7.10 (m, 2H), 7.23-7.28 (m, 1H), 7.29-7.31 (m, 1H), 7.38-7.41 (m, 1H), 7.69-7.79 (m, 3H), 8.08-8.10 (m, 2H), 8.73 (s, 1H). 1.178 A

2-氟-3-(((5-(3-(3-(甲基胺基)丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)苯甲酸 MS m/z [M+H] ⁺(ESI)：541.05； ¹H NMR (400 MHz, Methanol-d ₄) δ: 2.31-2.32 (m, 2H), 2.67 (s, 3H), 2.79 (s, 3H), 3.29-3.30 (m, 2H), 4.30-4.33 (m, 2H), 4.79 (s, 2H), 6.99-7.10 (m, 2H), 7.21-7.22 (m, 1H), 7.23-7.25 (m, 1H), 7.29-7.32 (m, 1H), 7.70-7.78 (m, 3H), 8.07-8.09 (m, 2H), 8.71 (s, 1H). 1.179 A

3-(((5-(3-(3-胺基-2,2-二氟丙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 MS m/z [M+H] ⁺: 562 1.180 A

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.88 (d, J= 2.8 Hz, 1H), 8.61 (d, J= 8.8 Hz, 1H), 8.39-8.24 (m, 3H), 8.04 (d, J= 2.4 Hz, 1H), 7.70 (d, J= 7.6 Hz, 1H), 7.21-7.15 (m, 1H), 7.07 (dd, J= 1.2, 7.6 Hz, 1H), 6.99 (dd, J= 1.2, 8.4 Hz, 1H), 4.74 (s, 2H), 4.52 (t, J= 4.8 Hz, 2H), 3.55 (t, J= 4.8 Hz, 2H), 3.02 (s, 3H) MS: m/z = 530.1 [M+H] ⁺ 1.181 A

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.89 (d, J= 2.4 Hz, 1H), 8.62 (d, J= 8.8 Hz, 1H), 8.40-8.28 (m, 3H), 8.04 (d, J= 2.4 Hz, 1H), 7.71 (d, J= 7.6 Hz, 1H), 7.24 (d, J= 3.2 Hz, 1H), 7.21 (d, J= 8.8 Hz, 1H), 6.87 (dd, J= 8.8 Hz, 3.2 Hz, 1H), 4.62 (s, 2H), 4.52 (t, J= 4.8 Hz, 2H), 3.55 (t, J= 4.8 Hz, 2H), 3.02 (s, 3H) MS: m/z = 530.2 [M+H] ⁺ 1.182 A

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.87 (d, J= 2.8 Hz, 1H), 8.62-8.54 (m, 1H), 8.35-8.19 (m, 3H), 8.04-7.98 (m, 1H), 7.69-7.62 (m, 1H), 7.27-7.17 (m, 1H), 7.05-6.91 (m, 2H), 4.73 (s, 2H), 4.51 (t, J= 4.8 Hz, 2H), 3.57-3.51 (m, 2H), 2.99 (s, 3H) MS: m/z = 574.0 [M+H] ⁺ 1.183 A

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.89 (d, J= 2.8 Hz, 1H), 8.61 (d, J= 8.8 Hz, 1H), 8.37-8.28 (m, 3H), 8.04 (d, J= 2.4 Hz, 1H), 7.70 (d, J= 7.6 Hz, 1H), 7.38 (d, J= 8.8 Hz, 1H),  7.22 (d, J= 2.8 Hz, 1H), 6.79 (dd, J= 8.4 Hz, 2.8 Hz, 1H), 4.62 (s, 2H), 4.52 (t, J= 5.2 Hz, 2H), 3.55 (t, J= 5.2 Hz, 2H), 3.02 (s, 3H) MS: m/z = 574.1 [M+H] ⁺ 1.184 A

3-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.89 (d, J= 2.8 Hz, 1H), 8.62 (d, J= 8.8 Hz, 1H), 8.39-8.27 (m, 3H), 8.04 (d, J= 2.4 Hz, 1H), 7.71 (d, J= 7.6 Hz, 1H), 7.20-7.16 (m, 1H), 7.08-7.00 (m, 2H), 4.70 (s, 2H), 4.53 (t, J= 4.8 Hz, 2H), 3.55 (t, J= 4.8 Hz, 2H), 3.03 (s, 3H) MS: m/z = 514.2 [M+H] ⁺ 1.185 A

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.90-8.87 (m, 1H), 8.60 (d, J= 8.8 Hz, 1H), 8.38-8.23 (m, 3H), 8.02 (d, J= 2.4 Hz, 1H), 7.67 (d, J= 6.8 Hz, 1H), 7.34-7.28 (m, 1H), 7.04-6.96 (m, 2H), 4.61 (s, 2H), 4.52 (t, J= 5.2 Hz, 2H), 3.57-3.53 (m, 2H), 2.98 (s, 3H) MS: m/z = 514.2 [M+H] ⁺ 1.186 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟苯胺 MS: m/z = 455 [M+H] ⁺ 1.187 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2,3-二氟苯胺 ¹H NMR (MeOD, 400 MHz) δ8.88 (d, J= 2.4 Hz, 1H), 8.62 (d, J= 8.8 Hz, 1H), 8.44-8.25 (m, 3H), 8.05 (s, 1H), 7.73 (d, J= 7.2 Hz, 1H), 6.97-6.84 (m, 1H), 6.65 (t, J= 7.6 Hz, 1H), 6.57-6.44 (m, 1H), 4.68 (s, 2H), 4.54 (s, 2H), 3.56 (s, 2H), 3.05 (s, 3H) MS: m/z = 488.2[M+H] ⁺ 1.188 A

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(甲磺醯基)苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 8.88 (d, J= 3.2 Hz, 1H), 8.60 (d, J= 8.8 Hz, 1H), 8.35-8.23 (m, 3H), 8.05-8.03 (m, 1H), 7.70-7.66 (m, 1H), 7.39-7.34 (m, 1H), 6.98 (d, J= 2.4 Hz, 1H), 6.81 (dd, J= 2.8, 8.8 Hz, 1H), 4.61 (s, 2H), 4.52 (s, 2H), 3.55 (s, 2H), 3.34 (s, 3H), 3.00 (s, 3H) MS: m/z = 651.0 [M+H] ⁺ 1.189 A

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(異丙基磺醯基)苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 8.89 (d, J= 2.4 Hz, 1H), 8.62 (d, J= 8.8 Hz, 1H), 8.41-8.25 (m, 3H), 8.05 (d, J= 2.0 Hz, 1H), 7.70 (d, J= 7.2 Hz, 1H), 7.36 (d, J= 8.8 Hz, 1H), 6.97 (d, J= 2.8 Hz, 1H), 6.81 (dd, J= 2.8, 8.8 Hz, 1H), 4.61 (s, 2H), 4.53 (t, J= 4.8 Hz, 2H), 3.83 (td, J= 7.2, 13.6Hz, 1H), 3.55 (t, J= 4.8 Hz, 2H), 3.02 (s, 3H), 1.44 (d, J= 6.8 Hz, 5H), 1.48-1.39 (m, 1H) MS: m/z =681.1 [M+H] ⁺ 1.190 A

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(三級丁基磺醯基)苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 8.89 (d, J= 2.8 Hz, 1H), 8.64 (d, J= 8.8 Hz, 1H), 8.45-8.27 (m, 3H), 8.06 (d, J= 2.4 Hz, 1H), 7.73 (d, J= 7.2 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 6.94 (d, J= 3.2 Hz, 1H), 6.80 (dd, J= 3.0, 8.9 Hz, 1H), 4.62 (s, 2H), 4.53 (t, J= 4.4 Hz, 2H), 3.55 (dd, J= 3.6, 5.2 Hz, 2H), 3.05 (s, 3H), 1.50 (s, 9H) MS: m/z = 693.1 [M+H] ⁺ 1.191 A

5-(((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(環丙基磺醯基)苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 8.88 (d, J= 2.4 Hz, 1H), 8.61 (d, J= 4.4 Hz, 1H), 8.39-8.23 (m, 3H), 8.04 (d, J= 3.2 Hz, 1H), 7.79 (d, J= 4.0 Hz, 1H), 7.36 (d, J= 4.4 Hz, 1H), 6.95 (d, J= 6.8 Hz, 1H), 6.81 (dd, J= 8.0, 2.0 Hz, 2H), 4.61 (s, 2H), 4.52 (t, J= 8.0 Hz, 2H), 3.55 (t, J= 8.0 Hz, 2H) 3.13-3.03 (m, 1H), 3.00 (s, 3H), 1.33-1.25 (m, 2H), 1.16-1.14 (m, 2H) MS: m/z = 679.1 [M+H] ⁺ 1.192 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(甲磺醯基)苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 8.78 (d, J= 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.89 (d, J= 2.8 Hz, 1H), 7.80 (t, J= 8.0 Hz, 1H), 7.74 (dd, J= 2.0, 8.8 Hz, 1H), 7.44-7.39 (m, 2H), 7.33 (d, J= 8.0 Hz, 1H), 6.86 (d, J= 2.8 Hz, 1H), 6.81 (dd, J= 2.8, 8.8 Hz, 1H), 4.74 (s, 2H), 4.47-4.41 (m, 2H), 3.51-3.47 (m, 2H), 3.36 (s, 3H), 2.69 (s, 3H)   MS: m/z = 650.1 [M+H] ⁺ 1.193 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(異丙基磺醯基)苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 8.78 (d, J= 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.89 (d, J= 2.4 Hz, 1H), 7.80 (t, J= 8.0 Hz, 1H), 7.73 (dd, J= 1.6, 8.8 Hz, 1H), 7.44-7.39 (m, 2H), 7.33 (d, J= 8.0 Hz, 1H), 6.85-6.78 (m, 2H), 4.73 (s, 2H), 4.44 (t, J= 4.8 Hz, 2H), 3.87-3.80 (m, 1H), 3.49 (t, J= 4.4 Hz, 2H), 2.69 (s, 3H), 1.45 (d, J= 6.8 Hz, 6H) MS: m/z =680.2 [M+H] ⁺ 1.194 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(三級丁基磺醯基)苯甲醯胺 ¹H NMR (MeOD, 400MHz) δ 8.78 (d, J= 2.8 Hz, 1H), 8.16-8.08 (m, 2H), 7.89 (d, J= 2.4 Hz, 1H), 7.79 (t, J= 8.0 Hz, 1H), 7.76-7.71 (m, 1H), 7.44-7.37 (m, 2H), 7.32 (d, J= 8.0 Hz, 1H), 6.81 (s, 2H), 4.74 (s, 2H), 4.44 (s, 2H), 3.51-3.46 (m, 2H), 2.69 (s, 3H), 1.51 (s, 9H) MS: m/z = 692.2 [M+H] ⁺ 1.195 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-溴-N-(環丙基磺醯基)苯甲醯胺 ¹H NMR (MeOD, 400 MHz) δ 8.78 (d, J= 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.87 (d, J= 2.4 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.41 (d, J= 8.4 Hz, 2H), 7.32 (d, J= 8.0 Hz, 1H), 6.85-6.78 (m, 2H), 4.73 (s, 2H), 4.44 (t, J= 4.4 Hz, 2H), 3.49 (t, J= 4.4 Hz, 2H), 3.13-3.05 (m, 1H), 2.69 (s, 3H), 1.31-1.29 (m, 2H), 1.17-1.15 (m, 2H) MS: m/z = 676.1 [M+H] ⁺ 1.196 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2,4-二氟苯胺 MS: m/z = 523 [M+H] ⁺ 1.197 A

N-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3,5-二氟苯胺 MS: m/z = 523 [M+H] ⁺ 1.198 A

3-(((5-(3-(2-(4-(4-乙醯基苯氧基)丁醯胺基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.61 (d, J= 2.8 Hz, 1H), 8.07-8.03 (m, 2H), 7.81-7.75 (m, 3H), 7.69-7.65 (m, 2H), 7.41 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.23-7.19 (m, 1H), 7.09 (t, J= 8.0 Hz, 1H), 7.02 (t, J= 8.0 Hz, 1H), 6.89 (d, J= 8.8 Hz, 2H), 4.81 (s, 2H), 4.16 (t, J= 5.2 Hz, 2H), 4.05 (t, J= 6.0 Hz, 2H), 3.89 (s, 3H), 3.66 (t, J= 5.2 Hz, 2H), 2.70 (s, 3H), 2.45 (t, J= 7.2 Hz, 2H), 2.39 (s, 3H), 2.11 (t, J= 6.4 Hz, 2H) MS: m/z = 731.3 [M+H] ⁺ 1.199 A

3-(((5-(3-(2-(4-(4-乙醯基苯氧基)丁醯胺基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.61 (d, J= 2.8 Hz, 1H), 8.07-8.03 (m, 2H), 7.81-7.75 (m, 3H), 7.69-7.66 (m, 2H), 7.41 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.23-7.19 (m, 1H), 7.08 (t, J= 8.0 Hz, 1H), 7.02-6.98 (m, 1H), 6.89 (d, J= 9.2 Hz, 2H), 4.82 (s, 2H), 4.16 (t, J= 5.2 Hz, 2H), 4.05 (t, J= 6.0 Hz, 2H), 3.66 (t, J= 5.2 Hz, 2H), 2.70 (s, 3H), 2.45 (t, J= 7.2 Hz, 2H), 2.42 (s, 3H), 2.11 (t, J= 6.8 Hz, 2H) MS: m/z = 717.3 [M+H] ⁺ 1.200 A

2-羥乙基 3-(((5-(3-(2-(4-(4-乙醯基苯氧基)丁醯胺基)乙氧基)喹啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸酯 ¹H NMR (MeOD, 400 MHz) δ 8.51 (s, 1H), 7.98 (s, 1H), 7.89 (d, J= 8.4 Hz, 2H), 7.79 (d, J= 8.8 Hz, 2H), 7.69-7.57 (m, 3H), 7.22-7.14 (m, 3H), 7.09-7.04 (m, 2H), 6.89 (d, J= 8.4 Hz, 2H), 4.59 (s, 2H), 4.36 (t, J= 4.4 Hz, 2H), 4.18 (s, 2H), 4.05 (t, J= 6.0 Hz, 2H), 3.84 (t, J= 4.4 Hz, 2H), 3.66 (t, J= 4.4 Hz, 2H), 2.51-2.42 (m, 8H), 2.13-2.08 (m, 2H) MS: m/z = 761.3 [M+H] ⁺ 1.201 A

N-(2-((6-(4-(6-(二氟甲基)吡啶-2-基)-2-(((2,3-二氟苯基)胺基)甲基)-1H-咪唑-5-基)喹啉-3-基)氧基)乙基)-5-肼基-5-側氧基戊醯胺 MS m/z [M+H] ⁺(ESI)：651.30； ¹H NMR (400 MHz, Methanol-d ₄) δ: 1.90-1.96 (m, 2H), 2.20-2.23 (m, 4H), 3.66-3.69 (m, 2H), 4.23-4.26 (m, 2H), 4.73 (s, 2H), 6.55-6.83 (m, 3H), 6.93-6.98 (m, 1H), 7.58-7.59 (m, 2H), 7.73-7.76 (m, 2H), 7.85-7.89 (m, 1H), 8.02-8.04 (m, 1H), 8.13 (s, 1H), 8.66 (s, 1H). 1.202 A

N-(3-((6-(2-(((2,3-二氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹啉-3-基)氧基)丙基)-5-肼基-5-側氧基戊醯胺 MS m/z [M+H] ⁺(ESI)：629.35； ¹H NMR (300 MHz, Methanol-d ₄) δ: 1.85-1.90 (m, 2H), 2.09-2.25 (m, 6H), 2.65 (s, 3H), 3.42-3.46 (m, 2H), 4.19-4.24 (m, 2H), 4.74 (s, 2H), 6.54-6.65 (m, 2H), 6.93-7.01 (m, 1H), 7.29-7.36 (m, 2H), 7.67-7.76 (m, 3H), 8.03-8.07 (m, 2H), 8.68 (s, 1H). 7.1 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.59 (s, 1H), 8.07 (d, J= 8.8 Hz, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.68 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 7.64 (dd, J= 7.2 Hz, 2.0 Hz, 1H), 7.44-7.40 (m, 1H), 7.31 (t, J= 8.8 Hz, 1H), 7.26-7.22 (m, 1H), 7.09 (t, J= 8.0 Hz, 1H), 6.99 (td, J= 8.0 Hz, 1.6 Hz, 1H), 4.80 (s, 2H), 4.73 (t, J= 4.8 Hz, 2H), 3.46 (t, J= 4.8 Hz, 2H) MS: m/z = 551.2 [M+H] ⁺ 7.2 A

3-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 1H NMR (MeOD, 400MHz) δ 8.59 (s, 1H), 8.05 (d, J= 8.8 Hz, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.66 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 7.53-7.50 (m, 2H), 7.27-7.18 (m, 3H), 7.10 (t, J= 8.0 Hz, 1H), 7.02-6.98 (m, 1H), 4.85 (s, 2H), 4.72 (t, J= 5.2 Hz, 2H), 3.46 (t, J= 5.2 Hz, 2H) MS: m/z = 517.2 [M+H] ⁺ 7.3 A

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.61 (s, 1H), 8.09 (d, J= 8.4 Hz, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.74-7.63 (m, 2H), 7.45-7.41 (m, 1H), 7.37-7.30 (m, 1H), 7.21 (dd, J= 3.2, 5.6 Hz, 1H), 7.11-7.02 (m, 1H), 7.00-6.92 (m, 1H), 4.78-4.70 (m, 4H), 3.50-3.43 (m, 2H) MS: m/z = 551.2 [M+H] ⁺ 7.4 A

5-(((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.59 (s, 1H), 8.07 (d, J= 8.8 Hz, 1H), 7.95 (d, J= 1.6 Hz, 1H), 7.67 (dd, J= 2.0, 8.8 Hz, 1H), 7.58-7.47 (m, 2H), 7.27-7.16 (m, 3H), 7.10-7.02 (m, 1H), 6.96 (td, J= 3.6, 8.8 Hz, 1H), 4.77-4.70 (m, 4H), 3.50-3.43 (m, 2H) MS: m/z = 517.2 [M+H] ⁺ 7.5 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ  8.75 (d, J= 2.8 Hz, 1H), 8.06 (d, J= 8.8 Hz, 1H), 8.00 (s, 1H), 7.78 (d, J= 2.8 Hz, 1H), 7.66-7.63 (m, 2H), 7.43-7.39 (m, 1H), 7.32 (t, J= 8.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.10 (t, J= 8.0 Hz, 1H), 7.01-6.97 (m, 1H), 4.85 (s, 2H), 4.41 (t, J= 4.8 Hz, 2H), 3.47 (t, J= 4.8 Hz, 2H) MS: m/z = 550.2 [M+H] ⁺ 7.6 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.74 (d, J= 2.8 Hz, 1H), 8.04 (d, J= 8.8 Hz, 1H), 8.00 (d, J= 1.6 Hz, 1H), 7.77 (d, J= 2.8 Hz, 1H), 7.63 (dd, J= 2.0, 8.8 Hz, 1H), 7.54-7.47 (m, 2H), 7.27 (dt, J= 1.6, 7.2 Hz, 1H), 7.24-7.17 (m, 2H), 7.11 (t, J= 7.6 Hz, 1H), 6.99 (dt, J= 1.6, 8.0 Hz, 1H), 4.86-4.84 (m, 2H), 4.40 (t, J= 4.8 Hz, 2H), 3.47 (t, J= 4.8 Hz, 2H) MS: m/z = 516.2[M+H] ⁺ 7.7 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.57 (d, J= 2.8 Hz, 1H), 7.91-7.84 (m, 2H), 7.63 (d, J= 2.8 Hz, 1H), 7.54 (dd, J= 1.6, 8.8 Hz, 1H), 7.47 (dd, J=2.0, 7.2 Hz, 1H), 7.28-7.32 (m,  1H), 7.13 (t, J= 8.8 Hz, 1H), 7.03 (dd, J= 3.2, 5.6 Hz, 1H), 6.83 (t, J= 9.2 Hz, 1H), 6.66 (td, J= 3.6, 8.4 Hz, 1H), 4.44 (s, 2H), 4.34 (t, J= 5.2 Hz, 2H), 3.44-3.38 (t, J= 5.2 Hz, 2H) MS: m/z = 550.2[M+H] ⁺ 7.8 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (400MHz, MeOD) δ 8.74 (d, J= 2.8 Hz, 1H), 8.05 (d, J= 8.4 Hz, 1H), 8.00 (d, J= 2.0 Hz, 1H), 7.77 (d, J= 2.8 Hz, 1H), 7.63 (dd, J= 2.0, 8.8 Hz, 1H), 7.54-7.48 (m, 2H), 7.25-7.17 (m, 3H), 7.11-7.03 (m, 1H), 7.00-6.94 (m, 1H), 4.80 (s, 2H), 4.48-4.36 (m, 2H), 3.47 (t, J= 4.8 Hz, 2H) MS: m/z = 516.2 [M+H] ⁺ 7.9 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.73 (d, J= 2.8 Hz, 1H), 8.04 (d, J= 8.8 Hz, 1H), 7.98 (d, J= 1.6 Hz, 1H), 7.75 (d, J= 2.8 Hz, 1H), 7.64 (dd, J= 2.0, 8.8 Hz, 1H), 7.50 (dd, J= 5.2, 8.8 Hz, 2H), 7.29-7.23 (m, 1H), 7.23-7.14 (m, 3H), 6.91 (dd, J= 1.2, 8.0 Hz, 1H), 4.91 (s, 2H), 4.40 (t, J= 4.8 Hz, 2H), 3.46 (t, J= 5.2 Hz, 2H) MS: m/z = 532.2[M+H] ⁺ 7.10 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.76 (d, J= 2.8 Hz, 1H), 8.12-7.96 (m, 2H), 7.78 (d, J= 2.4 Hz, 1H), 7.65 (dd, J= 2.0, 8.8 Hz, 1H), 7.52 (dd, J= 5.2, 8.8 Hz, 2H), 7.31 (d, J= 8.8 Hz, 1H), 7.27-7.14 (m, 3H), 6.88 (dd, J= 3.2, 8.8 Hz, 1H), 4.83 (s, 2H), 4.42 (t, J= 4.8 Hz, 2H), 3.52-3.46 (m, 2H) MS: m/z = 532.2 [M+H] ⁺ 7.11 A

3-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.74 (d, J= 2.8 Hz, 1H), 8.05 (d, J= 8.8 Hz, 1H), 7.98 (s, 1H), 7.77 (d, J= 2.4 Hz, 1H), 7.70-7.60 (m, 2H), 7.43-7.37 (m, 1H), 7.34-7.21 (m, 2H), 7.15 (d, J= 7.6 Hz, 1H), 6.91 (d, J= 8.0 Hz, 1H), 4.88 (s, 2H), 4.41 (t, J= 4.8 Hz, 2H), 3.46 (t, J= 4.4 Hz, 2H) MS: m/z = 566.1[M+H] ⁺ 7.12 A

5-(((5-(3-(2-胺基乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氯苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.75 (d, J= 2.8 Hz, 1H), 8.07 (d, J= 8.8 Hz, 1H), 7.99 (d, J= 1.6 Hz, 1H), 7.78 (d, J= 2.8 Hz, 1H), 7.68-7.61 (m, 2H), 7.44-7.37 (m, 1H), 7.36-7.27 (m, 2H), 7.17 (d, J= 3.2 Hz, 1H), 6.86 (dd, J= 2.8, 8.8 Hz, 1H), 4.79 (s, 2H), 4.41 (t, J= 4.8 Hz, 2H), 3.47 (t, J= 4.8 Hz, 2H) MS: m/z = 566.2 [M+H] ⁺ 7.13 A

(S)-3-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.72 (d, J= 2.4 Hz, 1H), 8.04-8.02 (m, 2H), 7.81 (d, J= 2.4 Hz, 1H), 7.63 (dd, J= 8.8 Hz, 1.6 Hz, 1H), 7.52-7.49 (m, 2H), 7.26 (t, J= 6.4 Hz, 1H), 7.20 (t, J= 8.8 Hz, 2H), 7.11 (t, J= 8.0 Hz, 1H), 6.99 (t, J= 7.6 Hz, 1H), 4.88 (s, 2H), 4.69 (dd, J= 10.8 Hz, 4.8 Hz, 1H), 4.59 (dd, J= 10.4 Hz, 2.8 Hz, 1H), 4.53-4.51 (m, 1H) MS: m/z = 560.2 [M+H] ⁺ 7.14 A

(S)-5-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.72 (d, J= 2.4 Hz, 1H), 8.05-8.03 (m, 2H), 7.82 (d, J= 1.6 Hz, 1H), 7.63 (dd, J= 8.4 Hz, 1.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.23-7.18 (m, 3H), 7.07 (t, J= 9.2 Hz, 1H), 6.99-6.95 (m, 1H), 4.80 (s, 2H), 4.70 (dd, J= 10.8 Hz, 4.8 Hz, 1H), 4.59 (dd, J= 10.8 Hz, 2.0 Hz, 1H), 4.56-4.54 (m, 1H) MS: m/z = 560.2 [M+H] ⁺ 7.15 A

(S)-3-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.72 (d, J= 2.4 Hz, 1H), 8.06-8.02 (m, 2H), 7.83 (d, J= 1.6 Hz, 1H), 7.65-7.63 (m, 2H), 7.42-7.39 (m, 1H), 7.31 (t, J= 8.8 Hz, 1H), 7.25 (t, J= 6.8 Hz, 1H), 7.10 (t, J= 8.0 Hz, 1H), 6.00 (t, J= 8.0 Hz, 1H), 4.85 (s, 2H), 4.69 (dd, J= 10.4 Hz, 4.8 Hz, 1H), 4.59 (dd, J= 10.4 Hz, 2.0 Hz, 1H), 4.54-4.51 (m, 1H) MS: m/z = 594.1 [M+H] ⁺ 7.16 A

(S)-5-(((5-(3-(2-胺基-2-羧乙氧基)喹啉-6-基)-4-(3-氯-4-氟苯基)-1H-咪唑-2-基)甲基)胺基)-2-氟苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.73 (d, J= 2.8 Hz, 1H), 8.06 (d, J= 8.4 Hz, 1H), 8.01 (d, J= 1.6 Hz, 1H), 7.83 (d, J= 2.4 Hz, 1H), 7.66-7.62 (m, 2H), 7.43-7.39 (m, 1H), 7.32 (t, J= 8.8 Hz, 1H), 7.22-7.20 (m, 1H), 7.07 (t, J= 8.8 Hz, 1H), 6.98-6.95 (m, 1H), 4.77 (s, 2H), 4.69 (dd, J= 10.4 Hz, 4.8 Hz, 1H), 4.59 (dd, J= 10.8 Hz, 2.8 Hz, 1H), 4.54-4.52 (m, 1H) MS: m/z = 594.1 [M+H] ⁺ 實施例2B ALK5抑制劑合成方法B 2-[7-[2- [2-(2- 氟苯基)乙基]-4-(6-甲基-2-吡啶基)-1 H-咪唑-5-基]喹㗁啉-2-基]氧基乙胺 （ 化合物 2.1 ）之合成 方法B

合成流程圖

步驟 1 ： N-[2-[7-[2-[2-(2-氟苯基)乙基]-4-(6-甲基-2-吡啶基)-1 H-咪唑-5-基]喹㗁啉-2-基]氧基乙基]胺甲酸三級丁酯（ 化合物 2.1-a）之製備

Compounds 1.3-1.66, as described in Table 15, can be prepared in a manner analogous to that described for compounds 1.1 and 1.2 with appropriate intermediates and according to Method A described herein. Table 15 Compounds 1.3-1.202 and 7.1-7.16 Compound number Method of preparation based on: structure / name ¹ H NMR/MS 1.3 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Fluoroaniline 1H NMR (DMSO-d6, 400 MHz) δ8.73 (d, J = 2.4 Hz, 1H), 8.16 (s, 1H), 8.09-7.94 (m, 4H), 7.88 (d, J = 2.4 Hz, 1H) ), 7.74 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 2.0, 8.8 Hz, 1H), 7.32 (dd, J = 7.6, 15.6 Hz, 2H), 7.07 (dd, J = 7.6, 12.0 Hz, 1H), 7.02-6.95 (m, 1H), 6.95-6.88 (m, 1H), 6.69-6.59 (m, 1H), 4.77 (s, 2H), 4.15 (t, J = 6.4 Hz, 2H ), 2.90-2.78 (m, 2H), 2.53 (s, 3H), 1.89-1.80 (m, 2H), 1.79-1.68 (m, 2H) MS: m/z = 497.3 [M+H]+ 1.4 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Chloroaniline 1H NMR (DMSO-d6, 400MHz) δ8.75 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.05-7.92 (m, 3H) , 7.88 (s, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8.8 Hz, 2H), 7.21-7.15 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 4.84 (s, 2H), 4.18 (t, J = 6.4 Hz, 2H), 2.89-2.85 (m, 2H), 2.58 (s, 3H), 1.91-1.83 (m, 2H), 1.82-1.72 (m, 2H). MS: m/z = 513.2 [ M+H]+ 1.5 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-methylaniline 1H NMR (DMSO-d6, 400MHz,) δ8.80 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.96 (s, 1H), 7.80-7.73 (m, 2H), 7.36 (t, J = 6.8 Hz, 2H), 7.03 (d, J = 4.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 7.6 Hz, 1H), 4.82 (s, 2H), 4.20 (t, J = 6.0 Hz, 2H), 2.88-2.85 (m, 2H), 2.54 (s, 3H), 2.23 (s, 3H), 1.93 -1.83 (m, 2H), 1.83-1.73 (m, 2H). MS: m/z = 493.2 [M+H]+ 1.6 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Methoxyaniline 1H NMR (MeOD, 400MHz) δ9.16 (d, J = 2.4 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.48 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H) ), 8.12 (t, J = 8.0 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.23-7.17 (m, 1H), 7.16-7.10 (m, 2H), 7.00-6.95 (m, 1H), 4.84 (s, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.98 (s, 3H), 3.08 (t, J = 7.6 Hz, 2H), 2.81 (s, 3H), 2.08-2.01 (m, 2H), 1.99-1.91 (m, 2H). MS: m/z = 509.3 [M+ H]+ 1.7 A

2-(((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzonitrile 1H NMR (DMSO-d6, 400MHz) δ8.76 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.11-8.00 (m, 3H), 7.92 (d, J = 2.4 Hz, 1H) , 7.79 (t, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H) , 7.30 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.79 (t, J=7.2 Hz, 1H), 4.89 (s, 2H), 4.18 (t, J= 6.0 Hz, 2H), 4.32-4.02 (m, 2H), 2.59 (s, 2H), 1.89-1.86 (m, 2H), 1.80-1.77 (m, 2H) MS: m/z = 504.3 [M+H ]+ 1.8 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3-Fluoroaniline 1H NMR (DMSO-d6, 400MHz) δ8.77 (d, J = 2.8 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.03 (s , 3H), 7.91 (d, J = 2.4 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.73 (dd, J = 1.6, 8.7 Hz, 1H), 7.39 (d, J = 7.6 Hz , 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.16 (q, J = 8.0 Hz, 1H), 6.58 (d, J = 8.8 Hz, 2H), 6.44 (t, J = 8.0 Hz, 1H) ), 4.74 (m, 1H), 4.19 (t, J = 6.0 Hz, 2H), 2.93-2.82 (m, 2H), 2.58 (s, 3H), 1.93-1.83 (m, 2H), 1.82-1.72 ( m, 2H) MS: m/z = 497.3 [M+H]+ 1.9 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3-Chloroaniline 1H NMR (DMSO-d6, 400MHz) δ8.81 (d, J = 2.8 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 8.8 Hz, 4H), 7.97 (d , J = 2.4 Hz, 1H), 7.84-7.72 (m, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.15 (t, J = 8.4 Hz, 1H), 6.82 (s, 1H), 6.75 -6.63 (m, 2H), 4.76 (s, 2H), 4.20 (t, J = 6.4 Hz, 2H), 2.97-2.75 (m, 2H), 2.56 (s, 3H), 1.92-1.70 (m, 4H) ) MS: m/z = 513.2 [M+H]+ 1.10 A

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzonitrile 1H NMR (DMSO-d6, 400MHz) δ8.78 (d, J = 2.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.13-8.00 (m, 4H), 7.93 (d, J = 2.4 Hz, 1H), 7.83-7.70 (m, 2H), 7.42-7.30 (m, 3H), 7.16 (s, 1H), 7.12-7.02 (m, 2H), 4.78 (s, 2H), 4.19 (t , J = 6.4 Hz, 2H), 2.89-2.86 (m, 2H), 2.57 (s, 3H), 1.90-1.83 (m, 2H), 1.82-1.70 (m, 2H) MS: m/z = 504.2 [ M+H]+ 1.11 A

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzamide 1H NMR (DMSO-d6, 400MHz) δ8.74 (d, J = 2.8 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 2.4 Hz , 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.30-7.13 (m, 4H), 6.87 (d, J = 7.6 Hz, 1H), 4.71 (s, 2H), 4.16 (t, J = 5.6 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.57 (s, 3H), 1.91 -1.80 (m, 2H), 1.80-1.69 (m, 2H) MS: m/z = 522.3 [M+H]+ 1.12 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,3-difluoroaniline 1H NMR (DMSO-d6, 400MHz) δ8.74 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.01-7.96 (m, 3H), 7.87 (d, J = 2.8 Hz, 1H), 7.81-7.74 (m, 1H), 7.71 (dd, J = 1.6, 8.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.05-6.97 (m, 1H), 6.77-6.58 (m, 3H), 4.82 (s, 2H), 4.19 (t, J = 6.0 Hz, 2H) ), 2.92-2.81 (m, 2H), 2.62-2.57 (m, 3H), 1.92-1.84 (m, 2H), 1.82-1.71 (m, 2H) MS: m/z = 515.2 [M+H]+ 1.13 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3,4-difluoroaniline 1H NMR (DMSO-d6, 400MHz) δ8.75 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.06-8.03 (m, 3H), 7.88 (d, J = 2.5 Hz, 1H), 7.81-7.69 (m, 2H), 7.35 (dd, J = 7.6, 19.2 Hz, 2H), 7.24-7.16 (m, 1H), 6.88-6.80 (m, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.70 (s, 2H), 4.18 (t, J = 6.0 Hz, 2H), 2.89-2.85 (m, 2H), 2.57 (s, 3H), 1.86 (d, J = 7.6 Hz, 2H), 1.81-1.72 (m, 2H) MS: m/z = 515.2 [M+H]+ 1.14 A

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-5-(dimethylamino)benzonitrile 1H NMR (MeOD-d4, 400MHz) δ = 8.69 (d, J = 2.8 Hz, 1H), 8.14-8.07 (m, 2H), 7.79-7.74 (m, 2H), 7.72-7.68 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.47-6.44 (m, 1H), 6.35 (s, 1H), 6.31 (J = 2.0 Hz, 1H), 4.74 (s, 2H), 4.23 (t, J = 5.6 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.94 (s, 6H), 2.68 (s, 3H), 2.02-1.89 (m , 4H) MS: m/z = 547.3 [M+H]+ 1.15 A

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-4-(dimethylamino)benzonitrile 1H NMR (DMSO-d6, 400MHz) δ8.71 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 2.4 Hz) , 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 1.6, 8.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz , 1H), 7.15-7.07 (m, 3H), 4.75 (s, 2H), 4.15 (t, J = 6.0 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.67 (s, 6H) , 2.59 (s, 3H), 1.90-1.81 (m, 2H), 1.79-1.70 (m, 2H) MS: m/z = 547.3 [M+H]+ 1.16 A

N3-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-4-Fluoro-N1,N1-xylene-1,3-diamine 1H NMR (DMSO-d6, 400 MHz) δ 8.86 (d, J = 2.8 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.17-8.10 (m, 4H), 8.04 (d, J = 2.4 Hz, 1H), 7.88-7.77 (m, 2H), 7.66 (d, J = 6.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H) , 7.26 (dd, J = 8.6, 11.2 Hz, 1H), 7.16-7.12 (m, 1H), 4.95 (s, 2H), 4.22 (t, J = 6.0 Hz, 2H), 3.15 (s, 6H), 2.91-2.84 (m, 2H), 2.52 (s, 3H), 1.91-1.84 (m, 2H), 1.83-1.72 (m, 2H) MS: m/z = 540.3 [M+H]+ 1.17 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Fluoro-5-nitroaniline 1H NMR (DMSO-d6, 400 MHz) δ8.77 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.13-7.99 (m, 4H), 7.92 (d, J = 2.4 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.75-7.69 (m, 2H), 7.62-7.55 (m, 1H), 7.44-7.36 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 4.90 (s, 2H), 4.19 (t, J = 6.0 Hz, 2H), 2.89-2.84 (m, 2H), 2.59 (s, 3H), 1.93-1.83 (m, 2H) ), 1.83-1.71 (m, 2H) MS: m/z = 542.3 [M+H]+ 1.18 A

N-((5-(3-(4-Amino-3,3-difluorobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole -2-yl)methyl)-2-fluoroaniline 1H NMR (MeOD, 400MHz) δ9.16 (d, J = 2.8 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.02 (dd, J = 2.0, 8.8 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.08-6.97 (m, 2H), 6.86-6.79 (m, 1H), 6.77-6.70 (m, 1H), 4.83 (s, 2H), 4.60 (t, J = 6.0 Hz, 2H), 3.70 (t, J = 16.0 Hz, 2H), 2.82-2.72 (m, 2H), 2.71 (s, 3H) MS: m/z = 533.2 [M+H]+ 1.19 A

2-Fluoro-N-((4-(6-methylpyridin-2-yl)-5-(3-(2-(piperidin-4-yl)ethoxy)quinolin-6-yl)- 1H-imidazol-2-yl)methyl)aniline 1H NMR (DMSO-d6, 400MHz) δ8.90-8.87 (m, 1H), 8.73 (d, J = 2.8 Hz, 1H), 8.70-8.66 (m, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.70 (dd, J = 1.6, 8.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 8.0, 12.2 Hz, 1H), 7.05-6.99 (m, 1H), 6.95-6.87 (m, 1H), 6.72-6.62 (m, 1H), 4.79 (s, 2H), 4.20 (t, J = 6.0 Hz, 2H), 3.24 (d, J = 12.0 Hz, 2H), 2.94 -2.78 (m, 2H), 2.58 (s, 3H), 1.88 (d, J =13.6 Hz, 2H), 1.80-1.74 (m, 3H), 1.49-1.35 (m, 2H) MS: m/z = 537.2 [M+H]+ 1.20 A

N-((5-(3-(2-(3,3-difluoropiperidin-4-yl)ethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl )-1H-imidazol-2-yl)methyl)-2-fluoroaniline 1H NMR (DMSO-d6, 400MHz) δ10.17-10.13 (m, 1H), 9.39-9.36 (m, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.20 (s, 1H), 8.09 ( d, J = 8.8 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.82-7.69 (m, 2H), 7.35 (dd, J = 7.6, 20.0 Hz, 2H), 7.15-6.87 (m , 3H), 6.73-6.63 (m, 1H), 4.80 (s, 2H), 4.34-4.22 (m, 2H), 3.72-3.68 (m, 1H), 3.57-3.37 (m, 1H), 3.24 (d , J = 12.8 Hz, 1H), 3.05-3.01 (m, 1H), 2.57 (s, 3H), 2.28-2.11 (m, 2H), 1.80-1.75 (m, 1H), 1.71-1.52 (m, 1H) ), 1.28-1.19 (m, 1H) MS: m/z = 573.2 [M+H]+ 1.21 A

N-((5-(3-(3-aminopropoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-fluoroaniline 1H NMR (METHANOL-d4, 400MHz) δ = 8.60 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 8.01 (t, J = 8.0 Hz) , 1H), 7.72 (dd, J = 8.4 Hz, J = 2.0Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.09 - 7.01 (m , 2H), 6.87 - 6.81 (m, 1H), 6.79 - 6.72 (m, 1H), 4.86 (s, 2H), 4.62 (t, J = 6.0 Hz, 2H), 3.20 (t, J = 7.2 Hz, 2H), 2.74 (s, 3H), 2.29 - 2.19 (m, 2H) MS: m/z = 484.2 [M+H]+ 1.22 A

N-((5-(3-(4-Aminobutoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-fluoroaniline 1H NMR (METHANOL-d4, 400MHz) δ = 8.55 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.78 (t, J = 8.0 Hz , 1H), 7.72 (dd, J = 2.0, 8.4 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.07 - 6.99 (m, 2H) , 6.83 - 6.77 (m, 1H), 6.76 - 6.69 (m, 1H), 4.79 (s, 2H), 4.55 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H), 2.68 (s, 3H), 2.02 - 1.94 (m, 2H), 1.93 - 1.84 (m, 2H) MS: m/z = 498.2 [M+H]+ 1.23 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoroaniline MS: m/z = 469 [M+H] ⁺ 1.24 A

2-Fluoro-N-((4-(6-methylpyridin-2-yl)-5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline 1H NMR (MeOD, 400 MHz) δ9.03 (d, J = 8.4 Hz, 1H), 8.53 (s, 1H), 8.33-8.18 (m, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.53-7.32 (m, 2H), 7.09-6.95 (m, 2H), 6.87-6.66 (m, 2H), 4.80 (s, 2H), 3.05 (s, 3H), 2.67 (s, 3H) MS: m/z =424.1 [M+H]+ 1.25 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3-Fluoroaniline 1H NMR (MeOD, 400MHz) δ9.17 (d, J = 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.49 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H) ), 8.09-7.93 (m, 2H), 7.64-7.47 (m, 2H), 7.24-7.08 (m, 1H), 6.59 (dd, J = 2.0, 8.4 Hz, 1H), 6.55-6.50 (m, 1H) ), 6.46 (dt, J = 2.4, 8.4 Hz, 1H), 4.80 (s, 2H), 4.63 (t, J = 4.8 Hz, 2H), 3.53 (t, J = 4.8 Hz, 2H), 2.73 (s , 3H) MS: m/z = 469.1 [M+H]+ 1.26 A

N-((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3-Fluoroaniline 1H NMR (MeOD, 400MHz) δ9.18 (d, J = 2.8 Hz, 1H), 8.73 (d, J = 2.8 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.05 (dd, J = 1.6, 8.8 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.61-7.54 (m, 1H), 7.51 (d, J = 7.8 Hz , 1H), 7.22-7.11 (m, 1H), 6.59 (dd, J = 1.6, 8.0 Hz, 1H), 6.52 (td, J = 2.4, 11.6 Hz, 1H), 6.46 (dt, J = 2.0, 8.4 Hz, 1H), 4.79 (s, 2H), 4.50 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.72 (s, 3H), 2.31 (q, J = 6.4 Hz, 2H) MS: m/z = 483.2 [M+H]+ 1.27 A

N-((5-(3-(2-(2-aminoethoxy)ethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole -2-yl)methyl)-3-fluoroaniline 1H NMR (MeOD, 400MHz) δ9.23 (d, J = 2.4 Hz, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.20 (t, J = 8.0 Hz, 1H), 8.07 (dd, J = 1.6, 8.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.25-7.16 (m, A1H), 6.66 (dd, J = 2.0, 8.4 Hz, 1H), 6.60 (td, J = 2.4, 11.6 Hz, 1H), 6.52 (dt, J = 2.4, 8.4 Hz, 1H), 4.87 (s, 2H), 4.62-4.54 (m, 2H), 4.07-3.98 (m, 2H), 3.89-3.79 (m, 2H), 3.17 (t, J = 4.8 Hz , 2H), 2.80 (s, 3H) MS: m/z = 513.2 [M+H]+ 1.28 A

N-((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Fluoroaniline 1H NMR (MeOD, 400MHz) δ9.17 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.03 (d , J = 8.8 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.59-7.45 (m, 2H), 7.10-6.97 (m, 2H), 6.89-6.67 (m, 2H), 4.84 ( s, 2H), 4.50 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.77-2.66 (m, 3H), 2.38-2.25 (m, 2H) MS: m/ z = 483.2 [M+H]+ 1.29 A

N-((5-(3-(2-(2-aminoethoxy)ethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole -2-yl)methyl)-2-fluoroaniline 1H NMR (MeOD, 400MHz) δ8.73 (d, J = 2.8 Hz, 1H), 8.17-8.05 (m, 2H), 7.83 (d, J = 2.4 Hz, 1H), 7.79-7.68 (m, 2H) , 7.39 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.08-6.98 (m, 2H), 6.84-6.68 (m, 2H), 4.80 (s, 2H), 4.41-4.32 (m, 2H), 4.04-3.94 (m, 2H), 3.86-3.78 (m, 2H), 3.17 (t, J = 4.8 Hz, 2H), 2.68 (s, 3H) MS: m/z = 513.2 [M+H]+ 1.31 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,3-difluoroaniline 1H NMR (MeOD, 400MHz) δ9.23 (d, J = 2.4 Hz, 1H), 8.87 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.16-8.04 (m, 2H), 7.75-7.62 (m, 2H), 7.04-6.93 (m, 1H), 6.70-6.55 (m, 2H), 4.90 (s, 2H), 4.66 (t, J = 4.8 Hz, 2H), 3.54 (t, J = 4.8 Hz, 2H), 2.77 (s, 3H) MS: m/z = 487.1 [M+H]+ 1.32 A

N-((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,3-difluoroaniline 1H NMR (MeOD, 400MHz) δ9.20 (d, J = 2.8 Hz, 1H), 8.75 (d, J = 2.8 Hz, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.11-7.93 (m, 2H), 7.66-7.47 (m, 2H), 6.98 (ddt, J = 2.0, 6.0, 8.4 Hz, 1H), 6.69-6.52 (m, 2H), 4.86 (s, 2H), 4.51 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.73 (s, 3H), 2.32 (q, J = 6.4 Hz, 2H) MS : m/z = 501.2 [M+H]+ 1.33 A

N-((5-(3-(2-(2-aminoethoxy)ethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole -2-yl)methyl)-2,3-difluoroaniline 1H NMR (MeOD, 400MHz) δ8.71 (d, J = 2.8 Hz, 1H), 8.10 (dd, J = 3.6, 5.2 Hz, 2H), 7.81-7.74 (m, 2H), 7.70 (dd, J = 2.0, 8.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.05-6.95 (m, 1H), 6.64-6.54 (m, 2H), 4.80 (s, 2H), 4.38-4.33 (m, 2H), 4.02-3.97 (m, 2H), 3.86-3.78 (m, 2H), 3.18 (t, J = 5.2 Hz, 2H), 2.69 (s, 3H) MS: m/z = 531.2 [M+H]+ 1.34 A

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinolin-2-ol 1H NMR (MeOD, 400MHz) δ7.98 (d, J = 9.4 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.67 (dd, J = 2.0, 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.09-6.96 (m , 2H), 6.81-6.64 (m, 3H), 4.79 (s, 2H), 2.68 (s, 3H) MS: m/z = 426.1 [M+H]+ 1.35 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base)-2,4-difluoroaniline 1H NMR (MeOD, 400MHz) δ = 8.65 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.82-7.74 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 5.91-6.97 (m, 1H), 6.85-6.75 (m, 2H), 4.78-4.71 (m, 4H), 3.51-3.45 (m, 2H), 2.68 (s, 3H) MS: m/z = 488.1 [M+H]+ 1.36 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base)-3,5-difluoroaniline 1H NMR (MeOD, 400MHz) δ8.66 (s, 1H), 8.20-8.07 (m, 2H), 7.97 (t, J = 8.4 Hz, 1H), 7.76 (dd, J = 2.2, 8.4 Hz, 1H) , 7.57 (d, J = 7.6 Hz, 1H), 7.52-7.45 (m, 1H), 6.39-6.31 (m, 2H), 6.24 (m, 1H), 4.78-4.74 (m, 4H), 3.51-3.46 (m, 2H), 2.74 (s, 3H) MS: m/z = 488.2 [M+H]+ 1.37 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-3-fluoroaniline 1H NMR (MeOD, 400 MHz) δ8.66 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.85-7.73 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.21-7.11 (m, 1H), 6.56-6.41 (m, 3H), 4.78-4.72 (m, 4H) , 3.51-3.45 (m, 2H), 2.69 (s, 3H) MS: m/z =470.3 [M+H]+ 1.38 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base)-2,3-difluoroaniline 1H NMR (MeOD, 400 MHz) δ8.68-8.65 (m, 1H), 8.16-8.10 (m, 3H), 7.78-7.68 (m, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.05 -6.95 (m, 1H), 6.70-6.57 (m, 2H), 4.91 (s, 2H), 4.81-4.73 (m, 2H), 3.53-3.46 (m, 2H), 2.78 (s, 3H) MS: m/z =488.3 [M+H]+ 1.39 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,4-difluoroaniline 1H NMR (MeOD, 400 MHz) δ9.18 (d, J = 2.8 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.08-7.97 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.00-6.92 (m, 1H), 6.88-6.80 (m, 2H), 4.82 (s, 2H), 4.63 (t, J = 4.8 Hz, 2H), 3.54 (t, J = 4.8 Hz, 2H), 2.73 (s, 3H) MS: m/ z=487.1 [M+H]+ 1.40 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-3,5-difluoroaniline 1H NMR (MeOD, 400 MHz) δ9.09 (d, J = 2.8 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.02-7.89 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.40-6.28 (m, 2H), 6.27-6.17 (m, 1H), 4.75 (s, 2H), 4.59 (t, J = 4.8 Hz, 2H), 3.53 (t, J = 4.4 Hz, 2H), 2.72 (s, 3H) MS: m/ z=487.2 [M+H]+ 1.41 A

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)-N-methylquinoline -3-Carboxamide 1H NMR (MeOD, 400 MHz) δ9.33 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 2.0, 8.8 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.08-6.98 (m, 2H), 6.80 (t, J = 7.6 Hz, 1H), 6.76-6.69 (m, 1H), 4.80 (s, 2H), 3.00 (s, 3H) ), 2.68 (s, 3H) MS: m/z =467.2 [M+H]+ 1.42 A

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)-N,N-dimethyl quinoline-3-carboxamide 1H NMR (MeOD, 400 MHz) δ9.02 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.95 (dd, J = 2.0, 8.8 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.07-6.99 (m, 2H), 6.82-6.76 (m, 1H), 6.76-6.69 (m, 1H), 4.79 (s, 2H), 3.19 (s, 3H), 3.11 (s, 3H), 2.68 (s, 3H) MS: m/z =481.2 [M+H]+ 1.43 A

(R)-N-((5-(3-((1-aminopropan-2-yl)oxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl) -1H-imidazol-2-yl)methyl)-2-fluoroaniline 1H NMR (MeOD, 400 MHz) δ8.61 (s, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.10 (s, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.75 ( d, J = 8.6 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.09-6.99 (m, 2H), 6.81 (t, J = 7.8 Hz, 1H), 6.73-6.75 (m, 1H), 5.63-5.65 (m, 1H), 4.82 (s, 2H), 3.43-3.35 (m, 2H), 2.70 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H) MS: m/z =484.2 [M+H]+ 1.44 A

(S)-N-((5-(3-((1-aminopropan-2-yl)oxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl) -1H-imidazol-2-yl)methyl)-2-fluoroaniline 1H NMR (MeOD, 400MHz) δ8.62 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H) ), 7.75 (dd, J = 1.6, 8.4 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.10-6.97 (m, 2H), 6.86 -6.68 (m, 2H), 5.65-5.63 (m, 1H), 4.82 (s, 2H), 3.42-3.32 (m, 2H), 2.70 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H ) MS: m/z = 484.2 [M+H]+ 1.45 A

N-((5-(3-((1-amino-2-methylpropan-2-yl)oxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl) )-1H-imidazol-2-yl)methyl)-2-fluoroaniline MS: m/z = 497 [M+H] ⁺ 1.46 A

N-((5-(3-(Tetrahydroazera-3-yloxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2- yl)methyl)-2-fluoroaniline 1H NMR (MeOD, 400 MHz) δ8.68 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.81-7.71 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.08-6.97 (m, 2H), 6.85-6.77 (m, 1H), 6.76-6.66 (m, 1H) , 5.76-5.62 (m, 1H), 4.76 (s, 2H), 4.64-4.59 (m, 2H), 4.34-4.30 (m, 2H), 2.65 (s, 3H) MS: m/z =482.2 [M +H]+ 1.47 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-(methoxymethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,3-difluoroaniline 1H NMR (300 MHz, Methanol-d4) δ: 1.90-2.03 (m, 4H), 3.05-3.10 (m, 2H), 3.51 (s, 3H), 4.25-4.28 (m, 2H), 4.65 (s, 2H), 4.90-4.92 (m, 2H), 6.58-6.67 (m, 2H), 6.97-7.01 (m, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.5 Hz , 1H), 7.73-7.79 (m, 2H), 7.90 (s, 1H), 8.13-8.19 (m, 2H), 8.77 (d, J = 2.7 Hz, 1H). MS m/z [MH]- ( ESI): 543 1.48 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline 1H NMR (300 MHz, Methanol-d4) δ: 1.91-2.03 (m, 4H), 3.05-3.09 (m, 2H), 3.29-3.31 (m, 2H), 4.23-4.26 (m, 2H), 6.57- 6.66 (m, 2H), 6.95-7.03 (m, 1H), 7.66-7.82 (m, 4H), 7.96-8.09 (m, 1H), 8.12-8.19 (m, 1H), 8.20 (s, 1H), 8.71 (d, J = 2.7 Hz, 1H). MS: m/z [M+H]+ (ESI): 569 1.49 A

N-((5-(3-(4-Aminobutoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2, 3-Difluoroaniline 1H NMR (400 MHz, Methanol-d4) δ: 1.93-2.03 (m, 4H), 3.06-3.09 (m, 2H), 4.24-4.27 (m, 2H), 4.84 (s, 2H), 6.59-6.64 ( m, 2H), 6.97-6.99 (m, 1H), 7.49-7.53 (m, 2H), 7.72-7.75 (m, 1H), 7.84-7.87 (m, 2H), 8.12-8.15 (m, 2H), 8.71-8.74 (m, 2H). MS: m/z [M+H]+ (ESI): 501 1.50 A

N-((5-(3-(2-aminoethyl)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2,3-difluoroaniline 1H NMR (300 MHz, Methanol-d4) δ: 2.64-2.70 (m, 3H), 3.47-3.61 (m, 4H), 4.83 (s, 2H), 6.57-6.65 (m, 2H), 6.93-7.03 ( m, 1H), 7.37-7.47 (m, 2H), 7.80-7.85 (m, 1H), 7.92-7.95 (m, 1H), 8.22 (d, J = 5.7 Hz, 1H), 8.34 (s, 1H) , 8.94 (s, 1H). MS: m/z [M+H]+ (ESI): 472 1.51 A

N-((5-(3-(Aminomethyl)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)- 2,3-Difluoroaniline MS: m/z = 457 [M+H] ⁺ 1.52 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(3-fluoro-6-methylpyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline MS: m/z = 504 [M+H] ⁺ 1.53 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(methoxymethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,3-difluoroaniline MS: m/z = 516 [M+H] ⁺ 1.54 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2, 3-Difluoroaniline 1H NMR (300 MHz, Methanol-d4) δ: 3.49-3.53 (m, 2H), 4.46-4.49 (m, 2H), 4.86 (s, 2H), 6.56-6.65 (m, 2H), 6.95-7.01 ( m, 1H), 7.50-7.54 (m, 2H), 7.76-7.79 (m, 1H), 7.85-7.94 (m, 2H), 8.14-8.19 (m, 2H), 8.72 (d, J = 5.1 Hz, 1H), 8.83 (d, J = 2.7 Hz, 1H). MS: m/z [M+H]+ (ESI): 473 1.55 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline 1H NMR (300 MHz, Methanol-d4) δ: 3.48-3.54 (m, 2H), 4.41-4.44 (m, 2H), 4.64-4.78 (m, 1H), 4.80-4.88 (m, 1H), 6.57- 6.65 (m, 2H), 6.94-7.00 (m, 1H), 7.64-7.67 (m, 1H), 7.80-7.83 (m, 3H), 7.91-8.00 (m, 1H), 8.12-8.20 (m, 1H) ), 8.21 (s, 1H), 8.79-8.80 (m, 1H). MS: m/z [M+H]+ (ESI): 541 1.56 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline 1H NMR (300 MHz, Methanol-d4) δ: 2.60 (s, 3H), 3.50-3.56 (m, 2H), 4.43-4.47 (m, 2H), 4.78-4.88 (m, 2H), 6.58-6.68 ( m, 2H), 6.97-7.04 (m, 1H), 7.25-7.29 (m, 1H), 7.42-7.48 (m, 1H), 7.74-7.77 (m, 1H), 7.86-7.87 (m, 1H), 8.13-8.15 (m, 2H), 8.79 (s, 1H). MS: m/z [M+H]+ (ESI): 505 1.57 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2 ,3-Difluoroaniline MS: m/z = 473 [M+H] ⁺ 1.58 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methan base)-2,3-difluoroaniline MS: m/z = 473 [M+H] ⁺ 1.59 A

N-((5-(3-((1r,3r)-3-aminocyclobutoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H- Imidazol-2-yl)methyl)-2-fluoroaniline 1H NMR (MeOD, 400 MHz) δ8.60 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.73 ( dd, J = 2.0, 8.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.08-6.99 (m, 2H), 6.81 (t, J = 7.6 Hz, 1H), 6.77-6.70 (m, 1H), 5.67-5.58 (m, 1H), 4.82 (s, 2H), 4.10-4.01 (m, 1H), 2.76 (t, J = 6.4 Hz, 4H), 2.70 (s, 3H) MS: m/z =496.2 [M+H]+ 1.60 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,3-difluoroaniline MS: m/z = 523 [M+H] ⁺ 1.61 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoroaniline MS: m/z = 620 [M+H] ⁺ 1.62 A

N-((5-(3-(2-aminoethyl)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl )-2-Fluoroaniline MS: m/z = 453 [M+H] ⁺ 1.63 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoroaniline MS: m/z = 487 [M+H] ⁺ 1.64 A

N-(2-Aminoethyl)-6-(2-(((2-fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 5-yl)quinoline-3-carboxamide 1H NMR (MeOD, 400 MHz) δ9.62 (d, J = 2.0 Hz, 1H), 9.48 (s, 1H), 8.60 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.25 ( d, J = 8.8 Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.09-6.97 ( m, 2H), 6.85-6.78 (m, 1H), 6.77-6.67 (m, 1H), 4.83 (s, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.27 (t, J = 5.6 Hz , 2H), 2.70 (s, 3H) MS: m/z =496.2 [M+H]+ 1.65 A

N-(2-Aminoethyl)-6-(2-(((2-fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 5-yl)-N-methylquinoline-3-carboxamide 1H NMR (MeOD, 400 MHz) δ9.08 (s, 1H), 8.58 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.97 ( dd, J = 2.0, 8.8 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.06- 6.99 (m, 2H), 6.80 (t, J = 8.4 Hz, 1H), 6.76-6.66 (m, 1H), 4.79 (s, 2H), 3.95-3.86 (m, 2H), 3.28-3.32 (m, 2H), 3.14 (s, 3H), 2.67 (s, 3H) MS: m/z =510.2 [M+H]+ 1.66 A

2-Amino-1-(6-(2-(((2-fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl )quinolin-3-yl)ethan-1-one MS: m/z = 466 [M+H] ⁺ 1.67 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoroaniline ¹ H NMR (MeOD, 400MHz) δ8.63 (s, 1H), 8.17-8.07 (m, 2H), 7.94-7.87 (m, 1H), 7.82 (dd, J = 1.6, 8.4 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.08-6.99 (m, 2H), 6.88-6.56 (m, 3H), 4.78 (s, 2H), 4.77- 4.73 (m, 2H), 3.49-3.45 (m, 2H) MS: m/z = 506.2 [M+H] ⁺ 1.68 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3-fluoroaniline ¹ H NMR (MeOD, 400MHz) δ 8.68 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.96-7.90 (m, 1H), 7.81 (dd, J = 2.0, 8.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.23-7.13 (m, 1H), 6.78 (t, J = 55.2 Hz, 1H), 6.57-6.43 (m, 3H), 4.84-4.84 (m, 2H), 4.78-4.73 (m, 2H), 3.51-3.45 (m, 2H) MS: m/z = 506.2 [M+H] ⁺ 1.69 A

N-(2-Aminoethyl)-6-(4-(6-(difluoromethyl)pyridin-2-yl)-2-(((2-fluorophenyl)amino)methyl)- 1H-imidazol-5-yl)quinoline-3-carboxamide ¹ H NMR (MeOD, 400 MHz) δ9.50 (d, J = 1.6 Hz, 1H), 9.17 (s, 1H), 8.51 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.14 (dd, J = 1.6, 8.8 Hz, 1H), 7.99-7.92 (m, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.12-6.99 ( m, 2H), 6.92-6.60 (m, 3H), 4.91 (s, 2H), 3.77 (t, J = 6.0 Hz, 2H), 3.25 (t, J = 6.0 Hz, 2H) MS: m/z = 532.1 [M+H] ⁺ 1.70 A

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-3-carboxylic acid methyl ester ¹ H NMR (MeOD, 400 MHz) δ 9.67 (s, 1H), 9.60 (s, 1H), 8.66 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.37-8.35 (m, 1H) ), 8.06 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.08-7.08 (m, 2H), 6.87 (t , J = 8.0 Hz, 1H), 6.79-6.73 (m, 1H), 4.85 (s, 2H), 4.09 (s, 3H), 2.72 (s, 3H) MS: m/z =468.2 [M+H] ⁺ 1.71 A

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-3-carboxylic acid ¹ H NMR (MeOD, 400 MHz) δ 9.33 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.93 (dd, J = 1.6 , 8.8 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.99-6.94 (m, 2H ), 6.87-6.83 (m, 1H), 6.66-6.60 (m, 1H), 4.57 (s, 2H), 2.49 (s, 3H) MS: m/z =454.2 [M+H] ⁺ 1.72 A

2-Aminoethyl 6-(2-(((2-fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline Linen-3-carboxylate ¹ H NMR (MeOD, 400MHz) δ 9.77 (s, 1H), 9.75 (s, 1H), 8.67 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 8.8 Hz , 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.08 - 6.99 (m, 2H), 6.81 -6.87 (m, 1H), 6.77-6.71 (m, 1H), 4.85 (s, 2H), 4.73 (t, J = 4.8 Hz, 2H), 3.48 (t, J = 4.8 Hz, 2H), 2.72 ( s, 3H) MS: m/z = 497.1 [M+H] ⁺ 1.73 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2- Fluoroaniline ¹ H NMR (MeOD, 400 MHz) δ 8.91 (d, J = 2.4 Hz, 1H), 8.71 (d, J = 5.6 Hz, 1H), 8.26 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.14 (s, 1H), 7.90-7.81 (m, 2H), 7.54-7.47 (m, 2H), 7.08-6.98 (m, 2H), 6.80 (t, J = 7.6 Hz, 1H), 6.77 -6.69 (m, 1H), 4.83 (s, 2H), 4.50 (t, J = 4.8 Hz, 2H), 3.50 (t, J = 4.8 Hz, 2H) MS: m/z =455.2 [M+H] ⁺ 1.74 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2 -Fluoroaniline ¹ H NMR (MeOD, 400MHz) δ 8.69-8.67 (m, 1H), 8.63 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.83 (dt, J = 1.6, 7.6 Hz, 1H), 7.77 (dd, J = 2.0, 8.4 Hz, 1H), 7.52-7.45 (m, 2H), 7.06-6.98 (m, 2H), 6.84-6.77 (m , 1H), 6.68-6.74 (m, 1H), 4.77 (s, 2H), 4.76-4.73 (m, 2H), 7.42 (t, J = 4.8 Hz, 2H) MS: m/z = 456.1 [M+ H] ⁺ 1.75 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2 ,4-Difluoroaniline MS m/z [M+H] ⁺ (ESI): 474; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.47-3.50 (m, 2H), 4.76-4.78 (m, 4H), 6.78- 6.86 (m, 2H), 6.92-6.97 (m, 1H), 7.48-7.53 (m, 2H), 7.77-7.88 (m, 2H), 8.12 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.65 (s, 1H), 8.70 (d, J = 5.2 Hz, 1H). 1.76 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-3 -Fluoroaniline MS m/z [M+H] ⁺ (ESI): 456; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.48-3.50 (m, 2H), 4.75-4.78 (m, 4H), 6.43- 6.56 (m, 3H), 7.14-7.20 (m, 1H), 7.51-7.54 (m, 2H), 7.78-7.80 (m, 1H), 7.84-7.89 (m, 1H), 8.10 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.72 (s, 1H), 8.73 (d, J = 1.6 Hz, 1H). 1.77 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-3 ,5-Difluoroaniline MS m/z [M+H] ⁺ : 473 1.78 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2, 4-Difluoroaniline MS m/z [M+H] ⁺ (ESI): 373; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 3.49-3.52 (m, 2H), 4.45-4.49 (m, 2H), 4.81 ( s, 2H), 6.80-6.85 (m, 2H), 6.92-6.99 (m, 1H), 7.51-7.54 (m, 2H), 7.77-7.94 (m, 3H), 8.15-8.19 (m, 2H), 8.72-8.74 (m, 1H), 8.84 (s, 1H). 1.79 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-3- Fluoroaniline MS m/z [M+H] ⁺ (ESI): 455; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 3.49-3.52 (m, 2H), 4.45-4.48 (m, 2H), 4.78 ( s, 2H), 6.45-6.57 (m, 3H), 7.13-7.19 (m, 1H), 7.47-7.53 (m, 2H), 7.76-7.91 (m, 3H), 8.14-8.18 (m, 2H), 8.72-8.74 (m, 1H), 8.82 (s, 1H). 1.80 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)-3, 5-Difluoroaniline MS m/z [M+H] ⁺ (ESI): 473; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.49-3.51 (m, 2H), 4.44-4.47 (m, 2H), 4.75 ( s, 2H), 6.21-6.24 (m, 1H), 6.26-6.37 (m, 2H), 7.50-7.54 (m, 2H), 7.75-7.78 (m, 1H), 7.86-7.89 (m, 2H), 8.14-8.17 (m, 2H), 8.71-8.72 (m, 1H), 8.81 (s, 1H). 1.81 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,4-difluoroaniline ¹ H NMR (MeOD, 400 MHz) δ8.68 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.97-7.90 (m, 1H) , 7.81 (dd, J = 2.0, 8.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.02-6.57 (m, 4H), 4.87 ( s, 2H), 4.78-4.72 (m, 2H), 3.48 (t, J = 4.8 Hz, 2H) MS: m/z =524.2 [M+H] ⁺ 1.82 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3,5-difluoroaniline ¹ H NMR (MeOD, 400 MHz) δ8.68 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.97-7.89 (m, 1H) , 7.82 (dd, J = 2.0, 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 6.93-6.62 (m, 1H), 6.38- 6.31 (m, 2H), 6.31-6.23 (m, 1H), 4.80-4.73 (m, 4H), 3.48 (t, J = 4.8 Hz, 2H) MS: m/z =524.2 [M+H] ⁺ 1.83 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methan base)-2,4-difluoroaniline MS: m/z = 473 [M+H] ⁺ 1.84 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methan base)-3,5-difluoroaniline MS: m/z = 473 [M+H] ⁺ 1.85 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,5-difluoroaniline ¹ H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.13 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.90 (t, J = 15.6 Hz, 1H), 7.82 (dd , J = 8.4, 12.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.0-6.97 (m, 1H), 6.87-6.57 (m, 2H), 6.41-6.35 (m, 1H), 4.78-4.73 (m, 4H), 3.47 (t, J = 9.6 Hz, 1H) MS: m/z = 524.2 [M+H] ⁺ 1.86 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3,4-difluoroaniline ¹ H NMR (MeOD, 400 MHz) δ 8.62 (s, 1H), 8.13-8.09 (m, 2H), 7.89 (t, J = 15.6 Hz, 1H), 7.82 (dd, J = 2.0, 8.4 Hz, 1H ), 7.65 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.05 (q, J = 28.8 Hz, 1H), 6.92-6.58 (m, 2H), 6.49-6.46 (m, 1H), 4.75 (t, J = 10 Hz, 2H), 4.64 (s, 2H), 3.47 (t, J = 10.4 Hz, 2H) MS: m/z =524.2 [M+H] ⁺ 1.87 A

6-(2-(((2-Fluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)-N-(2-hydroxyl) Ethyl)quinoline-3-carboxamide ¹ H NMR (MeOD, 400 MHz) δ 9.35 (d, J = 2.0 Hz, 1H), 8.83 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 2.0, 8.8 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.06-7.00 (m, 2H), 6.82-6.78 (m, 1H), 6.75-6.69 (m, 1H), 4.80 (s, 2H), 3.77 (t, J = 5.6 Hz , 2H), 3.59 (t, J = 5.6 Hz, 2H), 2.68 (s, 3H) MS: m/z =497.2 [M+H] ⁺ 1.88 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)-2-fluoroaniline ¹ H NMR (MeOD, 400MHz) δ 8.89 (d, J = 2.8 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.19-8.09 (m, 2H), 8.04 (d, J = 8.0 Hz , 1H), 7.97-7.93 (m, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 2H), 6.88-6.70 (m, 3H), 4.83 (s, 2H), 4.53 (t, J = 4.8 Hz, 2H), 3.53 (t, J = 4.8 Hz, 2H) MS: m/z = 506.1 [M+H] ⁺ 1.89 A

2-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)methyl benzoate ¹ H NMR (MeOD, 400MHz) δ 8.67 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 6.4 Hz, 1H) ), 7.92 (t, J = 8.0 Hz, 1H), 7.79 (dd, J = 2.0, 8.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H) ), 7.45 (t, J = 7.6 Hz, 1H), 6.93-6.63 (m, 3H), 5.03 (s, 2H), 4.78-4.70 (m, 2H), 3.90 (s, 3H), 3.47 (s, 2H) MS: m/z = 546.2 [M+H] ⁺ 1.90 A

2-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.16-8.07 (m, 2H), 7.98 (dd, J = 1.6, 8.0 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H) , 7.79 (dd, J = 1.6, 8.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H) , 6.88-6.56 (m, 3H), 4.91 (s, 2H), 4.75 (t, J = 5.2 Hz, 2H), 3.46 (t, J = 5.2 Hz, 2H) MS: m/z = 532.2 [M+ H] ⁺ 1.91 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)methyl benzoate ¹ H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.81 (dd, J = 2.0, 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.00 (dd, J = 1.6, 8.0 Hz, 1H), 6.76 (t, J = 54.8 Hz, 1H), 4.82-4.80 (m, 2H), 4.78-4.71 (m, 2H), 3.87 (s, 3H), 3.48 (t, J = 3.6 Hz, 2H) MS: m/z = 546.2[M+H ] ⁺ 1.92 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.16-8.10 (m, 2H), 7.90 (t, J = 15.6 Hz, 1H), 7.82 (dd, J = 2.0, 8.4 Hz, 1H ), 7.67 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.46-7.35 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 6.98 (dd , J = 1.6, 8.4 Hz, 1H), 6.71 (t, J = 55.2 Hz, 1H), 4.78-4.72 (m, 4H), 3.47 (t, J = 10.0 Hz, 2H) MS: m/z = 532.2 [M+H] ⁺ 1.93 A

4-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)methyl benzoate ¹ H NMR (MeOD, 400MHz) δ 8.68 (s, 1H), 8.21-8.12 (m, 2H), 7.94 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 6.94-6.64 (m, 3H), 4.94 (s, 2H) , 4.77 (t, J = 4.4 Hz, 2H), 3.83 (s, 3H), 3.45-3.51 (m, 2H) MS: m/z = 546.1 [M+H] ⁺ 1.94 A

4-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.62 (s, 1H), 8.13-8.11 (m, 2H), 7.94-7.85 (m, 3H), 7.81 (dd, J = 2.0, 8.4 Hz, 1H), 7.67 ( d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 6.88-6.56 (m, 3H), 4.79 (s, 2H), 4.77-4.72 (m, 2H), 3.47 ( t , J = 5.2 Hz, 2H) MS: m/z = 532.1 [M+H] ⁺ 1.95 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)methyl benzoate ¹ H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.18-8.07 (m, 3H), 7.77-7.68 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.50-7.43 (m, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.16-7.08 (m, 1H), 4.87 (s, 2H), 4.77 (t, J = 10.0 Hz, 2H), 3.87 (s, 3H), 3.49 (t, J = 9.6 Hz, 2H), 2.78 (s, 3H) MS: m/z = 510.2[M+H] ⁺ 1.96 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)benzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.80-7.74 (m, 2H), 7.44-7.36 (m, 3H), 7.35-7.24 (m, 2H), 6.98 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 4.79 (s, 2H), 4.77-4.72 (m, 2H), 3.52 -3.43 (m, 2H), 2.67 (s, 3H) MS: m/z = 496.2[M+H] ⁺ 1.97 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)methyl benzoate MS m/z [M+H] ⁺ (ESI): 509; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.69 (s, 3H), 3.48-3.51 (m, 2H), 3.88-3.92 ( m, 3H), 4.43-4.46 (m, 2H), 4.79 (s, 2H), 6.98-7.02 (m, 1H), 7.28-7.33 (m, 2H), 7.38-7.43 (m, 3H), 7.66- 7.78 (m, 2H), 7.85-7.86 (m, 1H), 8.11-8.14 (m, 2H), 8.79 (s, 1H). 1.98 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzoic acid MS m/z [M+H] ⁺ (ESI): 495; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.71 (s, 3H), 3.48-3.51 (m, 2H), 4.43-4.48 ( m, 2H), 4.81 (s, 2H), 6.98-7.01 (m, 1H), 7.28-7.33 (m, 2H), 7.39-7.44 (m, 3H), 7.73-7.78 (m, 2H), 7.86- 7.89 (m, 1H), 8.12-8.14 (m, 2H), 8.95 (s, 1H). 1.99 A

4-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)methyl benzoate MS m/z [M+H] ⁺ (ESI): 509; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.68 (s, 3H), 3.48-3.51 (m, 2H), 3.82-3.84 ( m, 3H), 4.44 (t, J = 5.1 Hz, 2H), 4.78 (s, 2H), 6.76-6.80 (m, 2H), 7.30-7.40 (m, 2H), 7.72-7.89 (m, 5H) , 8.09-8.15 (m, 2H), 8.80 (s, 1H). 1.100 A

4-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzoic acid MS m/z [M+H] ⁺ (ESI): 495; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.70 (s, 3H), 3.36-3.50 (m, 2H), 4.44 (t, J = 5.2 Hz, 2H), 4.82 (s, 2H), 6.76-6.79 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.73- 7.78 (m, 2H), 7.80-7.89 (m, 3H), 8.11-8.13 (m, 2H), 8.78 (s, 1H). 1.101 A

2-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)methyl benzoate MS m/z [M+H] ⁺ (ESI): 509.15; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.70 (s, 3H), 3.33 (s, 2H), 3.49-3.51 (m, 2H), 3.91 (s, 3H), 4.44 (t, J = 4.8 Hz, 2H), 6.73-6.77 (m, 1H), 6.85 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.42-7.46 (m, 2H), 7.72-7.85 (m, 3H), 7.96-7.99 (m, 1H), 8.11-8.13 (m, 2H), 8.79 (s, 1H). 1.102 A

2-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzoic acid MS m/z [M+H] ⁺ (ESI): 495.15; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.70 (s, 3H), 3.33 (s, 2H), 3.50 (t, J = 4.8 Hz, 2H), 4.45 (t, J = 4.8 Hz, 2H), 6.73-6.76 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H) , 7.41-7.45 (m, 2H), 7.73-7.86 (m, 3H), 7.99-8.01 (m, 1H), 8.11-8.13 (m, 2H), 8.79 (s, 1H). 1.103 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid methyl ester ¹ H NMR (MeOD, 400MHz) δ 8.66 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.92 (t, J = 7.6 Hz, 1H), 7.76 (d , J = 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 4.86 (s, 2H), 4.79-4.73 (m, 2H), 3.89 (s, 3H), 3.50-3.48 (m, 2H) , 2.72 (s, 3H) MS: m/z = 528.2 [M+H] ⁺ 1.104 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.82-7.73 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 6.4 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.00 (t , J = 7.2 Hz, 1H), 4.80 (s, 2H), 4.78-4.72 (m, 2H), 3.52-3.42 (m, 2H), 2.67 (s, 3H) MS: m/z = 514.2 [M+ H] ⁺ 1.105 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-4-fluorobenzoic acid methyl ester ¹ H NMR (MeOD, 400MHz) δ 8.66 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.91 (t, J = 8.0 Hz, 1H), 7.79-7.75 (m, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 3H), 7.16 (dd, J = 8.8, 11.4 Hz, 1H), 4.86 (s, 2H) , 4.79-4.73 (m, 2H), 3.85 (s, 3H), 3.50-3.48 (m, 2H), 2.72 (s, 3H) MS: m/z = 528.2 [M+H] ⁺ 1.106 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-4-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.64 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.85-7.74 (m, 2H), 7.49 -7.40 (m, 3H), 7.37 (d, J = 8.0 Hz, 1H), 7.14 (dd, J = 9.2, 11.2 Hz, 1H), 4.83 (s, 2H), 4.78-4.71 (m, 2H), 3.51-3.44 (m, 2H), 2.69 (s, 3H) MS: m/z = 514.2 [M+H] ⁺ 1.107 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-5-fluorobenzoic acid methyl ester ¹ H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.77 (dd, J = 2.0, 8.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.24-7.20 (m, 1H), 7.07-7.01 (m, 1H), 6.73 (td, J = 2.4, 11.2 Hz, 1H), 4.78 (s, 2H), 4.77-4.74 (m, 2H), 3.87 (s, 3H), 3.48 (t, J = 4.8 Hz, 2H), 2.71 (s, 3H) MS: m/z = 528.2[M+H] ⁺ 1.108 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-5-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.16-8.04 (m, 2H), 7.86-7.71 (m, 2H), 7.37 (dd, J = 8.0, 14.8 Hz, 2H), 7.22 (s, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.76-6.65 (m, 1H), 4.78-4.69 (m, 4H), 3.50-3.44 (m, 2H), 2.66 (s, 3H) ) MS: m/z = 514.2[M+H] ⁺ 1.109 A

5-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid methyl ester ¹ H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.83-7.71 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 3.2, 5.6 Hz, 1H), 7.11-7.02 (m, 1H), 7.00-6.92 (m, 1H), 4.77-4.73 (m, 2H), 4.72 (s, 2H), 3.88 (s, 3H), 3.50-3.44 (m, 2H), 2.67 (s, 3H) MS: m/z = 528.2[M+H] ⁺ 1.110 A

5-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.81-7.72 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 3.2, 5.6 Hz, 1H), 7.09-7.00 (m, 1H), 6.99-6.91 (m, 1H), 4.75 (d, J = 5.2Hz, 2H), 4.73 (s, 2H), 3.51-3.44 (m, 2H), 2.67 (s, 3H) MS: m/z = 514.2[M+ H] ⁺ 1.111 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan Methyl)amino)-2-fluorobenzoate MS m/z [M+H] ⁺ (ESI): 527; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.69 (s, 3H), 3.49-3.51 (m, 2H), 3.91 (s, 3H), 4.44 (t, J = 4.8 Hz, 2H), 4.82 (s, 2H), 7.03-7.09 (m, 2H), 7.11-7.25 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H) ), 7.41 (d, J = 7.6 Hz, 1H), 7.73-7.79 (m, 2H), 7.84-7.85 (m, 1H), 8.11-8.13 (m, 2H), 8.79 (s, 1H). 1.112 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 513.25; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.68 (s, 3H), 3.48 (t, J = 4.8 Hz, 2H), 4.43 (t, J = 4.8 Hz, 2H), 4.82 (s, 2H), 6.97-7.02 (m, 1H), 7.06-7.10 (m, 1H), 7.21-7.25 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.72-7.80 (m, 2H), 7.86-7.87 (m, 1H), 8.11-8.13 (m, 2H), 8.79 (s, 1H). 1.113 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan Methyl)amino)-4-fluorobenzoate MS m/z [M+H] ⁺ (ESI): 527; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.71 (s, 3H), 3.48-3.51 (m, 2H), 3.86 (s, 3H), 4.44 (t, J = 4.8 Hz, 2H), 4.84 (s, 2H), 7.14-7.19 (m, 1H), 7.33-7.35 (m, 1H), 7.37-7.51 (m, 3H), 7.74 -7.86 (m, 3H), 8.12-8.14 (m, 2H), 8.79 (s, 1H). 1.114 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-4-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 513.15; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.67 (s, 3H), 3.49 (t, J = 4.8 Hz, 2H), 4.43 (t, J = 4.8 Hz, 2H), 4.84 (s, 2H), 7.12-7.17 (m, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H) , 7.44-7.49 (m, 2H), 7.74-7.78 (m, 2H), 7.84 (s, 1H), 8.13-8.13 (m, 2H), 8.77 (s, 1H). 1.115 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan Methyl)amino)-5-fluorobenzoate MS m/z [M+H] ⁺ (ESI): 527; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.70 (s, 3H), 3.48-3.51 (m, 2H), 3.88 (s, 3H), 4.44 (t, J = 4.5 Hz, 2H), 4.76 (s, 2H), 6.71-6.75 (m, 1H), 7.03-7.06 (m, 1H), 7.22 (s, 1H), 7.33 (d , J = 8.1 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.73-7.85 (m, 3H), 8.11-8.14 (m, 2H), 8.79 (s, 1H). 1.116 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-5-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 513.15; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.69 (s, 3H), 3.55-3.57 (m, 2H), 4.44 (t, J = 5.1 Hz, 2H), 4.77 (s, 2H), 6.69-6.75 (m, 1H), 7.04-7.07 (m, 1H), 7.23-7.24 (m, 1H), 7.33 (d, J = 8.1 Hz , 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.74-7.78 (m, 2H), 7.85-7.86 (m, 1H), 8.12-8.14 (m, 2H), 8.79 (s, 1H). 1.117 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan Methyl)amino)-2-fluorobenzoate MS m/z [M+H] ⁺ (ESI): 527.15; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.68 (s, 3H), 3.46-3.49 (m, 2H), 3.87 (s, 3H), 4.42 (t, J = 4.8 Hz, 2H), 4.74 (s, 2H), 6.95-6.99 (m, 1H), 7.03-7.09 (m, 1H), 7.19-7.22 (m, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.72-7.78 (m, 2H), 7.85-7.86 (m, 1H), 8.11-8.14 (m, 2H), 8.79 (s, 1H). 1.118 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 513.25; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.64 (s, 3H), 3.45 (t, J = 4.5 Hz, 2H), 3.40 (t, J = 4.8 Hz, 2H), 4.71 (s, 2H), 6.91-7.05 (m, 2H), 7.18-7.21 (m, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.36 ( d, J = 7.8 Hz, 1H), 7.69-7.74 (m, 2H), 7.84 (s, 1H), 8.08-8.10 (m, 2H), 8.76 (s, 1H). 1.119 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid methyl ester ¹ H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.18-8.08 (m, 2H), 7.91 (t, J = 7.6 Hz, 1H), 7.81 (dd, J = 2.0, 8.4 Hz, 1H ), 7.68 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.26-7.18 (s, 1H), 7.07 (d, J = 10.0 Hz, 1H), 7.06-6.54 (m, 2H), 4.83 (s, 2H), 4.79-4.71 (m, 2H), 3.89 (s, 3H), 3.50-3.45 (m, 2H) MS: m/z = 564.2.[M+H] ⁺ 1.120 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.17-8.08 (m, 2H), 7.91 (t, J = 8.0 Hz, 1H), 7.81 (dd, J = 2.0, 8.8 Hz, 1H ), 7.67 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.26-7.20 (m, 1H), 7.12-7.06 (m, 1H), 7.05-6.98 (m, 1H), 6.89-6.53 (m, 1H), 4.82 (s, 2H), 4.77-4.73 (m, 2H), 3.50-3.44 (m, 2H) MS: m/z = 550.2[M+H] ⁺ 1.121 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-4-fluorobenzoic acid methyl ester ¹ H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.17-8.12 (m, 2H), 7.92 (t, J = 8.0 Hz, 1H), 7.86-7.77 (m, 1H), 7.70 (d , J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 10.4 Hz, 2H), 7.15 (dd, J = 9.2, 11.2 Hz, 1H), 6.91-6.58 (m, 1H), 4.79-4.71 (m, 2H), 3.86 (s, 3H), 3.51-3.44 (m, 2H), 3.31 (d, J = 0.8 Hz, 2H) MS: m/z = 564.2 [ M+H] ⁺ 1.122 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-4-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.65 (s, 1H), 8.18-8.11 (m, 2H), 7.92 (t, J = 8.0 Hz, 1H), 7.81 (dd, J = 2.0, 8.4 Hz, 1H) , 7.70 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49-7.40 (m, 2H), 7.15 (dd, J = 8.4, 11.2 Hz, 1H), 6.92- 6.58 (m, 1H), 4.91-4.90 (m, 2H), 4.78-4.73 (m, 2H), 3.51-3.43 (m, 2H) MS: m/z = 550.2 [M+H] ⁺ 1.123 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-5-fluorobenzoic acid methyl ester ¹ H NMR (MeOD, 400 MHz) δ 8.68 (s, 1H), 8.25-8.11 (m, 2H), 7.94 (t, J = 8.0 Hz, 1H), 7.82 (dd, J = 1.6, 8.4 Hz, 1H ), 7.74 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.96-6.59 (m , 2H), 4.90 (s, 2H), 4.79-4.72 (m, 2H), 3.88 (s, 3H), 3.48 (t, J = 4.4 Hz, 2H) MS: m/z = 564.2[M+H] ⁺ 1.124 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-5-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.68 (s, 1H), 8.23-8.11 (m, 2H), 7.94 (t, J = 8.0 Hz, 1H), 7.82 (dd, J = 1.6, 8.4 Hz, 1H ), 7.74 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.07 (d, J = 9.2 Hz, 1H), 6.95-6.61 (m , 2H), 4.90 (s, 2H), 4.79-4.74 (m, 2H), 3.48 (t, J = 4.8 Hz, 2H) MS: m/z = 550.2[M+H] ⁺ 1.125 A

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid methyl ester ¹ H NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.17-8.09 (m, 2H), 7.91 (t, J = 8.0 Hz, 1H), 7.82 (dd, J = 2.0, 8.4 Hz, 1H ), 7.68 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 3.2, 5.6 Hz, 1H), 7.09-7.02 (m, 1H), 7.01 -6.94 (m, 1H), 6.88-6.56 (m, 1H), 4.77-4.73 (m, 4H), 3.88 (s, 3H), 3.51-3.44 (m, 2H) MS: m/z = 564.2 [M +H] ⁺ 1.126 A

¹ H NMR (MeOD, 400MHz) δ 8.64 (s, 1H), 8.18-8.11 (m, 2H), 7.94-7.88 (m, 1H), 7.81 (dd, J = 2.0, 8.4 Hz, 1H), 7.70 ( d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.23 (dd, J = 3.2, 5.6 Hz, 1H), 7.09-7.02 (m, 1H), 7.00-6.94 (m , 1H), 6.90-6.59 (m, 1H), 4.79 (s, 2H), 4.77-4.74 (m, 2H), 3.50-3.45 (m, 2H) MS: m/z = 550.2 [M+H] ⁺ 1.127 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2- yl)methyl)-2-fluoroaniline MS m/z [M+H] ⁺ (ESI): 505.20; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 3.48 (t, J = 4.8 Hz, 2H), 4.42 (t, J = 5.1 Hz , 2H), 4.74 (s, 2H), 6.52-6.72 (m, 2H), 6.79-6.89 (m, 1H), 7.01-7.04 (m, 2H), 7.55 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.74-7.89 (m, 3H), 8.06 (d, J = 8.7 Hz, 1H), 8.15 (s, 1H), 8.73 (s, 1H). 1.128 A

N-((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2- yl)methyl)-2,3-difluoroaniline MS m/z [M+H] ⁺ (ESI): 523.15; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.50 (t, J = 5.2 Hz, 2H), 4.44 (t, J = 4.8 Hz , 2H), 4.86 (s, 2H), 6.59-6.65 (m, 3H), 6.97-7.03 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.71-7.78 (m, 1H), 7.80-7.85 (m, 1H), 7.86-7.93 (m, 2H), 8.13-8.19 (m, 2H), 8.79 (s, 1H). 1.129 A

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid methyl ester MS m/z [M+H] ⁺ (ESI): 563.20; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.48 (t, J = 4.8 Hz, 2H), 3.88 (s, 3H), 4.43 (t, J = 5.2 Hz, 2H), 4.84 (s, 2H), 6.74 (t, J = 55.2 Hz, 1H), 7.00-7.04 (m, 2H), 7.11-7.23 (m, 1H), 7.54 ( d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.75-7.77 (m, 1H), 7.83-7.89 (m, 2H), 8.09 (d, J = 8.8 Hz, 1H) ), 8.17 (s, 1H), 8.76 (s, 1H). 1.130 A

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 549.15; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.48-3.51 (m, 2H), 4.43-4.45 (m, 2H), 4.89 ( s, 2H), 6.78 (t, J = 55.2 Hz, 1H), 7.00-7.04 (m, 1H), 7.09-7.13 (m, 1H), 7.24-7.28 (m, 1H), 7.53-7.55 (m, 1H), 7.69-7.71 (m, 1H), 7.77-7.80 (m, 1H), 7.86-7.93 (m, 2H), 8.13-8.15 (m, 1H), 8.19 (s, 1H), 8.79 (s, 1H). 1.131 A

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-4-fluorobenzoic acid methyl ester MS m/z [M+H] ⁺ (ESI): 563.20; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.48-3.51 (m, 2H), 3.86 (s, 3H), 4.42-4.45 ( m, 2H), 4.88 (s, 2H), 6.77 (t, J = 55.2 Hz, 1H), 7.14-7.19 (m, 1H), 7.44-7.45 (m, 2H), 7.56 (d, J = 7.6 Hz , 1H), 7.69-7.79 (m, 1H), 7.81-7.89 (m, 3H), 8.12-8.14 (m, 1H), 8.20 (s, 1H), 8.78 (s, 1H). 1.132 A

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-4-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 549.15; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 3.46-3.54 (m, 2H), 4.40-4.44 (m, 2H), 4.89 ( s, 2H), 6.75 (t, J = 55.2 Hz, 1H), 7.11-7.18 (m, 1H), 7.42-7.48 (m, 2H), 7.52-7.55 (m, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.77-7.79 (m, 1H), 7.80-7.91 (m, 2H), 8.11 (d, J = 8.7 Hz, 1H), 8.18 (s, 1H), 8.77 (s, 1H). 1.133 A

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-5-fluorobenzoic acid methyl ester MS m/z [M+H] ⁺ (ESI): 563.15; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.48-3.51 (m, 2H), 3.88 (s, 3H), 4.44 (t, J = 5.2 Hz, 2H), 4.84 (s, 2H), 6.64-6.92 (m, 2H), 7.05-7.08 (m, 1H), 7.22-7.23 (m, 1H), 7.55 (d, J = 7.6 Hz , 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.78-7.81 (m, 1H), 7.86-7.93 (m, 2H), 8.14 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 8.80 (s, 1H). 1.134 A

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-5-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 549.15; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.48-3.51 (m, 2H), 4.44 (t, J = 4.8 Hz, 2H) , 4.87 (s, 2H), 6.65-6.93 (m, 2H), 7.06-7.09 (m, 1H), 7.21-7.22 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.72 (d , J = 7.6 Hz, 1H), 7.78-7.81 (m, 1H), 7.87-7.93 (m, 2H), 8.15 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 8.81 (s, 1H). 1.135 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid methyl ester MS m/z [M+H] ⁺ (ESI): 563.20; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 3.48 (t, J = 4.8 Hz, 2H), 3.85 (s, 3H), 4.42 (t, J = 4.8 Hz, 2H), 4.65 (s, 2H), 6.68 (t, J = 55.2 Hz, 1H), 6.93-7.06 (m, 2H), 7.20-7.23 (m, 1H), 7.57- 7.61 (m, 2H), 7.76-7.89 (m, 3H), 8.03-8.07 (m, 1H), 8.15 (s, 1H), 8.72 (s, 1H). 1.136 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 549.15; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 3.46-3.54 (m, 2H), 4.40-4.44 (m, 2H), 4.73 ( s, 2H), 6.73 (t, J = 55.2 Hz, 1H), 6.94-7.07 (m, 2H), 7.21-7.24 (m, 1H), 7.53-7.56 (m, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.76-7.91 (m, 3H), 8.08-8.11 (m, 1H), 8.17 (s, 1H), 8.75 (s, 1H). 1.137 A

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)methyl benzoate MS m/z [M+H] ⁺ (ESI): 545.15; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.48-3.51 (m, 2H), 3.88 (s, 3H), 4.44 (t, J = 4.8 Hz, 2H), 4.88 (s, 2H), 6.80 (t, J = 55.2 Hz, 1H), 6.99-7.02 (m, 1H), 7.30-7.38 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.77-7.80 (m, 1H), 7.87-7.93 (m, 2H), 8.16 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 8.81 (s, 1H). 1.138 A

3-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)benzoic acid MS m/z [M+H] ⁺ (ESI): 531.05; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 3.48-3.57 (m, 2H), 4.43-4.46 (m, 2H), 4.88 ( s, 2H), 6.80 (t, J = 55.2 Hz, 1H), 6.99-7.02 (m, 1H), 7.29-7.44 (m, 2H), 7.45-7.46 (m, 1H), 7.52-7.54 (m, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.81-7.94 (m, 2H), 8.15-8.21 (m, 2H), 8.82 (s, 1H) ). 1.139 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzamide ¹ H NMR (MeOD, 400MHz) δ 8.65 (s, 1H), 8.16-8.11 (m, 2H), 7.91 (t, J = 8.0 Hz, 1H), 7.81 (dd, J = 2.0, 8.4 Hz, 1H) , 7.70 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.31-7.26 (m, 1H), 7.25-7.21 (m, 2H), 6.97-6.92 (m, 1H) ), 6.75 (t, J = 55.2 Hz, 1H), 4.83 (s, 2H), 4.77-4.73 (m, 2H), 3.49-3.44 (m, 2H) MS: m/z = 553.1 [M+H] ⁺ 1.140 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzamide ¹ H NMR (MeOD, 400 MHz) δ8.63 (s, 1H), 8.13-8.10 (m, 2H), 7.90 (t, J = 8.0 Hz, 1H), 7.81 (dd, J = 2.0, 8.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.13-7.04 (m, 2H), 7.00-6.93 (m, 1H), 6.72 (t, J = 55.2 Hz, 1H),, 4.81 (s, 2H), 4.77-4.73 (m, 2H), 3.47 (t, J = 4.8 Hz, 2H) MS: m/z = 549.2.[M+H] ⁺ 1.141 A

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzamide ¹ H NMR (MeOD, 400 MHz) δ8.65 (s, 1H), 8.17-8.12 (m, 2H), 7.91 (t, J = 8.0 Hz, 1H), 7.81 (dd, J = 2.0, 8.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.14 (dd, J = 3.2, 6.0 Hz, 1H), 7.08 (dd, J = 9.2, 10.8 Hz, 1H), 6.96-6.90 (m, 1H), 6.74 (t, J = 56.0 Hz, 1H), 4.78 (s, 2H), 4.77-4.73 (t, J = 4.8 Hz, 2H), 3.50-3.45 (t, J = 5.2 Hz, 2H) MS: m/z = 549.2.[M+H] ⁺ 1.142 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2- ¹ H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.17-8.08 (m, 2H), 7.91 (t, J = 8.0 Hz, 1H), 7.82 (dd, J = 2.0, 8.8 Hz, 1H) , 7.67 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.96-6.90 (m, 1H), 6.88-6.57 ( m, 2H), 4.81-4.70 (m, 4H), 3.47 (t, J = 4.8 Hz, 2H) MS: m/z = 549.2 [M+H] ⁺ 1.143 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-4-fluorobenzamide ¹ H NMR (MeOD, 400MHz) δ 8.64 (s, 1H), 8.20-8.10 (m, 2H), 7.91 (t, J = 8.0 Hz, 1H), 7.81 (dd, J =1.8, 8.8 Hz, 1H) , 7.70 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.39-7.24 (m, 2H), 7.13 (dd, J = 8.4, 11.2 Hz, 1H), 6.75 ( t, J = 55.2 Hz, 1H), 4.90 (s, 2H), 4.75 (t, J = 4.8 Hz, 2H), 3.47 (t, J = 4.8 Hz, 2H) MS: m/z = 549.2 [M+ H] ⁺ 1.144 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-chlorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.14-8.11 (m, 2H), 7.91 (t, J = 8.0 Hz, 1H), 7.81 (dd, J = 1.6 Hz, J = 8.4 Hz , 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.13 (dd, J = 1.2, 7.6 Hz , 1H), 6.94 (dd, J = 1.2, 8.0 Hz, 1H), 6.78 (t, J = 55.2 Hz, 1H), 4.87 (br s, 2H), 4.75 (t, J = 4.8 Hz, 2H), 3.47 (t, J = 4.8 Hz, 2H) MS: m/z = 566.1 [M+H] ⁺ 1.145 A

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-chlorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ8.62 (s, 1H), 8.12 (dd, J = 3.2, 5.2 Hz, 2H), 7.96-7.87 (m, 1H), 7.81 (dd, J = 1.6, 8.8 Hz) , 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 3.2 Hz, 1H) ), 6.89-6.55 (m, 2H), 4.76 (t, J = 5.2 Hz, 2H), 4.74 (s, 2H), 3.51-3.44 (m, 2H) MS: m/z = 566.2 [M+H] ⁺ 1.146 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)benzamide MS m/z [M+H] ⁺ (ESI): 494.25; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.67 (s, 3H), 3.46-3.53 (m, 2H), 4.41-4.44 ( m, 2H), 4.79 (s, 2H), 6.92-6.96 (m, 1H), 7.20-7.31 (m, 4H), 7.33-7.39 (m, 1H), 7.71-7.79 (m, 2H), 7.84- 7.85 (m, 1H), 8.09-8.12 (m, 2H), 8.78 (s, 1H). 1.147 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzamide MS m/z [M+H] ⁺ (ESI): 512.20; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.69 (s, 3H), 3.49-3.51 (m, 2H), 4.45 (t, J = 4.4 Hz, 2H), 4.84 (s, 2H), 6.94-6.98 (m, 1H), 7.05-7.12 (m, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.73-7.82 (m, 2H), 7.87-7.88 (m, 1H), 8.11-8.15 (m, 2H), 8.80 (s, 1H). 1.148 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-4-fluorobenzamide MS m/z [M+H] ⁺ (ESI): 512.20; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.68 (s, 3H), 3.48 (t, J = 4.8 Hz, 2H), 4.43 (t, J = 5.1 Hz, 2H), 4.84 (s, 2H), 7.08-7.15 (m, 1H), 7.23-7.46 (m, 4H), 7.72-7.74 (m, 2H), 7.85-7.86 (m , 1H), 8.10-8.14 (m, 2H), 8.78 (s, 1H). 1.149 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-5-fluorobenzamide MS m/z [M+H] ⁺ (ESI): 512.10; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.70 (s, 3H), 3.48-3.51 (m, 2H), 4.44 (t, J = 5.2 Hz, 2H), 4.79 (s, 2H), 6.66-6.69 (m, 1H), 6.93-6.96 (m, 1H), 7.07 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H) ), 7.42 (d, J = 7.6 Hz, 1H), 7.74-7.71 (m, 2H), 7.86 (s, 1H), 8.11-8.15 (m, 2H), 8.79 (s, 1H). 1.150 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzamide MS m/z [M+H] ⁺ (ESI): 512.25; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.67 (s, 3H), 3.46-3.54 (m, 2H), 4.43 (t, J = 5.1 Hz, 2H), 4.75 (s, 2H), 6.89-6.94 (m, 1H), 7.03-7.16 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.33-7.36 (m , 1H), 7.72-7.77 (m, 2H), 7.85 (s, 1H), 8.10-8.13 (m, 2H), 8.78 (s, 1H). 1.151 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)-2,3-difluoroaniline ¹ H NMR (MeOD, 400MHz) δ8.81 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.12-8.02 ( m, 2H), 7.84 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.00-6.87 (m, 1H), 6.78-6.50 (m, 3H), 4.73 (s , 2H), 4.48 (t, J = 4.8 Hz, 2H), 3.51 (t, J = 4.4 Hz, 2H) MS: m/z = 524.2 [M+H] ⁺ 1.152 A

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)methyl benzoate ¹ H NMR (MeOD, 400 MHz) δ 8.87 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.37-8.30 ( m, 2H), 8.04 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.23 ( t, J = 8.0 Hz, 1H), 7.01-6.98 (m, 1H), 4.64 (s, 2H), 4.53 (t, J = 4.4 Hz, 2H), 3.84 (s, 3H), 3.55 (t, J = 4.4 Hz, 2H), 3.04 (s, 3H) MS: m/z = 510.2 [M+H] ⁺ 1.153 A

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)benzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.88 (d, J = 2.8 Hz, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.33-8.27 ( m, 2H), 8.04 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.24 ( t, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 4.65 (s, 2H), 4.52 (t, J = 4.8 Hz, 2H), 3.55 (t, J = 4.8 Hz, 2H), 3.01 (s, 3H) MS: m/z = 496.2 [M+H] ⁺ 1.154 A

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)- 1H-imidazol-2-yl)methyl)amino)methyl benzoate ¹ H NMR (MeOD, 400 MHz) δ 8.83 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.08-8.06 ( m, 2H), 7.86 (d, J = 2.8 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.27 (t, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.78 (t, J = 55.2 Hz, 1H), 4.75 (s, 2H), 4.49 (t, J = 4.8 Hz, 2H), 3.85 (s, 3H), 3.51 (t, J = 4.8 Hz, 2H) MS: m/z = 546.2 [M+H] ⁺ 1.155 A

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)- 1H-imidazol-2-yl)methyl)amino)benzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.83 (d, J = 2.8 Hz, 1H), 8.46 (d, J = 9.2 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.08-8.05 ( m, 2H), 7.87 (d, J = 2.4 Hz, 1H), 7.78-7.75 (m, 1H), 7.41-7.37 (m, 2H), 7.27 (t, J = 8.0 Hz, 1H), 6.99 (dd , J = 8.0 Hz, 1.6 Hz, 1H), 6.80 (t, J = 55.2 Hz, 1H), 4.77 (s, 2H), 4.49 (t, J = 4.8 Hz, 2H), 3.52 (t, J = 4.8 Hz, 2H) MS: m/z = 532.2 [M+H] ⁺ 1.156 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)benzamide ¹ H NMR (MeOD, 400MHz) δ 8.64 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.80-7.71 (m, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.35-7.25 (m, 2H), 7.24-7.19 (m, 2H), 6.96-6.89 (m, 1H), 4.81-4.69 (m, 4H), 3.52-3.43 (m, 2H), 2.67 (s, 3H) MS: m/z = 495.2 [M+H] ⁺ 1.157 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzamide ¹ H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.80 (s, 1H), 7.82- 7.73 (m, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.13-7.02 (m, 2H), 6.95 (dt, J = 2.4, 7.6 Hz , 1H), 4.81 (s, 2H), 4.74 (t, J = 5.2 Hz 2H), 3.52-3.43 (t, J = 4.8 Hz 2H), 2.68 (s, 3H) MS: m/z = 513.2[M +H] ⁺ 1.158 A

5-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzamide ¹ H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.81-7.74 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 3.2, 5.6 Hz, 1H), 7.06 (dd, J = 9.2, 10.8 Hz, 1H) ), 6.92 (td, J = 3.6, 8.8 Hz, 1H), 4.78-4.73 (m, 4H), 3.51-3.45 (m, 2H), 2.67 (s, 3H) MS: m/z = 513.2[M+ H] ⁺ 1.159 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-5-fluorobenzamide ¹ H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.16-8.07 (m, 2H), 7.83-7.74 (m, 2H), 7.44-7.33 (m, 2H), 7.06 (s, 1H), 6.92 (d, J = 9.6 Hz, 1H), 6.66 (d, J = 10.8 Hz, 1H), 4.78-4.72 (m, 4H), 3.52-3.44 (m, 2H), 2.68 (s, 3H) MS: m/z = 513.2 [M+H] ⁺ 1.160 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl) Methyl)amino)-4-fluorobenzamide ¹ H NMR (MeOD, 400MHz) δ 8.63 (s, 1H), 8.18-8.06 (m, 2H), 7.84-7.74 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.29-7.22 (m, 1H), 7.12 (dd, J = 8.4, 11.2 Hz, 1H), 4.82 (s, 2H), 4.78-4.72 (m, 2H), 3.52-3.43 (m, 2H), 2.68 (s, 3H) MS: m/z = 513.2 [M+H] ⁺ 1.161 A

3-(((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 527.25; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.23-2.32 (m, 2H), 2.70 (s, 3H), 3.22-3.27 ( m, 2H), 4.30-4.34 (m, 2H), 4.83 (s, 2H), 6.98-7.13 (m, 2H), 7.23-7.25 (m, 1H), 7.27-7.31 (m, 1H), 7.33- 7.43 (m, 1H), 7.71-7.81 (m, 3H), 8.09-8.12 (m, 2H), 8.74 (s, 1H). 1.162 A

5-(((5-(3-(3-aminopropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 527.15; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.25-2.29 (m, 2H), 2.69 (s, 3H), 3.19-3.29 ( m, 2H), 4.28-4.32 (m, 2H), 4.73 (s, 2H), 6.92-6.98 (m, 1H), 7.01-7.08 (m, 1H), 7.21-7.24 (m, 1H), 7.27- 7.39 (m, 2H), 7.69-7.79 (m, 3H), 8.08-8.10 (m, 2H), 8.71 (s, 1H). 1.163 A

3-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 541.25; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 1.77-1.93 (m, 4H), 2.58 (s, 3H), 2.93-2.98 ( m, 2H), 4.10-4.14 (m, 2H), 4.71 (s, 2H), 6.87-7.00 (m, 2H), 7.10-7.22 (m, 3H), 7.60-7.69 (m, 3H), 7.96- 7.99 (m, 2H), 8.57 (s, 1H). 1.164 A

5-(((5-(3-(4-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 541.20; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 1.93-2.05 (m, 4H), 2.68 (s, 3H), 3.05-3.09 ( m, 2H), 4.22-4.25 (m, 2H), 4.75 (s, 2H), 6.96-6.99 (m, 1H), 7.04-7.08 (m, 1H), 7.23-7.24 (m, 1H), 7.25- 7.29 (m, 1H), 7.31-7.40 (m, 1H), 7.73-7.78 (m, 3H), 8.09-8.14 (m, 2H), 8.69 (s, 1H). 1.165 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan (yl)amino)-2-chlorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.78 (d, J = 2.8 Hz, 1H), 8.15-8.08 (m, 2H), 7.84 (d, J = 2.8 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.73 (dd, J = 2.0, 8.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.13 (dd, J = 1.2, 7.6 Hz, 1H), 6.93 (dd, J = 1.2, 8.0 Hz, 1H), 4.86 (s, 2H), 4.43 (t, J = 4.8 Hz, 2H) ), 3.48 (t, J = 4.8 Hz, 2H), 2.69 (s, 3H) MS: m/z = 529.2[M+H] ⁺ 1.166 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan (yl)amino)-2-chlorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.78 (d, J = 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.85 (d, J = 2.4 Hz, 1H), 7.81-7.67 (m, 2H) , 7.40 (d, J = 7.6 Hz, 1H), 7.28 (dd, J = 8.4, 12.4 Hz, 2H), 7.17 (d, J = 2.8 Hz, 1H), 6.85 (dd, J = 2.8, 8.8 Hz, 1H), 4.75 (s, 2H), 4.43 (t, J = 4.8 Hz, 2H), 3.48 (t, J = 4.4 Hz, 2H), 2.68 (s, 3H) MS: m/z = 529.2 [M+ H] ⁺ 1.167 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-bromobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.77 (d, J = 2.8 Hz, 1H), 8.15-8.08 (m, 2H), 7.84 (d, J = 2.8 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.73 (dd, J = 2.0, 8.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.32 (d, J =8.0 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.05 (dd, J = 1.2, 7.6 Hz, 1H), 6.88 (dd, J = 1.2, 8.3 Hz, 1H), 4.86 (s, 2H), 4.42 (t, J = 4.8 Hz, 2H) ), 3.48 (t, J = 4.8 Hz, 2H), 2.69 (s, 3H) MS: m/z = 575.2[M+H] ⁺ 1.168 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2-bromobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.78 (d, J = 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.84 (d, J = 2.8 Hz, 1H), 7.80-7.70 (m, 2H) ), 7.44 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 6.78 (dd, J =3.2, 8.8 Hz, 1H), 4.75 (s, 2H), 4.42 (t, J = 4.8 Hz, 2H), 3.48 (t, J = 4.8 Hz, 2H), 2.68 (s, 3H ) MS: m/z = 575.2[M+H] ⁺ 1.169 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan group)amino)-2,6-difluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.79 (d, J = 3.2 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.74 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (d , J = 8.0 Hz, 1H), 6.93-6.88 (m, 2H), 4.79 (s, 2H), 4.45 (t, J = 4.8 Hz, 2H), 3.49 (t, J = 4.8 Hz, 2H), 2.68 (s, 3H) MS: m/z = 531.3 [M+H] ⁺ 1.170 A

(S)-3-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H -Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.76 (d, J = 2.8 Hz, 1H), 8.16-8.08 (m, 2H), 7.88 (d, J = 2.8 Hz, 1H), 7.82-7.69 (m, 2H) ), 7.40 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.27-7.18 (m, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.02-6.92 (m, 1H), 4.81 (s, 2H), 4.73-4.67 (m, 1H), 4.63-4.58 (m, 1H), 4.54 (dd, J = 3.2, 4.8 Hz, 1H), 2.68 (s, 3H) ) MS: m/z = 557.2[M+H] ⁺ 1.171 A

O-(6-(2-(((2,3-Difluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline olin-3-yl)-L-serine ¹ H NMR (MeOD, 400 MHz) δ 8.65 (d, J = 2.8 Hz, 1H), 8.17-7.88 (m, 2H), 7.86-7.41 (m, 3H), 7.16 (d, J = 7.2 Hz, 2H) ), 6.98-6.82 (m, 1H), 6.64 (t, J = 7.6 Hz, 1H), 6.54-6.34 (m, 1H), 4.63-4.55 (m, 3H), 4.54-4.47 (m, 1H), 4.11-4.00 (m, 1H), 2.51 (s, 3H) MS: m/z = 531.2[M+H] ⁺ 1.172 A

(S)-3-(((5-(3-(3-amino-3-carboxypropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H -Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.73 (d, J = 2.8 Hz, 1H), 8.16-8.04 (m, 2H), 7.84-7.68 (m, 3H), 7.40 (d, J = 7.6 Hz, 1H) , 7.30 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 6.4 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.03-6.96 (m, 1H), 4.82 (s, 2H), 4.46-4.34 (m, 2H), 4.28 (t, J = 6.4 Hz, 1H), 2.69 (s, 3H), 2.62-2.43 (m, 2H) MS: m/z = 571.2 [M+H ] ⁺ 1.173 A

O-(6-(2-(((2,3-Difluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline olin-3-yl)-L-homoserine ¹ H NMR (400MHz, MeOD) δ 8.73 (d, J =2.8 Hz, 1H), 8.15-8.06 (m, 2H), 7.83-7.67 (m, 3H), 7.42-7.37 (m, 1H), 7.32- 7.27 (m, 1H), 7.02-6.92 (m, 1H), 6.66-6.52 (m, 2H), 4.79 (s, 2H), 4.48-4.35 (m, 2H), 4.31-4.21 (m, 1H), 2.68 (s, 3H), 2.61-2.43 (m, 2H) MS: m/z = 545.2 [M+H] ⁺ 1.174 A

(R)-3-(((5-(3-(3-amino-2-methylpropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)- 1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 541.25; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 1.19-1.22 (m, 3H), 2.40-2.50 (m, 1H), 2.66 ( s, 3H), 3.04-3.06 (m, 1H), 3.19-3.21 (m, 1H), 4.09-4.12 (m, 1H), 4.20-4.22 (m, 1H), 4.78 (s, 2H), 6.99- 7.07 (m, 2H), 7.22-7.28 (m, 1H), 7.30-7.38 (m, 2H), 7.68-7.77 (m, 3H), 8.06-8.09 (m, 2H), 8.72 (s, 1H). 1.175 A

(S)-3-(((5-(3-(3-amino-2-methylpropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)- 1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 541.25; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 1.15-1.25 (m, 3H), 2.44-2.47 (m, 1H), 2.67 ( s, 3H), 3.04-3.05 (m, 1H), 3.19-3.21 (m, 1H), 4.07-4.12 (m, 1H), 4.21-4.24 (m, 1H), 4.79 (s, 2H), 6.98- 6.99 (m, 1H), 7.01-7.09 (m, 1H), 7.21-7.22 (m, 1H), 7.24-7.25 (m, 1H), 7.29-7.39 (m, 1H), 7.69-7.78 (m, 3H ), 8.07-8.09 (m, 2H), 8.72 (s, 1H). 1.176 A

(R)-3-(((5-(3-(3-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 541.10; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 1.42-1.46 (m, 3H), 2.16-2.19 (m, 1H), 2.26- 2.28 (m, 1H), 2.69 (s, 3H), 3.63-3.68 (m, 1H), 4.32-4.38 (m, 2H), 4.83 (s, 2H), 6.99-7.11 (m, 2H), 7.23- 7.25 (m, 1H), 7.26-7.27 (m, 1H), 7.31-7.42 (m, 1H), 7.71-7.82 (m, 3H), 8.10-8.12 (m, 2H), 8.74 (s, 1H). 1.177 A

(S)-3-(((5-(3-(3-aminobutoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ (ESI): 541.05; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 1.40-1.43 (m, 3H), 2.14-2.27 (m, 2H), 2.68 ( s, 3H), 3.60-3.67 (m, 1H), 4.29-4.36 (m, 2H), 4.81 (s, 2H), 6.99-7.10 (m, 2H), 7.23-7.28 (m, 1H), 7.29- 7.31 (m, 1H), 7.38-7.41 (m, 1H), 7.69-7.79 (m, 3H), 8.08-8.10 (m, 2H), 8.73 (s, 1H). 1.178 A

2-Fluoro-3-(((5-(3-(3-(methylamino)propoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H -Imidazol-2-yl)methyl)amino)benzoic acid MS m/z [M+H] ⁺ (ESI): 541.05; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.31-2.32 (m, 2H), 2.67 (s, 3H), 2.79 (s, 3H), 3.29-3.30 (m, 2H), 4.30-4.33 (m, 2H), 4.79 (s, 2H), 6.99-7.10 (m, 2H), 7.21-7.22 (m, 1H), 7.23-7.25 ( m, 1H), 7.29-7.32 (m, 1H), 7.70-7.78 (m, 3H), 8.07-8.09 (m, 2H), 8.71 (s, 1H). 1.179 A

3-(((5-(3-(3-Amino-2,2-difluoropropoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H- Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid MS m/z [M+H] ⁺ : 562 1.180 A

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-chlorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.88 (d, J = 2.8 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.39-8.24 (m, 3H), 8.04 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.21-7.15 (m, 1H), 7.07 (dd, J = 1.2, 7.6 Hz, 1H), 6.99 (dd, J = 1.2, 8.4 Hz , 1H), 4.74 (s, 2H), 4.52 (t, J = 4.8 Hz, 2H), 3.55 (t, J = 4.8 Hz, 2H), 3.02 (s, 3H) MS: m/z = 530.1 [M +H] ⁺ 1.181 A

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-chlorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.89 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.40-8.28 (m, 3H), 8.04 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 3.2 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 8.8 Hz, 3.2 Hz, 1H), 4.62 (s, 2H), 4.52 (t, J = 4.8 Hz, 2H), 3.55 (t, J = 4.8 Hz, 2H), 3.02 (s, 3H) MS: m/z = 530.2 [M+H] ⁺ 1.182 A

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.87 (d, J = 2.8 Hz, 1H), 8.62-8.54 (m, 1H), 8.35-8.19 (m, 3H), 8.04-7.98 (m, 1H), 7.69 -7.62 (m, 1H), 7.27-7.17 (m, 1H), 7.05-6.91 (m, 2H), 4.73 (s, 2H), 4.51 (t, J = 4.8 Hz, 2H), 3.57-3.51 (m , 2H), 2.99 (s, 3H) MS: m/z = 574.0 [M+H] ⁺ 1.183 A

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.89 (d, J = 2.8 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.37-8.28 (m, 3H), 8.04 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 6.79 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 4.62 (s, 2H), 4.52 (t, J = 5.2 Hz, 2H), 3.55 (t, J = 5.2 Hz, 2H), 3.02 (s, 3H) MS: m/z = 574.1 [M+H] ⁺ 1.184 A

3-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.89 (d, J = 2.8 Hz, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.39-8.27 (m, 3H), 8.04 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.20-7.16 (m, 1H), 7.08-7.00 (m, 2H), 4.70 (s, 2H), 4.53 (t, J = 4.8 Hz , 2H), 3.55 (t, J = 4.8 Hz, 2H), 3.03 (s, 3H) MS: m/z = 514.2 [M+H] ⁺ 1.185 A

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.90-8.87 (m, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.38-8.23 (m, 3H), 8.02 (d, J = 2.4 Hz, 1H) ), 7.67 (d, J = 6.8 Hz, 1H), 7.34-7.28 (m, 1H), 7.04-6.96 (m, 2H), 4.61 (s, 2H), 4.52 (t, J = 5.2 Hz, 2H) , 3.57-3.53 (m, 2H), 2.98 (s, 3H) MS: m/z = 514.2 [M+H] ⁺ 1.186 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl)methan yl)-3-fluoroaniline MS: m/z = 455 [M+H] ⁺ 1.187 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2,3-difluoroaniline ¹ H NMR (MeOD, 400 MHz) δ8.88 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.44-8.25 (m, 3H), 8.05 (s, 1H) , 7.73 (d, J = 7.2 Hz, 1H), 6.97-6.84 (m, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.57-6.44 (m, 1H), 4.68 (s, 2H), 4.54 (s, 2H), 3.56 (s, 2H), 3.05 (s, 3H) MS: m/z = 488.2[M+H] ⁺ 1.188 A

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromo-N-(methylsulfonyl)benzylamide ¹ H NMR (MeOD, 400 MHz) δ 8.88 (d, J = 3.2 Hz, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.35-8.23 (m, 3H), 8.05-8.03 (m, 1H) ), 7.70-7.66 (m, 1H), 7.39-7.34 (m, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 2.8, 8.8 Hz, 1H), 4.61 (s, 2H), 4.52 (s, 2H), 3.55 (s, 2H), 3.34 (s, 3H), 3.00 (s, 3H) MS: m/z = 651.0 [M+H] ⁺ 1.189 A

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromo-N-(isopropylsulfonyl)benzamide ¹ H NMR (MeOD, 400 MHz) δ 8.89 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.41-8.25 (m, 3H), 8.05 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.81 (dd, J = 2.8, 8.8 Hz, 1H), 4.61 (s, 2H), 4.53 (t, J = 4.8 Hz, 2H), 3.83 (td, J = 7.2, 13.6Hz, 1H), 3.55 (t, J = 4.8 Hz, 2H), 3.02 (s, 3H), 1.44 (d, J = 6.8 Hz, 5H), 1.48-1.39 (m, 1H) MS: m/z =681.1 [M+H] ⁺ 1.190 A

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromo-N-(tertiarybutylsulfonyl)benzamide ¹ H NMR (MeOD, 400 MHz) δ 8.89 (d, J = 2.8 Hz, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.45-8.27 (m, 3H), 8.06 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 3.2 Hz, 1H), 6.80 (dd, J = 3.0, 8.9 Hz, 1H), 4.62 (s, 2H), 4.53 (t, J = 4.4 Hz, 2H), 3.55 (dd, J = 3.6, 5.2 Hz, 2H), 3.05 (s, 3H), 1.50 (s, 9H) ) MS: m/z = 693.1 [M+H] ⁺ 1.191 A

5-(((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole- 2-yl)methyl)amino)-2-bromo-N-(cyclopropylsulfonyl)benzamide ¹ H NMR (MeOD, 400 MHz) δ 8.88 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.39-8.23 (m, 3H), 8.04 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 4.4 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.81 (dd, J = 8.0, 2.0 Hz, 2H), 4.61 (s, 2H), 4.52 (t, J = 8.0 Hz, 2H), 3.55 (t, J = 8.0 Hz, 2H) 3.13-3.03 (m, 1H), 3.00 (s, 3H) , 1.33-1.25 (m, 2H), 1.16-1.14 (m, 2H) MS: m/z = 679.1 [M+H] ⁺ 1.192 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-2-bromo-N-(methylsulfonyl)benzylamide ¹ H NMR (MeOD, 400 MHz) δ 8.78 (d, J = 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.89 (d, J = 2.8 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.74 (dd, J = 2.0, 8.8 Hz, 1H), 7.44-7.39 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H) ), 6.81 (dd, J = 2.8, 8.8 Hz, 1H), 4.74 (s, 2H), 4.47-4.41 (m, 2H), 3.51-3.47 (m, 2H), 3.36 (s, 3H), 2.69 ( s, 3H) MS: m/z = 650.1 [M+H] ⁺ 1.193 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-2-bromo-N-(isopropylsulfonyl)benzylamide ¹ H NMR (MeOD, 400 MHz) δ 8.78 (d, J = 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.73 (dd, J = 1.6, 8.8 Hz, 1H), 7.44-7.39 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 6.85-6.78 (m, 2H), 4.73 (s, 2H), 4.44 (t, J = 4.8 Hz, 2H), 3.87-3.80 (m, 1H), 3.49 (t, J = 4.4 Hz, 2H), 2.69 (s, 3H), 1.45 (d, J = 6.8 Hz, 6H) MS: m/z =680.2 [M+H] ⁺ 1.194 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-2-bromo-N-(tertiary butylsulfonyl)benzylamide ¹ H NMR (MeOD, 400MHz) δ 8.78 (d, J = 2.8 Hz, 1H), 8.16-8.08 (m, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.79 (t, J = 8.0 Hz , 1H), 7.76-7.71 (m, 1H), 7.44-7.37 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 6.81 (s, 2H), 4.74 (s, 2H), 4.44 ( s, 2H), 3.51-3.46 (m, 2H), 2.69 (s, 3H), 1.51 (s, 9H) MS: m/z = 692.2 [M+H] ⁺ 1.195 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)amino)-2-bromo-N-(cyclopropylsulfonyl)benzylamide ¹ H NMR (MeOD, 400 MHz) δ 8.78 (d, J = 2.8 Hz, 1H), 8.15-8.09 (m, 2H), 7.87 (d, J = 2.4 Hz, 1H), 7.81 - 7.71 (m, 2H) ), 7.41 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 6.85-6.78 (m, 2H), 4.73 (s, 2H), 4.44 (t, J = 4.4 Hz) , 2H), 3.49 (t, J = 4.4 Hz, 2H), 3.13-3.05 (m, 1H), 2.69 (s, 3H), 1.31-1.29 (m, 2H), 1.17-1.15 (m, 2H) MS : m/z = 676.1 [M+H] ⁺ 1.196 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)-2,4-difluoroaniline MS: m/z = 523 [M+H] ⁺ 1.197 A

N-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)-3,5-difluoroaniline MS: m/z = 523 [M+H] ⁺ 1.198 A

3-(((5-(3-(2-(4-(4-Acetylphenoxy)butamido)ethoxy)quinolin-6-yl)-4-(6-methyl Pyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid methyl ester ¹ H NMR (MeOD, 400 MHz) δ 8.61 (d, J = 2.8 Hz, 1H), 8.07-8.03 (m, 2H), 7.81-7.75 (m, 3H), 7.69-7.65 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23-7.19 (m, 1H), 7.09 (t, J = 8.0 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 4.81 (s, 2H), 4.16 (t, J = 5.2 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.66 (t, J = 5.2 Hz, 2H), 2.70 (s, 3H), 2.45 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.11 (t, J = 6.4 Hz, 2H) MS: m/z = 731.3 [M+H] ⁺ 1.199 A

3-(((5-(3-(2-(4-(4-Acetylphenoxy)butamido)ethoxy)quinolin-6-yl)-4-(6-methyl Pyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.61 (d, J = 2.8 Hz, 1H), 8.07-8.03 (m, 2H), 7.81-7.75 (m, 3H), 7.69-7.66 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23-7.19 (m, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.02-6.98 (m, 1H), 6.89 (d, J = 9.2 Hz, 2H), 4.82 (s, 2H), 4.16 (t, J = 5.2 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H), 3.66 (t, J = 5.2 Hz, 2H), 2.70 (s, 3H), 2.45 (t, J = 7.2 Hz, 2H), 2.42 (s, 3H), 2.11 (t, J = 6.8 Hz, 2H) MS: m/z = 717.3 [M+H] ⁺ 1.200 A

2-Hydroxyethyl 3-(((5-(3-(2-(4-(4-acetylphenoxy)butyramido)ethoxy)quinolin-6-yl)-4- (6-Methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)-2-fluorobenzoate ¹ H NMR (MeOD, 400 MHz) δ 8.51 (s, 1H), 7.98 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 7.69- 7.57 (m, 3H), 7.22-7.14 (m, 3H), 7.09-7.04 (m, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.59 (s, 2H), 4.36 (t, J = 4.4 Hz, 2H), 4.18 (s, 2H), 4.05 (t, J = 6.0 Hz, 2H), 3.84 (t, J = 4.4 Hz, 2H), 3.66 (t, J = 4.4 Hz, 2H), 2.51 -2.42 (m, 8H), 2.13-2.08 (m, 2H) MS: m/z = 761.3 [M+H] ⁺ 1.201 A

N-(2-((6-(4-(6-(difluoromethyl)pyridin-2-yl)-2-(((2,3-difluorophenyl)amino)methyl)-1H -Imidazol-5-yl)quinolin-3-yl)oxy)ethyl)-5-hydrazino-5-pendoxalylamine MS m/z [M+H] ⁺ (ESI): 651.30; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 1.90-1.96 (m, 2H), 2.20-2.23 (m, 4H), 3.66- 3.69 (m, 2H), 4.23-4.26 (m, 2H), 4.73 (s, 2H), 6.55-6.83 (m, 3H), 6.93-6.98 (m, 1H), 7.58-7.59 (m, 2H), 7.73-7.76 (m, 2H), 7.85-7.89 (m, 1H), 8.02-8.04 (m, 1H), 8.13 (s, 1H), 8.66 (s, 1H). 1.202 A

N-(3-((6-(2-(((2,3-difluorophenyl)amino)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazole-5 -yl)quinolin-3-yl)oxy)propyl)-5-hydrazino-5-side oxypentanamide MS m/z [M+H] ⁺ (ESI): 629.35; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 1.85-1.90 (m, 2H), 2.09-2.25 (m, 6H), 2.65 ( s, 3H), 3.42-3.46 (m, 2H), 4.19-4.24 (m, 2H), 4.74 (s, 2H), 6.54-6.65 (m, 2H), 6.93-7.01 (m, 1H), 7.29- 7.36 (m, 2H), 7.67-7.76 (m, 3H), 8.03-8.07 (m, 2H), 8.68 (s, 1H). 7.1 A

3-(((5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.59 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.64 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 7.44-7.40 (m, 1H), 7.31 (t, J = 8.8 Hz, 1H), 7.26-7.22 (m, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.99 (td, J = 8.0 Hz, 1.6 Hz, 1H), 4.80 (s, 2H), 4.73 (t, J = 4.8 Hz, 2H), 3.46 (t, J = 4.8 Hz, 2H) MS: m/z = 551.2 [M+H] ⁺ 7.2 A

3-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amine yl)-2-fluorobenzoic acid 1H NMR (MeOD, 400MHz) δ 8.59 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 8.4 Hz, 2.0 Hz , 1H), 7.53-7.50 (m, 2H), 7.27-7.18 (m, 3H), 7.10 (t, J = 8.0 Hz, 1H), 7.02-6.98 (m, 1H), 4.85 (s, 2H), 4.72 (t, J = 5.2 Hz, 2H), 3.46 (t, J = 5.2 Hz, 2H) MS: m/z = 517.2 [M+H] ⁺ 7.3 A

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl) Methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.61 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.74-7.63 (m, 2H), 7.45 -7.41 (m, 1H), 7.37-7.30 (m, 1H), 7.21 (dd, J = 3.2, 5.6 Hz, 1H), 7.11-7.02 (m, 1H), 7.00-6.92 (m, 1H), 4.78 -4.70 (m, 4H), 3.50-3.43 (m, 2H) MS: m/z = 551.2 [M+H] ⁺ 7.4 A

5-(((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amine yl)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.59 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 2.0, 8.8 Hz , 1H), 7.58-7.47 (m, 2H), 7.27-7.16 (m, 3H), 7.10-7.02 (m, 1H), 6.96 (td, J = 3.6, 8.8 Hz, 1H), 4.77-4.70 (m , 4H), 3.50-3.43 (m, 2H) MS: m/z = 517.2 [M+H] ⁺ 7.5 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.75 (d, J = 2.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.66-7.63 (m, 2H), 7.43-7.39 (m, 1H), 7.32 (t, J = 8.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.10 (t, J = 8.0 Hz , 1H), 7.01-6.97 (m, 1H), 4.85 (s, 2H), 4.41 (t, J = 4.8 Hz, 2H), 3.47 (t, J = 4.8 Hz, 2H) MS: m/z = 550.2 [M+H] ⁺ 7.6 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amino )-2-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.74 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.63 (dd, J = 2.0, 8.8 Hz, 1H), 7.54-7.47 (m, 2H), 7.27 (dt, J = 1.6, 7.2 Hz, 1H), 7.24-7.17 (m , 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.99 (dt, J = 1.6, 8.0 Hz, 1H), 4.86-4.84 (m, 2H), 4.40 (t, J = 4.8 Hz, 2H) , 3.47 (t, J = 4.8 Hz, 2H) MS: m/z = 516.2[M+H] ⁺ 7.7 A

5-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)methan group)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.57 (d, J = 2.8 Hz, 1H), 7.91-7.84 (m, 2H), 7.63 (d, J = 2.8 Hz, 1H), 7.54 (dd, J = 1.6 , 8.8 Hz, 1H), 7.47 (dd, J =2.0, 7.2 Hz, 1H), 7.28-7.32 (m, 1H), 7.13 (t, J = 8.8 Hz, 1H), 7.03 (dd, J = 3.2, 5.6 Hz, 1H), 6.83 (t, J = 9.2 Hz, 1H), 6.66 (td, J = 3.6, 8.4 Hz, 1H), 4.44 (s, 2H), 4.34 (t, J = 5.2 Hz, 2H) , 3.44-3.38 (t, J = 5.2 Hz, 2H) MS: m/z = 550.2[M+H] ⁺ 7.8 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amino )-2-fluorobenzoic acid ¹ H NMR (400MHz, MeOD) δ 8.74 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.63 (dd, J = 2.0, 8.8 Hz, 1H), 7.54-7.48 (m, 2H), 7.25-7.17 (m, 3H), 7.11-7.03 (m, 1H), 7.00- 6.94 (m, 1H), 4.80 (s, 2H), 4.48-4.36 (m, 2H), 3.47 (t, J = 4.8 Hz, 2H) MS: m/z = 516.2 [M+H] ⁺ 7.9 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amino )-2-chlorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.73 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H), 7.64 (dd, J = 2.0, 8.8 Hz, 1H), 7.50 (dd, J = 5.2, 8.8 Hz, 2H), 7.29-7.23 (m, 1H), 7.23-7.14 (m , 3H), 6.91 (dd, J = 1.2, 8.0 Hz, 1H), 4.91 (s, 2H), 4.40 (t, J = 4.8 Hz, 2H), 3.46 (t, J = 5.2 Hz, 2H) MS: m/z = 532.2[M+H] ⁺ 7.10 A

5-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazol-2-yl)methyl)amino )-2-chlorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.76 (d, J = 2.8 Hz, 1H), 8.12-7.96 (m, 2H), 7.78 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 2.0, 8.8 Hz, 1H), 7.52 (dd, J = 5.2, 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.27-7.14 (m, 3H), 6.88 (dd, J = 3.2, 8.8 Hz, 1H), 4.83 (s, 2H), 4.42 (t, J = 4.8 Hz, 2H), 3.52-3.46 (m, 2H) MS: m/z = 532.2 [M+H] ⁺ 7.11 A

3-(((5-(3-(2-aminoethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)methan (yl)amino)-2-chlorobenzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.74 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.70-7.60 (m, 2H), 7.43-7.37 (m, 1H), 7.34-7.21 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 8.0 Hz , 1H), 4.88 (s, 2H), 4.41 (t, J = 4.8 Hz, 2H), 3.46 (t, J = 4.4 Hz, 2H) MS: m/z = 566.1[M+H] ⁺ 7.12 A

5-(((5-(3-(2-Aminoethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)methan (yl)amino)-2-chlorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.75 (d, J = 2.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.68-7.61 (m, 2H), 7.44-7.37 (m, 1H), 7.36-7.27 (m, 2H), 7.17 (d, J = 3.2 Hz, 1H), 6.86 (dd, J = 2.8, 8.8 Hz, 1H), 4.79 (s, 2H), 4.41 (t, J = 4.8 Hz, 2H), 3.47 (t, J = 4.8 Hz, 2H) MS: m/z = 566.2 [M+ H] ⁺ 7.13 A

(S)-3-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.72 (d, J = 2.4 Hz, 1H), 8.04-8.02 (m, 2H), 7.81 (d, J = 2.4 Hz, 1H), 7.63 (dd, J = 8.8 Hz , 1.6 Hz, 1H), 7.52-7.49 (m, 2H), 7.26 (t, J = 6.4 Hz, 1H), 7.20 (t, J = 8.8 Hz, 2H), 7.11 (t, J = 8.0 Hz, 1H) ), 6.99 (t, J = 7.6 Hz, 1H), 4.88 (s, 2H), 4.69 (dd, J = 10.8 Hz, 4.8 Hz, 1H), 4.59 (dd, J = 10.4 Hz, 2.8 Hz, 1H) , 4.53-4.51 (m, 1H) MS: m/z = 560.2 [M+H] ⁺ 7.14 A

(S)-5-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(4-fluorophenyl)-1H-imidazole-2 -yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.72 (d, J = 2.4 Hz, 1H), 8.05-8.03 (m, 2H), 7.82 (d, J = 1.6 Hz, 1H), 7.63 (dd, J = 8.4 Hz , 1.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.23-7.18 (m, 3H), 7.07 (t, J = 9.2 Hz, 1H), 6.99-6.95 (m, 1H), 4.80 (s, 2H), 4.70 (dd, J = 10.8 Hz, 4.8 Hz, 1H), 4.59 (dd, J = 10.8 Hz, 2.0 Hz, 1H), 4.56-4.54 (m, 1H) MS: m/z = 560.2 [M +H] ⁺ 7.15 A

(S)-3-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H -Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.72 (d, J = 2.4 Hz, 1H), 8.06-8.02 (m, 2H), 7.83 (d, J = 1.6 Hz, 1H), 7.65-7.63 (m, 2H) , 7.42-7.39 (m, 1H), 7.31 (t, J = 8.8 Hz, 1H), 7.25 (t, J = 6.8 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.00 (t, J = 8.0 Hz, 1H), 4.85 (s, 2H), 4.69 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 4.59 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 4.54-4.51 (m , 1H) MS: m/z = 594.1 [M+H] ⁺ 7.16 A

(S)-5-(((5-(3-(2-Amino-2-carboxyethoxy)quinolin-6-yl)-4-(3-chloro-4-fluorophenyl)-1H -Imidazol-2-yl)methyl)amino)-2-fluorobenzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.73 (d, J = 2.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.66-7.62 (m, 2H), 7.43-7.39 (m, 1H), 7.32 (t, J = 8.8 Hz, 1H), 7.22-7.20 (m, 1H), 7.07 (t, J = 8.8 Hz, 1H), 6.98-6.95 (m, 1H), 4.77 (s, 2H), 4.69 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 4.59 (dd, J = 10.8 Hz, 2.8 Hz , 1H), 4.54-4.52 (m, 1H) MS: m/z = 594.1 [M+H] ⁺ Example 2B ALK5 inhibitor synthesis method B 2-[7-[2-[2-(2-Fluorophenyl)ethyl]-4-(6-methyl-2-pyridyl)-1 H-Imidazol-5-yl]quinoline-2-yl]oxyethylamine ( compound 2.1 )synthesis Method B

Synthesis flow chart

step 1 : N-[2-[7-[2-[2-(2-Fluorophenyl)ethyl]-4-(6-methyl-2-pyridyl)-1 H-Imidazol-5-yl]quinoline-2-yl]oxyethyl]carbamic acid tertiary butyl ester ( compound 2.1-a) preparation

NH ₄ OAc (132 mg, 1.72 mmol, 5.0 equiv) was added to the mixture containing N-[2-[7-[2-(6-methyl-2-pyridyl)-2- pendant oxygen at 25°C Acetyl]quinacetin-2-yl]oxyethyl]carbamic acid tert-butyl ester ( A2 ) (0.15 g, 343 umol, 1.0 equiv) and 3-(2-fluorophenyl)propanal ( 104 mg, 687 umol, 2.0 equiv) in THF (20 mL), and then stirred at 35 °C for 12 h. The mixture was added with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography ( _Si02 , petroleum ether/ethyl acetate=30/1 to 0:1). Compound N-[2-[7-[2-[2-(2-fluorophenyl)ethyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoline was obtained Tri-butyl quinolin-2-yl]oxyethyl]carbamate ( 2.1-a ) (0.14 g, 246 umol, 71.64% yield) as a yellow solid. Step 2 : N- [2-[7-[2-[2-(2-Fluorophenyl)ethyl]-4-(6-methyl-2-pyridyl) -1H -imidazol-5-yl Preparation of tert-butyl ]quinoline-2-yl]oxyethyl]carbamate ( compound 2.1 )

At 25°C, will contain N- [2-[7-[2-[2-(2-fluorophenyl)ethyl]-4-(6-methyl-2-pyridyl) -1H- Imidazol-5-yl]quinacetin-2-yl]oxyethyl]carbamic acid tert-butyl ester ( 2.1-a ) (0.14 g, 246 umol, 1 equiv) in HCl/EtOAc (4 M, 20 mL) ) solution was stirred for 1 hour. The mixture was concentrated under reduced pressure at 45°C. The compound 2-[7-[2-[2-(2-fluorophenyl)ethyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoline- 2-yl]oxyethylamine ( compound 2.1 ) (90 mg, 182 umol, 73.78% yield, 94.56% purity) as a yellow solid.

¹ H NMR (MeOD, 400 MHz) δ8.68 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.82-7.70 (m, 2H) , 7.41 (d, J = 7.8 Hz, 1H), 7.36-7.25 (m, 3H), 7.21-7.07 (m, 2H), 4.78 (t, J = 5.2 Hz, 2H), 3.49-3.51 (m, 2H) ), 3.39-3.41 (m, 2H), 3.34-3.32 (m, 2H), 2.65 (s, 3H).

HPLC: 94.56% (220 nm), 96.23% (254 nm).

LCMS (ESI): Calculated mass. m/z found to be _469.1 [M+H]+ for _{C27H25N6OF 468.21} .

2-((7-(2-(2-氟苄基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺 1H NMR (MeOD, 400 MHz) δ8.66 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 1.4 Hz, 1H), 7.76-7.79 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.45-7.38 (m, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.29-7.17 (m, 2H), 4.76 (t, J = 4.8 Hz, 1H), 4.49 (s, 2H), 3.48-3.50 (m, 2H), 2.66 (s, 3H) MS: m/z =455.2 [M+H]+       2.3 B

2-((7-(4-(6-(二氟甲基)吡啶-2-基)-2-(2-氟苄基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺 ¹H NMR (MeOD, 400MHz) δ 8.65 (s, 1H), 8.17-8.12 (m, 2H), 7.91 (t, J= 7.6, 1H), 7.82 (dd, J= 2.0, 8.4 Hz, 1H), 7.70 (d, J= 7.6 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.49-7.38 (m, 2H), 7.28-7.17 (m, 2H), 6.74 (t, J= 55.2 Hz, 1H), 4.78-4.70 (m, 2H), 4.50 (s, 2H), 3.47 (t, J= 1.6 Hz, 2H) MS: m/z = 491.1 [M+H] ⁺       2.4 B

3-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.15-8.13 (m, 3H), 8.01 (d, J= 7.6 Hz, 1H), 7.96 (t, J= 8.0 Hz, 1H), 7.76 (t, J= 8.4 Hz, 2H), 7.78-7.74 (m, 2H), 7.55-7.50 (m, 1H), 4.78 (t, J= 4.8 Hz, 2H), 4.57 (s, 2H), 3.49 (t, J= 4.8 Hz, 2H), 2.72 (s, 3H) MS: m/z = 495.2[M+H] ⁺       2.5 B

3-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.13 (d, J= 8.4 Hz, 1H), 8.11-8.09 (m, 2H), 8.00 (d, J= 8.0 Hz, 1H), 7.78 (dd, J= 2 Hz, 8.4 Hz, 1H), 7.73 (t, J= 8.0 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.53 (t, J= 8.0 Hz, 1H), 7.37 (d, J= 8.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 4.75 (t, J= 4.8 Hz, 2H), 4.50 (s, 2H), 3.48 (t, J= 4.8 Hz, 2H), 2.65 (s, 3H) MS: m/z = 481.1 [M+H] ⁺       2.6 B

3-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸甲酯 ¹H NMR (MeOD, 400MHz) δ 8.89 (s, 1H), 8.62 (d, J= 8.4 Hz, 1H), 8.39-8.23 (m, 3H), 8.06 (d, J= 10.8 Hz, 2H), 7.95 (d, J= 7.6 Hz, 1H), 7.69 (t, J= 7.6 Hz, 2H), 7.55-7.44 (m, 1H), 4.53 (t, J= 4.0 Hz, 2H), 4.39 (s, 2H), 3.89 (s, 3H), 3.55 (s, 2H), 3.02 (s, 3H) MS: m/z = 495.2 [M+H] ⁺       2.7 B

3-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸 ¹H NMR (MeOD, 400MHz) δ 8.92 (d, J= 2.8 Hz, 1H), 8.65 (d, J= 9.2 Hz, 1H), 8.44-8.37 (m, 2H), 8.31 (d, J= 8.8 Hz, 1H), 8.16-8.04 (m, 2H), 7.96 (d, J= 7.6 Hz, 1H), 7.81-7.75 (m, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.50 (t, J= 7.6 Hz, 1H), 4.57 (t, J= 4.8 Hz, 2H), 4.42 (s, 2H), 3.56 (s, 2H), 3.08 (s, 3H) MS: m/z = 481.2 [M+H] ⁺       2.8 B

3-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸 ¹H NMR (MeOD, 400 MHz) δ 8.83 (d, J= 2.8 Hz, 1H), 8.45 (d, J= 8.8 Hz, 1H), 8.13 (d, J= 8.8 Hz, 1H), 8.09 (s, 1H), 8.08 (s, 1H), 8.07 (d, J= 1.2 Hz, 1H), 7.98 (d, J= 7.6 Hz, 1H), 7.86 (d, J= 2.4 Hz, 1H), 7.75 (q, J= 4.4 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.51 (t, J= 7.6 Hz, 1H), 6.77 (t, J= 55.2 Hz, 1H), 4.51-4.46 (m, 4H), 3.51 (t, J= 4.8 Hz, 2H) MS: m/z = 517.2[M+H] ⁺       2.9 B

3-((5-(7-(2-胺基乙氧基)-1,5-萘啶-2-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)苯甲酸甲酯 ¹H NMR (MeOD, 400 MHz) δ 8.84 (d, J= 2.8 Hz, 1H), 8.46 (d, J= 8.8 Hz, 1H), 8.13 (d, J= 8.8 Hz, 1H), 8.10 (s, 1H), 8.09-8.05 (m, 2H), 7.98 (d, J= 7.6 Hz, 1H), 7.87 (d, J= 2.8 Hz, 1H), 7.79-7.74 (m, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.52 (t, J= 7.6 Hz, 1H), 6.79 (t, J= 55.2 Hz, 1H), 4.52-4.45 (m, 4H), 3.90 (s, 3H), 3.52 (t, J= 4.8 Hz, 2H) MS: m/z = 531.2[M+H] ⁺       6.1 B

2-((7-(2-(2-(5-氟吡啶-2-基)乙基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺 ¹H NMR (MeOD, 400MHz) δ 8.66 (s, 1H), 8.43 (d, J= 2.8 Hz, 1H), 8.17 (d, J= 8.4 Hz, 1H), 8.11 (d, J= 2.0 Hz, 1H), 7.79 (dd, J= 2.0, 8.4 Hz, 1H), 7.68 (t, J= 7.6 Hz, 1H), 7.60 (dt, J= 2.8, 8.4 Hz, 1H), 7.44 (dd, J= 4.4, 8.4 Hz, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 4.76 (t, J= 5.2 Hz, 2H), 3.53-3.47 (m, 4H), 3.44-3.39 (m, 2H), 2.64 (s, 3H) MS: m/z = 470.1 [M+H] ⁺       6.2 B

2-((7-(2-((5-氟吡啶-2-基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺 MS: m/z [M+H] ⁺= 455       6.3 B

2-((7-(2-(2-(2-氟吡啶-3-基)乙基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺 ¹H NMR (MeOD, 400MHz) δ 8.66 (s, 1H), 8.17 (d, J= 8.8 Hz, 1H), 8.13 (d, J= 4.8 Hz, 1H), 8.10 (d, J= 1.6 Hz, 1H), 7.86-7.91 (m, 1H), 7.77 (dd, J= 2.0, 8.4 Hz, 1H), 7.70 (t, J= 7.6 Hz, 1H), 7.36 (d, J= 7.6 Hz, 1H), 7.30-7.33 (m, 1H), 7.29 (d, J= 8.0 Hz, 1H), 4.80-4.70 (m, 2H), 3.49 (t, J= 4.8 Hz, 2H), 3.43-3.38 (m, 2H), 3.30-3.25 (m, 2H), 2.64 (s, 3H) MS: m/z = 470.1 [M+H] ⁺       6.4 B

2-((7-(2-((2-氟吡啶-3-基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺 ¹H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.21 (d, J= 5.6 Hz, 1H), 8.16 (d, J= 8.4 Hz, 1H), 8.11 (d, J= 2.0 Hz, 1H), 8.05 (t, J= 9.2 Hz, 1H), 7.86 (t, J= 8.0 Hz, 1H), 7.79 (dd, J= 2.0, 8.4 Hz, 1H), 7.47 (d, J= 7.6 Hz, 1H), 7.43-7.35 (m, 2H), 4.75 (t, J= 10 Hz, 2H), 4.48 (s, 2H), 3.48 (t, J= 28.8 Hz, 2H), 2.69 (s, 3H) MS: m/z =456.2 [M+H] ⁺    實施例2C ALK5抑制劑合成方法C 2-[7-[2-[(2-氟苯氧基)甲基]-4-(6-甲基-2-吡啶基)-1 H-咪唑-5-基]喹㗁啉-2-基]氧基乙胺（ 化合物 3.1）之合成 方法C

合成流程圖

步驟 1 ：1-(2,2-二乙氧基乙氧基)-2-氟苯（ 化合物 3.1-b）之製備

Compound 2.2, as described in Table 16, can be prepared in a manner analogous to that described for compound 2.1 with appropriate intermediates and according to Method B described herein. Table 16 Compounds 2.2-2.9 and 6.1-6.4 Compound number Method of preparation based on: structure / name 1H NMR/MS 2.2 B

2-((7-(2-(2-Fluorobenzyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-2-yl)oxy) Ethan-1-amine 1H NMR (MeOD, 400 MHz) δ8.66 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 1.4 Hz, 1H), 7.76-7.79 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.45-7.38 (m, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.29-7.17 (m, 2H), 4.76 (t, J = 4.8 Hz , 1H), 4.49 (s, 2H), 3.48-3.50 (m, 2H), 2.66 (s, 3H) MS: m/z =455.2 [M+H]+ 2.3 B

2-((7-(4-(6-(difluoromethyl)pyridin-2-yl)-2-(2-fluorobenzyl)-1H-imidazol-5-yl)quinoline-2-yl )oxy)ethan-1-amine ¹ H NMR (MeOD, 400MHz) δ 8.65 (s, 1H), 8.17-8.12 (m, 2H), 7.91 (t, J = 7.6, 1H), 7.82 (dd, J = 2.0, 8.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49-7.38 (m, 2H), 7.28-7.17 (m, 2H), 6.74 (t, J = 55.2 Hz , 1H), 4.78-4.70 (m, 2H), 4.50 (s, 2H), 3.47 (t, J = 1.6 Hz, 2H) MS: m/z = 491.1 [M+H] ⁺ 2.4 B

3-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base) methyl benzoate ¹ H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.15-8.13 (m, 3H), 8.01 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.76 (t, J = 8.4 Hz, 2H), 7.78-7.74 (m, 2H), 7.55-7.50 (m, 1H), 4.78 (t, J = 4.8 Hz, 2H), 4.57 (s, 2H), 3.49 (t, J = 4.8 Hz, 2H), 2.72 (s, 3H) MS: m/z = 495.2[M+H] ⁺ 2.5 B

3-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan base) benzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.64 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.11-8.09 (m, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.78 (dd, J = 2 Hz, 8.4 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H) , 7.37 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.75 (t, J = 4.8 Hz, 2H), 4.50 (s, 2H), 3.48 (t, J = 4.8 Hz, 2H), 2.65 (s, 3H) MS: m/z = 481.1 [M+H] ⁺ 2.6 B

3-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)methyl benzoate ¹ H NMR (MeOD, 400MHz) δ 8.89 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.39-8.23 (m, 3H), 8.06 (d, J = 10.8 Hz, 2H), 7.95 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 2H), 7.55-7.44 (m, 1H), 4.53 (t, J = 4.0 Hz, 2H), 4.39 (s, 2H) , 3.89 (s, 3H), 3.55 (s, 2H), 3.02 (s, 3H) MS: m/z = 495.2 [M+H] ⁺ 2.7 B

3-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2 -yl)methyl)benzoic acid ¹ H NMR (MeOD, 400MHz) δ 8.92 (d, J = 2.8 Hz, 1H), 8.65 (d, J = 9.2 Hz, 1H), 8.44-8.37 (m, 2H), 8.31 (d, J = 8.8 Hz , 1H), 8.16-8.04 (m, 2H), 7.96 (d, J = 7.6 Hz, 1H), 7.81-7.75 (m, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 4.57 (t, J = 4.8 Hz, 2H), 4.42 (s, 2H), 3.56 (s, 2H), 3.08 (s, 3H) MS: m/z = 481.2 [M+ H] ⁺ 2.8 B

3-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -imidazol-2-yl)methyl)benzoic acid ¹ H NMR (MeOD, 400 MHz) δ 8.83 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 8.08 (s, 1H), 8.07 (d, J = 1.2 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.75 (q, J = 4.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 6.77 (t, J = 55.2 Hz, 1H), 4.51-4.46 (m, 4H), 3.51 (t, J = 4.8 Hz, 2H) MS: m/z = 517.2[M+H] ⁺ 2.9 B

3-((5-(7-(2-Aminoethoxy)-1,5-naphthyridin-2-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H -Imidazol-2-yl)methyl)benzoic acid methyl ester ¹ H NMR (MeOD, 400 MHz) δ 8.84 (d, J = 2.8 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 8.09-8.05 (m, 2H), 7.98 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.79-7.74 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 6.79 (t, J = 55.2 Hz, 1H), 4.52-4.45 (m, 4H), 3.90 (s, 3H), 3.52 (t , J = 4.8 Hz, 2H) MS: m/z = 531.2[M+H] ⁺ 6.1 B

2-((7-(2-(2-(5-fluoropyridin-2-yl)ethyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quine olin-2-yl)oxy)ethan-1-amine ¹ H NMR (MeOD, 400MHz) δ 8.66 (s, 1H), 8.43 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H) ), 7.79 (dd, J = 2.0, 8.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.60 (dt, J = 2.8, 8.4 Hz, 1H), 7.44 (dd, J = 4.4, 8.4 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.76 (t, J = 5.2 Hz, 2H), 3.53-3.47 (m, 4H) , 3.44-3.39 (m, 2H), 2.64 (s, 3H) MS: m/z = 470.1 [M+H] ⁺ 6.2 B

2-((7-(2-((5-fluoropyridin-2-yl)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline- 2-yl)oxy)ethan-1-amine MS: m/z [M+H] ⁺ = 455 6.3 B

2-((7-(2-(2-(2-fluoropyridin-3-yl)ethyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quine olin-2-yl)oxy)ethan-1-amine ¹ H NMR (MeOD, 400MHz) δ 8.66 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 4.8 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H) ), 7.86-7.91 (m, 1H), 7.77 (dd, J = 2.0, 8.4 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.30 -7.33 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.80-4.70 (m, 2H), 3.49 (t, J = 4.8 Hz, 2H), 3.43-3.38 (m, 2H), 3.30-3.25 (m, 2H), 2.64 (s, 3H) MS: m/z = 470.1 [M+H] ⁺ 6.4 B

2-((7-(2-((2-fluoropyridin-3-yl)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline- 2-yl)oxy)ethan-1-amine ¹ H NMR (MeOD, 400 MHz) δ 8.66 (s, 1H), 8.21 (d, J = 5.6 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.05 (t, J = 9.2 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.79 (dd, J = 2.0, 8.4 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.43-7.35 (m, 2H), 4.75 (t, J = 10 Hz, 2H), 4.48 (s, 2H), 3.48 (t, J = 28.8 Hz, 2H), 2.69 (s, 3H) MS : m/z =456.2 [M+H] ⁺ Example 2C ALK5 inhibitor synthesis method C 2-[7-[2-[(2-fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl) -1H -imidazole-5 Synthetic method C of -yl]quinoline-2-yl]oxyethylamine ( compound 3.1 )

Synthesis flow chart

Step 1 : Preparation of 1-(2,2-diethoxyethoxy)-2-fluorobenzene ( compound 3.1-b )

At 25°C, K ₂ CO ₃ (5.55 g, 40.1 mmol, 1.5 equiv) was added to a mixture containing 2-fluorophenol ( 3.1-a ) (3 g, 26.7 mmol, 2.48 mL, 1.0 equiv) and 2-bromo -1,1-diethoxyethane (6.33 g, 32.1 mmol, 4.8 mL, 1.2 equiv) in DMF (20 mL) and then stirred at 100 °C for 12 h. The reaction mixture was quenched by addition of _H2O (40 mL) at 20 °C, and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to obtain compound 1-(2,2-diethoxyethoxy)-2- Fluorobenzene ( 3.1-b ) (3.2 g, 14.0 mmol, 52.39% yield) as a yellow oil.

¹ H NMR (CDCl ₃ , 400MHz) δ7.10-6.97 (m, 3H), 6.94-6.87 (m, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.07 (d, J = 5.2 Hz, 2H), 3.83-3.73 (m, 2H), 3.70-3.62 (m, 2H), 1.27-1.24 (m, 6H). Step 2 : Preparation of 2-(2-Fluorophenoxy)acetaldehyde ( Compound 3.1-c )

HCl (12 M, 14.9 mL, 29.2 equiv) was added to the mixture containing 1-(2,2-diethoxyethoxy)-2-fluorobenzene ( 3.1-b ) (1.40 g, 6.13 mmol, 1.0 equiv) in a mixture of THF (20 mL) and H ₂ O (15 mL), and then stirred at 20 °C for 12 h. The reaction mixture was quenched by addition of _H2O (20 mL), diluted with aqueous _NaHCO3 (1 M) until pH was between 8 and 9. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to give compound 2-(2-fluorophenoxy)acetaldehyde ( 3.1-c ) ( 700 mg, 4.54 mmol, 74.0% yield) as a yellow oil.

¹ H NMR (CDCl ₃ , 400 MHz) δ 9.95-9.86 (m, 1H), 7.18-6.89 (m, 4H), 4.65 (d, J = 0.8 Hz, 2H). Step 3 : N- [2-[7-[2-[(2-Fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl) -1H -imidazol-5-yl] Preparation of quinoline-2-yl]oxyethyl]carbamic acid tertiary butyl ester ( compound 3.1-d )

NH ₄ OAc (132 mg, 1.72 mmol, 5.0 equiv) was added to the mixture containing N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxyethanoyl]quino Tri-butyl quinolin-2-yl]oxyethyl]carbamate ( A2 ) (150 mg, 343 umol, 1.0 equiv) and 2-(2-fluorophenoxy)acetaldehyde (3.1-c) ( 79 mg, 515 umol, 1.5 equiv) in THF (3 mL), and then stirred at 35 °C for 12 h. The reaction mixture was quenched by addition of _H2O (10 mL) at 20 °C, and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 200 x 40mm x 10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 18%-48%, 8 min) to give compound N -[2-[7-[2-[(2-Fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl) -1H -imidazol-5-yl]quinoline- Tertiary butyl 2-yl]oxyethyl]carbamate ( 3.1-d ) (150 mg, 146 umol, 42.51% yield, TFA salt) as a yellow solid.

¹ H NMR (MeOD, 400MHz) δ8.57 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.75 (dd, J = 2.0, 8.4 Hz, 1H), 7.56 (dd, J = 8.0, 12.4 Hz, 2H), 7.31 (t, J = 8.4 Hz, 1H), 7.21-7.13 (m, 2H) ), 7.07-7.00 (m, 1H), 5.41 (s, 2H), 4.53 (t, J = 5.2 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.78 (s, 3H), 1.42 (s, 9H). Step 4 : 2-[7-[2-[(2-Fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl) -1H -imidazol-5-yl]quinoline Preparation of -2-yl]oxyethylamine ( compound 3.1 )

At 20 °C, the containing N-[2-[7-[2-[(2-fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl)-1H-imidazole- 5-yl]quinoline-2-yl]oxyethyl]carbamic acid tert-butyl ester ( 3.1-d ) (150 mg, 263 umol, 1.0 equiv) in HCl/EtOAc (4 M, 10 mL) Stir for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The compound 2-[7-[2-[(2-fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoline-2 was obtained -yl]oxyethylamine ( compound 3.1 ) (74 mg, 120 umol, 45.67% yield, HCl salt) as a yellow solid.

¹ H NMR (MeOD, 400MHz) δ8.67 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.10 (t, J = 8.0 Hz, 1H), 7.81 ( d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.36-7.31 (m, 1H), 7.21-7.14 (m, 2H ), 7.09-7.02 (m, 1H), 5.45 (s, 2H), 4.80-4.75 (m, 2H), 3.52-3.46(m, 2H), 2.80 (s, 3H).

HPLC: 94.71% (220 nm), 96.21% (254 nm).

MS (ESI): Calculated mass. m/z found to be 471.1 _[ M ^+H]+ _{for C26H23FN6O2 470.19} .

3-((7-(2-((2-氟苯氧基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)丙-1-胺 1H NMR (METHANOL-d4, 400MHz) δ = 8.59 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.78 (dd, J = 2.0, 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.31 (dt, J = 1.6, 8.4 Hz, 1H), 7.20 - 7.13 (m, 2H), 7.07 - 7.01 (m, 1H), 5.40 (s, 2H), 4.63 (t, J = 6.0 Hz, 2H), 3.20 (t, J = 7.2 Hz, 2H), 2.76 (s, 3H), 2.21 - 2.28 (m, 2H) MS: m/z = 485.2 [M+H]+       3.3 C

4-((7-(2-((2-氟苯氧基)甲基)-4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)丁-1-胺 1H NMR (METHANOL-d4, 400MHz) δ = 8.57 (s, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.77 (dd, J = 2.0, 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.32 (dt, J = 1.6, 8.4 Hz, 1H), 7.21 - 7.14 (m, 2H), 7.08 - 7.01 (m, 1H), 5.42 (s, 2H), 4.57 (t, J = 6.0 Hz, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.79 (s, 3H), 2.03 - 1.95 (m, 2H), 1.94 - 1.87 (m, 2H) MS: m/z = 499.2 [M+H]+    實施例2D ALK5抑制劑合成方法D N-[[5-[3-(2-胺基乙氧基)喹㗁啉-6-基]-4-(6-甲基-2-吡啶基)-1H-咪唑-2-基]甲基]-5-氟-吡啶-2-胺（ 化合物 4.1）之合成

合成流程圖

步驟 1 ： N-[2-[7-[2-(二甲氧基甲基)-4-(6-甲基-2-吡啶基)-1 H-咪唑-5-基]喹㗁啉-2-基]氧基乙基]胺甲酸三級丁酯（ 化合物 4.1-a）之製備

Compounds 3.2 and 3.3, as described in Table 17, can be prepared in a manner analogous to that described for compound 3.1 with appropriate intermediates and according to Method C described herein. Table 17 Compounds 3.2-3.3 Compound number Method of preparation based on: structure / name 1H NMR/MS 3.2 C

3-((7-(2-((2-Fluorophenoxy)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-2- yl)oxy)propan-1-amine 1H NMR (METHANOL-d4, 400MHz) δ = 8.59 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.98 (t, J = 8.0 Hz) , 1H), 7.78 (dd, J = 2.0, 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.31 (dt, J = 1.6, 8.4 Hz, 1H), 7.20 - 7.13 (m, 2H), 7.07 - 7.01 (m, 1H), 5.40 (s, 2H), 4.63 (t, J = 6.0 Hz, 2H), 3.20 (t, J = 7.2 Hz, 2H), 2.76 (s, 3H), 2.21 - 2.28 (m, 2H) MS: m/z = 485.2 [M+H]+ 3.3 C

4-((7-(2-((2-Fluorophenoxy)methyl)-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoline-2- yl)oxy)butan-1-amine 1H NMR (METHANOL-d4, 400MHz) δ = 8.57 (s, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 8.04 (t, J = 8.0 Hz , 1H), 7.77 (dd, J = 2.0, 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.32 (dt, J = 1.6, 8.4 Hz, 1H), 7.21 - 7.14 (m, 2H), 7.08 - 7.01 (m, 1H), 5.42 (s, 2H), 4.57 (t, J = 6.0 Hz, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.79 (s, 3H), 2.03 - 1.95 (m, 2H), 1.94 - 1.87 (m, 2H) MS: m/z = 499.2 [M+H]+ Example 2D ALK5 inhibitor synthesis method D N -[[5-[3-(2-aminoethoxy)quinoline-6-yl]-4-(6-methyl-2-pyridyl)- Synthesis of 1H-imidazol-2-yl]methyl]-5-fluoro-pyridin-2-amine ( compound 4.1 )

Synthesis flow chart

Step 1 : N- [2-[7-[2-(dimethoxymethyl)-4-(6-methyl-2-pyridyl) -1H -imidazol-5-yl]quinoline- Preparation of tertiary butyl 2-yl]oxyethyl]carbamate ( compound 4.1-a )

NH ₄ OAc (1.77 g, 22.9 mmol, 5.0 equiv) was added to the mixture containing N-[2-[7-[2-(6-methyl-2-pyridinyl)-2-oxyethanoyl]quinoline Tri-butyl phospholin-2-yl]oxyethyl]carbamate ( A2 ) (2 g, 4.58 mmol, 1.0 equiv) and 2,2-dimethoxyacetaldehyde (954 mg, 9.16 mmol, 830 uL, 2.0 equiv) in THF (20 mL), and then stirred at 35 °C for 12 h. The reaction mixture was poured into ice water (20 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=2/1 to 1/1) to obtain compound N- [2-[7-[2-(dimethoxymethyl) )-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoline-2-yl]oxyethyl]carbamic acid tert-butyl ester ( 4.1-a ) ( 1.8 g, 3.46 mmol, 75.46% yield) as a yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ8.47 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m, 1H), 7.38-7.31 (m, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.61 (s, 1H), 5.01 (s, 1H), 4.54 (t, J = 5.2 Hz, 2H), 3.65-3.60 (m, 2H), 3.50 (s, 6H), 2.60 (s, 3H), 1.46 (s, 9H). Step 2 : 5-[3-(2-Aminoethoxy)quinoline-6-yl]-4-(6-methyl-2-pyridyl) -1H -imidazole-2-carbaldehyde ( compound 4.1-b ) Preparation

At 25°C, TFA (5.12 mL, 20 equiv.) was added dropwise to a solution containing N-[2-[7-[2-(dimethoxymethyl)-4-(6-methyl-2- Pyridinyl)-1H-imidazol-5-yl] quinacetin -2-yl]oxyethyl]carbamic acid tert-butyl ester ( 4.1-a ) (1.8 g, 3.46 mmol, 1.0 equiv) in DCM ( 20 mL) solution, and then stirred at this temperature for 12 hours. The mixture was concentrated under reduced pressure to give 5-(3-(2-aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl) -1H -imidazole- 2-Carboxaldehyde ( 4.1-b ) (1.5 g crude) as a yellow oil. Step 3 : N- [2-[7-[2-Carboxylin-4-(6-methyl-2-pyridyl) -1H -imidazol-5-yl]quinoline-2-yl]oxy Preparation of tertiary butyl ethyl]carbamate ( compound 4.1-c )

At 25°C, _NaHCO3 (584 mg, 6.94 mmol, 2 equiv) in _H2O ( ₂ mL) and Boc2O (909 mg, 4.17 mmol, 957 uL, 1.2 equiv) were added to a mixture containing 5-[ 3-(2-Aminoethoxy)quinoline-6-yl]-4-(6-methyl-2-pyridyl)-1H-imidazole-2-carbaldehyde ( 4.1-b ) (1.3 g, 3.47 mmol, 1 equiv) in THF (20 mL), and then stirred at 25 °C for 1 h. The mixture was added water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was triturated with MTBE (20 mL) for 30 min at 25 ^o C. The compound N-[2-[7-[2-carbamoyl-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoline-2-yl]oxyethyl was obtained tert-butyl]carbamate ( 4.1-c ) (1.4 g, 2.95 mmol, 84.97% yield) as a yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ9.86 (s, 1H), 8.52 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.91-7.84 (m, 1H), 7.51-7.45 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 4.56 (t, J = 5.2 Hz) , 2H), 3.64-3.61 (m, 2H), 2.63 (s, 3H), 1.54 (s, 9H). Step 4 : N- [2-[7-[2-[[(5-Fluoro-2-pyridyl)amino]methyl]-4-(6-methyl-2-pyridyl)-1H-imidazole Preparation of -5-yl]quineline-2-yl]oxyethyl]carbamic acid tertiary butyl ester ( compound 4.1-d )

AcOH (16.4 mg, 273 umol, 15.6 uL, 1.0 equiv) was added to the mixture containing N-[2-[7-[2-carbamoyl-4-(6-methyl-2-pyridine) at 25°C ( 4.1-c ) (0.13 g, 273 umol, 1.0 equiv) with 5-fluoropyridine -2-amine (92.1 mg, 821 umol, 3.0 equiv) in DCE (20 mL) and then stirred at 70 °C for 12 h. The mixture was cooled to 0°C, MeOH (2 mL) and _NaBH3CN (25.8 mg, 410 umol, 1.5 equiv) were added, and it was stirred at 0°C for 1 hour. The pH of the reaction mixture was adjusted to ~7 with aqueous NaHCO ₃ , and then extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residues were purified by preparative HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-38%, 8 min). The compound N- [2-[7-[2-[[(5-fluoro-2-pyridyl)amino]methyl]-4-(6-methyl-2-pyridyl)-1H-imidazole- Tertiary butyl 5-yl]quinacetin-2-yl]oxyethyl]carbamate ( 4.1-d ) (0.1 g, 175 umol, 63.97% yield) as a yellow solid.

¹ H NMR (MeOH, 400 MHz) δ8.56 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.92-7.94 (m, 1H), 7.74-7.67 ( m, 2H), 7.42-7.34 (m, 2H), 7.27 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 3.2, 9.4 Hz, 1H), 4.87 (s, 2H), 4.53 (t , J = 5.4 Hz, 2H), 3.52 (t, J = 5.4 Hz, 2H), 2.64 (s, 3H), 1.41 (s, 9H). Step 5 : N -[[5-[3-(2-Aminoethoxy)quinoline-6-yl]-4-(6-methyl-2-pyridyl) -1H -imidazole-2 Preparation of -yl]methyl]-5-fluoro-pyridin-2-amine ( compound 4.1 )

HCl/EtOAc (4 M, 10 mL) was added to the mixture containing N-[2[7-[2-[[(5-fluoro-2-pyridyl)amino]methyl]-4 at 25°C -(6-Methyl-2-pyridyl)-1H-imidazol-5-yl]quinoline-2-yl]oxyethyl]carbamic acid tert-butyl ester ( 4.1-d ) (0.1 g, 175 umol, 1.0 equiv) in EtOAc (10 mL) and then stirred for 1 hour. The mixture was concentrated under reduced pressure at 45°C. The compound N-[[5-[3-(2-aminoethoxy)quinoline-6-yl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2-yl was obtained ]methyl]-5-fluoro-pyridin-2-amine ( compound 4.1 ) (56 mg, 116 umol, 66.67% yield, 98.16% purity, 4HCl) as a yellow solid.

¹ H NMR (MeOD, 400 MHz) δ8.65 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 8.01-8.03 (m, 1H) , 7.96 (t, J = 8.0 Hz, 1H), 7.75-7.79 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 4.0, 9.8 Hz, 1H), 4.93 (s, 2H), 4.76 (t, J = 4.8 Hz, 1H), 3.48-3.50 (m, 2H), 2.75 (s, 3H).

HPLC: 98.16% (220 nm), 99.39% (254 nm).

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)嘧啶-4-胺  MS: m/z = 453 [M+H]+       4.3 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟吡啶-4-胺 MS: m/z = 470 [M+H] ⁺       4.4 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲基嘧啶-4-胺 MS: m/z = 467 [M+H] ⁺       4.5 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-5-氟吡啶-3-胺 MS: m/z = 470 [M+H] ⁺       4.6 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)嘧啶-5-胺 1H NMR (MeOD, 400MHz) δ8.86 (s, 1H), 8.80 (s, 2H), 8.66 (s, 1H), 8.18-8.05 (m, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 4.92 (s, 2H), 4.80-4.74 (m, 2H), 3.47-3.50 (m, 2H), 2.81 (s, 3H) MS: m/z = 454.1 [M+H]+       4.7 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟吡啶-3-胺 1H NMR (MeOD, 400MHz) δ8.56 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.23-7.15 (m, 1H), 7.09-7.03 (m, 1H), 4.78 (s, 2H), 4.69-4.64 (m, 2H), 3.38-3.40 (m, 2H), 2.66 (s, 3H) MS: m/z = 471.0 [M+H]+       4.8 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-4-甲基嘧啶-5-胺 1H NMR (MeOD, 400MHz) δ8.63 (s, 1H), 8.46 (s, 1H), 8.15-8.11 (m, 2H), 8.07 (d, J = 2.0 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.76 (dd, J = 1.6, 8.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 4.86 (s, 2H), 4.77-4.72 (m, 2H), 3.50-3.45 (m, 2H), 2.71 (s, 3H), 2.54 (s, 3H) MS: m/z = 468.1 [M+H]+       4.9 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)苯并[d][1,3]二氧呃-5-胺 MS: m/z = 495 [M+H] ⁺       4.10 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-5-氟吡啶-2-胺 ¹H NMR (MeOD, 400MHz) δ8.68 (s, 1H), 8.20-8.18 (m, 2H), 8.07 (t, J= 2.0 Hz, 1H), 7.94 (t, J= 8.0 Hz, 1H), 7.84-7.77 (m, 2H), 7.74 (d, J= 8.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.13 (dd, J= 4.0, 9.6 Hz, 1H), 6.78 (t, J= 55.2 Hz, 1H), 5.12 (s, 2H), 4.78-4.76 (m, 2H), 3.49 (t, J= 4.8 Hz, 2H) MS: m/z = 507.2 [M+H] ⁺       4.11 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-氟吡啶-3-胺 ¹H NMR (MeOD, 400MHz) δ8.68 (s, 1H), 8.22-8.12 (m, 2H), 7.94 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 2.0, 8.4 Hz, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.52 (d, J= 4.8 Hz, 1H), 7.30-7.23 (m, 1H), 7.20-7.15 (m, 1H), 6.78 (t, J= 55.2 Hz, 1H), 4.95 (s, 2H), 4.79-4.73 (m, 2H), 3.48 (t, J= 4.8 Hz, 2H) MS: m/z = 507.2 [M+H] ⁺       4.12 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3-氟吡啶-2-胺 ¹H NMR (MeOD, 400 MHz) δ 8.68 (s, 1H), 8.19-8.17 (m, 2H), 7.95 (t, J= 8.0 Hz, 1H), 7.90 (dd, J= 1.2 Hz, 5.6 Hz, 1H), 7.83 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 7.74-7.70 (m, 2H), 7.59 (d, J= 8.0 Hz, 1H), 6.97-6.93 (m, 1H), 6.78 (t, J= 55.2 Hz, 1H), 5.26 (s, 2H), 4.78 (t, J= 4.8 Hz, 2H), 3.49 (t, J= 4.8 Hz, 2H) MS: m/z =507.2 [M+H] ⁺       4.13 A

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-3,4-二氟吡啶-2-胺 MS: m/z =524 [M+H] ⁺       4.14 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲氧基嘧啶-4-胺 ¹H NMR (MeOD, 400 MHz) δ 8.62 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.95 (d, J= 7.2 Hz, 1H), 7.93-7.86 (m, 1H), 7.77 (dd, J= 2.0, 8.4 Hz, 1H), 7.52-7.40 (m, 2H), 6.60 (d, J= 7.2 Hz, 1H), 5.08 (s, 2H), 4.80-4.67 (m, 2H), 4.13 (s, 3H), 3.47 (t, J= 9.6 Hz, 2H), 2.71 (s, 3H) MS: m/z = 484.1[M+H] ⁺       4.15 D

N-((5-(3-(2-胺基乙氧基)喹㗁啉-6-基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-2-基)甲基)-2-甲氧基嘧啶-5-胺 ¹H NMR (MeOD, 400 MHz) δ 8.68 (s, 1H), 8.37 (s, 2H), 8.26-8.15 (m, 2H), 7.94 (t, J= 8.0 Hz, 1H), 7.87-7.81 (m, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 6.78 (t, J= 54.8 Hz, 1H), 4.94 (s, 2H), 4.77 (t, J= 5.2 Hz, 2H), 4.05 (s, 3H), 3.49 (t, J= 4.8 Hz, 2H) MS: m/z =520.2 [M+H] ⁺    實施例2E ALK5抑制劑合成方法E 2-[7-[2-三級丁基-4-(6-甲基-2-吡啶基)-1 H-咪唑-5-基]喹㗁啉-2-基]氧基乙胺（ 化合物 5.1）之合成

合成流程圖

步驟 1 ： N-[2-[7-[2-三級丁基-4-(6-甲基-2-吡啶基)-1 H-咪唑-5-基]喹㗁啉-2-基]氧基乙基]胺甲酸三級丁酯（ 化合物 5.1-a）之製備

MS (ESI): Calculated mass. m/z found to be _471.1 [M+H] ⁺ for _{C25H23FN8O 470.20} . Compounds 4.2-4.9, as described in Table 18, can be prepared in a manner analogous to that described for compound 4.1 with appropriate intermediates and according to Method D described herein. Table 18 Compounds 4.2-4.15 Compound number Method of preparation based on: structure / name 1H NMR/MS 4.2 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)pyrimidin-4-amine MS: m/z = 453 [M+H]+ 4.3 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-3-fluoropyridin-4-amine MS: m/z = 470 [M+H] ⁺ 4.4 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-methylpyrimidin-4-amine MS: m/z = 467 [M+H] ⁺ 4.5 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-5-fluoropyridin-3-amine MS: m/z = 470 [M+H] ⁺ 4.6 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)pyrimidin-5-amine 1H NMR (MeOD, 400MHz) δ8.86 (s, 1H), 8.80 (s, 2H), 8.66 (s, 1H), 8.18-8.05 (m, 3H), 7.79 (d, J = 8.4 Hz, 1H) , 7.64 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 4.92 (s, 2H), 4.80-4.74 (m, 2H), 3.47-3.50 (m, 2H), 2.81 (s, 3H) MS: m/z = 454.1 [M+H]+ 4.7 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-fluoropyridin-3-amine 1H NMR (MeOD, 400MHz) δ8.56 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.65 (d , J = 8.4 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.23-7.15 (m , 1H), 7.09-7.03 (m, 1H), 4.78 (s, 2H), 4.69-4.64 (m, 2H), 3.38-3.40 (m, 2H), 2.66 (s, 3H) MS: m/z = 471.0 [M+H]+ 4.8 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-4-methylpyrimidin-5-amine 1H NMR (MeOD, 400MHz) δ8.63 (s, 1H), 8.46 (s, 1H), 8.15-8.11 (m, 2H), 8.07 (d, J = 2.0 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.76 (dd, J = 1.6, 8.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 4.86 (s, 2H) , 4.77-4.72 (m, 2H), 3.50-3.45 (m, 2H), 2.71 (s, 3H), 2.54 (s, 3H) MS: m/z = 468.1 [M+H]+ 4.9 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)benzo[d][1,3]diox-5-amine MS: m/z = 495 [M+H] ⁺ 4.10 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-5-fluoropyridin-2-amine ¹ H NMR (MeOD, 400MHz) δ8.68 (s, 1H), 8.20-8.18 (m, 2H), 8.07 (t, J = 2.0 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.84-7.77 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.13 (dd, J = 4.0, 9.6 Hz, 1H), 6.78 (t , J = 55.2 Hz, 1H), 5.12 (s, 2H), 4.78-4.76 (m, 2H), 3.49 (t, J = 4.8 Hz, 2H) MS: m/z = 507.2 [M+H] ⁺ 4.11 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-fluoropyridin-3-amine ¹ H NMR (MeOD, 400MHz) δ8.68 (s, 1H), 8.22-8.12 (m, 2H), 7.94 (t, J = 8.0 Hz, 1H), 7.81 (dd, J = 2.0, 8.4 Hz, 1H ), 7.74 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.30-7.23 (m, 1H), 7.20-7.15 (m, 1H), 6.78 (t, J = 55.2 Hz, 1H), 4.95 (s, 2H), 4.79-4.73 (m, 2H), 3.48 (t, J = 4.8 Hz, 2H) MS: m/z = 507.2 [M+H] ⁺ 4.12 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3-fluoropyridin-2-amine ¹ H NMR (MeOD, 400 MHz) δ 8.68 (s, 1H), 8.19-8.17 (m, 2H), 7.95 (t, J = 8.0 Hz, 1H), 7.90 (dd, J = 1.2 Hz, 5.6 Hz, 1H), 7.83 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.74-7.70 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 6.97-6.93 (m, 1H), 6.78 ( t, J = 55.2 Hz, 1H), 5.26 (s, 2H), 4.78 (t, J = 4.8 Hz, 2H), 3.49 (t, J = 4.8 Hz, 2H) MS: m/z =507.2 [M+ H] ⁺ 4.13 A

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-3,4-difluoropyridin-2-amine MS: m/z =524 [M+H] ⁺ 4.14 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methan yl)-2-methoxypyrimidin-4-amine ¹ H NMR (MeOD, 400 MHz) δ 8.62 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.93-7.86 (m, 1H), 7.77 (dd, J = 2.0, 8.4 Hz, 1H), 7.52-7.40 (m, 2H), 6.60 (d, J = 7.2 Hz, 1H), 5.08 (s , 2H), 4.80-4.67 (m, 2H), 4.13 (s, 3H), 3.47 (t, J = 9.6 Hz, 2H), 2.71 (s, 3H) MS: m/z = 484.1[M+H] ⁺ 4.15 D

N-((5-(3-(2-Aminoethoxy)quinoline-6-yl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazole-2 -yl)methyl)-2-methoxypyrimidin-5-amine ¹ H NMR (MeOD, 400 MHz) δ 8.68 (s, 1H), 8.37 (s, 2H), 8.26-8.15 (m, 2H), 7.94 (t, J = 8.0 Hz, 1H), 7.87-7.81 (m , 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 6.78 (t, J = 54.8 Hz, 1H), 4.94 (s, 2H), 4.77 (t , J = 5.2 Hz, 2H), 4.05 (s, 3H), 3.49 (t, J = 4.8 Hz, 2H) MS: m/z =520.2 [M+H] ⁺ Example 2E ALK5 inhibitor synthesis method E 2-[7-[2-tert-butyl-4-(6-methyl-2-pyridyl)-1 H -imidazol-5-yl]quinoline-2 Synthesis of -yl]oxyethylamine ( Compound 5.1 )

Synthesis flow chart

Step 1 : N- [2-[7-[2-tert-butyl-4-(6-methyl-2-pyridinyl) -1H -imidazol-5-yl]quinoline-2-yl] Preparation of tertiary butyl oxyethyl]carbamate ( compound 5.1-a )

2,2-Dimethylpropanal (59.2 mg, 687 umol, 76.0 uL, 2.0 equiv) and _NH4OAc (132 mg, 1.72 mmol, 5.0 equiv) were added to a mixture containing N-[2-[7-[2 -(6-Methyl-2-pyridinyl)-2-oxyacetyl]quinoline-2-yl]oxyethyl]carbamic acid tertiary butyl ester ( A2 ) (150 mg, 344 umol , 1.0 equiv) in THF (9 mL), and then stirred at 35 °C for 12 h. Pour the mixture into ice water (w/w = 1/1) (20 mL). The aqueous phase was extracted with ethyl acetate (25 mL*3). The combined organic phases were washed with brine (25 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1). The compound N-[2-[7-[2-tert-butyl-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoline-2-yl]oxy Tertiary butyl ethyl]carbamate ( 5.1-a ) (115 mg, 229 umol, 66.6% yield) as a yellow oil.

¹ H NMR (MeOD, 400 MHz) δ8.44 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.71-7.57 (m, 2H) , 7.29-7.17 (m, 2H), 4.52 (t, J = 5.6 Hz, 2H), 3.51 (t, J = 5.6 Hz, 2H), 2.54 (s, 3H), 1.49 (s, 9H), 1.42 ( s, 9H). Step 2 : 2-[7-[2-Tertiarybutyl-4-(6-methyl-2-pyridyl) -1H -imidazol-5-yl]quinoline-2-yl]oxyethyl Preparation of amine ( compound 5.1 )

HCl/EtOAc (4 M, 20 mL) was added to the mixture containing N-[2-[7-[2-tert-butyl-4-(6-methyl-2-pyridyl)-1H-imidazole-5- yl]quinolin-2-yl]oxyethyl]carbamic acid tert-butyl ester ( 5.1-a ) (115 mg, 229 umol, 1.0 equiv) in EtOAc (5 mL), and then in 25 Stir for 30 minutes at °C. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 1%-30%, 8 min). The compound 2-[7-[2-tert-butyl-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoline-2-yl]oxyethylamine ( Compound 5.1 ) (37.1 mg, 42.0 umol, 18.4% yield, 97.2% purity, 4TFA) as a yellow oil.

¹ H NMR (MeOD, 400MHz) δ8.65 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.78-7.70 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.75 (t, J = 5.6 Hz, 2H), 3.48 (t, J = 5.6 Hz, 2H), 2.65 ( s, 3H), 1.61 (s, 9H).

HPLC: 97.18% (220 nm), 98.37% (254 nm).

2-((7-(2-(三級丁基)-4-(6-(二氟甲基)吡啶-2-基)-1H-咪唑-5-基)喹㗁啉-2-基)氧基)乙-1-胺 MS: m/z = 438 [M+H] ⁺    實施例3：連接子修飾之有效負載之合成 實施例3A： ALK5抑制劑合成方法A 4-((17 S,20 S)-1-(2,5-二側氧基-2,5-二氫-1 H-吡咯-1-基)-17-異丙基-15,18-二側氧基-20-(3-脲基丙基)-3,6,9,12-四氧雜-16,19-二氮雜二十一烷-21-醯胺基)苄基(2-((7-(2-(((2-氟苯基)胺基)甲基)-4-(6-甲基吡啶-2-基)-1 H-咪唑-5-基)喹㗁啉-2-基)氧基)乙基)胺甲酸酯(三氟乙酸鹽)（ 化合物 [1.2-CIIIa.1]）之合成

步驟 A. 化合物 [1.2-CIIIa.1] 之製備

Compound 5.2, as described in Table 19, can be prepared in a manner analogous to that described for compound 5.1 with appropriate intermediates and according to Method E described herein. Table 19 Compound 5.2 Compound number Method of preparation based on: structure / name 1H NMR/MS 5.2 E

2-((7-(2-(tertiarybutyl)-4-(6-(difluoromethyl)pyridin-2-yl)-1H-imidazol-5-yl)quinoline-2-yl) oxy)ethan-1-amine MS: m/z = 438 [M+H] ⁺ Example 3: Synthesis of Linker-Modified Payload Example 3A: ALK5 Inhibitor Synthesis Method A 4-((17S, 20S )-1-(2,5-dioxy-2,5-di Hydrogen- 1H -pyrrol-1-yl)-17-isopropyl-15,18-dioxy-20-(3-ureidopropyl)-3,6,9,12-tetraoxa- 16,19-diazahecosane-21-amido)benzyl(2-((7-(2-(((2-fluorophenyl)amino)methyl)-4-(6 -Methylpyridin-2-yl)-1H-imidazol-5-yl) quinacetin -2-yl)oxy)ethyl)carbamate (trifluoroacetate) ( compound [1.2-CIIIa. 1] ) synthesis

Step A. Preparation of compound [1.2-CIIIa.1]

22 mg of mal-PEG4-Val-Cit-PAB-PNP (Broad Pharm; CAS 2112738-09-5) and 15 uL of DIPEA were added to a 2.5 mL DMF solution containing 12.0 mg of compound 1.2 . The reaction mixture was stirred at room temperature for 1 hour and then purified without HPLC treatment (10% to 75% MeCN with 0.1% TFA/ _H2O with 0.1% TFA). The product spikes were collected and lyophilized to yield the TFA salt of compound [1.2-CIIIa.1] . LCMS(M+H) = 1202.5.

1202.5 [M+H]+    [1.8-CIIIb.3]

1009.5 [M+H]+    [1.3-CIIIb.2]

1095.5 [M+H]+    [1.4CIIIb.2]

1111.5 [M+H]+    [1.5CIIIb.2]

1091.5 [M+H]+    [1.7CIIIb.2]

1102.5 [M+H]+    [1.8-CIIIb.2]

1095.5 [M+H]+    [1.9-CIIIb.2]

1111.5 [M+H]+    [1.10-CIIIb.2]

1102.5 [M+H]+    [1.17-CIIIb.2]

1139.5 [M+H]+    [1.19-CIIIb.2]

1135.6 [M+H]+    [1.8-CIIIb.20]

1066.5 [M+H]+    [1.8-CIIIb.21]

1114.5 [M+H]+    [1.8-CIIIc.8]

1229.6 [M+H]+    [1.12-CIIIc.8]

1247.6 [M+H]+    [1.13-CIIIc.8]

1247.6 [M+H]+    [1.18-CIIIc.8]

1265.6 [M+H]+    [1.21-CIIIc.8]

1216.6 [M+H]+    [1.22-CIIIc.8]

1230.6 [M+H]+    [1.25-CIIIc.8]

1201.5 [M+H]+    [1.27-CIIIc.8]

1245.6 [M+H]+    [1.1-CIIIc.8]

1201.5 [M+H]+    [3.1-CIIIc.8]

1203.5 [M+H]+    [3.2-CIIIc.8]

1217.5 [M+H]+    [3.3-CIIIc.8]

1231.6 [M+H]+    [1.35-CIIIc.8]

1220.5 [M+H]+    [1.36-CIIIc.8]

1220.5 [M+H]+    [1.37-CIIIc.8]

1202.5 [M+H]+    [1.38-CIIIc.8]

1220.5 [M+H]+    [1.44-CIIIc.8]

1216.6 [M+H]+    [1.47-CIIIc.8]

1277.4 [M+H]+    [2.2-CIIIc.8]

1187.5 [M+H]+    [1.59-CIIIc.8]

1228.6 [M+H]+    [1.8-CIIIc.9]

1143.5 [M+H]+    [1.8-CIIIa.9]

1214.6 [M+H]+    [1.8-CIIIb.22]

1224.6 [M+H]+    [1.12-CIIIb.22]

1242.6 [M+H]+    [1.13-CIIIb.22]

1242.6 [M+H]+    [1.38-CIIIb.22]

1215.5 [M+H]+    [1.38-CIIIa.10]

1420.6 [M+H]+    [1.1-CIIIc.10]

1330.6 [M+H]+    [1.31-CIIIc.10]

1348.6 [M+H]+    [5.1-CIIIc.10]

1264.6 [M+H]+    [1.64-CIIIc.10]

1357.6 [M+H]+    [1.100--CIIIc.8]

1227.5 [M+H]+    [1.102-CIIIc.8]

1227.5 [M+H]+    [1.112-CIIIc.8]

1244.5 [M+H]+    [1.114-CIIIc.8]

1245.5 [M+H]+    [1.116-CIIIc.8]

1245.5 [M+H]+    [1.118-CIIIc.8]

1245.5 [M+H]+    [1.120-CIIIc.8]

1282.5 [M+H]+    [1.126-CIIIc.8]

   1282.5 [M+H]+    [1.130-CIIIc.8]

1281.5 [M+H]+    [1.131-CIIIc.8]

   1295.5 [M+H]+    [1.132-CIIIc.8]

1281.5 [M+H]+    [1.134-CIIIc.8]

1281.5 [M+H]+    [1.136-CIIIc.8]

1281.5 [M+H]+    [1.138-CIIIc.8]

1263.5 [M+H]+    [1.145-CIIIc.8]

1298.5 [M+H]+    [1.153-CIIIc.8]

1228.5 [M+H]+    [1.155-CIIIc.8]

1264.5 [M+H]+    [1.163-CIIIc.8]

1273.6 [M+H]+    [1.164-CIIIc.8]

1273.6 [M+H]+    [1.165-CIIIc.8]

1261.5 [M+H]+    [1.166-CIIIc.8]

1261.5 [M+H]+    [1.167-CIIIc.8]

1305.4 [M+H]+    [1.168-CIIIc.8]

1305.4 [M+H]+    [1.169-CIIIc.8]

1263.5 [M+H]+    [1.170-CIIIc.8]

1289.5 [M+H]+    [1.171-CIIIc.8]

1263.5 [M+H]+    [1.172-CIIIc.8]

1303.5 [M+H]+    [1.173-CIIIc.8]

1277.5 [M+H]+    [1.174-CIIIc.8]

1273.6 [M+H]+    [1.175-CIIIc.8]

1273.6 [M+H]+    [1.176-CIIIc.8]

1273.6 [M+H]+    [1.177-CIIIc.8]

1273.6 [M+H]+    [1.178-CIIIc.8]

1273.6 [M+H]+    [1.180-CIIIc.8]

1262.5 [M+H]+    [1.181-CIIIc.8]

1262.5 [M+H]+    [1.182-CIIIc.8]

1306.4 [M+H]+    [1.183-CIIIc.8]

1306.4 [M+H]+    [1.184-CIIIc.8]

1246.5 [M+H]+    [1.185-CIIIc.8]

1246.5 [M+H]+    [1.188-CIIIc.8]

1383.4 [M+H]+    [1.189-CIIIc.8]

1411.4 [M+H]+    [1.190-CIIIc.8]

1425.5 [M+H]+    [1.191-CIIIc.8]

1409.4 [M+H]+    [1.192-CIIIc.8]

1382.4 [M+H]+    [1.193-CIIIc.8]

1410.4 [M+H]+    [1.194-CIIIc.8]

1424.5 [M+H]+    [1.195-CIIIc.8]

1408.5 [M+H]+    [1.8-CIIIc.10]

1358.7 [M+H]+    [1.2-CIIIc.10]

1331.6 [M+H]+    [1.23-CIIIc.10]

1331.5 [M+H]+    [1.1-CIIIc.10]

1330.5 [M+H]+    [1.54-CIIIc.10]

1334.4 [M+H]+    [1.56-CIIIc.10]

1366.5 [M+H]+    [1.57-CIIIc.10]

1335.5 [M+H]+    [2.2-CIIIc.10]

1316.5 [M+H]+    [1.60-CIIIc.10]

1385.5 [M+H]+    [1.67-CIIIc.10]

1367.5 [M+H]+    [1.68-CIIIc.10]

1367.5 [M+H]+    [4.10-CIIIc.10]

1368.5 [M+H]+    [2.3-CIIIc.10]

1352.5 [M+H]+    [1.72-CIIIc.10]

1358.5 [M+H]+    [1.85-CIIIc.10]

1385.5 [M+H]+    [1.86-CIIIc.10]

1385.5 [M+H]+    [4.12-CIIIc.10]

1368.6 [M+H]+    [1.89-CIIIc.10]

1407.6 [M+H]+    [1.90-CIIIc.10]

1393.6 [M+H]+    [1.91-CIIIc.10]

1407.6 [M+H]+    [1.92-CIIIc.10]

1393.6 [M+H]+    [1.93-CIIIc.10]

1407.6 [M+H]+    [1.94-CIIIc.10]

1393.6 [M+H]+    [2.4-CIIIc.10]

1356.6 [M+H]+    [1.95-CIIIc.10]

1371.6 [M+H]+    [1.96-CIIIc.10]

1357.6 [M+H]+    [1.98-CIIIc.10]

1356.6 [M+H]+    [1.99-CIIIc.10]

1370.6 [M+H]+    [1.103-CIIIc.10]

1389.6 [M+H]+    [1.104-CIIIc.10]

1375.6 [M+H]+    [1.105-CIIIc.10]

1389.6 [M+H]+    [1.106-CIIIc.10]

1375.6 [M+H]+    [1.108-CIIIc.10]

1375.6 [M+H]+    [1.109-CIIIc.10]

1389.6 [M+H]+    [1.110-CIIIc.10]

1375.6 [M+H]+    [1.113-CIIIc.10]

1388.6 [M+H]+    [1.115-CIIIc.10]

1388.6 [M+H]+    [1.122-CIIIc.10]

1411.5 [M+H]+    [1.140-CIIIc.10]

1410.5 [M+H]+    [1.143-CIIIc.10]

1410.5 [M+H]+    [1.147-CIIIc.10]

1373.6 [M+H]+    [1.148-CIIIc.10]

1373.6 [M+H]+    [1.150-CIIIc.10]

1373.6 [M+H]+    [1.157-CIIIc.10]

1374.6 [M+H]+    [1.32-CIIIc.11]

1477.2 [M+H]+    [1.91-CIIIc.11]

1536.6 [M+H]+    [1.92-CIIIc.11]

1522.6 [M+H]+    [1.32-CIIIc.12]

1606.6 [M+H]+    [1.201-CIc.1]

947 [M+H]+    [7.1-CIIIc.8]

1283.5 [M+H]+    [7.2-CIIIc.8]

1249.5 [M+H]+    [7.3-CIIIc.8]

1283.4 [M+H]+       [7.4-CIIIc.8]

1249.5 [M+H]+    [7.5-CIIIc.8]

1282.4 [M+H]+    [7.6-CIIIc.8]

1248.5 [M+H]+    [7.7-CIIIc.8]

1282.4 [M+H]+    [7.8-CIIIc.8]

1248.5 [M+H]+ 實施例4 通過非基因工程抗體之原始雙硫鍵的部分還原產生抗體-TGFβ抑制劑共軛物 Compound-linkers, as described in Table 20, can be prepared in a manner analogous to that described for compound [1.2-CIIIa.1] using the appropriate compounds as starting materials. Table 20 Compounds - Linkers Compound number structure Mass spectrum, m/z [1.2-CIIIa.1]

1202.5 [M+H]+ [1.8-CIIIb.3]

1009.5 [M+H]+ [1.3-CIIIb.2]

1095.5 [M+H]+ [1.4CIIIb.2]

1111.5 [M+H]+ [1.5CIIIb.2]

1091.5 [M+H]+ [1.7CIIIb.2]

1102.5 [M+H]+ [1.8-CIIIb.2]

1095.5 [M+H]+ [1.9-CIIIb.2]

1111.5 [M+H]+ [1.10-CIIIb.2]

1102.5 [M+H]+ [1.17-CIIIb.2]

1139.5 [M+H]+ [1.19-CIIIb.2]

1135.6 [M+H]+ [1.8-CIIIb.20]

1066.5 [M+H]+ [1.8-CIIIb.21]

1114.5 [M+H]+ [1.8-CIIIc.8]

1229.6 [M+H]+ [1.12-CIIIc.8]

1247.6 [M+H]+ [1.13-CIIIc.8]

1247.6 [M+H]+ [1.18-CIIIc.8]

1265.6 [M+H]+ [1.21-CIIIc.8]

1216.6 [M+H]+ [1.22-CIIIc.8]

1230.6 [M+H]+ [1.25-CIIIc.8]

1201.5 [M+H]+ [1.27-CIIIc.8]

1245.6 [M+H]+ [1.1-CIIIc.8]

1201.5 [M+H]+ [3.1-CIIIc.8]

1203.5 [M+H]+ [3.2-CIIIc.8]

1217.5 [M+H]+ [3.3-CIIIc.8]

1231.6 [M+H]+ [1.35-CIIIc.8]

1220.5 [M+H]+ [1.36-CIIIc.8]

1220.5 [M+H]+ [1.37-CIIIc.8]

1202.5 [M+H]+ [1.38-CIIIc.8]

1220.5 [M+H]+ [1.44-CIIIc.8]

1216.6 [M+H]+ [1.47-CIIIc.8]

1277.4 [M+H]+ [2.2-CIIIc.8]

1187.5 [M+H]+ [1.59-CIIIc.8]

1228.6 [M+H]+ [1.8-CIIIc.9]

1143.5 [M+H]+ [1.8-CIIIa.9]

1214.6 [M+H]+ [1.8-CIIIb.22]

1224.6 [M+H]+ [1.12-CIIIb.22]

1242.6 [M+H]+ [1.13-CIIIb.22]

1242.6 [M+H]+ [1.38-CIIIb.22]

1215.5 [M+H]+ [1.38-CIIIa.10]

1420.6 [M+H]+ [1.1-CIIIc.10]

1330.6 [M+H]+ [1.31-CIIIc.10]

1348.6 [M+H]+ [5.1-CIIIc.10]

1264.6 [M+H]+ [1.64-CIIIc.10]

1357.6 [M+H]+ [1.100--CIIIc.8]

1227.5 [M+H]+ [1.102-CIIIc.8]

1227.5 [M+H]+ [1.112-CIIIc.8]

1244.5 [M+H]+ [1.114-CIIIc.8]

1245.5 [M+H]+ [1.116-CIIIc.8]

1245.5 [M+H]+ [1.118-CIIIc.8]

1245.5 [M+H]+ [1.120-CIIIc.8]

1282.5 [M+H]+ [1.126-CIIIc.8]

1282.5 [M+H]+ [1.130-CIIIc.8]

1281.5 [M+H]+ [1.131-CIIIc.8]

1295.5 [M+H]+ [1.132-CIIIc.8]

1281.5 [M+H]+ [1.134-CIIIc.8]

1281.5 [M+H]+ [1.136-CIIIc.8]

1281.5 [M+H]+ [1.138-CIIIc.8]

1263.5 [M+H]+ [1.145-CIIIc.8]

1298.5 [M+H]+ [1.153-CIIIc.8]

1228.5 [M+H]+ [1.155-CIIIc.8]

1264.5 [M+H]+ [1.163-CIIIc.8]

1273.6 [M+H]+ [1.164-CIIIc.8]

1273.6 [M+H]+ [1.165-CIIIc.8]

1261.5 [M+H]+ [1.166-CIIIc.8]

1261.5 [M+H]+ [1.167-CIIIc.8]

1305.4 [M+H]+ [1.168-CIIIc.8]

1305.4 [M+H]+ [1.169-CIIIc.8]

1263.5 [M+H]+ [1.170-CIIIc.8]

1289.5 [M+H]+ [1.171-CIIIc.8]

1263.5 [M+H]+ [1.172-CIIIc.8]

1303.5 [M+H]+ [1.173-CIIIc.8]

1277.5 [M+H]+ [1.174-CIIIc.8]

1273.6 [M+H]+ [1.175-CIIIc.8]

1273.6 [M+H]+ [1.176-CIIIc.8]

1273.6 [M+H]+ [1.177-CIIIc.8]

1273.6 [M+H]+ [1.178-CIIIc.8]

1273.6 [M+H]+ [1.180-CIIIc.8]

1262.5 [M+H]+ [1.181-CIIIc.8]

1262.5 [M+H]+ [1.182-CIIIc.8]

1306.4 [M+H]+ [1.183-CIIIc.8]

1306.4 [M+H]+ [1.184-CIIIc.8]

1246.5 [M+H]+ [1.185-CIIIc.8]

1246.5 [M+H]+ [1.188-CIIIc.8]

1383.4 [M+H]+ [1.189-CIIIc.8]

1411.4 [M+H]+ [1.190-CIIIc.8]

1425.5 [M+H]+ [1.191-CIIIc.8]

1409.4 [M+H]+ [1.192-CIIIc.8]

1382.4 [M+H]+ [1.193-CIIIc.8]

1410.4 [M+H]+ [1.194-CIIIc.8]

1424.5 [M+H]+ [1.195-CIIIc.8]

1408.5 [M+H]+ [1.8-CIIIc.10]

1358.7 [M+H]+ [1.2-CIIIc.10]

1331.6 [M+H]+ [1.23-CIIIc.10]

1331.5 [M+H]+ [1.1-CIIIc.10]

1330.5 [M+H]+ [1.54-CIIIc.10]

1334.4 [M+H]+ [1.56-CIIIc.10]

1366.5 [M+H]+ [1.57-CIIIc.10]

1335.5 [M+H]+ [2.2-CIIIc.10]

1316.5 [M+H]+ [1.60-CIIIc.10]

1385.5 [M+H]+ [1.67-CIIIc.10]

1367.5 [M+H]+ [1.68-CIIIc.10]

1367.5 [M+H]+ [4.10-CIIIc.10]

1368.5 [M+H]+ [2.3-CIIIc.10]

1352.5 [M+H]+ [1.72-CIIIc.10]

1358.5 [M+H]+ [1.85-CIIIc.10]

1385.5 [M+H]+ [1.86-CIIIc.10]

1385.5 [M+H]+ [4.12-CIIIc.10]

1368.6 [M+H]+ [1.89-CIIIc.10]

1407.6 [M+H]+ [1.90-CIIIc.10]

1393.6 [M+H]+ [1.91-CIIIc.10]

1407.6 [M+H]+ [1.92-CIIIc.10]

1393.6 [M+H]+ [1.93-CIIIc.10]

1407.6 [M+H]+ [1.94-CIIIc.10]

1393.6 [M+H]+ [2.4-CIIIc.10]

1356.6 [M+H]+ [1.95-CIIIc.10]

1371.6 [M+H]+ [1.96-CIIIc.10]

1357.6 [M+H]+ [1.98-CIIIc.10]

1356.6 [M+H]+ [1.99-CIIIc.10]

1370.6 [M+H]+ [1.103-CIIIc.10]

1389.6 [M+H]+ [1.104-CIIIc.10]

1375.6 [M+H]+ [1.105-CIIIc.10]

1389.6 [M+H]+ [1.106-CIIIc.10]

1375.6 [M+H]+ [1.108-CIIIc.10]

1375.6 [M+H]+ [1.109-CIIIc.10]

1389.6 [M+H]+ [1.110-CIIIc.10]

1375.6 [M+H]+ [1.113-CIIIc.10]

1388.6 [M+H]+ [1.115-CIIIc.10]

1388.6 [M+H]+ [1.122-CIIIc.10]

1411.5 [M+H]+ [1.140-CIIIc.10]

1410.5 [M+H]+ [1.143-CIIIc.10]

1410.5 [M+H]+ [1.147-CIIIc.10]

1373.6 [M+H]+ [1.148-CIIIc.10]

1373.6 [M+H]+ [1.150-CIIIc.10]

1373.6 [M+H]+ [1.157-CIIIc.10]

1374.6 [M+H]+ [1.32-CIIIc.11]

1477.2 [M+H]+ [1.91-CIIIc.11]

1536.6 [M+H]+ [1.92-CIIIc.11]

1522.6 [M+H]+ [1.32-CIIIc.12]

1606.6 [M+H]+ [1.201-CIc.1]

947 [M+H]+ [7.1-CIIIc.8]

1283.5 [M+H]+ [7.2-CIIIc.8]

1249.5 [M+H]+ [7.3-CIIIc.8]

1283.4 [M+H]+ [7.4-CIIIc.8]

1249.5 [M+H]+ [7.5-CIIIc.8]

1282.4 [M+H]+ [7.6-CIIIc.8]

1248.5 [M+H]+ [7.7-CIIIc.8]

1282.4 [M+H]+ [7.8-CIIIc.8]

1248.5 [M+H]+ Example 4 Generation of Antibody-TGFβ Inhibitor Conjugates by Partial Reduction of Original Disulfide Bonds of Non-Engineered Antibodies

mAbs (3-8 mg/mL in PBS) were exchanged into HEPES (100 mM, pH 7.0, 1 mM DTPA) by MWCO centrifugal filtration (Millipore, 30 kDa). Pipette the resulting mAb solution into a 50 mL conical tube. mAb concentrations were determined by A ₂₈₀ to be 3-8 mg/mL. TCEP (2.0-4.0 equiv, 1 mM stock) was added to the mAb solution at room temperature, and the resulting mixture was incubated at 20-37°C for 30-90 min with gentle shaking. After cooling to room temperature, a stir bar was added to the reaction tube. The linker-payload (5-10 equiv, 10 mM DMSO) was added dropwise with stirring. The resulting reaction mixture was stirred at ambient temperature for 30-60 minutes, at which time N-ethylmaleimide (3.0 equiv, 100 mM DMA) was added. After an additional 15 minutes of stirring, N-Acetylcysteine (6.0-11.0 equiv, 50 mM HEPES) was added. Crude ADCs were then exchanged into PBS and purified by preparative SEC (eg HiLoad 26/600, Superdex 200 pg) with PBS as mobile phase. The pure fractions were concentrated by MWCO centrifugal filtration (Millipore, 30 kDa), sterile filtered, and transferred to 15 mL conical tubes. Drug-antibody construct ratios (molar ratios) are determined by the methods described herein. Example 5 General Procedure for Determining Drug-Antibody Ratio Hydrophobic Interaction Chromatography

10 µL of the 6 mg/mL conjugate solution was injected into an HPLC system equipped with a TOSOH TSKgel Butyl-NPR ^™ Hydrophobic Interaction Chromatography (HIC) column (2.5 µM particle size, 4.6 mm x 35 mm). Then, over the course of 18 minutes, a method was run in which the mobile phase gradient was run from 100% mobile phase A to 100% mobile phase B for 12 minutes, followed by 6 minutes of re-equilibration of 100% mobile phase A. The flow rate was 0.8 mL/min and the detector was set to 280 nM. Mobile phase A was 1.5 M ammonium sulfate, 25 mM sodium phosphate (pH 7). Mobile phase B was 25 mM sodium phosphate (pH 7) containing 25% isopropanol. After the run, the chromatograms were integrated and the molar ratio was determined by summing the weighted peak areas. Example 6 TGFβ reporter assay material and general procedure

The TGFβ/SMAD signaling pathway SBE reporter cell line was obtained from BPS Bioscience. Cells were passaged, expanded, and stored in liquid nitrogen according to the supplier's instructions, except that the growth medium was replaced with DMEM-C (DMEM supplemented with 10% fetal bovine serum, Geneticin) containing Geneticin. 1X NEAA, 1 mM pyruvate, 2 mM glutamic acid, 50 μg/mL penicillin, 50 U/mL streptomycin, and 400 μg/mL geneticin). The assay medium was MEM supplemented with 0.5% fetal bovine serum, 1X NEAA, 1 mM pyruvate, 50 μg/mL penicillin, and 50 U/mL streptomycin.

with formula (I'), (I''), (I), (II'), (II''), (II), (III'), (III''), (III), (IV' ), (IV''), (IV), (V'), (V''), (V), (VI'), (VI''), and (VI) compounds were tested and determined as ALK5 inhibitor activity. Enzyme Inhibition Test

ALK5 enzyme inhibition assays were performed by Reaction Biology Corp (Malvern, PA). 1 mg/mL peptide substrate (casein) and 10 uM ATP were prepared in fresh reaction buffer mix. The kinase is delivered to the gently mixed substrate solution. Compounds in 100% DMSO were added to the kinase reaction mixture by acoustic techniques (Echo550; nanoliter range), and the mixture was incubated at room temperature for 20 minutes. ³³ P-ATP (specific activity of 10 uCi/uL) was added to the reaction mixture to initiate the reaction, and the reaction mixture was incubated at room temperature for 2 hours. Radioactivity was detected by filter binding and the kinase activity data in the test samples were expressed as a percentage of remaining kinase activity compared to the vehicle (dimethylsulfite) reaction. _IC50 values and curve fit were obtained using Prism (GraphPad Software). In Table 21 below, compounds with _IC50 values between 0.1 nM and 25 nM are indicated as ++++, between 25 nM and 100 nM as +++, and between 100 nM and 1000 nM as ++ , and >1000 nM is denoted as +. Table 21 ALK5 inhibition by compounds described herein Compound number IC50 1.1 ++++ 1.2 ++++ 1.3 ++++ 1.4 ++++ 1.5 ++++ 1.6 ++++ 1.7 ++++ 1.8 ++++ 1.9 ++++ 1.10 ++++ 1.11 ++++ 1.12 ++++ 1.13 ++++ 1.14 ++++ 1.15 ++++ 1.16 ++++ 1.17 ++++ 1.18 NT 1.19 ++++ 1.20 NT 1.21 ++++ 1.22 ++++ 1.23 NT 1.24 NT 1.25 ++++ 1.26 ++++ 1.27 ++++ 1.28 ++++ 1.29 ++++ 1.31 ++++ 1.32 ++++ 1.33 ++++ 1.34 + 1.35 +++ 1.36 +++ 1.37 +++ 1.38 ++++ 1.39 ++++ 1.40 ++++ 1.41 ++++ 1.42 ++ 1.43 +++ 1.44 ++ 1.45 NT 1.46 +++ 1.47 +++ 1.48 +++ 1.49 ++++ 1.50 ++ 1.51 ++ 1.52 +++ 1.53 ++++ 1.54 ++++ 1.55 +++ 1.56 ++++ 1.57 +++ 1.58 NT 1.59 +++ 1.60 +++ 1.61 +++ 1.62 ++ 1.63 ++++ 1.64 ++++ 1.65 ++ 1.66 NT 1.67 ++++ 1.68 ++++ 1.69 +++ 1.70 ++++ 1.71 +++ 1.72 ++++ 1.73 +++ 1.74 ++ 1.75 ++ 1.76 +++ 1.77 NT 1.78 ++ 1.79 +++ 1.80 +++ 1.81 ++++ 1.82 ++++ 1.83 NT 1.84 NT 1.85 +++ 1.86 +++ 1.87 +++ 1.88 +++ 1.89 ++ 1.90 +++ 1.91 ++++ 1.92 ++++ 1.93 ++ 1.94 +++ 1.95 +++ 1.96 ++++ 1.97 ++++ 1.98 ++++ 1.99 +++ 1.100 ++++ 1.101 ++++ 1.102 ++++ 1.103 ++++ 1.104 ++++ 1.105 +++, ++ 1.106 ++++ 1.107 ++++ 1.108 ++++ 1.109 +++ 1.110 ++++ 1.111 ++++ 1.112 ++++ 1.113 ++++ 1.114 ++++ 1.115 ++++ 1.116 ++++ 1.117 +++ 1.118 ++++ 1.119 +++ 1.120 ++++ 1.121 +++ 1.122 +++ 1.123 +++ 1.124 ++++ 1.125 ++++ 1.126 ++++ 1.127 ++++ 1.128 ++++ 1.129 ++++ 1.130 ++++ 1.131 ++++ 1.132 ++++ 1.133 +++ 1.134 ++++ 1.135 ++++ 1.136 ++++ 1.137 ++++ 1.138 ++++ 1.139 ++++ 1.140 ++++ 1.141 ++++ 1.142 ++++ 1.143 +++ 1.144 ++++ 1.145 ++++ 1.146 ++++ 1.147 ++++ 1.148 ++++ 1.149 ++++ 1.150 ++++ 1.151 +++ 1.152 ++++ 1.153 ++++ 1.154 +++ 1.155 ++++ 1.156 ++++ 1.157 ++++ 1.158 ++++ 1.159 ++++ 1.160 +++ 1.161 ++++ 1.162 ++++ 1.163 ++++ 1.164 ++++ 1.165 ++++ 1.166 ++++ 1.167 ++++ 1.168 ++++ 1.169 ++++ 1.170 ++++ 1.171 ++++ 1.172 ++++ 1.173 ++++ 1.174 ++++ 1.175 ++++ 1.176 ++++ 1.177 ++++ 1.178 ++++ 1.179 NT 1.180 ++++ 1.181 ++++ 1.182 ++++ 1.183 ++++ 1.184 ++++ 1.185 ++++ 1.186 NT 1.187 +++ 1.188 ++++ 1.189 ++++ 1.190 ++++ 1.191 ++++ 1.192 ++++ 1.193 ++++ 1.194 +++ 1.195 ++++ 1.196 NT 1.197 NT 1.198 ++ 1.199 +++ 1.200 +++ 1.201 +++ 1.202 +++ 2.1 ++++ 2.2 +++ 2.3 + 2.4 ++ 2.5 ++++ 2.6 +++ 2.7 +++ 2.8 ++++ 2.9 ++ 3.1 +++ 3.2 ++++ 3.3 ++++ 4.1 +++ 4.2 +++ 4.3 ++ 4.4 ++ 4.5 +++ 4.6 ++ 4.7 +++ 4.8 ++ 4.9 +++ 4.10 +++ 4.11 +++ 4.12 +++ 4.13 NT 4.14 +++ 4.15 ++ 5.1 ++ 5.2 NT 6.1 +++ 6.2 NT 6.3 +++ 6.4 ++ 7.1 ++++ 7.2 ++++ 7.3 ++++ 7.4 +++ 7.5 ++++ 7.6 ++++ 7.7 ++++ 7.8 ++++ 7.9 +++ 7.10 ++++ 7.11 ++++ 7.12 ++++ 7.13 ++ 7.14 ++ 7.15 ++++ 7.16 ++++ TGFb reporter assay

The TGFb/SMAD signaling pathway SBE reporter cell line was obtained from BPS Bioscience. Cells were passaged, expanded, and stored in liquid nitrogen according to the supplier's instructions, except that the growth medium was replaced with DMEM-C containing Geneticin (DMEM supplemented with 10% fetal bovine serum, 1X NEAA, 1 mM pyruvate, 2 mM glutamic acid, 50 μg/mL penicillin, 50 U/mL streptomycin, and 400 μg/mL geneticin). The assay medium was MEM supplemented with 0.5% fetal bovine serum, 1X NEAA, 1 mM pyruvate, 50 μg/mL penicillin, and 50 U/mL streptomycin.

After removing the medium from the flask and rinsing the cells with PBS, reporter cells were harvested from the tissue culture flask by incubating with a small amount of Versene for 3 to 5 minutes at room temperature. Cells were counted and diluted in assay medium at a concentration of ~0.8 x ¹⁰⁶ cells per milliliter, followed by addition to 96-well assay plates at 50 uL per well. Add test samples (diluted to desired concentration in assay medium) to assay plates containing 50uL of cells (or medium only) per well, humidified with 5% _CO at 37°C Incubate for 5-6 hours. Subsequently, 15 uL of TGFb diluted to 12.5 ng/mL in assay medium was added to the assay dish. Controls included titration of TGFb without inhibitor (25 to 0 ng/mL), and medium only (without cells, inhibitor, or TGFb). The assay plates were incubated for 18 hours at 37°C in a 5% CO ₂ humidified incubator. Subsequently, 75 uL of luciferase substrate solution was added to each well, incubated with shaking at room temperature for 10 minutes with closed light, and the luminescence was measured with a luminometer. In Table 22 below, compounds with _EC50 values between 0.1 nM and 25 nM are indicated as ++++, between 25 nM and 100 nM as +++, and between 100 nM and 1000 nM as + +, and >1000 nM is denoted as +. Table 22 TGFβ reporter activity of compounds described herein Compound number IC50 1.1 ++++ 1.2 ++++ 1.3 +++ 1.4 +++ 1.5 +++ 1.6 +++ 1.7 +++ 1.8 +++ 1.9 +++ 1.10 +++ 1.11 ++ 1.12 +++ 1.13 +++ 1.14 ++ 1.15 ++ 1.16 ++ 1.17 +++ 1.18 +++ 1.19 ++ 1.20 ++ 1.21 +++ 1.22 +++ 1.23 +++ 1.24 + 1.25 +++ 1.26 +++ 1.27 +++ 1.28 +++ 1.29 +++ 1.31 +++ 1.32 ++ 1.33 +++ 1.34 + 1.35 ++++ 1.36 +++ 1.37 ++++ 1.38 ++++ 1.39 +++ 1.40 ++++ 1.41 ++++ 1.42 +++ 1.43 +++ 1.44 +++ 1.45 NT 1.46 +++ 1.47 +++ 1.48 +++ 1.49 ++++ 1.50 +++ 1.51 ++ 1.52 +++ 1.53 +++ 1.54 ++++ 1.55 ++ 1.56 +++ 1.57 ++++ 1.58 NT 1.59 +++ 1.60 +++ 1.61 ++ 1.62 +++ 1.63 +++ 1.64 ++ 1.65 ++ 1.66 NT 1.67 ++++ 1.68 +++ 1.69 ++ 1.70 ++++ 1.71 + 1.72 ++ 1.73 +++ 1.74 ++++ 1.75 +++ 1.76 +++ 1.77 NT 1.78 +++ 1.79 +++ 1.80 +++ 1.81 ++++ 1.82 +++ 1.83 NT 1.84 NT 1.85 +++ 1.86 ++++ 1.87 +++ 1.88 NT 1.89 +++ 1.90 + 1.91 +++ 1.92 ++ 1.93 +++ 1.94 +++ 1.95 +++ 1.96 + 1.97 ++++ 1.98 ++ 1.99 ++ 1.100 ++ 1.101 +++ 1.102 ++ 1.103 ++ 1.104 + 1.105 +++ 1.106 + 1.107 +++ 1.108 + 1.109 ++ 1.110 ++ 1.111 +++ 1.112 + 1.113 +++ 1.114 ++ 1.115 +++ 1.116 ++ 1.117 ++ 1.118 + 1.119 +++ 1.120 + 1.121 +++ 1.122 + 1.123 +++ 1.124 ++ 1.125 +++ 1.126 ++ 1.127 +++ 1.128 +++ 1.129 +++ 1.130 ++ 1.131 +++ 1.132 ++ 1.133 ++ 1.134 + 1.135 +++ 1.136 ++ 1.137 +++ 1.138 ++ 1.139 ++ 1.140 ++ 1.141 ++ 1.142 ++ 1.143 ++ 1.144 + 1.145 + 1.146 ++ 1.147 ++ 1.148 ++ 1.149 ++ 1.150 ++ 1.151 +++ 1.152 +++ 1.153 + 1.154 +++ 1.155 + 1.156 ++ 1.157 + 1.158 ++ 1.159 ++ 1.160 ++ 1.161 ++ 1.162 ++ 1.163 + 1.164 + 1.165 + 1.166 ++ 1.167 + 1.168 ++ 1.169 ++ 1.170 + 1.171 ++ 1.172 + 1.173 ++ 1.174 + 1.175 ++ 1.176 + 1.177 ++ 1.178 ++ 1.179 NT 1.180 + 1.181 ++ 1.182 + 1.183 ++ 1.184 + 1.185 + 1.186 NT 1.187 +++ 1.188 ++ 1.189 + 1.190 NT 1.191 ++ 1.192 ++ 1.193 + 1.194 + 1.195 + 1.196 NT 1.197 NT 1.198 NT 1.199 NT 1.200 + 1.201 + 1.202 + 2.1 ++++ 2.2 ++++ 2.3 ++++ 2.4 +++ 2.5 + 2.6 +++ 2.7 ++ 2.8 + 2.9 +++ 3.1 ++ 3.2 ++ 3.3 ++ 4.1 +++ 4.2 ++ 4.3 ++ 4.4 +++ 4.5 +++ 4.6 ++ 4.7 +++ 4.8 + 4.9 +++ 4.10 +++ 4.11 +++ 4.12 +++ 4.13 NT 4.14 ++ 4.15 ++ 5.1 +++ 5.2 NT 6.1 +++ 6.2 NT 6.3 +++ 6.4 +++ 7.1 + 7.2 ++ 7.3 + 7.4 + 7.5 ++ 7.6 + 7.7 + 7.8 + 7.9 + 7.10 + 7.11 ++ 7.12 ++ 7.13 + 7.14 + 7.15 + 7.16 + Example 7 Generation of Exemplary ASGR1 Antibodies

ASGR1 4A2 heavy and light chain DNAs were cloned into different expression vectors to generate human IgG1 antibodies. The heavy chain vector construct was transiently co-expressed with the light chain vector construct in the ExpiCHO ^™ system to generate the 4A2 IgGl antibody. The protein in the recovered ExpiCHO ^™ supernatant was purified to homogeneity using a Protein A column on a GE AKTA Pure ^™ system and confirmed for purity by analytical grade HPLC-SEC. If needed, additional purification was performed on a preparative SEC column to remove aggregates. ASGR1 72G9 and 176H4 IgG1 antibodies were produced in the same way. The heavy and light chain sequences of the 4A2, 72G9, and 176H4 antibodies are as shown in WO2017/058944, which is incorporated herein by reference in its entirety for all purposes.

In addition, the service provider uses its proprietary procedure to generate fusionomas producing monoclonal antibodies (mAbs) specific for human ASGR1 from Balb/C mice vaccinated with ASGR1-AviHis. Antibody heavy and light chain sequences were obtained, amplified and cloned. Colony supernatants containing mAbs were screened for binding to the human ASGR1-IgG1 Fc fusion protein, and those screened for binding by enzyme-binding immunosorbent assay (ELISA) to HepG2 cells (which express ASGR1) were positive signaler. Based on the initial selection criteria, sixteen (16) mAbs were expressed and isolated. The isolated mAbs were further analyzed for other characteristics, eg, titer, low aggregate content after protein A purification, high titer, lack of cross-blocking of ligand GalNac, calcium sensitivity, and cross-reactivity with rat ASGR1 protein. A total of five (5) clones (G2D, K2E, J4F, L4L, and H8K) that exhibited strong signals in these experiments were humanized and subjected to epitope binning (see Example 2). ), and compared to known anti-ASGR mAbs 4A2, 72G9, and 4F3 (see, e.g., PCT Publication Nos. WO 2017/058944 and WO 2014/023709), referred to herein as ASGR1 mAb-A, ASGR1 mAb-B, and ASGR1, respectively mAb-C. Humanization of mAb G2D

For humanization of the G2D VH region (SEQ ID NO:38), the 3 CDR loops defined by Kabat were grafted to the human germline sequence VH1-03 containing JH6 to generate hzG2D VH (SEQ ID NO:43 ). In addition, several variants of hzG2D VH were constructed to contain one or more mouse backmutations (FR1), CDR2, framework region 3 (FR3) at the junction of CDR2, FR3, or any combination thereof ( See SEQ ID NOS: 44-51 and 82-88). Several of the humanized heavy chains were further altered to remove potential deamidation sites by adding mutations in CDR2, namely N54Q or G55A (see SEQ ID NOS: 52-81).

For humanization of the G2D VL regions (SEQ ID NO: 126) of clones 1-16, 19-21, 26-29, 31, and 33, the 3 CDR loops defined by Kabat were grafted to contain JK4 The human germline sequence VKI-L1 to generate hzG2D VL _a (SEQ ID NO: 131). In addition, mutations were introduced into the CDR2/FR3 junction of the humanized light chain (ie, D56S or D56E) to remove potential isomerization sites (see SEQ ID NOS: 132-133).

For humanization of the G2D VL regions (SEQ ID NO: 126) of clones 22, 23, 30, 32, and 34-37, the 3 CDR loops defined by Kabat were grafted into the human germline containing JK4 Sequence VKI-O2 to generate hzG2D _VLb (SEQ ID NO: 361). In addition, mutations were introduced into the CDR2/FR3 junction of the humanized light chain (ie, D56S) to remove potential isomerization sites (see SEQ ID NO: 362).

For humanization of the G2D VL region (SEQ ID NO: 126) of clones 24 and 25, the 3 CDR loops defined by Kabat were grafted to the human germline sequence VKI-A20 containing JK4 to generate hzG2D VL _c (SEQ ID NO: 363).

The heavy chain variable region sequence was cloned into a vector containing a signal peptide sequence and a human IgG1 antibody region (SEQ ID NO: 230), while the light chain variable region was cloned into a vector containing a signal peptide sequence and a human kappa light chain constant region (SEQ ID NO: 232) in the vector. A total of 22 humanized heavy chains were paired with 6 humanized light chains to generate mAbs that were analyzed to have the desired characteristics described above. Table 23 Confirmation of humanized G2D clones name VH (IgG1) VL (κ) titermg /L % POI Guava HepG2 Screening HepG2 _EC50 G2D-C G2D VH (SEQ ID NO:38) G2D VL (SEQ ID NO: 126) 250 98 187/145 0.4 hzG2D-1 hzG2D VH V109L (SEQ ID NO:43) hzG2D VL _a (SEQ ID NO: 131) 9 32/19 hzG2D-2 hzG2.1D VH T28S, V109L (SEQ ID NO:44) hzG2D VL _a (SEQ ID NO: 131) 19 38/20 hzG2D-3 hzG2.45D VH A93T, R94S, V109L (SEQ ID NO:88) hzG2D VL _a (SEQ ID NO: 131) 59 131/95 hzG2D-4 hzG2.39D VH R66K, V67A, V109L (SEQ ID NO:82) hzG2D VL _a (SEQ ID NO: 131) 12 55/22 hzG2D-5 hzG2.8D VH T28S, A93T, R94S, V109L (SEQ ID NO:51) hzG2D VL _a (SEQ ID NO: 131) 75 91/55 hzG2D-6 hzG2.43D VH T68S, I69L, R71V, V109L (SEQ ID NO:86) hzG2D VLa (SEQ ID NO: 131) twenty four 39/23 hzG2D-7 hzG2.2D VH T28S, R66K, V67A, V109L (SEQ ID NO:45) hzG2D VLa (SEQ ID NO: 131) 12 46/22 hzG2D-8 hzG2.6D VH T28S, T68S, I69L, R71V, V109L (SEQ ID NO:49) hzG2D VLa (SEQ ID NO: 131) twenty three 31/21 hzG2D-9 hzG2.40D VH R66K, V67A, A93T, R94S, V109L (SEQ ID NO:83) hzG2D VL _a (SEQ ID NO: 131) twenty three 81 155/117 hzG2D-10 hzG2.44D VH T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:87) hzG2D VL _a (SEQ ID NO: 131) 102 30 149/63 hzG2D-11 hzG2.41D VH R66K, V67A, T68S, I69L, R71V, V109L (SEQ ID NO:84) hzG2D VL _a (SEQ ID NO: 131) 10 68 very low hzG2D-12 hzG2.3D VH T28S, R66K, V67A, A93T, R94S, V109L (SEQ ID NO:46) hzG2D VL _a (SEQ ID NO: 131) 19 67 158/113 hzG2D-13 hzG2.7D VH T28S, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:50) hzG2D VL _a (SEQ ID NO: 131) 54 46 140/83 hzG2D-14 hzG2.4D VH T28S, R66K, V67A, T68S, I69L, R71V, V109L (SEQ ID NO:47) hzG2D VL _a (SEQ ID NO: 131) 10 37/16 hzG2D-15 hzG2.42D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:85) hzG2D VL _a (SEQ ID NO: 131) 45 45 172/119 hzG2D-16 hzG2.5D VH T28S, R66K, V67A, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:48) hzG2D VL _a (SEQ ID NO: 131) 39 40 165/108 hzG2D-17 hzG2.41D VH R66K, V67A, T68S, I69L, R71V, V109L (SEQ ID NO:84) G2D VL (SEQ ID NO: 126) 80 very low hzG2D-18 hzG2.42D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:85) G2D VL (SEQ ID NO: 126) 206 76 ND hzG2D-19 G2D VH (SEQ ID NO:38) hzG2D VLa (SEQ ID NO: 131) 33 90 ND hzG2D-20 hzG2.46D VH R66K, V67A, T68S, I69L, R71V (SEQ ID NO:352) hzG2D VL _a (SEQ ID NO: 131) 30 very low hzG2D-21 hzG2.47D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:353) hzG2D VL _a (SEQ ID NO: 131) 40 199/127 hzG2D-22 hzG2.46D VH R66K, V67A, T68S, I69L, R71V (SEQ ID NO:352) hzG2D _VLb (SEQ ID NO:361) 115 None hzG2D-23 hzG2.47D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:353) hzG2D _VLb (SEQ ID NO:361) 215 98 198/131 0.3 hzG2D-24 hzG2.46D VH R66K, V67A, T68S, I69L, R71V (SEQ ID NO:352) hzG2D VL _c (SEQ ID NO: 363) 3 None hzG2D-25 hzG2.47D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:353) hzG2D VL _c (SEQ ID NO: 363) 58 None hzG2D-26 hzG2.47D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:353) hzG2.3D VL _a K45E, S46T (SEQ ID NO:358) 72 93 185/114 hzG2D-27 hzG2.47D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:353) hzG2.4D VL _a Q79E, P80Y (SEQ ID NO:359) 165 98 191/116 hzG2D-28 hzG2.47D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:353) hzG2.5D VL _a F71Y, T72S (SEQ ID NO:360) 72 66 145/92 hzG2D-29 hzG2.49D VH R38K, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:355) hzG2D VL _a (SEQ ID NO: 131) 57 72 189/108 hzG2D-30 hzG2.49D VH R38K, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:355) hzG2D _VLb (SEQ ID NO:361) 189 96 198/115 hzG2D-31 hzG2.50D VH R66K, V67A, T68S, I69L, R71V, L82F, S82aH, A93T, R94S (SEQ ID NO:356) hzG2D VL _a (SEQ ID NO: 131) 41 73 168/95 hzG2D-32 hzG2.50D VH R66K, V67A, T68S, I69L, R71V, L82F, S82aH, A93T, R94S (SEQ ID NO:356) hzG2D _VLb (SEQ ID NO:361) 153 94 167/103 hzG2D-33 hzG2.51D VH R66K, V67A, T68S, I69L, R71V, R84T, A93T, R94S (SEQ ID NO:357) hzG2D VL _a (SEQ ID NO: 131) 60 61 164/85 hzG2D-34 hzG2.51D VH R66K, V67A, T68S, I69L, R71V, R84T, A93T, R94S (SEQ ID NO:357) hzG2D _VLb (SEQ ID NO:361) 198 86 194/109 hzG2D-35 hzG2.47D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:353) hzG2.6D VL _b D56S (SEQ ID NO: 362) 262 99 ND 0.3 hzG2D-36 hzG2.48D VH G55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:354) hzG2D _VLb (SEQ ID NO:361) 94 82 ND 0.3 hzG2D-37 hzG2.48D VH G55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:354) hzG2.6D VL _b D56S (SEQ ID NO: 362) 403 98 ND 0.3 Humanization of mAb K2E

Germline VH1-46 containing JH6 was used for CDR grafting variable heavy chain (SEQ ID NO:39) and germline VKI-L1 containing JK2 was used for CDR grafting variable light chain (SEQ ID NO:127 ). CDR grafting was performed using Kabat-defined CDRs to generate hzK2E VH (SEQ ID NO: 89) and hzK2E VL (SEQ ID NO: 134). Several hzK2E VH (SEQ ID NOS: 90-93) and hzK2E VL (SEQ ID NO: 135) variants contained the resulting mouse framework backmutations and were sequenced with 3D structural models to confirm residue pair CDR structures potential impact. In addition, mutations were introduced into the CDR2/FR3 junction of the humanized light chain (ie, D56E) to remove potential isomerization sites (see SEQ ID NOS: 136-137). The variable heavy chain region sequence was cloned into a vector containing the signal peptide sequence and the IgG1 constant region. The variable light chain region is cloned into a vector containing a signal peptide sequence and a kappa constant region.

The 5 humanized heavy chains were each paired with each other into 4 different humanized light chains to generate mAbs that were analyzed to have the desired characteristics described above (see Table 24 ). The humanized sequence was further modified by adding an additional mutation (ie, D56E) at the light chain CDR2/FR3 junction to remove a potential isomerization reaction site. Table 24 Confirmation of humanized K2E clones name VH (IgG1) VL (κ) titermg /L % POI HepG2 _EC50 K2E-C K2E VH (SEQ ID NO: 39) K2E VL (SEQ ID NO: 127) 512 99 0.50 hzK2E-1 hzK2E VH (SEQ ID NO:89) hzK2E VL (SEQ ID NO: 134) 479 100 0.53 hzK2E-2 hzK2.1E VH R66K, V67T (SEQ ID NO:90) hzK2E VL (SEQ ID NO: 134) 445 99 0.41 hzK2E-3 hzK2.4E VH M69L, R71A (SEQ ID NO:93) hzK2E VL (SEQ ID NO: 134) 455 99 0.68 hzK2E-4 hzK2.2E VH R66K, V67T, M69L, R71A (SEQ ID NO:91) hzK2E VL (SEQ ID NO: 134) 401 100 0.90 hzK2E-5 hzK2.3E VH R66K, V67T, M69L, R71A, T73K (SEQ ID NO:92) hzK2E VL (SEQ ID NO: 134) 386 100 0.54 hzK2E-6 hzK2E VH (SEQ ID NO:89) hzK2.1E VL S46T (SEQ ID NO: 135) 435 99 hzK2E-7 hzK2.1E VH R66K, V67T (SEQ ID NO:90) hzK2.1E VL S46T (SEQ ID NO: 135) 440 100 hzK2E-8 hzK2.4E VH M69L, R71A (SEQ ID NO:93) hzK2.1E VL S46T (SEQ ID NO: 135) 440 99 hzK2E-9 hzK2.2E VH R66K, V67T, M69L, R71A (SEQ ID NO:91) hzK2.1E VL S46T (SEQ ID NO: 135) 422 99 hzK2E-10 hzK2.3E VH R66K, V67T, M69L, R71A, T73K (SEQ ID NO:92) hzK2.1E VL S46T (SEQ ID NO: 135) 451 100 0.50 hzK2E-11 hzK2E VH (SEQ ID NO:89) hzK2.2E VL D56E (SEQ ID NO: 136) 479 99 0.46 hzK2E-12 hzK2.1E VH R66K, V67T (SEQ ID NO:90) hzK2.2E VL D56E (SEQ ID NO: 136) 393 393 0.45 hzK2E-13 hzK2.4E VH M69L, R71A (SEQ ID NO:93) hzK2.2E VL D56E (SEQ ID NO: 136) 389 389 0.92 hzK2E-14 hzK2.2E VH R66K, V67T, M69L, R71A (SEQ ID NO:91) hzK2.2E VL D56E (SEQ ID NO: 136) 411 411 0.77 hzK2E-15 hzK2.3E VH R66K, V67T, M69L, R71A, T73K (SEQ ID NO:92) hzK2.2E VL D56E (SEQ ID NO: 136) 427 427 hzK2E-16 hzK2E VH (SEQ ID NO:89) hzK2.3E VL S46T D56E (SEQ ID NO: 137) 432 432 hzK2E-17 hzK2.1E VH R66K, V67T (SEQ ID NO:90) hzK2.3E VL S46T D56E (SEQ ID NO: 137) 384 384 hzK2E-18 hzK2.4E VH M69L, R71A (SEQ ID NO:93) hzK2.3E VL S46T D56E (SEQ ID NO: 137) 380 380 hzK2E-19 hzK2.2E VH R66K, V67T, M69L, R71A (SEQ ID NO:91) hzK2.3E VL S46T D56E (SEQ ID NO: 137) 361 361 hzK2E-20 hzK2.3E VH R66K, V67T, M69L, R71A, T73K (SEQ ID NO:92) hzK2.3E VL S46T D56E (SEQ ID NO: 137) 363 363 Humanization of mAb L4L

Germline VH4-31 containing JH6 was used for CDR grafting variable heavy chain (SEQ ID NO:40) and germline VKI-02 containing JK4 was used for CDR grafting variable light chain (SEQ ID NO:128 ). CDR grafting was performed using Kabat-defined CDRs to generate hzL4L VH (SEQ ID NO: 94) and hzL4L VL (SEQ ID NO: 138). Several hzL4L VH (SEQ ID NOS: 95-102) variants contained the mouse framework backmutations generated and were sequenced with 3D structural models to confirm the potential impact of residues on CDR structure. The variable heavy chain region sequences were cloned into a vector containing the signal peptide sequence and the IgG1 constant region. The variable light chain region is cloned into a vector containing a signal peptide sequence and a kappa constant region.

Nine humanized heavy chains were individually co-transfected with four different humanized light chains (see Table 25 ) into the ExpiCHO™ Expression System in 30 mL of medium, benchmarked against the parental chimeric antibody (L4L) . The antibody-containing supernatant was purified and further modified. The humanized sequence was further modified by additional mutations added at the light chain CDR2/FR3 junction, namely D56S (SEQ ID NO: 139), D56E (SEQ ID NO: 140), or G57A (SEQ ID NO: 141) hzL4L-10 to hzL4L-14 to remove potential isomerization sites. A decrease in percent purity, as measured by analytical particle size sieve chromatography (percent protein of interest (POI)), was seen in chimeras with hzL4L-1, -2, and -6. Surprisingly, the G27Y mutation appeared to help stabilize the structure, resulting in more homogeneous recoveries (see Table 25 ). Table 25 Confirmation of humanized L4L clones name VH (IgG1) VL (κ) titermg /L % POI Guava HepG2 Screening Mobile HepG2 EC ₅₀ L4L L4L VH (SEQ ID NO: 40) L4L VL (SEQ ID NO: 128) 327 65 good 1.9 hzL4L-1 hzL4L VH (SEQ ID NO:94) hzL4L VL (SEQ ID NO: 138) 462 72 bad hzL4L-2 hzL4L VH S30T, V67I, T68S, S70T, V71R hzL4.1L (SEQ ID NO:95) hzL4L VL (SEQ ID NO: 138) 495 71 good hzL4L-3 hzL4L VH G27Y, S30T, V67I, T68S, S70T, V71R hzL4.2L VH (SEQ ID NO:96) hzL4L VL (SEQ ID NO: 138) 289 98 good 1.5 hzL4L-4 hzL4L VH G27Y, S30T hzL4.3L VH (SEQ ID NO:97) hzL4L VL (SEQ ID NO: 138) 337 91 bad 1.8 hzL4L-5 hzL4L VH G27Y, V67I, T68S, S70T, V71R hzL4.4L VH (SEQ ID NO:98) hzL4L VL (SEQ ID NO: 138) 237 99 good hzL4L-6 hzL4L VH G27Y, S30T, S70T, V71R hzL4.5L VH (SEQ ID NO:99) hzL4L VL (SEQ ID NO: 138) 620 82 good hzL4L-7 hzL4L VH G27Y, S70T, V71R hzL4.6L VH (SEQ ID NO: 100) hzL4L VL (SEQ ID NO: 138) 407 97 good 2.1 hzL4L-8 hzL4L VH G27Y, S30T, V67I, T68S hzL4.7L VH (SEQ ID NO: 101) hzL4L VL (SEQ ID NO: 138) 316 99 bad hzL4L-9 hzL4L VH G27Y, V67I, T68S hzL4.8L VH (SEQ ID NO: 102) hzL4L VL (SEQ ID NO: 138) 291 98 bad hzL4L-10 hzL4L VH G27Y, S30T, V67I, T68S, S70T, V71R hzL4.2L VH (SEQ ID NO:96) hzL4L VL D56S hzL4.1L VL (SEQ ID NO: 139) 158 91 good hzL4L-11 hzL4L VH G27Y, S30T, V67I, T68S, S70T, V71R hzL4.2L VH (SEQ ID NO:96) hzL4L VL D56E hzL4.2L VL (SEQ ID NO: 140) 282 96 good 2.0 hzL4L-12 hzL4L VH G27Y, S30T, V67I, T68S, S70T, V71R hzL4.2L VH (SEQ ID NO:96) hzL4L VL G57A hzL4.3L VL (SEQ ID NO: 141) ND ND ND ND hzL4L-13 hzL4L VH G27Y, V67I, T68S, S70T, V71R hzL4.4L VH (SEQ ID NO:98) hzL4L VL D56E hzL4.2L VL (SEQ ID NO: 140) 429 99 ND 1.3 hzL4L-14 hzL4L VH G27Y, S70T, V71R hzL4.6L VH (SEQ ID NO: 100) hzL4L VL D56E hzL4.2L VL (SEQ ID NO: 140) 659 97 ND 1.4 Humanization of mAb H8K

Germline VH lines containing JH6 were used for CDR grafting of variable heavy chains (SEQ ID NO: 41) and germline VL lines containing JK4 were used for CDR grafting variable light chains (SEQ ID NO: 129). CDR grafting was performed using Kabat-defined CDRs to generate hzH8K VH (SEQ ID NO: 103) and hzH8K VL (SEQ ID NO: 142). Several variants containing mouse framework backmutations (SEQ ID NOS: 104-112) were generated and sequenced with 3D structural models to confirm the potential impact of residues on CDR structure. The variable heavy chain region sequences were cloned into a vector containing the signal peptide sequence and the IgG1 constant region. The variable light chain region is cloned into a vector containing a signal peptide sequence and a kappa constant region.

Individually, 10 humanized heavy chains and 1 humanized light chain were co-transfected into the ExpiCHO™ Expression System in 30 mL of medium, based on the parental chimeric antibody (H8K). The supernatant was purified and further confirmed as shown in Table 26 . Table 26 Humanized H8K clones name VH (IgG1) VL (κ) titermg /L % POI HepG2 _EC50 H8K-C H8K VH (SEQ ID NO: 41) H8K VL (SEQ ID NO: 129) 364 99 3.1 hzH8K-1 hzH8K VH (SEQ ID NO: 103) hzH8K VL (SEQ ID NO: 142) 435 99 3.4 hzH8K-2 hzH8K VH S30T hzH8.1K VH (SEQ ID NO: 104) hzH8K VL (SEQ ID NO: 142) 438 99 2.5 hzH8K-3 hzH8K VH G27F, S30T hzH8.2K VH (SEQ ID NO: 105) hzH8K VL (SEQ ID NO: 142) 442 99 3.2 hzH8K-4 hzH8K VH V67I, T68S, S70T, V71R hzH8.3K VH (SEQ ID NO: 106) hzH8K VL (SEQ ID NO: 142) 373 96 2.2 hzH8K-5 hzH8K VH S30T, V67I, T68S, S70T, V71R hzH8.4K (SEQ ID NO: 107) hzH8K VL (SEQ ID NO: 142) 421 94 3.6 hzH8K-6 hzH8K VH G27F, S30T, V67I, T68S, S70T, V71R hzH8.5K (SEQ ID NO: 108) hzH8K VL (SEQ ID NO: 142) 318 94 4.9 hzH8K-7 hzH8K VH S30T, V67I, T68S hzH8.6K (SEQ ID NO: 109) hzH8K VL (SEQ ID NO: 142) 617 98 3.1 hzH8K-8 hzH8K VH S30T, S70T, V71R hzH8.7K (SEQ ID NO: 110) hzH8K VL (SEQ ID NO: 142) 587 92 3.5 hzH8K-9 hzH8K VH V67I, T68S hzH8.8K (SEQ ID NO: 111) hzH8K VL (SEQ ID NO: 142) 440 97 2.1 hzH8K-10 hzH8K VH S70T, V71R hzH8.9K (SEQ ID NO: 112) hzH8K VL (SEQ ID NO: 142) 744 96 2.2 Humanization of J4F

Germline VH1-46 containing JH6 was used for CDR grafting variable heavy chain (SEQ ID NO: 42) and germline VL containing JK4 was used for CDR grafting variable light chain (SEQ ID NO: 130). CDR grafting was performed using Kabat-defined CDRs to generate hzJ4F VH (SEQ ID NO: 113) and hzJ4F VL (SEQ ID NO: 143). Several variants containing mouse framework backmutations were generated (SEQ ID NOS: 114-125 for VH and SEQ ID NOS: 144-149 for VL) and sequenced with a 3D structural model to confirm the residues' contribution to the CDR structure. potential impact. The variable heavy chain region sequences were cloned into a vector containing the signal peptide sequence and the IgG1 constant region. The variable light chain region is cloned into a vector containing a signal peptide sequence and a kappa constant region.

Thirteen humanized heavy chains were individually co-transfected with each of 7 different humanized light chains into 30 mL of medium in the ExpiCHO™ Expression System, benchmarked against the parental chimeric antibody (J4F). The humanized variants hzJ4F-1 to hzJ4F-20 showed decreased binding compared to the parental chimeric mAb J4F (see Table 27 ). Therefore, additional humanized variable region sequences were designed to screen hzJ4F heavy and light chain combinations (hzJ4F-21 - hzJ4F-58) for binding similar to or better than the parental chimeric mAb J4F. Table 27 Humanized J4F clones name VH (IgG1) VL (κ) combine J4F J4F VH (SEQ ID NO: 42) J4F VL (SEQ ID NO: 130) ++++ hzJ4F-1 hzJ4F VH (SEQ ID NO: 113) hzJ4F VL (SEQ ID NO: 143) ++++ hzJ4F-2 hzJ4F VH R66K, V67A, M69L, R71V hzJ4.8F VH (SEQ ID NO: 121) hzJ4F VL (SEQ ID NO: 143) ++ hzJ4F-3 hzJ4F VH R66K, V67A hzJ4.5F VH (SEQ ID NO: 118) hzJ4F VL (SEQ ID NO: 143) ++ hzJ4F-4 hzJ4F VH M69L, R71V hzJ4.9F VH (SEQ ID NO: 122) hzJ4F VL (SEQ ID NO: 143) + hzJ4F-5 hzJ4F VH R71V hzJ4.10F VH (SEQ ID NO: 123) hzJ4F VL (SEQ ID NO: 143) - / + hzJ4F-6 hzJ4F VH (SEQ ID NO: 113) hzJ4F VL Q3V hzJ4.1F VL (SEQ ID NO: 144) ++ hzJ4F-7 hzJ4F VH R66K, V67A, M69L, R71V hzJ4.8F VH (SEQ ID NO: 121) hzJ4F VL Q3V hzJ4.1F VL (SEQ ID NO: 144) ++ hzJ4F-8 hzJ4F VH R66K, V67A hzJ4.5F VH (SEQ ID NO: 118) hzJ4F VL Q3V hzJ4.1F VL (SEQ ID NO: 144) ++ hzJ4F-9 hzJ4F VH M69L, R71V hzJ4.9F VH (SEQ ID NO: 122) hzJ4F VL Q3V hzJ4.1F VL (SEQ ID NO: 144) + hzJ4F-10 hzJ4F VH R71V hzJ4.10F VH (SEQ ID NO: 123) hzJ4F VL Q3V hzJ4.1F VL (SEQ ID NO: 144) ++ hzJ4F-11 hzJ4F VH (SEQ ID NO: 113) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) ++ hzJ4F-12 hzJ4F VH R66K, V67A, M69L, R71V hzJ4.8F VH (SEQ ID NO: 121) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) ++ hzJ4F-13 hzJ4F VH R66K, V67A hzJ4.5F VH (SEQ ID NO: 118) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) ++ hzJ4F-14 hzJ4F VH M69L, R71V hzJ4.9F VH (SEQ ID NO: 122) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) ++ hzJ4F-15 hzJ4F VH R71V hzJ4.10F VH (SEQ ID NO: 123) hzJ4F VKL L46A hzJ4.3F VL (SEQ ID NO: 146) ++ hzJ4F-16 hzJ4F VH (SEQ ID NO: 113) hzJ4F VL Q3V L46A hzJ4.2F VL (SEQ ID NO: 145) ++ hzJ4F-17 hzJ4F VH R66K, V67A, M69L, R71V hzJ4.8F VH (SEQ ID NO: 121) hzJ4F VL Q3V L46A hzJ4.2F VL (SEQ ID NO: 145) ++ hzJ4F-18 hzJ4F VH R66K, V67A hzJ4.5F VH (SEQ ID NO: 118) hzJ4F VL Q3V L46A hzJ4.2F VL (SEQ ID NO: 145) ++ hzJ4F-19 hzJ4F VH M69L, R71V hzJ4.9F VH (SEQ ID NO: 122) hzJ4F VL Q3V L46A hzJ4.2F VL (SEQ ID NO: 145) ++ hzJ4F-20 hzJ4F VH R71V hzJ4.10F VH (SEQ ID NO: 123) hzJ4F VL Q3V L46A hzJ4.2F VL (SEQ ID NO: 145) ++ hzJ4F-21 hzJ4F VH V37I hzJ4.1F VH (SEQ ID NO: 114) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) hzJ4F-22 hzJF4 VH V37I, R38K, M48I hzJ4.2F VH (SEQ ID NO: 115) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) hzJ4F-23 hzJ4F VH V37I, R66K, V67A hzJ4.3F VH (SEQ ID NO: 116) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) hzJ4F-24 hzJ4F VH V37I, R38K, M48I, R66K, V67A hzJ4.4F VH (SEQ ID NO: 117) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) hzJ4F-25 hzJ4F VH V78A hzJ4.11F VH (SEQ ID NO: 124) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) hzJ4F-26 hzJ4F VH V78A, M80I, E81Q hzJ4.12F VH (SEQ ID NO: 125) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) hzJ4F-27 hzJ4F VH R66K, V67A, V78A hzJ4.6F VH (SEQ ID NO: 119) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) hzJ4F-28 hzJ4F VH R66K, V67A, V78A, M80I, E81Q hzJ4.7F VH (SEQ ID NO: 120) hzJ4F VL L46A hzJ4.3F VL (SEQ ID NO: 146) hzJ4F-29 hzJ4F VH (SEQ ID NO: 113) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-30 hz9C5.1 VH R66K, V67A hzJ4.5F VH (SEQ ID NO: 118) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-31 hzJ4F VH V37I hzJ4.1F VH (SEQ ID NO: 114) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-32 hzJF4 VH V37I, R38K, M48I hzJ4.2F VH (SEQ ID NO: 115) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-33 hzJ4F VH V37I, R66K, V67A hzJ4.3F VH (SEQ ID NO: 116) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-34 hzJ4F VH V37I, R38K, M48I, R66K, V67A hzJ4.4F VH (SEQ ID NO: 117) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-35 hzJ4F VH V78A hzJ4.11F VH (SEQ ID NO: 124) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-36 hzJ4F VH V78A, M80I, E81Q hzJ4.12F VH (SEQ ID NO: 125) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-37 hzJ4F VH R66K, V67A, V78A hzJ4.6F VH (SEQ ID NO: 119) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-38 hzJ4F VH R66K, V67A, V78A, M80I, E81Q hzJ4.7F VH (SEQ ID NO: 120) hzJ4F VL L46A, L47V hzJ4.4F VL (SEQ ID NO: 147) hzJ4F-39 hzJ4F VH (SEQ ID NO: 113) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-40 hz9C5.1 VH R66K, V67A hzJ4.5F VH (SEQ ID NO: 118) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-41 hzJ4F VH V37I hzJ4.1F VH (SEQ ID NO: 114) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-42 hzJF4 VH V37I, R38K, M48I hzJ4.2F VH (SEQ ID NO: 115) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-43 hzJ4F VH V37I, R66K, V67A hzJ4.3F VH (SEQ ID NO: 116) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-44 hzJ4F VH V37I, R38K, M48I, R66K, V67A hzJ4.4F VH (SEQ ID NO: 117) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-45 hzJ4F VH V78A hzJ4.11F VH (SEQ ID NO: 124) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-46 hzJ4F VH V78A, M80I, E81Q hzJ4.12F VH (SEQ ID NO: 125) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-47 hzJ4F VH R66K, V67A, V78A hzJ4.6F VH (SEQ ID NO: 119) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-48 hzJ4F VH R66K, V67A, V78A, M80I, E81Q hzJ4.7F VH (SEQ ID NO: 120) hzJ4F VL L46A, L47V, F62L hzJ4.5F VL (SEQ ID NO: 148) hzJ4F-49 hzJ4F VH (SEQ ID NO: 113) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) hzJ4F-50 hzJ4F VH R66K, V67A hzJ4.5F VH (SEQ ID NO: 118) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) hzJ4F-51 hzJ4F VH V37I hzJ4.1F VH (SEQ ID NO: 114) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) hzJ4F-52 hzJF4 VH V37I, R38K, M48I hzJ4.2F VH (SEQ ID NO: 115) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) hzJ4F-53 hzJ4F VH V37I, R66K, V67A hzJ4.3F VH (SEQ ID NO: 116) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) hzJ4F-54 hzJ4F VH V37I, R38K, M48I, R66K, V67A hzJ4.4F VH (SEQ ID NO: 117) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) hzJ4F-55 hzJ4F VH V78A hzJ4.11F VH (SEQ ID NO: 124) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) hzJ4F-56 hzJ4F VH V78A, M80I, E81Q hzJ4.12F VH (SEQ ID NO: 125) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) hzJ4F-57 hzJ4F VH R66K, V67A, V78A hzJ4.6F VH (SEQ ID NO: 119) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) hzJ4F-58 hzJ4F VH R66K, V67A, V78A, M80I, E81Q hzJ4.7F VH (SEQ ID NO: 120) hzJ4F VL L46A, L47V, S60D, F62L, S63T hzJ4.6F VL (SEQ ID NO: 149) Example 8 Conjugate activity

The linker payloads in Table 14 were covalently linked to the anti-ASGR1 antibodies of the invention. Anti-ASGR1 antibodies conjugated to ALK5 inhibitors were tested by a cellular reporter assay. Briefly, HEK293 SBE-LUC reporter cells were transfected to stably express full-length human ASGR1 and seeded at 40,000 cells per well in 96-well assay plates containing minimal essential medium in assay medium containing 0.5% Fetal bovine serum, 1% non-essential amino acids, 1% sodium pyruvate, and 1% penicillin/streptomycin. Anti-ASGR1-ALK5 inhibitor conjugates and controls were added to assay wells containing HEK293 SBE-LUC and ASGR1-HEK293 SBE-LUC cells at dose titrations ranging from 5 μM to 0.064 nM. After 6 hours of incubation at 37°C in 5% CO ₂ , human TGFβ1 (PeproTech Inc.) was added to a final concentration of 1.6 ng/ml, followed by an additional 18 hours of incubation under the same conditions. Luciferase Steady- ^Glo® reagent (Promega Corporation) was added at 70 μl per well and incubated with shaking for 10 minutes. Luminescence was measured with an ^EnVision® plate reader (Perkin-Elmer Inc.) to determine luciferase activity. Four-parameter nonlinear regression fits were performed on the data with Prism Software v7.04 (GraphPad Inc.), and _IC50 values were calculated.

Overall, the activity of the antibody drug conjugate was proportional to or higher than that of the free small molecule observed in the cell-based reporter assay. Example 9 Antibody Drug Conjugates

The structures of the antibody-drug conjugates (ADCs) in Figures 1-4 are illustrated in Tables 28-31 below. In the figure, Ab control A corresponds to mAb.A and Ab control B corresponds to mAb.B. Table 28 Antibody Drug Conjugates of Figure 1 Antibody Drug Conjugate Number construct DAR ADC-1.31 mAb.B-CIIIC.10-1.31 3.17 ADC-1.38 mAb.A-CIIIC.8-1.38 3.20 ADC-1.96 mAb.A-CIIIC.10-1.96 3.77 ADC-1.98 mAb.A-CIIIc.10-1.98 3.58 ADC-1.112 mAb.A-CIIIc.8-1.112 3.66 ADC-1.130 mAb.A-CIIIc.8-1.130 3.59 ADC-1.104 mAb.A-CIIIc.10-1.104 3.59 Table 29 Antibody Drug Conjugates of Figure 2 Antibody Drug Conjugate Number construct DAR ADC-1.98 mAb.A-CIIIc.10-1.98 3.58 ADC-1.112 mAb.A-CIIIc.8-1.112 3.66 ADC-1.114 mAb.A-CIIIc.8-1.114 3.58 ADC-1.116 mAb.A-CIIIc.8-1.116 3.54 ADC-1.120 mAb.A-CIIIc.8-1.120 3.56 ADC-1.118 mAb.A-CIIIc.8-1.118 3.56 ADC-1.168 mAb.A-CIIIc.8-1.168 4.03 Table 30 Figure 3 Antibody Drug Conjugates Antibody Drug Conjugate Number construct DAR ADC-1.153 mAb.A-CIIIc.8-1.153 3.56 ADC-1.180 mAb.A-CIIIc.8-1.180 3.92 ADC-1.181 mAb.A-CIIIc.8-1.181 4.00 ADC-1.182 mAb.A-CIIIc.8-1.182 3.96 ADC-1.183 mAb.A-CIIIc.8-1.183 3.89 ADC-1.153 mAb.A-CIIIc.8-1.153 3.87 ADC-1.184 mAb.A-CIIIc.8-1.184 4.03 Table 31 Antibody Drug Conjugates of Figure 4 Antibody Drug Conjugate Number construct DAR ADC-1.181 mAb.A-CIIIc.8-1.181 4.00 ADC-1.182 mAb.A-CIIIc.8-1.182 3.96 ADC-1.183 mAb.A-CIIIc.8-1.183 3.89 ADC-1.153 mAb.A-CIIIc.8-1.153 3.87 SEQUENCES >G2D VH CDR1(SEQ ID NO: 1) GYYMH >K2E VH CDR1(SEQ ID NO: 2) SYTMH >L4L VH CDR1(SEQ ID NO: 3) SDYAWN >H8K VH CDR1(SEQ ID NO: 4) SDYAWN >J4F VH CDR1(SEQ ID NO: 5) SYWIN >G2D VH CDR2(SEQ ID NO: 6) RINPNNGATNYNQNFKD >G2.1D VH CDR2(SEQ ID NO: 7) RINPNQGATNYNQNFKD >G2.2D VH CDR2(SEQ ID NO: 8) RINPNNAATNYNQNFKD >K2E VH CDR2(SEQ ID NO: 9) YISPSSGYTEYNQKFKD >L4L VH CDR2(SEQ ID NO: 10) YISYSGSTRYNPSLKS >H8K VH CDR2(SEQ ID NO: 11) YRSYRGSTSYNPSLKS >J4F VH CDR2(SEQ ID NO: 12) RIVPGSGSTYYNEMFKD >G2D VH CDR3(SEQ ID NO: 13) VNFYY >K2E VH CDR3(SEQ ID NO: 14) KFDY >L4L VH CDR3(SEQ ID NO: 15) RYRYDEGYGMDY >H8K VH CDR3(SEQ ID NO: 16) RGYYGSSSHWYFDV >J4F VH CDR3(SEQ ID NO: 17) KPNFDV >G2D VL CDR1(SEQ ID NO: 18) KASQVINSYLS >K2E VL CDR1(SEQ ID NO: 19) KASQDINSYLS >L4L VL CDR1(SEQ ID NO: 20) RASENIYSNLA >H8K VL CDR1(SEQ ID NO: 21) RASENIYSYLA >J4F VL CDR1(SEQ ID NO: 22) KASQNVGTNVA >G2D VL CDR2(SEQ ID NO: 23) RANTLVD >G2.1D VL CDR2(SEQ ID NO: 24) RANTLVS >G2.2D VL CDR2(SEQ ID NO: 25) RANTLVE >K2E VL CDR2(SEQ ID NO: 26) RANRLVD >K2.1E VL CDR2(SEQ ID NO: 27) RANRLVE >L4L VL CDR2(SEQ ID NO: 28) AATNLAD >L4.1L VLCDR2 (SEQ ID NO: 29) AATNLAS >L4.2L VLCDR2 (SEQ ID NO:30) AATNLAE >H8K VL CDR2(SEQ ID NO: 31) NAKTLAE >J4F VL CDR2(SEQ ID NO: 32) SASYRFS >G2D VL CDR3(SEQ ID NO: 33) LQYAEFPYT >K2E VL CDR3(SEQ ID NO: 34) LQYDEFPFT >L4L VL CDR3(SEQ ID NO: 35) QHFWGTPPWT >H8K VL CDR3(SEQ ID NO: 36) QHHYGTPLT >J4F VL CDR3(SEQ ID NO: 37) QQYNSYPLT >G2D VH(SEQ ID NO: 38) EVQLQQSGPELVKPGASVKISCKASGYSFTGYYMHWVKQSHVKSLEWIGRINPNNGATNYNQNFKDKASLTVDKSSSTAYMEFHSLTSEDSAVYYCTSVNFYYWGQGTTLTVSS >K2E VH(SEQ ID NO: 39) QVQLQQSAAELARPGASVKMSCKASGYTFTSYTMHWVKQRPGQGLEWIGYISPSSGYTEYNQKFKDKTTLTADKSSSTAYMQLSSLTSEDSAVYYCARKFDYWGQGTTLTVSS >L4L VH(SEQ ID NO: 40) DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGSTRYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCARRYRYDEGYGMDYWGQGTSVTVSS >H8K VH(SEQ ID NO: 41) DVQLQESGPGLVKPSQSLSLTCTVTGFSITSDYAWNWIRQFPGNQLEWMGYRSYRGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCARRGYYGSSSHWYFDVWGAGTTVTVSS >J4F VH(SEQ ID NO: 42) QVQLQQSGDDLVKPGASVKLSCKASGYTFTSYWINWIKQRPGQGLEWIGRIVPGSGSTYYNEMFKDKATLTVDTSSSTAYIQLSSLSSEDSAVYFCARKPNFDVWGAGTTVTVSS ＞hzG2D VH V109L(SEQ ID NO: 43) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.1D VHT28S, V109L (SEQ ID NO:44) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.2D VHT28S, R66K, V67A, V109L (SEQ ID NO:45) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.3D VHT28S, R66K, V67A, A93T, R94S, V109L (SEQ ID NO:46) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.4D VHT28S, R66K, V67A, T68S, I69L, R71V, V109L (SEQ ID NO:47) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.5D VHT28S, R66K, V67A, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:48) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.6D VHT28S, T68S, I69L, R71V, V109L (SEQ ID NO:49) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.7D VHT28S, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:50) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.8D VHT28S, A93T, R94S, V109L (SEQ ID NO:51) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.9D VHT28S, N54Q (SEQ ID NO:52) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.10D VHT28S, N54Q, R66K, V67A (SEQ ID NO:53) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.11D VHT28S, N54Q, R66K, V67A, A93T, R94S (SEQ ID NO:54) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.12D VHT28S, N54Q, R66K, V67A, T68S, I69L, R71V (SEQ ID NO:55) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.13D VHT28S, N54Q, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:56) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.14D VHT28S, N54Q, T68S, I69L, R71V (SEQ ID NO:57) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.15D VHT28S, N54Q, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:58) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.16D VHT28S, N54Q, A93T, R94S (SEQ ID NO:59) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.17D VHT28S, G55A (SEQ ID NO:60) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.18D VHT28S, G55A, R66K, V67A (SEQ ID NO:61) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.19D VHT28S, G55A, R66K, V67A, A93T, R94S (SEQ ID NO:62) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.20D VHT28S, G55A, R66K, V67A, T68S, I69L, R71V (SEQ ID NO:63) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.21D VHT28S, G55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:64) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.22D VHT28S, G55A, T68S, I69L, R71V (SEQ ID NO:65) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.23D VHT28S, G55A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:66) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.24D VHT28S, G55A, A93T, R94S (SEQ ID NO:67) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.25D VHN54Q, R66K, V67A (SEQ ID NO:68) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.26D VHN54Q, R66K, V67A, A93T, R94S (SEQ ID NO:69) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.27D VHN54Q, R66K, V67A, T68S, I69L, R71V (SEQ ID NO:70) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.28D VHN54Q, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:71) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.29D VHN54Q, T68S, I69L, R71V (SEQ ID NO:72) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.30D VHN54Q, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:73) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.31D VHN54Q, A93T, R94S (SEQ ID NO:74) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.32D VHG55A, R66K, V67A (SEQ ID NO:75) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.33D VHG55A, R66K, V67A, A93T, R94S (SEQ ID NO:76) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.34D VHG55A, R66K, V67A, T68S, I69L, R71V (SEQ ID NO:77) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.35D VHG55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:78) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.36D VHG55A, T68S, I69L, R71V (SEQ ID NO:79) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.37D VHG55A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:80) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.38D VHG55A, A93T, R94S (SEQ ID NO:81) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.39D VHR66K, V67A, V109L (SEQ ID NO:82) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.40D VHR66K, V67A, A93T, R94S, V109L (SEQ ID NO:83) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.41D VHR66K, V67A, T68S, I69L, R71V, V109L (SEQ ID NO:84) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.42D VHR66K, V67A, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:85) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.43D VHT68S, I69L, R71V, V109L (SEQ ID NO:86) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.44D VHT68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:87) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzG2.45D VHA93T, R94S, V109L (SEQ ID NO:88) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS >hzK2E VH(SEQ ID NO: 89) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSS >hzK2.1E VHR66K, V67T (SEQ ID NO:90) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDKTTMTRDTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSS >hzK2.2E VHR66K, V67T, M69L, R71A (SEQ ID NO:91) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDKTTLTADTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSS >hzK2.3E VHR66K, V67T, M69L, R71A, T73K (SEQ ID NO:92) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDKTTLTADKSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSS >hzK2.4E VHM69L, R71A (SEQ ID NO: 93) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDRVTLTADTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSS >hzL4L VH(SEQ ID NO: 94) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS >hzL4.1L VHS30T, V67I, T68S, S70T, V71R (SEQ ID NO:95) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS >hzL4.2L VHG27Y, S30T, V67I, T68S, S70T, V71R (SEQ ID NO:96) QVQLQESGPGLVKPSQTLSLTCTVSGYSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS >hzL4.3L VHG27Y, S30T (SEQ ID NO: 97) QVQLQESGPGLVKPSQTLSLTCTVSGYSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS >hzL4.4L VHG27Y, V67I, T68S, S70T, V71R (SEQ ID NO:98) QVQLQESGPGLVKPSQTLSLTCTVSGYSISSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS >hzL4.5L VHG27Y, S30T, S70T, V71R (SEQ ID NO:99) QVQLQESGPGLVKPSQTLSLTCTVSGYSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRVTITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS >hzL4.6L VHG27Y, S70T, V71R (SEQ ID NO: 100) QVQLQESGPGLVKPSQTLSLTCTVSGYSISSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRVTITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS >hzL4.7L VHG27Y, S30T, V67I, T68S (SEQ ID NO: 101) QVQLQESGPGLVKPSQTLSLTCTVSGYSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISISVDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS >hzL4.8L VHG27Y, V67I, T68S (SEQ ID NO: 102) QVQLQESGPGLVKPSQTLSLTCTVSGYSISSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISISVDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS >hzH8K VH(SEQ ID NO: 103) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS >hzH8.1K VHS30T (SEQ ID NO: 104) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS >hzH8.2K VHG27F, S30T (SEQ ID NO: 105) QVQLQESGPGLVKPSQTLSLTCTVSGFSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS ＞hzH8.3K VHV67I, T68S, S70T, V71R (SEQ ID NO: 106) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS >hzH8.4KVH S30T, V67I, T68S, S70T, V71R (SEQ ID NO: 107) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS >hzH8.5KVH G27F, S30T, V67I, T68S, S70T, V71R (SEQ ID NO: 108) QVQLQESGPGLVKPSQTLSLTCTVSGFSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS >hzH8.6KVH S30T, V67I, T68S (SEQ ID NO: 109) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS >hzH8.7KVH S30T, S70T, V71R (SEQ ID NO: 110) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS >hzH8.8KVH V67I, T68S (SEQ ID NO: 111) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS >hzH8.9KVH S70T, V71R (SEQ ID NO: 112) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS >hzJ4F VH(SEQ ID NO: 113) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.1F VHV37I (SEQ ID NO: 114) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWIRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.2F VHV37I, R38K, M48I (SEQ ID NO: 115) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWIKQAPGQGLEWIGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.3F VHV37I, R66K, V67A (SEQ ID NO: 116) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWIRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.4F VHV37I, R38K, M48I, R66K, V67A (SEQ ID NO: 117) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWIKQAPGQGLEWIGRIVPGSGSTYYNEMFKDKATMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.5F VHR66K, V67A (SEQ ID NO: 118) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.6F VHR66K, V67A, V78A (SEQ ID NO: 119) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATMTRDTSTSTAYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.7F VHR66K, V67A, V78A, M80I, E81Q (SEQ ID NO: 120) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATMTRDTSTSTAYIQLSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.8F VHR66K, V67A, M69L, R71V (SEQ ID NO: 121) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATLTVDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.9F VHM69L, R71V (SEQ ID NO: 122) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTLTVDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.10F VHR71V (SEQ ID NO: 123) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTVDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.11F VHV78A (SEQ ID NO: 124) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTAYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >hzJ4.12F VHV78A, M80I, E81Q (SEQ ID NO: 125) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTAYIQLSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS >G2D VL(SEQ ID NO: 126) DIKMTQSPSSMYASLGERVTITCKASQVINSYLSWFQQKPGKSPETLIYRANTLVDGVPSRFSGSGSGQDYSLTISSLEYEDLGIYYCLQYAEFPYTFGGGTKLEIK >K2E VL(SEQ ID NO: 127) DIKMTQSPSSMYASLGERVTITCKASQDINSYLSWFQQKPGKSPKTLIYRANRLVDGVPSRFSGSGSGQDFSLTISSLEYEDMGIYYCLQYDEFPFTFGSGTKLEIK >L4L VL(SEQ ID NO: 128) DIQMTQSPASLSVFVGEIVTITCRASENIYSNLAWYQQKQGKSPQLLVYAATNLADGVPSRFTGSGSGTQFSLKINSLQSEDFGNYYCQHFWGTPPWTFGGGTKLEIK >H8K VL(SEQ ID NO: 129) DIQMTQSPASLSASVGETVTITCRASENIYSYLAWYQQKQGKSPQLLVYNAKTLAEGVPSRFSGSGSGTQFSLKINSLQPEDFGSYYCQHHYGTPLTFGSGTKLELK >J4F VL(SEQ ID NO: 130) DIVMTQSQKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKAVIYSASYRFSGVPDRLTGSGSGTDFTLTITNVQSEDLAEYFCQQYNSYPLTFGAGTKLELK >hzG2D VL _a (SEQ ID NO: 131) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK >hzG2.1D VL _a D56S (SEQ ID NO: 132) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK >hzG2.2D VL _a D56E (SEQ ID NO: 133) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK >hzK2E VL(SEQ ID NO: 134) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKSLIYRANRLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIK >hzK2.1E VLS46T (SEQ ID NO: 135) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKTLIYRANRLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIK >hzK2.2E VLD56E (SEQ ID NO: 136) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKSLIYRANRLVEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIK >hzK2.3E VLS46T D56E (SEQ ID NO: 137) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKTLIYRANRLVEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIK >hzL4L VL(SEQ ID NO: 138) DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWGTPPWTFGGGTKVEIK >hzL4.1L VLD56S (SEQ ID NO: 139) DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWGTPPWTFGGGTKVEIK >hzL4.2L VLD56E (SEQ ID NO: 140) DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATNLAEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWGTPPWTFGGGTKVEIK >hzL4.3L VLG57A (SEQ ID NO: 141) DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATNLADAVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWGTPPWTFGGGTKVEIK >hzH8K VL(SEQ ID NO: 142) DIQMTQSPSSLSASVGDRVTITCRASENIYSYLAWYQQKPGKAPKLLIYNAKTLAEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHHYGTPLTFGGGTKVEIK >hzJ4F VL(SEQ ID NO: 143) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKLLIYSASYRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK >hzJ4.1F VLQ3V (SEQ ID NO: 144) DIVMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKLLIYSASYRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK >hzJ4.2F VLQ3V L46A (SEQ ID NO: 145) DIVMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASYRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK >hzJ4.3F VLL46A (SEQ ID NO: 146) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASYRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK >hzJ4.4F VLL46A, L47V (SEQ ID NO: 147) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKAVIYSASYRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK >hzJ4.5F VLL46A, L47V, F62L (SEQ ID NO: 148) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKAVIYSASYRFSGVPSRLSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK >hzJ4.6F VLL46A, L47V, S60D, F62L, S63T (SEQ ID NO: 149) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKAVIYSASYRFSGVPDRLTGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK ＞chG2D Heavy Chain(SEQ ID NO: 150) EVQLQQSGPELVKPGASVKISCKASGYSFTGYYMHWVKQSHVKSLEWIGRINPNNGATNYNQNFKDKASLTVDKSSSTAYMEFHSLTSEDSAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞chK2E Heavy Chain(SEQ ID NO: 151) QVQLQQSAAELARPGASVKMSCKASGYTFTSYTMHWVKQRPGQGLEWIGYISPSSGYTEYNQKFKDKTTLTADKSSSTAYMQLSSLTSEDSAVYYCARKFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞chL4L Heavy Chain(SEQ ID NO: 152) DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGSTRYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCARRYRYDEGYGMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞chH8K Heavy Chain(SEQ ID NO: 153) DVQLQESGPGLVKPSQSLSLTCTVTGFSITSDYAWNWIRQFPGNQLEWMGYRSYRGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCARRGYYGSSSHWYFDVWGAGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞chJ4F Heavy Chain(SEQ ID NO: 154) QVQLQQSGDDLVKPGASVKLSCKASGYTFTSYWINWIKQRPGQGLEWIGRIVPGSGSTYYNEMFKDKATLTVDTSSSTAYIQLSSLSSEDSAVYFCARKPNFDVWGAGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2D Heavy Chain V109L(SEQ ID NO: 155) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.1D Heavy ChainT28S, V109L (SEQ ID NO: 156) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.2D Heavy ChainT28S, R66K, V67A, V109L (SEQ ID NO: 157) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.3D Heavy ChainT28S, R66K, V67A, A93T, R94S, V109L (SEQ ID NO: 158) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.4D Heavy ChainT28S, R66K, V67A, T68S, I69L, R71V, V109L (SEQ ID NO: 159) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.5D Heavy ChainT28S, R66K, V67A, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO: 160) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.6D Heavy ChainT28S, T68S, I69L, R71V, V109L (SEQ ID NO: 161) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.7D Heavy ChainT28S, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO: 162) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.8D Heavy ChainT28S, A93T, R94S, V109L (SEQ ID NO: 163) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.9D Heavy ChainT28S, N54Q (SEQ ID NO: 164) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.10D Heavy ChainT28S, N54Q, R66K, V67A (SEQ ID NO: 165) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.11D Heavy ChainT28S, N54Q, R66K, V67A, A93T, R94S (SEQ ID NO: 166) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.12D Heavy ChainT28S, N54Q, R66K, V67A, T68S, I69L, R71V (SEQ ID NO: 167) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.13D Heavy ChainT28S, N54Q, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 168) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.14D Heavy ChainT28S, N54Q, T68S, I69L, R71V (SEQ ID NO: 169) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.15D Heavy ChainT28S, N54Q, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 170) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.16D Heavy ChainT28S, N54Q, A93T, R94S (SEQ ID NO: 171) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.17D Heavy ChainT28S, G55A (SEQ ID NO: 172) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.18D Heavy ChainT28S, G55A, R66K, V67A (SEQ ID NO: 173) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.19D Heavy ChainT28S, G55A, R66K, V67A, A93T, R94S (SEQ ID NO: 174) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.20D Heavy ChainT28S, G55A, R66K, V67A, T68S, I69L, R71V (SEQ ID NO: 175) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.21D Heavy ChainT28S, G55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 176) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.22D Heavy ChainT28S, G55A, T68S, I69L, R71V (SEQ ID NO: 177) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.23D Heavy ChainT28S, G55A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 178) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.24D Heavy ChainT28S, G55A, A93T, R94S (SEQ ID NO: 179) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.25D Heavy ChainN54Q, R66K, V67A (SEQ ID NO: 180) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.26D Heavy ChainN54Q, R66K, V67A, A93T, R94S (SEQ ID NO: 181) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.27D Heavy ChainN54Q, R66K, V67A, T68S, I69L, R71V (SEQ ID NO: 182) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.28D Heavy ChainN54Q, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 183) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.29D Heavy ChainN54Q, T68S, I69L, R71V (SEQ ID NO: 184) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.30D Heavy ChainN54Q, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 185) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.31D Heavy ChainN54Q, A93T, R94S (SEQ ID NO: 186) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.32D Heavy ChainG55A, R66K, V67A (SEQ ID NO: 187) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.33D Heavy ChainG55A, R66K, V67A, A93T, R94S (SEQ ID NO: 188) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.34D Heavy ChainG55A, R66K, V67A, T68S, I69L, R71V (SEQ ID NO: 189) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.35D Heavy ChainG55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 190) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.36D Heavy ChainG55A, T68S, I69L, R71V (SEQ ID NO: 191) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.37D Heavy ChainG55A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 192) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.38D Heavy ChainG55A, A93T, R94S (SEQ ID NO: 193) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.39D Heavy ChainR66K, V67A, V109L (SEQ ID NO: 194) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.40D Heavy ChainR66K, V67A, A93T, R94S, V109L (SEQ ID NO: 195) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.41D Heavy ChainR66K, V67A, T68S, I69L, R71V, V109L (SEQ ID NO: 196) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.42D Heavy ChainR66K, V67A, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO: 197) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.43D Heavy ChainT68S, I69L, R71V, V109L (SEQ ID NO: 198) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.44D Heavy ChainT68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO: 199) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzG2.45D Heavy ChainA93T, R94S, V109L (SEQ ID NO:200) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzK2E Heavy Chain(SEQ ID NO: 201) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzK2.1E Heavy ChainR66K, V67T (SEQ ID NO:202) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDKTTMTRDTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzK2.2E Heavy ChainR66K, V67T, M69L, R71A (SEQ ID NO:203) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDKTTLTADTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzK2.3E Heavy ChainR66K, V67T, M69L, R71A, T73K (SEQ ID NO:204) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDKTTLTADKSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞hzK2.4E Heavy ChainM69L, R71A (SEQ ID NO:205) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDRVTLTADTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞chG2D Light Chain(SEQ ID NO: 206) DIKMTQSPSSMYASLGERVTITCKASQVINSYLSWFQQKPGKSPETLIYRANTLVDGVPSRFSGSGSGQDYSLTISSLEYEDLGIYYCLQYAEFPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞chK2E Light Chain(SEQ ID NO: 207) DIKMTQSPSSMYASLGERVTITCKASQDINSYLSWFQQKPGKSPKTLIYRANRLVDGVPSRFSGSGSGQDFSLTISSLEYEDMGIYYCLQYDEFPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞chL4L Light Chain(SEQ ID NO: 208) DIQMTQSPASLSVFVGEIVTITCRASENIYSNLAWYQQKQGKSPQLLVYAATNLADGVPSRFTGSGSGTQFSLKINSLQSEDFGNYYCQHFWGTPPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞chH8K Light Chain(SEQ ID NO: 209) DIQMTQSPASLSASVGETVTITCRASENIYSYLAWYQQKQGKSPQLLVYNAKTLAEGVPSRFSGSGSGTQFSLKINSLQPEDFGSYYCQHHYGTPLTFGSGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞chJ4F Light Chain(SEQ ID NO: 210) DIVMTQSQKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKAVIYSASYRFSGVPDRLTGSGSGTDFTLTITNVQSEDLAEYFCQQYNSYPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞hzG2D Light Chain(SEQ ID NO: 211) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞hzG2.1D Light ChainD56S (SEQ ID NO: 212) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞hzG2.2D Light ChainD56E (SEQ ID NO: 213) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞hzK2E Light Chain(SEQ ID NO: 214) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKSLIYRANRLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞hzK2.1E Light ChainS46T (SEQ ID NO: 215) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKTLIYRANRLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞hzK2.2E Light ChainD56E (SEQ ID NO: 216) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKSLIYRANRLVEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞hzK2.3E Light ChainS46T D56E (SEQ ID NO: 217) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKTLIYRANRLVEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >ASGR1 mAb-C VH CDR1(SEQ ID NO: 218) SYAMS >ASGR1 mAb-C VH CDR2(SEQ ID NO: 219) AISGSGGSTYYADSVKG >ASGR1 mAb-C VH CDR3(SEQ ID NO: 220) DFSSRRWYLEY >ASGR1 mAb-C VL CDR1(SEQ ID NO: 221) QGDSLRSYYAS >ASGR1 mAb-C VL CDR2(SEQ ID NO: 222) GKNNRPS >ASGR1 mAb-C VL CDR3(SEQ ID NO: 223) NSLERIGYLSYV >ASGR1 mAb-C VH(SEQ ID NO: 224) evqllesggglvqpggslrlscaasgftfssyamswvrqapgkglewvsaisgsggstyyadsvkgrftisrdnskntlylqmnslraedtavyycakdfssrrwyleywgqgtlvtvss >ASGR1 mAb-CVL (SEQ ID NO:225)sseltqdpavsvalgqtvritcqgdslrsyyaswyqqkpgqapvlviygknnrpsgipdrfsgsssgntasltitgaqaedeadyycnslerigylsyvfgggtkltvl >mzASGR1 mAb-C VH(SEQ ID NO: 226) EVKLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQTPEKRLEWVSAISGSGGSTYYADSVKGRFTISRDNAKNTLYLQMSSLRSEDTAMYYCAKDFSSRRWYLEYWGQGTTLTVSS >mzASGR1 mAb-C VL(SEQ ID NO: 227) QAVLTQEPALSVSLGQTVTLTCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGVPARFSGSLIGDKAALTITGAQTEDEAIYYCNSLERIGYLSYVFGGGTKVTVL >mzASGR1 mAb-C Heavy Chain (VH-IgG2a)(SEQ ID NO: 228) EVKLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQTPEKRLEWVSAISGSGGSTYYADSVKGRFTISRDNAKNTLYLQMSSLRSEDTAMYYCAKDFSSRRWYLEYWGQGTTLTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK >mzASGR1 mAb-C Light Chain (VL-κ)(SEQ ID NO: 229) QAVLTQEPALSVSLGQTVTLTCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGVPARFSGSLIGDKAALTITGAQTEDEAIYYCNSLERIGYLSYVFGGGTKVTVLRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC ＞Human IgG1 Heavy Chain Constant Region(SEQ ID NO: 230) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞Human IgG1null Heavy Chain Constant Region(SEQ ID NO: 231) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ＞Human Kappa Light Chain Constant Region(SEQ ID NO: 232) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ＞Mouse IgG2a Heavy Chain Constant Region(SEQ ID NO: 233) AKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK ＞Mouse Kappa Light Chain Constant Region(SEQ ID NO: 234) RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC ＞Rat IgG2b Heavy Chain Constant Region(SEQ ID NO: 235) AQTTAPSVYPLAPGCGDTTSSTVTLGCLVKGYFPEPVTVTWNSGALSSDVHTFPAVLQSGLYTLTSSVTSSTWPSQTVTCNVAHPASSTKVDKKVERRNGGIGHKCPTCPTCHKCPVPELLGGPSVFIFPPKPKDILLISQNAKVTCVVVDVSEEEPDVQFSWFVNNVEVHTAQTQPREEQYNSTFRVVSALPIQHQDWMSGKEFKCKVNNKALPSPIEKTISKPKGLVRKPQVYVMGPPTEQLTEQTVSLTCLTSGFLPNDIGVEWTSNGHIEKNYKNTEPVMDSDGSFFMYSKLNVERSRWDSRAPFVCSVVHEGLHNHHVEKSISRPP ＞Rat kappa Light Chain Constant Region(SEQ ID NO: 236) RADAAPTVSIFPPSTEQLATGGASVVCLMNNFYPRDISVKWKIDGTERRDGVLDSVTDQDSKDSTYSMSSTLSLTKADYESHNLYTCEVVHKTSSSPVVKSFNRNEC >Antibody to TNFR2 variant 1 HCDR1 (SEQ ID NO: 237) GYTFTDYN >Antibody to TNFR2 variant 1 HCDR2 (SEQ ID NO: 238) INPNYEST >Antibody to TNFR2 variant 1 HCDR3 (SEQ ID NO: 239) RDKGWYFDV >Antibody to TNFR2 variant 1 LCDR1 (SEQ ID NO: 240) SSVKN >Antibody to TNFR2 variant 1 LCDR2 (SEQ ID NO: 241) YTS >Antibody to TNFR2 variant 1 LCDR3 (SEQ ID NO: 242) QQFTSSPYT >Antibody to TNFR2 variant 2 HCDR1 (SEQ ID NO: 243) GFSLSTSGMG >Antibody to TNFR2 variant 2 HCDR2 (SEQ ID NO: 244) IWWDDDK >Antibody to TNFR2 variant 2 HCDR3 (SEQ ID NO: 245) ARLTGTRYFDY >Antibody to TNFR2 variant 2 LCDR1 (SEQ ID NO: 246) QDINKF >Antibody to TNFR2 variant 2 LCDR2 (SEQ ID NO: 247) YTS >Antibody to TNFR2 variant 2 LCDR3 (SEQ ID NO: 248) LQYGNLWT >Antibody to TNFR2 variant 3 HCDR1 (SEQ ID NO: 249) GYTFTDYS >Antibody to TNFR2 variant 3 HCDR2 (SEQ ID NO: 250) INTETGEP >Antibody to TNFR2 variant 3 HCDR3 (SEQ ID NO: 251) ATYYGSSYVPDY >Antibody to TNFR2 variant 3 LCDR1 (SEQ ID NO:252) QNVGTA >Antibody to TNFR2 variant 3 LCDR2 (SEQ ID NO: 253) WTS >Antibody to TNFR2 variant 3 LCDR3 (SEQ ID NO: 254) QYSDYPYT >Antibody to TNFR2 variant 4 HCDR1 (SEQ ID NO: 255) GYTFTDY >Antibody to TNFR2 variant 4 HCDR2 (SEQ ID NO: 256) WVDPEYGS >Antibody to TNFR2 variant 4 HCDR3 (SEQ ID NO: 257) ARDDGSYSPFDY >Antibody to TNFR2 variant 4 LCDR1 (major) (SEQ ID NO: 258) QNINKY >Antibody to TNFR2 variant 4 LCDR2 (major) (SEQ ID NO: 259) YTS >Antibody to TNFR2 variant 4 LCDR3 (major) (SEQ ID NO: 260) LQYVNLLT >Antibody to TNFR2 variant 4 LCDR1 (minor) (SEQ ID NO: 261) ENVVTY >Antibody to TNFR2 variant 4 LCDR2 (minor) (SEQ ID NO: 262) GAS >Antibody to TNFR2 variant 4 LCDR3 (minor) (SEQ ID NO: 263) QGYSYPYT >Antibody to TNFR2 variant 1 VH (SEQ ID NO: 264) EVQLQQSGAELVKPGASVKISCKASGYTFTDYNMDWVKQSHGKSLEWIGDINPNYESTSYNQKFKGKATLTVDKSSSTAYMEVRSLTSEDTAVFYCARDKGWYFDVWGAGTTVTVSS >Antibody to TNFR2 variant 1 VL (SEQ ID NO: 265) ENVLTQSPAIMSASLGEKVTMSCRASSSVKNMYWYQQKSDASPKLWIYYTSNLAPGVPARFSGSGSGNSYSLTISSMEGEDAATYYCQQFTSSPYTFGGGTKLELK >Antibody to TNFR2 variant 2 VH (SEQ ID NO: 266) QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDDKFYNPSLKSQLTISKDTSRNQVFLKLTSVVTADTATYYCARLTGTRYFDYWGQGTTLTVSS >Antibody to TNFR2 variant 2 VL (SEQ ID NO: 267) DVQMTQSPSSLSASLGGKVTITCKASQDINKFIAWYQHKPGKGPRLLIHYTSTLQPGIPSKFSGSGSGRDYSFSISNLEPEDIATYYCLQYGNLWTFGGGTKLEIT >Antibody to TNFR2 variant 3 VH (SEQ ID NO: 268) QIQLVQSGPELKKPGETVKISCKASGYTFTDYSMHWVKQAPGKGLKWMGWINTETGEPTYADDFKGRFAFSSETSTSTAYLQINNLKNDDTTTYFCATYYGSSYVPDYWGQGTSLTVSS >Antibody to TNFR2 variant 3 VL (SEQ ID NO: 269) DIVMTQSHKFMSTSVGDRVSITCKASQNVGTAVAWYQHKPGQSPKLLIYWTSSRHTGVPDRFTGSGSGTEFTLTISNVQSEDLADYFCHQYSDYPYTFGGGTKLEIK >Antibody to TNFR2 variant 4 VH (SEQ ID NO: 270) EVQLQQSGPEVGRPGSSVKISCKASGYTFTDYIMHWVKQSPGQGLEWIGWVDPEYGSTDYAEKFKKKATLTADTSSNTAYIQLSSLTSEDTATYFCARDDGSYSPFDYWGQGVMVTVSS >Antibody to TNFR2 variant 4 VL (major) (SEQ ID NO: 271) DIQMTQSPPSLSASLGDKVTITCQASQNINKYIAWYQQKPGKAPRLLIRYTSTLESGTPSRFSGSGSGRDYSFSISNVESEDIASYYCLQYVNLLTFGAGTKLEIK >Antibody to TNFR2 variant 4 VL (minor) (SEQ ID NO: 272) NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYGASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFGGGTKLEIK >Antibody to TNFR2 variant 5 VH (SEQ ID NO: 273) EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYAMSWVRQAPGKGLEWVAVISENGSDTYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDRGGAVSYFDVWGQGTLVTVSS >Antibody to TNFR2 variant 5 VL (SEQ ID NO: 274) DIQMTQSPSSLSASVGDRVTITCRASQDVSSYLAWYQQKPGKAPKLLIYAASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSLPYTFGQGTKVEIKRT >Antibody to GITR HCDR1 (SEQ ID NO: 275) sygmh >Antibody to GITR HCDR2 (SEQ ID NO: 276) viwyegsnkyyadsvkg >Antibody to GITR HCDR3 (SEQ ID NO: 277) ggsmvrgdyyygmdv >Antibody to GITR LCDR1 (SEQ ID NO: 278) rasqgissala >Antibody to GITR LCDR2 (SEQ ID NO: 279) dassles >Antibody to GITR LCDR3 (SEQ ID NO: 280) qqfnsypyt ＞Antibody to GITR V _H(SEQ ID NO: 281) QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVWGQGTTVTVSS ＞Antibody to GITR V _L(SEQ ID NO: 282) AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPYTFGQGTKLEIK >Antibody to LAG-3 HCDR1 (SEQ ID NO: 283) DYYWN >Antibody to LAG-3 HCDR2 (SEQ ID NO: 284) EINHRGSTNSNPSLKS >Antibody to LAG-3 HCDR3 (SEQ ID NO: 285) GYSDYEYNWFDP >Antibody to LAG-3 LCDR1 (SEQ ID NO: 286) RASQSISSYLA >Antibody to LAG-3 LCDR2 (SEQ ID NO: 287) DASNRAT >Antibody to LAG-3 LCDR3 (SEQ ID NO: 288) QQRSNWPLT ＞Antibody to LAG-3 V _H(SEQ ID NO: 289) qvqlqqwgagllkpsetlsltcavyggsfsdyywnwirqppgkglewigeinhrgstnsnpslksrvtlsldtsknqfslklrsvtaadtavyycafgysdyeynwfdpwgqgtlvtvss ＞Antibody to LAG-3 V _L(SEQ ID NO: 290) eivltqspatlslspgeratlscrasqsissylawyqqkpgqaprlliydasnratgiparfsgsgsgtdftltisslepedfavyycqqrsnwpltfgqgtnleik ＞Antibody to GARP variant 1 V _H(SEQ ID NO: 291) mavlallfclvtfpscilsqvqlkesgpglvapsqslsitctvsgfsltgyginwvrqppgkglewlgmiwsdgstdynsvltsrlriskdnsnsqvflkmnslqvddtaryycardrnyydydgamdywgqgtsvtvss ＞Antibody to GARP variant 1 V _L(SEQ ID NO: 292) qvqlkesgpglvapsqslsitctvsgfsltgyginwvrqppgkglewlgmiwsdgstdynsvltsrlriskdnsnsqvflkmnslqvddtaryycardrnyydydgamdywgqgtsvtvss >Antibody to GARP variant 2 V _H(SEQ ID NO: 293) mkfpsqlllfllfritgiicdiqvtqsssylsvslgdrvtitckasdhiknwlawyqqkpgiaprllvsgatsleagvpsrfsgsgsgknftlsitslqtedvatyycqqywstpwtfgggttleir >Antibody to GARP variant 2 V _L(SEQ ID NO: 294) diqvtqsssylsvslgdrvtitckasdhiknwlawyqqkpgiaprllvsgatsleagvpsrfsgsgsgknftlsitslqtedvatyycqqywstpwtfgggttleir >Antibody to GARP variant 3 VH (SEQ ID NO: 295) EVQLVQPGAELRNSGASVKVSCKASGYRFTSYYIDWVRQAPGQGLEWMGRIDPEDGGTKYAQKFQGRVTFTADTSTSTAYVELSSLRSEDTAVYYCARNEWETVVVGDLMYEYEYWGQGTQVTVSS >Antibody to GARP variant 3 VL (SEQ ID NO: 296) DIQMTQSPTSLSASLGDRVTITCQASQSISSYLAWYQQKPGQAPKLLIYGASRLQTGVPSRFSGSGSGTSFTLTISGLEAEDAGTYYCQQYDSLPVTFGQGTKVELK >Antibody to GARP variant 3 VL (SEQ ID NO: 297) DIQMTQSPSSLSASLGDRVTITCQASQSIVSYLAWYQQKPGQAPKLLIYGASRLQTGVPSRFSGSGSGTSFTLTISGLEAEDAGTYYCQQYASAPVTFGQGTGVELK >Antibody to GARP variant 3 VL (SEQ ID NO: 298) DIQMTQSPSSLSASLGDRVTITCQASQSISSYLAWYQQKPGQAPKLLIYGTSRLKTGVPSRFSGSGSGTSFTLTISGLEAEDAGTYYCQQYYSAPVTFGQGTKVELK >Antibody to GARP variant 3 VL (SEQ ID NO: 299) DIQMTQSPSSLSPSLGDRVTITCQASQTISSFLAWYHQKPGQPPKLLIYRASIPQTGVPSRFSGSGSGTSFTLTIGGLEAEDAGTYYCQQYVSAPPTFGQGTKVELK >Antibody to GARP variant 3 VL (SEQ ID NO: 300) DIQMTQSPSSLSASLGDRVTITCQASQSISSYLAWYQQKPGQAPNILIYGASRLKTGVPSRFSGSGSGTSFTLTISGLEAEDAGTYYCQQYASVPVTFGQGTKVELK >Utomilumab HCDR1 (SEQ ID NO:301) GYSFSTYW >Utomilumab HCDR2 (SEQ ID NO:302) IYPGDSYT >Utomilumab HCDR3 (SEQ ID NO:303) ARGYGIFDY >Utomilumab LCDR1 (SEQ ID NO: 304) NIGDQY >Utomilumab LCDR2 (SEQ ID NO: 305) QDK >Utomilumab LCDR3 (SEQ ID NO: 306) ATYTGFGSLAV >Antibody to 4-1BB variant 1 VH (SEQ ID NO:307) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQSPEKGLEWIGEINHGGYVTYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYGPGNYDWYFDLWGRGTLVTVSS >Antibody to 4-1BB variant 1 VL (SEQ ID NO: 308) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPALTFGGGTKVEIK >Antibody to 4-1BB variant 2 VH (SEQ ID NO:309) EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYWMSWVRQAPGKGLEWVADIKNDGSYTNYAPSLTNRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARELTGTWGQGTMVTVSS >Antibody to 4-1BB variant 2 VL (SEQ ID NO: 310) DIVMTQSPDSLAVSLGERATINCKSSQSLLSSGNQKNYLAWYQQKPGQPPKLLIYYASTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCLQYDRYPFTFGQGTKLEIK >Utomilumab VH (SEQ ID NO:311) EVQLVQSGAEVKKPGESLRISCKGSGYSFSTYWISWVRQMPGKGLEWMGKIYPGDSYTNYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGYGIFDYWGQGTLVTVSS >Utomilumab VL (SEQ ID NO: 312) SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVLVIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYTGFGSLAVFGGGTKLTVL >Antibody to ICOS variant 1 VL (SEQ ID NO: 313) DIQMTQSPSSVSASVGDRVTITCRASQGISRLLAWYQQKPGKAPKLLIYVASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPWTFGQGTKVEIK >Antibody to ICOS variant 1 VH (SEQ ID NO:314) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPHSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARTYYYDSSGYYHDAFDIWGQGTMVTVSS >Antibody to ICOS variant 2 VH (SEQ ID NO:315) EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYWMDWVRQAPGKGLVWVSNIDEDGSITEYSPFVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCTRWGRFGFDSWGQGTLVTVSS >Antibody to ICOS variant 2 VL (SEQ ID NO: 316) DIVMTQSPDSLAVSLGERATINCKSSQSLLSGSFNYLTWYQQKPGQPPKLLIFYASTRHTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCHHHYNAPPTFGPGTKVDIK >Antibody to CD73 VL (SEQ ID NO: 317) DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK >Antibody to CD73 VH (SEQ ID NO: 318) QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVILYDGSNKYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGSSWYPDSFDIWGQGTMVTVSS >Antibody to Integrin αvβ8 VH (SEQ ID NO: 319) EVQLVESGGGLVQPGSLRLSCAVSGFVFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYTSSLKDRFTISRDNAKNSLYLQMNSLRAEDTAVYYCASLITTEDYWGQGTTVTVSS >Antibody to Integrin αvβ8 VL (SEQ ID NO:320) EIVLTQSPSSLSLSPGERVTITCKASQDINSYLSWYQQKPGKAPKLLIYYANRLVDGVPARFSGSGSGQDYTLTISSLEPEDFAVYYCLQYDEFPYTFGGGTKLEIKR >Antibody to FAP variant 1 VH (SEQ ID NO:321) QVQLQESGPGLVKPSQTLSLTCAISGDSVSSNSVTWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKGRITINPDTSKNQFYLQLKSVTPEDAAVYYCARDSSILYGDYWGQGTLVTVSS >Antibody to FAP variant 1 VH (SEQ ID NO:322) QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSVTWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKGRITINPDTSKNQFYLQLKSVTPEDAAVYYCARDSSILYGDYWGQGTLVTVS >Antibody to FAP variant 1 VL (SEQ ID NO: 323) QAVLTQPSSLSASPGASASLTCTLPSGINVGTYRIFWFQQKPGSPPQYLLSYKSDSDNHQGSGVPSRFSGSKDASANAGILLISGLQSEDEADYYCMIWHSSAWVFGGGTKLTVL >Antibody to FAP variant 2 VH (SEQ ID NO:324) QVQLVQSGAEVKKPGASVKVSCKTSGYTFTDYYIHWVRQAPGQGLEWMGWINPNRGGTNYAQKFQGRVTMTRDTSIATAYMELSRLRSDDTAVYYCATASLKIAAVGTFDCWGQGTLVTVSS >Antibody to FAP variant 2 VL (SEQ ID NO:325) SYELTQPPSVSVSPGQTARITCSGDALSKQYAFWFQQKPGQAPILVIYQDTKRPSGIPGRFSGSSSGTTVTLTISGAQADDEADYYCQSADSSGTYVFGTGTKVTVL >Antibody to FAP variant 3 VH (SEQ ID NO:326) EVQLVETGGGVVQPGRSLRLSCAASGFSFSTHGMYWVRQPPGKGLEWVAVISYDGSDKKYADSVKGRFTISRDNSKNTVYLEMSSVRAEDTALYYCFCRRDAFDLWGQGTMVTVSS >Antibody to FAP variant 3 VL (SEQ ID NO:327) SYVLTQPPSVSVSPGQTARITCSGDALPKKYAYWYQQKSGQAPVLVIYEDTKRPSGIPERFSGSSSGTMATLTISGAQVEDEADYYCYSTDSSGNYWVFGGGTEVTVL >Antibody to FAP variant 4 VH (SEQ ID NO:328) EVQLVESGGGLVEPGGSLRLSCAASGFTFSDAWMNWVRQAPGKGLEWVGRIKTKSDGGTTDYAAPVRGRFSISRDDSKNTLFLEMNSLKTEDTAIYYCFITVIVVSSESPLDHWGQGTLVTVSS >Antibody to FAP variant 4 VL (SEQ ID NO: 329) SYELTQPPSVSVSPGQTARITCSGDELPKQYAYWYQQKPGQAPVLVIYKDRQRPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSAYSINTYVIFGGGTKLTVL >Antibody to FAP variant 5 VH (SEQ ID NO: 330) EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWISYISSGSSYTNYADSVKGRFTISRDNAKKSVYLEVNGLTVEDTAVYYCARVRYGDREMATIGGFDFWGQGTLVTVSS >Antibody to FAP variant 5 VL (SEQ ID NO:331) SYELTQPPSVSVSPGQTARITCSGDALPKQYAYWYQQSPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSGGTSRIFGGGTKLTVL >Antibody to FAP variant 6 VH (SEQ ID NO:332) QVQLQESGPGLVRSTETLSLTCLVSGDSINSHYWSWLRQSPGRGLEWIGYIYYTGPTNYNPSLKSRVSISLGTSKDQFSLKLSSVTAADTARYYCARNKVFWRGSDFYYYMDVWGKGTTVTVSS >Antibody to FAP variant 6 VL (SEQ ID NO: 333) EIVLTQSPGTLSLSLGERATLSCRASQSLANNYLAWYQQKPGQAPRLLMYDASTRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQFVTSHHMYIFGQGTKVEIK >Antibody to FAP variant 7 VH (SEQ ID NO:334) HVQLQESGPGLVKPSETLSLTCTVSGGSISSNNYYWGWIRQTPGKGLEWIGSIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGARWQARPATRIDGVAFDIWGQGTMVTVSS >Antibody to FAP variant 7 VH (SEQ ID NO:335) QVQLQESGPGLVKPSETLSLTCTVSGGSISSNNYYWGWIRQTPGKGLEWIGSIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGARWQARPATRIDGVAFDIWGQGTMVTVSS >Antibody to FAP variant 7 VH (SEQ ID NO:336) EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDWSRSGYYLPDYWGQGTLVTVSS >Antibody to FAP variant 7 VL (SEQ ID NO:337) ETTLTQSPGTLSLSPGERATLSCRASQTVTRNYLAWYQQKPGQAPRLLMYGASNRAAGVPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQFGSPYTFGQGTKVEIK >Antibody to FAP variant 7 VL (SEQ ID NO: 338) DVVMTQSPLSLPVTLGQPASISCRSSQSLLHSNGYNYLDWYLQRPGQSPHLLIFLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGIYYCMQALQTPPTFGQGTKVEIK >Antibody to Integrin αv variant 1 VH (SEQ ID NO:339) QVQLVESGGGVVQPGRSRRLSCAASGFTFSRYTMHWVRQAPGKGLEWVAVISFDGSNKYYVDSVKGRFTISRDNSENTLYLQVNILRAEDTAVYYCAREARGSYAFDIWGQGTMVTVSS >Antibody to Integrin αv variant 1 VL (SEQ ID NO: 340) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPFTFGPGTKVDIK >Antibody to Integrin αv variant 2 VL (SEQ ID NO:341) DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPKLLIYYTSKIHSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQGNTFPYTFGQGTKVEIK >Antibody to Integrin αv variant 2 VH (SEQ ID NO:342) QVQLQQSGGELAKPGASVKVSCKASGYTFSSFWMHWVRQAPGQGLEWIGYINPRSGYTEYNEIFRDKATMTTDTSTSTAYMELSSLRSEDTAVYYCASFLGRGAMDYWGQGTTVTVSS >Antibody to Integrin αvβ6 variant 1 VH (SEQ ID NO:343) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGVYYWTWIRQHPGNGLEWIGYIYYSGSTSYNPSLKSRVTISVDTSKKQFSLNLTSVTAADTAVYYCAREGPLRGDYYYGLDVWGQGTTVTVSS >Antibody to Integrin αvβ6 variant 1 VL (SEQ ID NO:344) EIVLTQSPGTLSLSPGERATLSCRAGQTISSRYLAWYQQKPGQAPRPLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPRTFGQGTKVEIK >Antibody to Integrin αvβ6 variant 2 VH (SEQ ID NO:345) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAMYYCARYRGPAAGRGDFYYFGMDVWGQGTTVTVSS >Antibody to Integrin αvβ6 variant 2 VL (SEQ ID NO:346) DIVMTQTPLSLSVTPGQPASIFCKSSQSLLNSDGKTYLCWYLQKPGQPPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGIQLPWAFFGQGTKVEIK >Antibody to Integrin αvβ6 variant 3 VH (SEQ ID NO:347) QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYGGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLAARRGDYYYYGMDVWGQGTTVTVSS >Antibody to Integrin αvβ6 variant 3 VL (SEQ ID NO:348) SSELTQDPVVSVALGQTVRITCQGDSLRSYYLSWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSNSGNTASLTITGAQAEDEADYYCNSRDSSGNHLFGGGTKLTVL >Antibody to Integrin αvβ6 variant 4 VH (SEQ ID NO:349) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGRTYNNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARVATGRADYHFYAMDVWGQGTTVTVSS >Antibody to Integrin αvβ6 variant 4 VL (SEQ ID NO:350) SYELTQPSSVSVSPGQTARITCSGDVLAKKSARWFHQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGAQVEDEAAYYCYSAADNNLVFGGGTKLTVL >LPXTG recognition motif (SEQ ID NO:351) LPXTG >hzG2.46D VH R66K, V67A, T68S, I69L, R71V (SEQ ID NO: 352)QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTVTVSS >hzG2.47D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 353)QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTVTVSS >hzG2.48D VH G55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO: 354)QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTVTVSS >hzG2.49D VH R38K, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:355)QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVKQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTVTVSS >hzG2.50D VH R66K, V67A, T68S, I69L, R71V, L82F, S82aH, A93T, R94S (SEQ ID NO: 356)QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMEFHSLRSEDTAVYYCTSVNFYYWGQGTTVTVSS >hzG2.51D VH R66K, V67A, T68S, I69L, R71V, R84T, A93T, R94S (SEQ ID NO: 357)QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLTSEDTAVYYCTSVNFYYWGQGTTVTVSS >hzG2.3D VL _a K45E, S46T (SEQ ID NO: 358)DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPETLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK >hzG2.4D VL _a Q79E, P80Y (SEQ ID NO: 359)DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLEYEDFATYYCLQYAEFPYTFGGGTKVEIK >hzG2.5D VL _a F71Y, T72S (SEQ ID NO: 360)DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVDGVPSRFSGSGSGTDYSLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK >hzG2D VL _b (SEQ ID NO: 361)DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWYQQKPGKAPKLLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK >hzG2.6D VL _b D56S (SEQ ID NO: 362)DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWYQQKPGKAPKLLIYRANTLVSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK >hzG2D VL _c (SEQ ID NO: 363) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWYQQKPGKVPKLLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQYAEFPYTFGGGTKVEIK ＞G2D VH CDR1 (SEQ ID NO:364) GYYMH ＞G2.2D VH CDR2 (SEQ ID NO:365) RINPNNAATNYNQNFKD ＞G2D VH CDR3 (SEQ ID NO:366) VNFYY ＞G2D VL CDR1 (SEQ ID NO:367) KASQVINSYLS > G2D VL CDR2 (SEQ ID NO: 368) RANTLVD > G2D VL CDR3 (SEQ ID NO: 369) LQYAEFPYT > G2D VH CDR2 (SEQ ID NO: 370) RINPNNGATNYNQNFKD > K2E VH CDR1 (SEQ ID NO: 371) SYTMH > K2E VH CDR2 (SEQ ID NO: 372) YISPSSGYTEYNQKFKD > K2E VH CDR3 (SEQ ID NO: 373) KFDY > K2E VL CDR1 (SEQ ID NO: 374) KASQDINSYLS > K2E VL CDR2 (SEQ ID NO: 375) RANRLVD > K2E VL CDR3 (SEQ ID NO:376) LQYDEFPFT>G2.1D VH CDR2 (SEQ ID NO:377) RINPNQGATNYNQNFKD>G2.1D VL CDR2 (SEQ ID NO:378) RANTLVS>G2.2D VL CDR2 (SEQ ID NO:379) RANTLVE > K2.1E VL CDR2 (SEQ ID NO: 380) RANRLVE > J4F VH CDR1 (SEQ ID NO: 381) SYWIN > J4F VH CDR2 (SEQ ID NO: 382) RIVPGSGSTYYNEMFKD > J4F VH CDR3 (SEQ ID NO: 383) KPNFDV > J4F VL CDR1 (SEQ ID NO: 384) KASQNVGTNVA > J4F VL CDR2 (SEQ ID NO: 385) SASYRFS > J4F VL CDR3 ( SEQ ID NO: 386) QQYNSYPLT > L4L VH CDR1 (SEQ ID NO: 387) SDYAWN > L4L VH CDR2 (SEQ ID NO: 388) YISYSGSTRYNPSLKS > L4L VH CDR3 (SEQ ID NO: 389) RYRYDEGYGMDY > L4L VL CDR1 (SEQ ID NO: 389) NO: 390) RASENIYSNLA > L4L VL CDR2 (SEQ ID NO: 391) AATNLAD > L4.1L VL CDR2 (SEQ ID NO: 392) AATNLAS > L4.2L VL CDR2 (SEQ ID NO: 393) AATNLAE > L4L VL CDR3 ( SEQ ID NO: 394) QHFWGTPPWT > H8K VH CDR1 (SEQ ID NO: 395) SDYAWN > H8K VH CDR2 (SEQ ID NO: 396) YRSYRGSTSYNPSLKS > H8K VH CDR3 (SEQ ID NO: 397) RGYYGSSSHWYFDV > H8K VL CDR1 (SEQ ID NO: 397) NO:398) RASENIYSYLA ＞H8K VL CDR2 (SEQ ID NO:399) NAKTLAE ＞H8K VL CDR3 (SEQ ID NO:400) QHHYGTPLT ＞hzG2D VLa (SEQ ID NO:401) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK ＞hzG2.1D VLa D56S (SEQ ID NO :402) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK>hzG2.2D VLa D56E (SEQ ID NO: 403) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKQQQDFSLIYRANTLVEGVPSRFSEDFAGTTL TKVEIK ＞hzG2.3D VLa K45E, S46T (SEQ ID NO:404) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPETLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK ＞hzG2.4D VLa Q79E, P80Y (SEQ ID NO:405) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLEYEDFATYYCLQYAEFPYTFGGGTKVEIK ＞hzG2.5D VLa F71Y, T72S (SEQ ID NO:406) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWFQQKPGKAPKSLIYRANTLVDGVPSRFSGSGSGTDYSLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK ＞ hzG2D VLb (SEQ ID NO:407) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWYQQKPGKAPKLLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK ＞hzG2.6D VLb D56S (SEQ ID NO:408) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWYQQKPGKAPKLLIYRANTLVSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYAEFPYTFGGGTKVEIK ＞hzG2D VLc (SEQ ID NO:409) DIQMTQSPSSLSASVGDRVTITCKASQVINSYLSWYQQKPGKVPKLLIYRANTLVDGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQYAEFPYTFGGGTKVEIK ＞hzG2D VH V109L (SEQ ID NO:410) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWG QGTTLTVSS ＞hzG2.1D VH T28S, V109L (SEQ ID NO:411) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.2D VH T28S, R66K, V67A, V109L (SEQ ID NO:412) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.3D VH T28S, R66K, V67A, A93T, R94S, V109L (SEQ ID NO:413) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.4D VH T28S, R66K, V67A, T68S, I69L, R71V, V109L (SEQ ID NO:414) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.5D VH T28S, R66K, V67A, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:415) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.6D VH T28S, T68S, I69L, R71V, V109L (SEQ ID NO:416) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMG RINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.7D VH T28S, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:417) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.8D VH T28S, A93T, R94S, V109L (SEQ ID NO:418) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2. 9D VH T28S, N54Q (SEQ ID NO:419) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.10D VH T28S, N54Q, R66K, V67A (SEQ ID NO:420) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.11D VH T28S, N54Q, R66K, V67A, A93T, R94S ( SEQ ID NO: 421) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS>hzG2.12D VH T28S, N54Q, R66K, V67A, T68S, I69L, R71V (SEQ ID NO: QS422V) QVQLV KPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.13D VH T28S, N54Q, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:423) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.14D VH T28S, N54Q, T68S, I69L, R71V (SEQ ID NO: 424) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.15D VH T28S, N54Q, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:425) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.16D VH T28S, N54Q, A93T, R94S (SEQ ID NO:426) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞ hzG2.17D VH T28S, G55A (SEQ ID NO: 427) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS >hzG2.18D VH T28S, G 55A, R66K, V67A (SEQ ID NO:428) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.19D VH T28S, G55A, R66K, V67A, A93T, R94S (SEQ ID NO:429) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.20D VH T28S, G55A, R66K, V67A, T68S, I69L, R71V (SEQ ID NO:430) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.21D VH T28S, G55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:431) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.22D VH T28S, G55A, T68S, I69L, R71V (SEQ ID NO:432) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.23D VH T28S, G55A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:433) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMG RINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.24D VH T28S, G55A, A93T, R94S (SEQ ID NO:434) QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.25D VH N54Q, R66K, V67A (SEQ ID NO:435) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.26D VH N54Q, R66K, V67A, A93T, R94S (SEQ ID NO:436) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.27D VH N54Q, R66K, V67A, T68S, I69L, R71V (SEQ ID NO:437) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.28D VH N54Q, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:438) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDKASLTVDTSASSTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS>hzG2.29D VH N54Q, T68S, I69L, R71V QVQS39 QVLVEV:4 KKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.30D VH N54Q, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:440) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.31D VH N54Q, A93T, R94S (SEQ ID NO:441) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNQGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.32D VH G55A, R66K, V67A (SEQ ID NO:442) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.33D VH G55A, R66K, V67A, A93T, R94S (SEQ ID NO:443) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.34D VH G55A, R66K, V67A, T68S, I69L, R71V ( SEQ ID NO: 444) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS>hzG2.35D VH G55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:445) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.36D VH G55A, T68S, I69L, R71V (SEQ ID NO:446) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.37D VH G55A, T68S, I69L, R71V, A93T, R94S ( SEQ ID NO:447) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.38D VH G55A, A93T, R94S (SEQ ID NO:448) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.39D VH R66K, V67A, V109L (SEQ ID NO:449) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.40D VH R66K, V67A, A93T, R94S, V109L (SEQ ID NO: 450) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKATITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS>hzG2.41D VH R66K, V67A, T68S, I69L, R71V, V109L (SEQ ID NO:451) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.42D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:452) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2 .43D VH T68S, I69L, R71V, V109L (SEQ ID NO:453) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTLTVSS ＞hzG2.44D VH T68S, I69L, R71V, A93T, R94S, V109L (SEQ ID NO:454) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVSLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.45D VH A93T, R94S , V109L (SEQ ID NO:455) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTLTVSS ＞hzG2.46D VH R66K, V67A, T68S, I69L, R71V (SEQ ID NO:456) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKAS LTVDTSASTAYMELSSLRSEDTAVYYCARVNFYYWGQGTTVTVSS ＞hzG2.47D VH R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:457) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTVTVSS ＞hzG2.48D VH G55A, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:458) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNAATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTVTVSS ＞hzG2.49D VH R38K, R66K, V67A, T68S, I69L, R71V, A93T, R94S (SEQ ID NO:459) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVKQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLRSEDTAVYYCTSVNFYYWGQGTTVTVSS ＞hzG2.50D VH R66K, V67A, T68S, I69L, R71V, L82F, S82aH, A93T, R94S (SEQ ID NO:460) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMEFHSLRSEDTAVYYCTSVNFYYWGQGTTVTVSS ＞hzG2.51D VH R66K, V67A, T68S, I69L, R71V, R84T, A93T, R94S (SEQ ID NO:461) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQRLEWMGRINPNNGATNYNQNFKDKASLTVDTSASTAYMELSSLTSEDTAVYYCTSVNFYYWGQGTTVTVS S ＞hzK2E VL (SEQ ID NO:462) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKSLIYRANRLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIK ＞hzK2.1E VL S46T (SEQ ID NO:463) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKTLIYRANRLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIK ＞hzK2.2E VL D56E (SEQ ID NO:464) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKSLIYRANRLVEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIK ＞hzK2.3E VL S46T D56E (SEQ ID NO:465) DIQMTQSPSSLSASVGDRVTITCKASQDINSYLSWFQQKPGKAPKTLIYRANRLVEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDEFPFTFGQGTKLEIK ＞hzK2E VH (SEQ ID NO:466) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSS ＞hzK2.1E VH R66K, V67T (SEQ ID NO:467) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDKTTMTRDTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSS ＞hzK2.2E VH R66K, V67T, M69L, R71A (SEQ ID NO:468 ) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDKTTLTADTSTSTVYMELSSLRSEDTA VYYCARKFDYWGQGTTVTVSS ＞hzK2.3E VH R66K, V67T, M69L, R71A, T73K (SEQ ID NO:469) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDKTTLTADKSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSS ＞hzK2.4E VH M69L, R71A (SEQ ID NO:470) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYTMHWVRQAPGQGLEWMGYISPSSGYTEYNQKFKDRVTLTADTSTSTVYMELSSLRSEDTAVYYCARKFDYWGQGTTVTVSS ＞hzJ4F VL (SEQ ID NO:471) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKLLIYSASYRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK ＞hzJ4.1F VL Q3V (SEQ ID NO:472) DIVMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKLLIYSASYRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK ＞hzJ4.2F VL Q3V L46A (SEQ ID NO:473) DIVMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASYRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK ＞hzJ4.3F VL L46A (SEQ ID NO:474) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASYRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK ＞hzJ4.4F VL L46A, L47V (SEQ ID NO: 475) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKAVIYSASYRF SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK ＞hzJ4.5F VL L46A, L47V, F62L (SEQ ID NO:476) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKAVIYSASYRFSGVPSRLSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK ＞hzJ4.6F VL L46A, L47V, S60D, F62L, S63T (SEQ ID NO:477) DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKAVIYSASYRFSGVPDRLTGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK ＞hzJ4F VH (SEQ ID NO:478 ) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.1F VH V37I (SEQ ID NO:479) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWIRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.2F VH V37I, R38K, M48I (SEQ ID NO:480) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWIKQAPGQGLEWIGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.3F VH V37I, R66K, V67A (SEQ ID NO:481 ) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWIRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS>hzJ4.4F VH V37I , R38K, M48I, R66K, V67A (SEQ ID NO:482) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWIKQAPGQGLEWIGRIVPGSGSTYYNEMFKDKATMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.5F VH R66K, V67A (SEQ ID NO:483) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATMTRDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.6F VH R66K, V67A, V78A (SEQ ID NO:484) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATMTRDTSTSTAYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.7F VH R66K, V67A, V78A, M80I, E81Q (SEQ ID NO:485) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATMTRDTSTSTAYIQLSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.8F VH R66K, V67A, M69L, R71V (SEQ ID NO:486) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDKATLTVDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.9F VH M69L, R71V (SEQ ID NO: 487) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTLTVDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS>hzJ4.10F VH R71V (SEQ ID NO: 488 ) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTVDTSTSTVYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.11F VH V78A (SEQ ID NO:489) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTAYMELSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzJ4.12F VH V78A, M80I, E81Q (SEQ ID NO:490) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGRIVPGSGSTYYNEMFKDRVTMTRDTSTSTAYIQLSSLRSEDTAVYYCARKPNFDVWGQGTTVTVSS ＞hzL4L VL (SEQ ID NO:491) DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWGTPPWTFGGGTKVEIK ＞hzL4.1L VL D56S (SEQ ID NO:492) DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWGTPPWTFGGGTKVEIK ＞hzL4.2L VL D56E (SEQ ID NO:493) DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATNLAEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWGTPPWTFGGGTKVEIK ＞hzL4.3L VL G57A (SEQ ID NO:494) DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATNLADAVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWGTPPWTFGGGTKVEIK ＞hzL4L VH (SEQ ID NO:495) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS ＞hzL4.1L VH S30T, V67I, T68S, S70T, V71R (SEQ ID NO:496) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS ＞hzL4.2L VH G27Y, S30T, V67I, T68S, S70T, V71R (SEQ ID NO :497) QVQLQESGPGLVKPSQTLSLTCTVSGYSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS ＞hzL4.3L VH G27Y, S30T (SEQ ID NO:498) QVQLQESGPGLVKPSQTLSLTCTVSGYSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS ＞hzL4.4L VH G27Y, V67I, T68S, S70T, V71R (SEQ ID NO:499) QVQLQESGPGLVKPSQTLSLTCTVSGYSISSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS ＞hzL4.5L VH G27Y, S30T , S70T, V71R (SEQ ID NO: 500) QVQLQESGPGLVKPSQTLSLTCTVSGYSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRVTITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGY GMDYWGQGTTVTVSS ＞hzL4.6L VH G27Y, S70T, V71R (SEQ ID NO:501) QVQLQESGPGLVKPSQTLSLTCTVSGYSISSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRVTITRDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS ＞hzL4.7L VH G27Y, S30T, V67I, T68S (SEQ ID NO:502) QVQLQESGPGLVKPSQTLSLTCTVSGYSITSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISISVDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS ＞hzL4.8L VH G27Y, V67I, T68S ( SEQ ID NO:503) QVQLQESGPGLVKPSQTLSLTCTVSGYSISSDYAWNWIRQHPGKGLEWIGYISYSGSTRYNPSLKSRISISVDTSKNQFSLKLSSVTAADTAVYYCARRYRYDEGYGMDYWGQGTTVTVSS ＞hzH8K VL (SEQ ID NO:504) DIQMTQSPSSLSASVGDRVTITCRASENIYSYLAWYQQKPGKAPKLLIYNAKTLAEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHHYGTPLTFGGGTKVEIK ＞hzH8K VH (SEQ ID NO:505) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS ＞hzH8.1K VH S30T (SEQ ID NO:506) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS ＞hzH8.2K VH G27F, S30T (SEQ ID NO: 50 7) QVQLQESGPGLVKPSQTLSLTCTVSGFSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS ＞hzH8.3K VH V67I, T68S, S70T, V71R (SEQ ID NO:508) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS ＞hzH8.4K VH S30T, V67I, T68S, S70T, V71R (SEQ ID NO:509) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS ＞hzH8.5K VH G27F, S30T, V67I, T68S, S70T, V71R (SEQ ID NO:510) QVQLQESGPGLVKPSQTLSLTCTVSGFSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS ＞hzH8.6K VH S30T, V67I, T68S (SEQ ID NO:511) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS ＞hzH8.7K VH S30T, S70T, V71R (SEQ ID NO:512) QVQLQESGPGLVKPSQTLSLTCTVSGGSITSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQG TTVTVSS ＞hzH8.8K VH V67I, T68S (SEQ ID NO:513) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRISISVDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS ＞hzH8.9K VH S70T, V71R (SEQ ID NO:514) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSDYAWNWIRQHPGKGLEWIGYRSYRGSTSYNPSLKSRVTITRDTSKNQFSLKLSSVTAADTAVYYCARRGYYGSSSHWYFDVWGQGTTVTVSS SEQ ID NO: 658 -Heavy chain Consensus Sequence QVQLVQSGAE VKKPGSSVKV SCKASGX ¹X ²F X ³GYTMNWVRQA PGQGLEWMGL ITPYN X ⁴ASSY NQKFRG X ⁵X ⁶T X ⁷T X ⁸DKSTSTAY MELSSLRSED TAVYYCARGG YDGRGFDYWG QGTTVTVSS X ¹is G or Y (G27Y) X ²is T or S (T28S) X ³is S or T (S30T) X ⁴is G or A (G55A) X ⁵is R or K (R66K) X ⁶is V or A (V67A) X ⁷is I or L (I69L) X ⁸is A or V (A71V) SEQ ID NO: 659- Light chain Consensus Sequence For VKIII and for CDRsX ¹IVLTQSPATLSLSPGERATLSCSSSSSVSYMHWYQQKPGQAPRX ²LIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSKHPLTFGGGTKVEIK X ¹is E or D (E1D) X ²is L or R (L46R) SEQ ID NO: 660 -VH1-e CDRgraft G55A QVQLVQSGAE VKKPGSSVKV SCKASGGTFS GYTMNWVRQA PGQGLEWMGL ITPYNAASSY NQKFRGRVTI TADKSTSTAY MELSSLRSED TAVYYCARGG YDGRGFDYWG QGTTVTVSS SEQ ID NO: 661 -VH1-e CDRgraft IgG1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGYTMNWVRQAPGQGLEWMGLITPYNGASSYNQKFRGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGGYDGRGFDYWGQGTTVTVSS SEQ ID NO:662-CDR1 heavy chain GYTMN SEQ ID NO: 663 -CDR2 heavy chain G55A LITPYNAASSY NQKFRG SEQ ID NO: 664 -CDR2 heavy chain unmodified LITPYNGASSY NQKFRG SEQ ID NO: 665CDR3 heavy chain GGYDGRGFDY SEQ ID NO: 666CDR1 light chain SASSSVSYMH SEQ ID NO: 667CDR2 light chain DTSKLAS SEQ ID NO: 668CDR3 light chain QQWSKHPLT SEQ ID NO: 669 -VH1- G27Y, T28S, S30T QVQLVQSGAE VKKPGSSVKV SCKASGYSFT GYTMNWVRQA PGQGLEWMGL ITPYNGASSY NQKFRGRVTI TADKSTSTAY MELSSLRSED TAVYYCARGG YDGRGFDYWG QGTTVTVSS SEQ ID NO: 670 -VH1-e R66K, V67A, I69L, A71V QVQLVQSGAE VKKPGSSVKV SCKASGGTFS GYTMNWVRQA PGQGLEWMGL ITPYNGASSY NQKFRGKATL TVDKSTSTAY MELSSLRSED TAVYYCARGG YDGRGFDYWG QGTTVTVSS SEQ ID NO:671 -VH1-e G27Y, T28S, S30T R66K, V67A, I69L, A71V QVQLVQSGAE VKKPGSSVKV SCKASGYSFT GYTMNWVRQA PGQGLEWMGL ITPYNGASSY NQKFRGKATL TVDKSTSTAY MELSSLRSED TAVYYCARGG YDGRGFDYWG QGTTVTVSS SEQ ID NO:672-VH1-e G27Y, T28S, S30T, R66K, V67A, A71V - QVQLVQSGAE VKKPGSSVKV SCKASGYSFT GYTMNWVRQA PGQGLEWMGL ITPYNGASSY NQKFRGKATI TVDKSTSTAY MELSSLRSED TAVYYCARGG YDGRGFDYWG QGTTVTVSS SEQ ID NO: 673 -VH1-e G27Y, R66K, V67A, A71V - QVQLVQSGAE VKKPGSSVKV SCKASGYTFS GYTMNWVRQA PGQGLEWMGL ITPYNGASSY NQKFRGKATI TVDKSTSTAY MELSSLRSED TAVYYCARGG YDGRGFDYWG QGTTVTVSS SEQ ID NO: 674 -VH1-e G27Y, G55A, R66K, V67A, A71V QVQLVQSGAE VKKPGSSVKV SCKASGYTFS GYTMNWVRQA PGQGLEWMGL ITPYNAASSY NQKFRGKATI TVDKSTSTAY MELSSLRSED TAVYYCARGG YDGRGFDYWG QGTTVTVSS SEQ ID NO: 675- VKIII-L6 CDRgraft EIVLTQSPATLSLSPGERATLSCSSSSSVSYMHWYQQKPGQAPRLLIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSKHPLTFGGGTKVEIK SEQ ID NO: 676- VKIII-L6 E1D - DIVLTQSPATLSLSPGERATLSCSSSSSVSYMHWYQQKPGQAPRLLIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSKHPLTFGGGTKVEIK SEQ ID NO: 677- VKIII-L6 L46R - EIVLTQSPATLSLSPGERATLSCSSSSSVSYMHWYQQKPGQAPRRLIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSKHPLTFGGGTKVEIK SEQ ID NO: 678VKIII-L6 E1D L46R DIVLTQSPATLSLSPGERATLSCSSSSSVSYMHWYQQKPGQAPRRLIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSKHPLTFGGGTKVEIK SEQ ID NO: 679VKI-L12 CDRgraft DIQMTQSPSTLSASVGDRVTITCSSSSSVSYMHWYQQKPGKAPKLLIYDTSKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQWSKHPLTFGGGTKVEIK SEQ ID NO: 680SS1 heavy chain variable region QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASSYNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGSGTPVTVSS SEQ ID NO: 681SS1 heavy chain variable region G55A QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNAASSYNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGSGTPVTVSS SEQ ID NO: 682SS1 light chain variable region DIELTQSPAIMSASPGEKVTMTCSSSSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGNSYSLTISSVEAEDDATYYCQQWSKHPLTFGSGTKVEIK SEQ ID NO:857 anti-MSLN heavy chain constant region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 858 anti-MSLN light chain constant region RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC D6C VH CDR1 (SEQ ID NO: 859) NYDMS D6C VH CDR2 (SEQ ID NO: 860) TISSGGSYTYYVDSVKG D6C VH CDR3 (SEQ ID NO: 861) QELGSYYAMDY D6C and D6.1C VL CDR1 (SEQ ID NO: 862) RSSQSIVHSNGNTYLE D6C VL CDR2 (SEQ ID NO: 863) KVSNRFS D6C VL CDR3 (SEQ ID NO: 864) FQGSHVPYT D6C VH (SEQ ID NO: 865) EVMLVESGGALVKPGGSLKLSCVASGFTFSNYDMSWVRQTPEKRLEWVATISSGGSYTYYVDSVKGRFTISRDNARNTLHLQMSSLRSKDTAMYYCARQELGSYYAMDYWGQGTSVTVSS D6C Heavy Chain (VH-IgG1) (SEQ ID NO: 867) EVMLVESGGALVKPGGSLKLSCVASGFTFSNYDMSWVRQTPEKRLEWVATISSGGSYTYYVDSVKGRFTISRDNARNTLHLQMSSLRSKDTAMYYCARQELGSYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK D6C Light Chain (VL- κ) (SEQ ID NO: 868) DVVMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECHK D6.2C and D6.5C VL CDR1 (SEQ ID NO: 869) RSSQSIVHSNANTYLE D6.3C and D6.4C VL CDR1 (SEQ ID NO: 870) RSSQSIVHSQGNTYLE hzD6C VH (SEQ ID NO: 871) EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYDMSWVRQAPGKGLEWVATISSGGSYTYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQELGSYYAMDYWGQGTTVTVSS D6C VL (SEQ ID NO: 866) DVVMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIK hzD6C VL (SEQ ID NO: 872) DIVMTQTPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIK hzD6.1C VL (SEQ ID NO: 873) DVVMTQTPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIK hzD6.2C VL (SEQ ID NO: 874) DIVMTQTPLSLPVTPGEPASISCRSSQSIVHSNANTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIK hzD6.3C VL (SEQ ID NO: 875) DIVMTQTPLSLPVTPGEPASISCRSSQSIVHSQGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIK hzD6.4C VL (SEQ ID NO: 876) DVVMTQTPLSLPVTPGEPASISCRSSQSIVHSQGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIK hzD6.5C VL (SEQ ID NO: 877) DVVMTQTPLSLPVTPGEPASISCRSSQSIVHSNANTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIK hzD6C Heavy Chain (hzVH-IgG1) (SEQ ID NO: 878) EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYDMSWVRQAPGKGLEWVATISSGGSYTYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQELGSYYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK hzD6C Light Chain (VL- κ) (SEQ ID NO: 879) DIVMTQTPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC hzD6.1C Light Chain (VL.1- κ) (SEQ ID NO: 880) DVVMTQTPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECHK hzD6.2C Light Chain (VL.2- κ) (SEQ ID NO: 881) DIVMTQTPLSLPVTPGEPASISCRSSQSIVHSNANTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC hzD6.3C Light Chain (VL.3- κ) (SEQ ID NO: 882) DIVMTQTPLSLPVTPGEPASISCRSSQSIVHSQGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC hzD6.4C Light Chain (VL.4- κ) (SEQ ID NO: 883) DVVMTQTPLSLPVTPGEPASISCRSSQSIVHSQGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECHK hzD6.5C Light Chain (VL.5- κ) (SEQ ID NO: 884) DVVMTQTPLSLPVTPGEPASISCRSSQSIVHSNANTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECHK The above-described embodiments can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications cited in this specification and/or listed in the Application Data Sheet are hereby incorporated by reference in their entirety. as reference material. The aspect of the specific embodiments can be modified, as desired, using the concepts of various patents, applications, and publications to provide further specific embodiments. These and other modifications can be made to specific embodiments in light of the above-detailed description. In general, in the appended claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible implementations Examples and the full scope of equivalents to which such claims are entitled. Accordingly, the scope of the patent application is not limited by the present invention.

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Figure 1 shows a graph of reporter activity (%) versus drug amount (Log nM) showing the effect of structural variation on the activity of imidazole-based inhibitors (as conjugates).

Figure 2 shows a graph of reporter activity (%) versus drug amount (Log nM) showing the effect of halogenation on the activity of quinoline-containing inhibitors (as conjugates).

Figure 3 shows a graph of reporter activity (%) versus amount of drug (Log nM) showing the effect of halogenation on the activity of 1,5-ethylene-containing inhibitors (as conjugates).

Figure 4 shows a graph of reporter activity (%) versus drug amount (Log nM) showing the effect of tether identity on the activity of quinoline-containing inhibitors (as conjugates).

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                                  sequence listing
           <![CDATA[ <110> Silverback Therapeutics, Inc.]]>
           <![CDATA[ <120> ALK5 inhibitors, conjugates and their uses]]>
           <![CDATA[ <130> 21P0392]]>
           <![CDATA[ <150> US 63/047246]]>
           <![CDATA[ <151> 2020-07-01]]>
           <![CDATA[ <150> US 63/090168]]>
           <![CDATA[ <151> 2020-10-09]]>
           <![CDATA[ <160> 914 ]]>
           <![CDATA[ <170> PatentIn version 3.5]]>
           <![CDATA[ <210> 1]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 1]]>
          Gly Tyr Tyr Met His
          1 5
           <![CDATA[ <210> 2]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 2]]>
          Ser Tyr Thr Met His
          1 5
           <![CDATA[ <210> 3]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 3]]>
          Ser Asp Tyr Ala Trp Asn
          1 5
           <![CDATA[ <210> 4]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
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           <![CDATA[ <400> 4]]>
          Ser Asp Tyr Ala Trp Asn
          1 5
           <![CDATA[ <210> 5]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
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           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 5]]>
          Ser Tyr Trp Ile Asn
          1 5
           <![CDATA[ <210> 6]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
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           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 6]]>
          Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 7]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
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           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 7]]>
          Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 8]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 8]]>
          Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 9]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 9]]>
          Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 10]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 10]]>
          Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 11]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 11]]>
          Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 12]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 12]]>
          Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 13]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 13]]>
          Val Asn Phe Tyr Tyr
          1 5
           <![CDATA[ <210> 14]]>
           <![CDATA[ <211> 4]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 14]]>
          Lys Phe Asp Tyr
          1               
           <![CDATA[ <210> 15]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 15]]>
          Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 16]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 16]]>
          Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
          1 5 10
           <![CDATA[ <210> 17]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 17]]>
          Lys Pro Asn Phe Asp Val
          1 5
           <![CDATA[ <210> 18]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 18]]>
          Lys Ala Ser Gln Val Ile Asn Ser Tyr Leu Ser
          1 5 10
           <![CDATA[ <210> 19]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 19]]>
          Lys Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser
          1 5 10
           <![CDATA[ <210> 20]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 20]]>
          Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala
          1 5 10
           <![CDATA[ <210> 21]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 21]]>
          Arg Ala Ser Glu Asn Ile Tyr Ser Tyr Leu Ala
          1 5 10
           <![CDATA[ <210> 22]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 22]]>
          Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala
          1 5 10
           <![CDATA[ <210> 23]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 23]]>
          Arg Ala Asn Thr Leu Val Asp
          1 5
           <![CDATA[ <210> 24]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 24]]>
          Arg Ala Asn Thr Leu Val Ser
          1 5
           <![CDATA[ <210> 25]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 25]]>
          Arg Ala Asn Thr Leu Val Glu
          1 5
           <![CDATA[ <210> 26]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 26]]>
          Arg Ala Asn Arg Leu Val Asp
          1 5
           <![CDATA[ <210> 27]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 27]]>
          Arg Ala Asn Arg Leu Val Glu
          1 5
           <![CDATA[ <210> 28]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 28]]>
          Ala Ala Thr Asn Leu Ala Asp
          1 5
           <![CDATA[ <210> 29]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 29]]>
          Ala Ala Thr Asn Leu Ala Ser
          1 5
           <![CDATA[ <210> 30]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 30]]>
          Ala Ala Thr Asn Leu Ala Glu
          1 5
           <![CDATA[ <210> 31]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 31]]>
          Asn Ala Lys Thr Leu Ala Glu
          1 5
           <![CDATA[ <210> 32]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 32]]>
          Ser Ala Ser Tyr Arg Phe Ser
          1 5
           <![CDATA[ <210> 33]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 33]]>
          Leu Gln Tyr Ala Glu Phe Pro Tyr Thr
          1 5
           <![CDATA[ <210> 34]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 34]]>
          Leu Gln Tyr Asp Glu Phe Pro Phe Thr
          1 5
           <![CDATA[ <210> 35]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 35]]>
          Gln His Phe Trp Gly Thr Pro Pro Trp Thr
          1 5 10
           <![CDATA[ <210> 36]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 36]]>
          Gln His His Tyr Gly Thr Pro Leu Thr
          1 5
           <![CDATA[ <210> 37]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 37]]>
          Gln Gln Tyr Asn Ser Tyr Pro Leu Thr
          1 5
           <![CDATA[ <210> 38]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 38]]>
          Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Lys Gln Ser His Val Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Phe His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 39]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 39]]>
          Gln Val Gln Leu Gln Gln Ser Ala Ala Glu Leu Ala Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Leu Thr Ala Asp Lys Ser Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 40]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 40]]>
          Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
                  35 40 45
          Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
          65 70 75 80
          Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Ser Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 41]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 41]]>
          Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Phe Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Gln Leu Glu Trp
                  35 40 45
          Met Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
          65 70 75 80
          Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 42]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 42]]>
          Gln Val Gln Leu Gln Gln Ser Gly Asp Asp Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Ile Gln Leu Ser Ser Leu Ser Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 43]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 43]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 44]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 44]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 45]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 45]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 46]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 46]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 47]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 47]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 48]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 48]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 49]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 49]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 50]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 50]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 51]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 51]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 52]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 52]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 53]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 53]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 54]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 54]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 55]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 55]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 56]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 56]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 57]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 57]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 58]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 58]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 59]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 59]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 60]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 60]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 61]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 61]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 62]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 62]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 63]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 63]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 64]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 64]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 65]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 65]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 66]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 66]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 67]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 67]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 68]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 68]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 69]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 69]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 70]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 70]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 71]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 71]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 72]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 72]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 73]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 73]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 74]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 74]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 75]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 75]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 76]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 76]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 77]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 77]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 78]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 78]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 79]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 79]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 80]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 80]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 81]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 81]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 82]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 82]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 83]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 83]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 84]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 84]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 85]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 85]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 86]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 86]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 87]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 87]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 88]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 88]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 89]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 89]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 90]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 90]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 91]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 91]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 92]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 92]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 93]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 93]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Arg Val Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 94]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 94]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 95]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 95]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 96]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 96]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 97]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 97]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 98]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 98]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 99]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 99]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 100]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 100]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 101]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 101]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 102]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 102]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 103]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 103]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 104]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 104]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 105]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 105]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 106]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 106]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 107]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 107]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 108]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 108]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 109]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 109]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 110]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 110]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 111]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 111]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 112]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 112]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 113]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 113]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 114]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 114]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 115]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 115]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 116]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 116]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 117]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 117]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 118]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 118]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 119]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 119]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 120]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 120]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Ile Gln Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 121]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 121]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 122]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 122]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 123]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 123]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 124]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 124]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 125]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 125]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Ile Gln Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 126]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 126]]>
          Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
          1 5 10 15
          Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Glu Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr
          65 70 75 80
          Glu Asp Leu Gly Ile Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 127]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 127]]>
          Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
          1 5 10 15
          Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Gln Asp Phe Ser Leu Thr Ile Ser Ser Leu Glu Tyr
          65 70 75 80
          Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 128]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 128]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Val Phe Val Gly
          1 5 10 15
          Glu Ile Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Ser
          65 70 75 80
          Glu Asp Phe Gly Asn Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 129]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 129]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
                  35 40 45
          Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu
                          85 90 95
          Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys
                      100 105
           <![CDATA[ <210> 130]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 130]]>
          Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Val Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Leu Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser
          65 70 75 80
          Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
                      100 105
           <![CDATA[ <210> 131]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 131]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 132]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 132]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 133]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 133]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 134]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 134]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 135]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 135]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 136]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 136]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 137]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 137]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 138]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 138]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 139]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 139]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 140]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 140]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 141]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 141]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 142]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 142]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 143]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 143]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 144]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 144]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 145]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 145]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 146]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 146]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 147]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 147]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Val Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 148]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 148]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Val Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Leu Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 149]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 149]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Val Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Leu Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 150]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 150]]>
          Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Lys Gln Ser His Val Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Phe His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 151]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 151]]>
          Gln Val Gln Leu Gln Gln Ser Ala Ala Glu Leu Ala Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Leu Thr Ala Asp Lys Ser Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 152]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 152]]>
          Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
                  35 40 45
          Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
          65 70 75 80
          Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 153]]>
           <![CDATA[ <211> 453]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 153]]>
          Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Phe Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Gln Leu Glu Trp
                  35 40 45
          Met Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
          65 70 75 80
          Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
                  115 120 125
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
              130 135 140
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
          145 150 155 160
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
                          165 170 175
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
                      180 185 190
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
                  195 200 205
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
              210 215 220
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
          225 230 235 240
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                          245 250 255
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                      260 265 270
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
                  275 280 285
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
              290 295 300
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
          305 310 315 320
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
                          325 330 335
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                      340 345 350
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
                  355 360 365
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
              370 375 380
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
          385 390 395 400
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
                          405 410 415
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
                      420 425 430
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
                  435 440 445
          Leu Ser Pro Gly Lys
              450
           <![CDATA[ <210> 154]]>
           <![CDATA[ <211> 445]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 154]]>
          Gln Val Gln Leu Gln Gln Ser Gly Asp Asp Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Ile Gln Leu Ser Ser Leu Ser Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
                  115 120 125
          Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
              130 135 140
          Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
          145 150 155 160
          Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
                          165 170 175
          Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
                      180 185 190
          Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
                  195 200 205
          Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
              210 215 220
          Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
          225 230 235 240
          Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
                          245 250 255
          Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
                      260 265 270
          Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
                  275 280 285
          Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
              290 295 300
          Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
          305 310 315 320
          Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
                          325 330 335
          Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
                      340 345 350
          Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
                  355 360 365
          Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
              370 375 380
          Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
          385 390 395 400
          Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
                          405 410 415
          Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
                      420 425 430
          His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 155]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 155]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 156]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 156]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 157]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 157]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 158]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 158]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 159]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 159]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 160]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 160]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 161]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 161]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 162]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 162]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 163]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 163]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 164]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 164]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 165]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 165]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 166]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 166]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 167]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 167]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 168]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 168]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 169]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 169]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 170]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 170]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 171]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 171]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 172]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 172]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 173]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 173]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 174]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 174]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 175]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 175]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 176]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 176]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 177]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 177]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 178]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 178]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 179]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 179]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 180]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 180]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 181]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 181]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 182]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 182]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 183]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 183]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 184]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 184]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 185]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 185]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 186]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 186]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 187]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 187]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 188]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 188]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 189]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 189]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 190]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 190]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 191]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 191]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 192]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 192]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 193]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 193]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 194]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 194]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 195]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 195]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 196]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 196]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 197]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 197]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 198]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 198]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 199]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 199]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 200]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 200]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
                  115 120 125
          Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
              130 135 140
          Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
          145 150 155 160
          Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
                          165 170 175
          Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
                      180 185 190
          Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
                  195 200 205
          Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
              210 215 220
          Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 201]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 201]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 202]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 202]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 203]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 203]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 204]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 204]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 205]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 205]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Arg Val Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 206]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 206]]>
          Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
          1 5 10 15
          Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Glu Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr
          65 70 75 80
          Glu Asp Leu Gly Ile Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 207]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 207]]>
          Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
          1 5 10 15
          Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Gln Asp Phe Ser Leu Thr Ile Ser Ser Leu Glu Tyr
          65 70 75 80
          Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 208]]>
           <![CDATA[ <211> 215]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 208]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Val Phe Val Gly
          1 5 10 15
          Glu Ile Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Ser
          65 70 75 80
          Glu Asp Phe Gly Asn Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
                      100 105 110
          Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
                  115 120 125
          Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
              130 135 140
          Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
          145 150 155 160
          Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
                          165 170 175
          Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
                      180 185 190
          Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
                  195 200 205
          Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 209]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 209]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
                  35 40 45
          Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu
                          85 90 95
          Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 210]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 210]]>
          Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Val Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Leu Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser
          65 70 75 80
          Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 211]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 211]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 212]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 212]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 213]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 213]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 214]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 214]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 215]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 215]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 216]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 216]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 217]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 217]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 218]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 218]]>
          Ser Tyr Ala Met Ser
          1 5
           <![CDATA[ <210> 219]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 219]]>
          Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 220]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 220]]>
          Asp Phe Ser Ser Arg Arg Trp Tyr Leu Glu Tyr
          1 5 10
           <![CDATA[ <210> 221]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 221]]>
          Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser
          1 5 10
           <![CDATA[ <210> 222]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 222]]>
          Gly Lys Asn Asn Arg Pro Ser
          1 5
           <![CDATA[ <210> 223]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 223]]>
          Asn Ser Leu Glu Arg Ile Gly Tyr Leu Ser Tyr Val
          1 5 10
           <![CDATA[ <210> 224]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 224]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Phe Ser Ser Arg Arg Trp Tyr Leu Glu Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 225]]>
           <![CDATA[ <211> 109]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 225]]>
          Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
          1 5 10 15
          Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
                      20 25 30
          Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
                  35 40 45
          Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
              50 55 60
          Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
          65 70 75 80
          Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Leu Glu Arg Ile Gly Tyr Leu
                          85 90 95
          Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
                      100 105
           <![CDATA[ <210> 226]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 226]]>
          Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
          1 5 10 15
          Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Phe Ser Ser Arg Arg Trp Tyr Leu Glu Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Thr Leu Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 227]]>
           <![CDATA[ <211> 109]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 227]]>
          Gln Ala Val Leu Thr Gln Glu Pro Ala Leu Ser Val Ser Leu Gly Gln
          1 5 10 15
          Thr Val Thr Leu Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
                      20 25 30
          Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
                  35 40 45
          Gly Lys Asn Asn Arg Pro Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
              50 55 60
          Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr Glu
          65 70 75 80
          Asp Glu Ala Ile Tyr Tyr Cys Asn Ser Leu Glu Arg Ile Gly Tyr Leu
                          85 90 95
          Ser Tyr Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu
                      100 105
           <![CDATA[ <210> 228]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 228]]>
          Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
          1 5 10 15
          Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Phe Ser Ser Arg Arg Trp Tyr Leu Glu Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser Val
                  115 120 125
          Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr
              130 135 140
          Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr
          145 150 155 160
          Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val
                          165 170 175
          Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser
                      180 185 190
          Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala
                  195 200 205
          Ser Ser Thr Lys Val Asp Lys Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile
              210 215 220
          Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly
          225 230 235 240
          Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile
                          245 250 255
          Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp
                      260 265 270
          Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His
                  275 280 285
          Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg
              290 295 300
          Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys
          305 310 315 320
          Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu
                          325 330 335
          Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr
                      340 345 350
          Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu
                  355 360 365
          Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp
              370 375 380
          Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val
          385 390 395 400
          Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu
                          405 410 415
          Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His
                      420 425 430
          Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro
                  435 440 445
          Gly Lys
              450
           <![CDATA[ <210> 229]]>
           <![CDATA[ <211> 216]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 229]]>
          Gln Ala Val Leu Thr Gln Glu Pro Ala Leu Ser Val Ser Leu Gly Gln
          1 5 10 15
          Thr Val Thr Leu Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
                      20 25 30
          Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
                  35 40 45
          Gly Lys Asn Asn Arg Pro Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
              50 55 60
          Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala Gln Thr Glu
          65 70 75 80
          Asp Glu Ala Ile Tyr Tyr Cys Asn Ser Leu Glu Arg Ile Gly Tyr Leu
                          85 90 95
          Ser Tyr Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Arg Ala Asp
                      100 105 110
          Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr
                  115 120 125
          Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys
              130 135 140
          Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly
          145 150 155 160
          Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser
                          165 170 175
          Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn
                      180 185 190
          Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val
                  195 200 205
          Lys Ser Phe Asn Arg Asn Glu Cys
              210 215
           <![CDATA[ <210> 230]]>
           <![CDATA[ <211> 330]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 230]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                          325 330
           <![CDATA[ <210> 231]]>
           <![CDATA[ <211> 330]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 231]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                          325 330
           <![CDATA[ <210> 232]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 232]]>
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
          1 5 10 15
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
                      20 25 30
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
                  35 40 45
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
              50 55 60
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
          65 70 75 80
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                          85 90 95
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
                      100 105
           <![CDATA[ <210> 233]]>
           <![CDATA[ <211> 330]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 233]]>
          Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly
          1 5 10 15
          Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
              50 55 60
          Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile
          65 70 75 80
          Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
                          85 90 95
          Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys
                      100 105 110
          Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro
                  115 120 125
          Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp
          145 150 155 160
          Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg
                          165 170 175
          Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln
                      180 185 190
          His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn
                  195 200 205
          Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly
              210 215 220
          Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu
          225 230 235 240
          Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met
                          245 250 255
          Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu
                      260 265 270
          Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe
                  275 280 285
          Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn
              290 295 300
          Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr
          305 310 315 320
          Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
                          325 330
           <![CDATA[ <210> 234]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 234]]>
          Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
          1 5 10 15
          Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
                      20 25 30
          Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
                  35 40 45
          Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
              50 55 60
          Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
          65 70 75 80
          Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
                          85 90 95
          Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
                      100 105
           <![CDATA[ <210> 235]]>
           <![CDATA[ <211> 331]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 235]]>
          Ala Gln Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Gly Cys Gly
          1 5 10 15
          Asp Thr Thr Ser Ser Thr Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Ser Ser
                  35 40 45
          Asp Val His Thr Phe Pro Ala Val Leu Gln Ser Gly Leu Tyr Thr Leu
              50 55 60
          Thr Ser Ser Val Thr Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys
          65 70 75 80
          Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Val Glu
                          85 90 95
          Arg Arg Asn Gly Gly Ile Gly His Lys Cys Pro Thr Cys Pro Thr Cys
                      100 105 110
          His Lys Cys Pro Val Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Ile
                  115 120 125
          Phe Pro Pro Lys Pro Lys Asp Ile Leu Leu Ile Ser Gln Asn Ala Lys
              130 135 140
          Val Thr Cys Val Val Val Asp Val Ser Glu Glu Glu Pro Asp Val Gln
          145 150 155 160
          Phe Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln
                          165 170 175
          Pro Arg Glu Glu Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Ala Leu
                      180 185 190
          Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys
                  195 200 205
          Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Lys Thr Ile Ser Lys
              210 215 220
          Pro Lys Gly Leu Val Arg Lys Pro Gln Val Tyr Val Met Gly Pro Pro
          225 230 235 240
          Thr Glu Gln Leu Thr Glu Gln Thr Val Ser Leu Thr Cys Leu Thr Ser
                          245 250 255
          Gly Phe Leu Pro Asn Asp Ile Gly Val Glu Trp Thr Ser Asn Gly His
                      260 265 270
          Ile Glu Lys Asn Tyr Lys Asn Thr Glu Pro Val Met Asp Ser Asp Gly
                  275 280 285
          Ser Phe Phe Met Tyr Ser Lys Leu Asn Val Glu Arg Ser Arg Trp Asp
              290 295 300
          Ser Arg Ala Pro Phe Val Cys Ser Val Val His Glu Gly Leu His Asn
          305 310 315 320
          His His Val Glu Lys Ser Ile Ser Arg Pro Pro
                          325 330
           <![CDATA[ <210> 236]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 236]]>
          Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Thr Glu
          1 5 10 15
          Gln Leu Ala Thr Gly Gly Ala Ser Val Val Cys Leu Met Asn Asn Phe
                      20 25 30
          Tyr Pro Arg Asp Ile Ser Val Lys Trp Lys Ile Asp Gly Thr Glu Arg
                  35 40 45
          Arg Asp Gly Val Leu Asp Ser Val Thr Asp Gln Asp Ser Lys Asp Ser
              50 55 60
          Thr Tyr Ser Met Ser Ser Thr Leu Ser Leu Thr Lys Ala Asp Tyr Glu
          65 70 75 80
          Ser His Asn Leu Tyr Thr Cys Glu Val Val His Lys Thr Ser Ser Ser
                          85 90 95
          Pro Val Val Lys Ser Phe Asn Arg Asn Glu Cys
                      100 105
           <![CDATA[ <210> 237]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 237]]>
          Gly Tyr Thr Phe Thr Asp Tyr Asn
          1 5
           <![CDATA[ <210> 238]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 238]]>
          Ile Asn Pro Asn Tyr Glu Ser Thr
          1 5
           <![CDATA[ <210> 239]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 239]]>
          Arg Asp Lys Gly Trp Tyr Phe Asp Val
          1 5
           <![CDATA[ <210> 240]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 240]]>
          Ser Ser Val Lys Asn
          1 5
           <![CDATA[ <210> 241]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 241]]>
          Tyr Thr Ser
          1           
           <![CDATA[ <210> 242]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 242]]>
          Gln Gln Phe Thr Ser Ser Pro Tyr Thr
          1 5
           <![CDATA[ <210> 243]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 243]]>
          Gly Phe Ser Leu Ser Thr Ser Gly Met Gly
          1 5 10
           <![CDATA[ <210> 244]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 244]]>
          Ile Trp Trp Asp Asp Asp Lys
          1 5
           <![CDATA[ <210> 245]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 245]]>
          Ala Arg Leu Thr Gly Thr Arg Tyr Phe Asp Tyr
          1 5 10
           <![CDATA[ <210> 246]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 246]]>
          Gln Asp Ile Asn Lys Phe
          1 5
           <![CDATA[ <210> 247]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 247]]>
          Tyr Thr Ser
          1           
           <![CDATA[ <210> 248]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 248]]>
          Leu Gln Tyr Gly Asn Leu Trp Thr
          1 5
           <![CDATA[ <210> 249]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 249]]>
          Gly Tyr Thr Phe Thr Asp Tyr Ser
          1 5
           <![CDATA[ <210> 250]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 250]]>
          Ile Asn Thr Glu Thr Gly Glu Pro
          1 5
           <![CDATA[ <210> 251]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 251]]>
          Ala Thr Tyr Tyr Gly Ser Ser Tyr Val Pro Asp Tyr
          1 5 10
           <![CDATA[ <210> 252]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 252]]>
          Gln Asn Val Gly Thr Ala
          1 5
           <![CDATA[ <210> 253]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 253]]>
          Trp Thr Ser
          1           
           <![CDATA[ <210> 254]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 254]]>
          Gln Tyr Ser Asp Tyr Pro Tyr Thr
          1 5
           <![CDATA[ <210> 255]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 255]]>
          Gly Tyr Thr Phe Thr Asp Tyr
          1 5
           <![CDATA[ <210> 256]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 256]]>
          Trp Val Asp Pro Glu Tyr Gly Ser
          1 5
           <![CDATA[ <210> 257]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 257]]>
          Ala Arg Asp Asp Gly Ser Tyr Ser Pro Phe Asp Tyr
          1 5 10
           <![CDATA[ <210> 258]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 258]]>
          Gln Asn Ile Asn Lys Tyr
          1 5
           <![CDATA[ <210> 259]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 259]]>
          Tyr Thr Ser
          1           
           <![CDATA[ <210> 260]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 260]]>
          Leu Gln Tyr Val Asn Leu Leu Thr
          1 5
           <![CDATA[ <210> 261]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 261]]>
          Glu Asn Val Val Thr Tyr
          1 5
           <![CDATA[ <210> 262]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 262]]>
          Gly Ala Ser
          1           
           <![CDATA[ <210> 263]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 263]]>
          Gln Gly Tyr Ser Tyr Pro Tyr Thr
          1 5
           <![CDATA[ <210> 264]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 264]]>
          Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Asp Ile Asn Pro Asn Tyr Glu Ser Thr Ser Tyr Asn Gln Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Val Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Phe Tyr Cys
                          85 90 95
          Ala Arg Asp Lys Gly Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 265]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 265]]>
          Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
          1 5 10 15
          Glu Lys Val Thr Met Ser Cys Arg Ala Ser Ser Ser Val Lys Asn Met
                      20 25 30
          Tyr Trp Tyr Gln Gln Lys Ser Asp Ala Ser Pro Lys Leu Trp Ile Tyr
                  35 40 45
          Tyr Thr Ser Asn Leu Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser
              50 55 60
          Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Gly Glu
          65 70 75 80
          Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Phe Thr Ser Ser Pro Tyr Thr
                          85 90 95
          Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
                      100 105
           <![CDATA[ <210> 266]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 266]]>
          Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
                      20 25 30
          Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
                  35 40 45
          Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Phe Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Gln Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val
          65 70 75 80
          Phe Leu Lys Leu Thr Ser Val Val Thr Ala Asp Thr Ala Thr Tyr Tyr
                          85 90 95
          Cys Ala Arg Leu Thr Gly Thr Arg Tyr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Leu Thr Val Ser Ser
                  115
           <![CDATA[ <210> 267]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 267]]>
          Asp Val Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
          1 5 10 15
          Gly Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Phe
                      20 25 30
          Ile Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Arg Leu Leu Ile
                  35 40 45
          His Tyr Thr Ser Thr Leu Gln Pro Gly Ile Pro Ser Lys Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Asn Leu Glu Pro
          65 70 75 80
          Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Gly Asn Leu Trp Thr
                          85 90 95
          Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
                      100 105
           <![CDATA[ <210> 268]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 268]]>
          Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
          1 5 10 15
          Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
                  35 40 45
          Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
              50 55 60
          Lys Gly Arg Phe Ala Phe Ser Ser Glu Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Leu Gln Ile Asn Asn Leu Lys Asn Asp Asp Thr Thr Thr Tyr Phe Cys
                          85 90 95
          Ala Thr Tyr Tyr Gly Ser Ser Tyr Val Pro Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Ser Leu Thr Val Ser Ser
                  115
           <![CDATA[ <210> 269]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 269]]>
          Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
                      20 25 30
          Val Ala Trp Tyr Gln His Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Trp Thr Ser Ser Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
          65 70 75 80
          Glu Asp Leu Ala Asp Tyr Phe Cys His Gln Tyr Ser Asp Tyr Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 270]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 270]]>
          Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Val Gly Arg Pro Gly Ser
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Ile Met His Trp Val Lys Gln Ser Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Val Asp Pro Glu Tyr Gly Ser Thr Asp Tyr Ala Glu Lys Phe
              50 55 60
          Lys Lys Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
          65 70 75 80
          Ile Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys
                          85 90 95
          Ala Arg Asp Asp Gly Ser Tyr Ser Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Val Met Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 271]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 271]]>
          Asp Ile Gln Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Ser Leu Gly
          1 5 10 15
          Asp Lys Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Asn Lys Tyr
                      20 25 30
          Ile Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu Ile
                  35 40 45
          Arg Tyr Thr Ser Thr Leu Glu Ser Gly Thr Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Asn Val Glu Ser
          65 70 75 80
          Glu Asp Ile Ala Ser Tyr Tyr Cys Leu Gln Tyr Val Asn Leu Leu Thr
                          85 90 95
          Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 272]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 272]]>
          Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Met Ser Val Gly
          1 5 10 15
          Glu Arg Val Thr Leu Thr Cys Lys Ala Ser Glu Asn Val Val Thr Tyr
                      20 25 30
          Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ala
          65 70 75 80
          Glu Asp Leu Ala Asp Tyr His Cys Gly Gln Gly Tyr Ser Tyr Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 273]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 273]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Glu Asn Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Asp Arg Gly Gly Ala Val Ser Tyr Phe Asp Val Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 274]]>
           <![CDATA[ <211> 109]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 274]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
                      100 105
           <![CDATA[ <210> 275]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 275]]>
          Ser Tyr Gly Met His
          1 5
           <![CDATA[ <210> 276]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 276]]>
          Val Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 277]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 277]]>
          Gly Gly Ser Met Val Arg Gly Asp Tyr Tyr Tyr Gly Met Asp Val
          1 5 10 15
           <![CDATA[ <210> 278]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 278]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala
          1 5 10
           <![CDATA[ <210> 279]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 279]]>
          Asp Ala Ser Ser Leu Glu Ser
          1 5
           <![CDATA[ <210> 280]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 280]]>
          Gln Gln Phe Asn Ser Tyr Pro Tyr Thr
          1 5
           <![CDATA[ <210> 281]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 281]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Ser Met Val Arg Gly Asp Tyr Tyr Tyr Gly Met Asp
                      100 105 110
          Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 282]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 282]]>
          Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 283]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 283]]>
          Asp Tyr Tyr Trp Asn
          1 5
           <![CDATA[ <210> 284]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 284]]>
          Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 285]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 285]]>
          Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro
          1 5 10
           <![CDATA[ <210> 286]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 286]]>
          Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ala
          1 5 10
           <![CDATA[ <210> 287]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 287]]>
          Asp Ala Ser Asn Arg Ala Thr
          1 5
           <![CDATA[ <210> 288]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 288]]>
          Gln Gln Arg Ser Asn Trp Pro Leu Thr
          1 5
           <![CDATA[ <210> 289]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 289]]>
          Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr
                      20 25 30
          Tyr Trp Asn Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys
              50 55 60
          Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
          65 70 75 80
          Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 290]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 290]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
                          85 90 95
          Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 291]]>
           <![CDATA[ <211> 140]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 291]]>
          Met Ala Val Leu Ala Leu Leu Phe Cys Leu Val Thr Phe Pro Ser Cys
          1 5 10 15
          Ile Leu Ser Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala
                      20 25 30
          Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu
                  35 40 45
          Thr Gly Tyr Gly Ile Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu
              50 55 60
          Glu Trp Leu Gly Met Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ser
          65 70 75 80
          Val Leu Thr Ser Arg Leu Arg Ile Ser Lys Asp Asn Ser Asn Ser Gln
                          85 90 95
          Val Phe Leu Lys Met Asn Ser Leu Gln Val Asp Asp Thr Ala Arg Tyr
                      100 105 110
          Tyr Cys Ala Arg Asp Arg Asn Tyr Tyr Asp Tyr Asp Gly Ala Met Asp
                  115 120 125
          Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
              130 135 140
           <![CDATA[ <210> 292]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 292]]>
          Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
          1 5 10 15
          Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr
                      20 25 30
          Gly Ile Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
                  35 40 45
          Gly Met Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ser Val Leu Thr
              50 55 60
          Ser Arg Leu Arg Ile Ser Lys Asp Asn Ser Asn Ser Gln Val Phe Leu
          65 70 75 80
          Lys Met Asn Ser Leu Gln Val Asp Asp Thr Ala Arg Tyr Tyr Cys Ala
                          85 90 95
          Arg Asp Arg Asn Tyr Tyr Asp Tyr Asp Gly Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Ser Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 293]]>
           <![CDATA[ <211> 127]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 293]]>
          Met Lys Phe Pro Ser Gln Leu Leu Leu Phe Leu Leu Phe Arg Ile Thr
          1 5 10 15
          Gly Ile Ile Cys Asp Ile Gln Val Thr Gln Ser Ser Ser Tyr Leu Ser
                      20 25 30
          Val Ser Leu Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His
                  35 40 45
          Ile Lys Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Ile Ala Pro
              50 55 60
          Arg Leu Leu Val Ser Gly Ala Thr Ser Leu Glu Ala Gly Val Pro Ser
          65 70 75 80
          Arg Phe Ser Gly Ser Gly Ser Gly Lys Asn Phe Thr Leu Ser Ile Thr
                          85 90 95
          Ser Leu Gln Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp
                      100 105 110
          Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Thr Leu Glu Ile Arg
                  115 120 125
           <![CDATA[ <210> 294]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 294]]>
          Asp Ile Gln Val Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Lys Asn Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Ile Ala Pro Arg Leu Leu Val
                  35 40 45
          Ser Gly Ala Thr Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Lys Asn Phe Thr Leu Ser Ile Thr Ser Leu Gln Thr
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Trp
                          85 90 95
          Thr Phe Gly Gly Gly Thr Thr Leu Glu Ile Arg
                      100 105
           <![CDATA[ <210> 295]]>
           <![CDATA[ <211> 126]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 295]]>
          Glu Val Gln Leu Val Gln Pro Gly Ala Glu Leu Arg Asn Ser Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Arg Phe Thr Ser Tyr
                      20 25 30
          Tyr Ile Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asp Pro Glu Asp Gly Gly Thr Lys Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Phe Thr Ala Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Val Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Asn Glu Trp Glu Thr Val Val Val Gly Asp Leu Met Tyr Glu
                      100 105 110
          Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 296]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 296]]>
          Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Leu Ser Ala Ser Leu Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Ser Arg Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Ser Phe Thr Leu Thr Ile Ser Gly Leu Glu Ala
          65 70 75 80
          Glu Asp Ala Gly Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Leu Pro Val
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
                      100 105
           <![CDATA[ <210> 297]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 297]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Val Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Ser Arg Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Ser Phe Thr Leu Thr Ile Ser Gly Leu Glu Ala
          65 70 75 80
          Glu Asp Ala Gly Thr Tyr Tyr Cys Gln Gln Tyr Ala Ser Ala Pro Val
                          85 90 95
          Thr Phe Gly Gln Gly Thr Gly Val Glu Leu Lys
                      100 105
           <![CDATA[ <210> 298]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 298]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Gly Thr Ser Arg Leu Lys Thr Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Ser Phe Thr Leu Thr Ile Ser Gly Leu Glu Ala
          65 70 75 80
          Glu Asp Ala Gly Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Ala Pro Val
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
                      100 105
           <![CDATA[ <210> 299]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 299]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Pro Ser Leu Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Thr Ile Ser Ser Phe
                      20 25 30
          Leu Ala Trp Tyr His Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Arg Ala Ser Ile Pro Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Ser Phe Thr Leu Thr Ile Gly Gly Leu Glu Ala
          65 70 75 80
          Glu Asp Ala Gly Thr Tyr Tyr Cys Gln Gln Tyr Val Ser Ala Pro Pro
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
                      100 105
           <![CDATA[ <210> 300]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 300]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Asn Ile Leu Ile
                  35 40 45
          Tyr Gly Ala Ser Arg Leu Lys Thr Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Ser Phe Thr Leu Thr Ile Ser Gly Leu Glu Ala
          65 70 75 80
          Glu Asp Ala Gly Thr Tyr Tyr Cys Gln Gln Tyr Ala Ser Val Pro Val
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
                      100 105
           <![CDATA[ <210> 301]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 301]]>
          Gly Tyr Ser Phe Ser Thr Tyr Trp
          1 5
           <![CDATA[ <210> 302]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 302]]>
          Ile Tyr Pro Gly Asp Ser Tyr Thr
          1 5
           <![CDATA[ <210> 303]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 303]]>
          Ala Arg Gly Tyr Gly Ile Phe Asp Tyr
          1 5
           <![CDATA[ <210> 304]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 304]]>
          Asn Ile Gly Asp Gln Tyr
          1 5
           <![CDATA[ <210> 305]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 305]]>
          Gln Asp Lys
          1           
           <![CDATA[ <210> 306]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 306]]>
          Ala Thr Tyr Thr Gly Phe Gly Ser Leu Ala Val
          1 5 10
           <![CDATA[ <210> 307]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 307]]>
          Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
                      20 25 30
          Tyr Trp Ser Trp Ile Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Asn His Gly Gly Tyr Val Thr Tyr Asn Pro Ser Leu Glu
              50 55 60
          Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Arg Asp Tyr Gly Pro Gly Asn Tyr Asp Trp Tyr Phe Asp Leu Trp Gly
                      100 105 110
          Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 308]]>
           <![CDATA[ <211> 109]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 308]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
                          85 90 95
          Ala Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 309]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 309]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Asp Ile Lys Asn Asp Gly Ser Tyr Thr Asn Tyr Ala Pro Ser Leu
              50 55 60
          Thr Asn Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Glu Leu Thr Gly Thr Trp Gly Gln Gly Thr Met Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 310]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 310]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Ser Ser
                      20 25 30
          Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
                  35 40 45
          Pro Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Arg Gln Ser Gly Val
              50 55 60
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
          65 70 75 80
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Leu Gln
                          85 90 95
          Tyr Asp Arg Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
                      100 105 110
          Lys
           <![CDATA[ <210> 311]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 311]]>
          Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
          1 5 10 15
          Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Thr Tyr
                      20 25 30
          Trp Ile Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
                  35 40 45
          Gly Lys Ile Tyr Pro Gly Asp Ser Tyr Thr Asn Tyr Ser Pro Ser Phe
              50 55 60
          Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
          65 70 75 80
          Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Tyr Gly Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 312]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 312]]>
          Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
          1 5 10 15
          Thr Ala Ser Ile Thr Cys Ser Gly Asp Asn Ile Gly Asp Gln Tyr Ala
                      20 25 30
          His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
                  35 40 45
          Gln Asp Lys Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
              50 55 60
          Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
          65 70 75 80
          Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Tyr Thr Gly Phe Gly Ser Leu
                          85 90 95
          Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
                      100 105
           <![CDATA[ <210> 313]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 313]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Arg Leu
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Val Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 314]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 314]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Asn Pro His Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Thr Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr His Asp Ala Phe
                      100 105 110
          Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 315]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 315]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Trp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val Trp Val
                  35 40 45
          Ser Asn Ile Asp Glu Asp Gly Ser Ile Thr Glu Tyr Ser Pro Phe Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Arg Trp Gly Arg Phe Gly Phe Asp Ser Trp Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 316]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 316]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Ser Gly
                      20 25 30
          Ser Phe Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Phe Tyr Ala Ser Thr Arg His Thr Gly Val Pro Asp
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
          65 70 75 80
          Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys His His His Tyr
                          85 90 95
          Asn Ala Pro Pro Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
                      100 105 110
           <![CDATA[ <210> 317]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 317]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 318]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 318]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
                      20 25 30
          Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Leu Tyr Asp Gly Ser Asn Lys Tyr Tyr Pro Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Ser Ser Trp Tyr Pro Asp Ser Phe Asp Ile Trp Gly
                      100 105 110
          Gln Gly Thr Met Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 319]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 319]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Val Phe Ser Arg Tyr
                      20 25 30
          Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Asn Pro Asp Ser Ser Ser Thr Ile Asn Tyr Thr Ser Ser Leu
              50 55 60
          Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ser Leu Ile Thr Thr Glu Asp Tyr Trp Gly Gln Gly Thr Thr Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 320]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 320]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Tyr Ala Asn Arg Leu Val Asp Gly Val Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Gln Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
                      100 105
           <![CDATA[ <210> 321]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 321]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
                      20 25 30
          Ser Val Thr Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
                  35 40 45
          Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala
              50 55 60
          Val Ser Val Lys Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn
          65 70 75 80
          Gln Phe Tyr Leu Gln Leu Lys Ser Val Thr Pro Glu Asp Ala Ala Val
                          85 90 95
          Tyr Tyr Cys Ala Arg Asp Ser Ser Ile Leu Tyr Gly Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 322]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 322]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
                      20 25 30
          Ser Val Thr Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
                  35 40 45
          Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala
              50 55 60
          Val Ser Val Lys Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn
          65 70 75 80
          Gln Phe Tyr Leu Gln Leu Lys Ser Val Thr Pro Glu Asp Ala Ala Val
                          85 90 95
          Tyr Tyr Cys Ala Arg Asp Ser Ser Ile Leu Tyr Gly Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser
                  115 120
           <![CDATA[ <210> 323]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 323]]>
          Gln Ala Val Leu Thr Gln Pro Ser Ser Leu Ser Ala Ser Pro Gly Ala
          1 5 10 15
          Ser Ala Ser Leu Thr Cys Thr Leu Pro Ser Gly Ile Asn Val Gly Thr
                      20 25 30
          Tyr Arg Ile Phe Trp Phe Gln Gln Lys Pro Gly Ser Pro Pro Gln Tyr
                  35 40 45
          Leu Leu Ser Tyr Lys Ser Asp Ser Asp Asn His Gln Gly Ser Gly Val
              50 55 60
          Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly Ile
          65 70 75 80
          Leu Leu Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys
                          85 90 95
          Met Ile Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu
                      100 105 110
          Thr Val Leu
                  115
           <![CDATA[ <210> 324]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 324]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Asn Pro Asn Arg Gly Gly Thr Asn Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ala Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Thr Ala Ser Leu Lys Ile Ala Ala Val Gly Thr Phe Asp Cys Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 325]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 325]]>
          Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
          1 5 10 15
          Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Ser Lys Gln Tyr Ala
                      20 25 30
          Phe Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
                  35 40 45
          Gln Asp Thr Lys Arg Pro Ser Gly Ile Pro Gly Arg Phe Ser Gly Ser
              50 55 60
          Ser Ser Gly Thr Thr Val Thr Leu Thr Ile Ser Gly Ala Gln Ala Asp
          65 70 75 80
          Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ala Asp Ser Ser Gly Thr Tyr
                          85 90 95
          Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
                      100 105
           <![CDATA[ <210> 326]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 326]]>
          Glu Val Gln Leu Val Glu Thr Gly Gly Gly Val Val Gln Pro Gly Arg
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Thr His
                      20 25 30
          Gly Met Tyr Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser Asp Lys Lys Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
          65 70 75 80
          Leu Glu Met Ser Ser Val Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
                          85 90 95
          Phe Cys Arg Arg Asp Ala Phe Asp Leu Trp Gly Gln Gly Thr Met Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 327]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 327]]>
          Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
          1 5 10 15
          Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Pro Lys Lys Tyr Ala
                      20 25 30
          Tyr Trp Tyr Gln Gln Lys Ser Gly Gln Ala Pro Val Leu Val Ile Tyr
                  35 40 45
          Glu Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
              50 55 60
          Ser Ser Gly Thr Met Ala Thr Leu Thr Ile Ser Gly Ala Gln Val Glu
          65 70 75 80
          Asp Glu Ala Asp Tyr Tyr Cys Tyr Ser Thr Asp Ser Ser Gly Asn Tyr
                          85 90 95
          Trp Val Phe Gly Gly Gly Thr Glu Val Thr Val Leu
                      100 105
           <![CDATA[ <210> 328]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 328]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Glu Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala
                      20 25 30
          Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Gly Arg Ile Lys Thr Lys Ser Asp Gly Gly Thr Thr Asp Tyr Ala Ala
              50 55 60
          Pro Val Arg Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
          65 70 75 80
          Leu Phe Leu Glu Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr
                          85 90 95
          Tyr Cys Phe Ile Thr Val Ile Val Val Ser Ser Glu Ser Pro Leu Asp
                      100 105 110
          His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 329]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 329]]>
          Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
          1 5 10 15
          Thr Ala Arg Ile Thr Cys Ser Gly Asp Glu Leu Pro Lys Gln Tyr Ala
                      20 25 30
          Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
                  35 40 45
          Lys Asp Arg Gln Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
              50 55 60
          Ser Ser Gly Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu
          65 70 75 80
          Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ala Tyr Ser Ile Asn Thr Tyr
                          85 90 95
          Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
                      100 105
           <![CDATA[ <210> 330]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 330]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Ser Ser Gly Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Val Tyr
          65 70 75 80
          Leu Glu Val Asn Gly Leu Thr Val Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Arg Tyr Gly Asp Arg Glu Met Ala Thr Ile Gly Gly Phe
                      100 105 110
          Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 331]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 331]]>
          Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
          1 5 10 15
          Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Pro Lys Gln Tyr Ala
                      20 25 30
          Tyr Trp Tyr Gln Gln Ser Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
                  35 40 45
          Lys Asp Ser Glu Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
              50 55 60
          Ser Ser Gly Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu
          65 70 75 80
          Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ala Asp Ser Gly Gly Thr Ser
                          85 90 95
          Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
                      100 105
           <![CDATA[ <210> 332]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 332]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Ser Thr Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Leu Val Ser Gly Asp Ser Ile Asn Ser His
                      20 25 30
          Tyr Trp Ser Trp Leu Arg Gln Ser Pro Gly Arg Gly Leu Glu Trp Ile
                  35 40 45
          Gly Tyr Ile Tyr Tyr Thr Gly Pro Thr Asn Tyr Asn Pro Ser Leu Lys
              50 55 60
          Ser Arg Val Ser Ile Ser Leu Gly Thr Ser Lys Asp Gln Phe Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Arg Tyr Tyr Cys Ala
                          85 90 95
          Arg Asn Lys Val Phe Trp Arg Gly Ser Asp Phe Tyr Tyr Tyr Met Asp
                      100 105 110
          Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 333]]>
           <![CDATA[ <211> 110]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 333]]>
          Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Ala Asn Asn
                      20 25 30
          Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
                  35 40 45
          Met Tyr Asp Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
              50 55 60
          Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
          65 70 75 80
          Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Val Thr Ser His
                          85 90 95
          His Met Tyr Ile Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 334]]>
           <![CDATA[ <211> 129]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 334]]>
          His Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asn
                      20 25 30
          Asn Tyr Tyr Trp Gly Trp Ile Arg Gln Thr Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Gly Ala Arg Trp Gln Ala Arg Pro Ala Thr Arg Ile Asp
                      100 105 110
          Gly Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser
                  115 120 125
          Ser
           <![CDATA[ <210> 335]]>
           <![CDATA[ <211> 129]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 335]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asn
                      20 25 30
          Asn Tyr Tyr Trp Gly Trp Ile Arg Gln Thr Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Gly Ala Arg Trp Gln Ala Arg Pro Ala Thr Arg Ile Asp
                      100 105 110
          Gly Val Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser
                  115 120 125
          Ser
           <![CDATA[ <210> 336]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 336]]>
          Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
              50 55 60
          Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Asp Trp Ser Arg Ser Gly Tyr Tyr Leu Pro Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 337]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 337]]>
          Glu Thr Thr Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Thr Arg Asn
                      20 25 30
          Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
                  35 40 45
          Met Tyr Gly Ala Ser Asn Arg Ala Ala Gly Val Pro Asp Arg Phe Ser
              50 55 60
          Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
          65 70 75 80
          Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Gly Ser Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 338]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 338]]>
          Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
          1 5 10 15
          Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
                      20 25 30
          Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln Ser
                  35 40 45
          Pro His Leu Leu Ile Phe Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ala
                          85 90 95
          Leu Gln Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 339]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 339]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
          1 5 10 15
          Ser Arg Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Glu Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Val Asn Ile Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Glu Ala Arg Gly Ser Tyr Ala Phe Asp Ile Trp Gly Gln Gly
                      100 105 110
          Thr Met Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 340]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 340]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
                          85 90 95
          Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
                      100 105
           <![CDATA[ <210> 341]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 341]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Tyr Thr Ser Lys Ile His Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 342]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 342]]>
          Gln Val Gln Leu Gln Gln Ser Gly Gly Glu Leu Ala Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Phe
                      20 25 30
          Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Tyr Ile Asn Pro Arg Ser Gly Tyr Thr Glu Tyr Asn Glu Ile Phe
              50 55 60
          Arg Asp Lys Ala Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ser Phe Leu Gly Arg Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 343]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 343]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
                      20 25 30
          Val Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Asn Gly Leu Glu
                  35 40 45
          Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Lys Gln Phe
          65 70 75 80
          Ser Leu Asn Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Glu Gly Pro Leu Arg Gly Asp Tyr Tyr Tyr Gly Leu Asp
                      100 105 110
          Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 344]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 344]]>
          Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Gly Gln Thr Ile Ser Ser Arg
                      20 25 30
          Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu
                  35 40 45
          Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
              50 55 60
          Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
          65 70 75 80
          Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
                          85 90 95
          Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 345]]>
           <![CDATA[ <211> 128]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 345]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr
                          85 90 95
          Cys Ala Arg Tyr Arg Gly Pro Ala Ala Gly Arg Gly Asp Phe Tyr Tyr
                      100 105 110
          Phe Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 346]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 346]]>
          Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
          1 5 10 15
          Gln Pro Ala Ser Ile Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
                      20 25 30
          Asp Gly Lys Thr Tyr Leu Cys Trp Tyr Leu Gln Lys Pro Gly Gln Pro
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
                          85 90 95
          Ile Gln Leu Pro Trp Ala Phe Phe Gly Gln Gly Thr Lys Val Glu Ile
                      100 105 110
          Lys
           <![CDATA[ <210> 347]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 347]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Trp Tyr Gly Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Asp Leu Ala Ala Arg Arg Gly Asp Tyr Tyr Tyr Tyr Gly Met
                      100 105 110
          Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 348]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 348]]>
          Ser Ser Glu Leu Thr Gln Asp Pro Val Val Ser Val Ala Leu Gly Gln
          1 5 10 15
          Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Leu
                      20 25 30
          Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
                  35 40 45
          Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
              50 55 60
          Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
          65 70 75 80
          Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
                          85 90 95
          Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
                      100 105
           <![CDATA[ <210> 349]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 349]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Arg Thr Tyr Asn Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Val Ala Thr Gly Arg Ala Asp Tyr His Phe Tyr Ala Met
                      100 105 110
          Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 350]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 350]]>
          Ser Tyr Glu Leu Thr Gln Pro Ser Ser Val Ser Val Ser Pro Gly Gln
          1 5 10 15
          Thr Ala Arg Ile Thr Cys Ser Gly Asp Val Leu Ala Lys Lys Ser Ala
                      20 25 30
          Arg Trp Phe His Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
                  35 40 45
          Lys Asp Ser Glu Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
              50 55 60
          Ser Ser Gly Thr Thr Val Thr Leu Thr Ile Ser Gly Ala Gln Val Glu
          65 70 75 80
          Asp Glu Ala Ala Tyr Tyr Cys Tyr Ser Ala Ala Asp Asn Asn Leu Val
                          85 90 95
          Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
                      100 105
           <![CDATA[ <210> 351]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <222> (3)..(3)]]>
           <![CDATA[ <223> Xaa can be any naturally occurring amino acid]]>
           <![CDATA[ <400> 351]]>
          Leu Pro Xaa Thr Gly
          1 5
           <![CDATA[ <210> 352]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 352]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 353]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 353]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 354]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 354]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 355]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 355]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 356]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 356]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Phe His Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 357]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 357]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 358]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 358]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Glu Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 359]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 359]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Tyr
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 360]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 360]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 361]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 361]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 362]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 362]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 363]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 363]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 364]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 364]]>
          Gly Tyr Tyr Met His
          1 5
           <![CDATA[ <210> 365]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 365]]>
          Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 366]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 366]]>
          Val Asn Phe Tyr Tyr
          1 5
           <![CDATA[ <210> 367]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 367]]>
          Lys Ala Ser Gln Val Ile Asn Ser Tyr Leu Ser
          1 5 10
           <![CDATA[ <210> 368]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 368]]>
          Arg Ala Asn Thr Leu Val Asp
          1 5
           <![CDATA[ <210> 369]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 369]]>
          Leu Gln Tyr Ala Glu Phe Pro Tyr Thr
          1 5
           <![CDATA[ <210> 370]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 370]]>
          Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 371]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 371]]>
          Ser Tyr Thr Met His
          1 5
           <![CDATA[ <210> 372]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 372]]>
          Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 373]]>
           <![CDATA[ <211> 4]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 373]]>
          Lys Phe Asp Tyr
          1               
           <![CDATA[ <210> 374]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 374]]>
          Lys Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser
          1 5 10
           <![CDATA[ <210> 375]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 375]]>
          Arg Ala Asn Arg Leu Val Asp
          1 5
           <![CDATA[ <210> 376]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 376]]>
          Leu Gln Tyr Asp Glu Phe Pro Phe Thr
          1 5
           <![CDATA[ <210> 377]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 377]]>
          Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 378]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 378]]>
          Arg Ala Asn Thr Leu Val Ser
          1 5
           <![CDATA[ <210> 379]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 379]]>
          Arg Ala Asn Thr Leu Val Glu
          1 5
           <![CDATA[ <210> 380]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 380]]>
          Arg Ala Asn Arg Leu Val Glu
          1 5
           <![CDATA[ <210> 381]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 381]]>
          Ser Tyr Trp Ile Asn
          1 5
           <![CDATA[ <210> 382]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 382]]>
          Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 383]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 383]]>
          Lys Pro Asn Phe Asp Val
          1 5
           <![CDATA[ <210> 384]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 384]]>
          Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala
          1 5 10
           <![CDATA[ <210> 385]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 385]]>
          Ser Ala Ser Tyr Arg Phe Ser
          1 5
           <![CDATA[ <210> 386]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 386]]>
          Gln Gln Tyr Asn Ser Tyr Pro Leu Thr
          1 5
           <![CDATA[ <210> 387]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 387]]>
          Ser Asp Tyr Ala Trp Asn
          1 5
           <![CDATA[ <210> 388]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 388]]>
          Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 389]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 389]]>
          Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 390]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 390]]>
          Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala
          1 5 10
           <![CDATA[ <210> 391]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 391]]>
          Ala Ala Thr Asn Leu Ala Asp
          1 5
           <![CDATA[ <210> 392]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 392]]>
          Ala Ala Thr Asn Leu Ala Ser
          1 5
           <![CDATA[ <210> 393]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 393]]>
          Ala Ala Thr Asn Leu Ala Glu
          1 5
           <![CDATA[ <210> 394]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 394]]>
          Gln His Phe Trp Gly Thr Pro Pro Trp Thr
          1 5 10
           <![CDATA[ <210> 395]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 395]]>
          Ser Asp Tyr Ala Trp Asn
          1 5
           <![CDATA[ <210> 396]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 396]]>
          Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 397]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 397]]>
          Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
          1 5 10
           <![CDATA[ <210> 398]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 398]]>
          Arg Ala Ser Glu Asn Ile Tyr Ser Tyr Leu Ala
          1 5 10
           <![CDATA[ <210> 399]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 399]]>
          Asn Ala Lys Thr Leu Ala Glu
          1 5
           <![CDATA[ <210> 400]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 400]]>
          Gln His His Tyr Gly Thr Pro Leu Thr
          1 5
           <![CDATA[ <210> 401]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 401]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 402]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 402]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 403]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 403]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 404]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 404]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Glu Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 405]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 405]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Tyr
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 406]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 406]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 407]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 407]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 408]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 408]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 409]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 409]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Val Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Thr Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Glu Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 410]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 410]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 411]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 411]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 412]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 412]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 413]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 413]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 414]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 414]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 415]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 415]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 416]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 416]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 417]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 417]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 418]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 418]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 419]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 419]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 420]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 420]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 421]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 421]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 422]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 422]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 423]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 423]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 424]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 424]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 425]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 425]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 426]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 426]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 427]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 427]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 428]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 428]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 429]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 429]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 430]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 430]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 431]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 431]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 432]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 432]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 433]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 433]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 434]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 434]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 435]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 435]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 436]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 436]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 437]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 437]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 438]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 438]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 439]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 439]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 440]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 440]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 441]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 441]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Gln Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 442]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 442]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 443]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 443]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 444]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 444]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 445]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 445]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 446]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 446]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 447]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 447]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 448]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 448]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 449]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 449]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 450]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 450]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 451]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 451]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 452]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 452]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 453]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 453]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 454]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 454]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 455]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 455]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 456]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 456]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 457]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 457]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 458]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 458]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 459]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 459]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 460]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 460]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Phe His Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 461]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 461]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
                      20 25 30
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asn Pro Asn Asn Gly Ala Thr Asn Tyr Asn Gln Asn Phe
              50 55 60
          Lys Asp Lys Ala Ser Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ser Val Asn Phe Tyr Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
                      100 105 110
          Ser Ser
           <![CDATA[ <210> 462]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 462]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 463]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 463]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 464]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 464]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 465]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 465]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
                      20 25 30
          Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile
                  35 40 45
          Tyr Arg Ala Asn Arg Leu Val Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 466]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 466]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 467]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 467]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 468]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 468]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 469]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 469]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Lys Thr Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 470]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 470]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
              50 55 60
          Lys Asp Arg Val Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 471]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 471]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 472]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 472]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 473]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 473]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 474]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 474]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 475]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 475]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Val Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 476]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 476]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Val Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Ser Arg Leu Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 477]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 477]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Val Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Leu Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 478]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 478]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 479]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 479]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 480]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 480]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 481]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 481]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 482]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 482]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Ile Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 483]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 483]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 484]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 484]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 485]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 485]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Ile Gln Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 486]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 486]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Lys Ala Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 487]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 487]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 488]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 488]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 489]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 489]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 490]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 490]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Met Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Ile Gln Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Lys Pro Asn Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 491]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 491]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 492]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 492]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 493]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 493]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 494]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 494]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
                          85 90 95
          Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 495]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 495]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 496]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 496]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 497]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 497]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 498]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 498]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 499]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 499]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 500]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 500]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 501]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 501]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 502]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 502]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 503]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 503]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 504]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 504]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 505]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 505]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 506]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 506]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 507]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 507]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 508]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 508]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 509]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 509]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 510]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 510]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 511]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 511]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 512]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 512]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 513]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 513]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Ser Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 514]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 514]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Val Thr Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 515]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 515]]>
          Gly Tyr Ser Phe Thr Gly Tyr
          1 5
           <![CDATA[ <210> 516]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 516]]>
          Gly Tyr Ser Phe Thr Gly Tyr Tyr Met His
          1 5 10
           <![CDATA[ <210> 517]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 517]]>
          Thr Gly Tyr Tyr Met His
          1 5
           <![CDATA[ <210> 518]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 518]]>
          Gly Tyr Ser Phe Thr Gly Tyr Tyr
          1 5
           <![CDATA[ <210> 519]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 519]]>
          Asn Pro Asn Asn Ala Ala
          1 5
           <![CDATA[ <210> 520]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 520]]>
          Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn
          1 5 10
           <![CDATA[ <210> 521]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 521]]>
          Trp Met Gly Arg Ile Asn Pro Asn Asn Ala Ala Thr Asn
          1 5 10
           <![CDATA[ <210> 522]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 522]]>
          Ile Asn Pro Asn Asn Ala Ala Thr
          1 5
           <![CDATA[ <210> 523]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 523]]>
          Thr Ser Val Asn Phe Tyr
          1 5
           <![CDATA[ <210> 524]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 524]]>
          Thr Ser Val Asn Phe Tyr Tyr
          1 5
           <![CDATA[ <210> 525]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 525]]>
          Asn Ser Tyr Leu Ser Trp Phe
          1 5
           <![CDATA[ <210> 526]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 526]]>
          Gln Val Ile Asn Ser Tyr
          1 5
           <![CDATA[ <210> 527]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 527]]>
          Ser Leu Ile Tyr Arg Ala Asn Thr Leu Val
          1 5 10
           <![CDATA[ <210> 528]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 528]]>
          Leu Gln Tyr Ala Glu Phe Pro Tyr
          1 5
           <![CDATA[ <210> 529]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 529]]>
          Gly Tyr Thr Phe Thr Ser Tyr
          1 5
           <![CDATA[ <210> 530]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 530]]>
          Gly Tyr Thr Phe Thr Ser Tyr Thr Met His
          1 5 10
           <![CDATA[ <210> 531]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 531]]>
          Thr Ser Tyr Thr Met His
          1 5
           <![CDATA[ <210> 532]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 532]]>
          Gly Tyr Thr Phe Thr Ser Tyr Thr
          1 5
           <![CDATA[ <210> 533]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 533]]>
          Ser Pro Ser Ser Gly Tyr
          1 5
           <![CDATA[ <210> 534]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 534]]>
          Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu
          1 5 10
           <![CDATA[ <210> 535]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 535]]>
          Trp Met Gly Tyr Ile Ser Pro Ser Ser Gly Tyr Thr Glu
          1 5 10
           <![CDATA[ <210> 536]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 536]]>
          Ile Ser Pro Ser Ser Gly Tyr Thr
          1 5
           <![CDATA[ <210> 537]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 537]]>
          Ala Arg Lys Phe Asp
          1 5
           <![CDATA[ <210> 538]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 538]]>
          Ala Arg Lys Phe Asp Tyr
          1 5
           <![CDATA[ <210> 539]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 539]]>
          Gln Asp Ile Asn Ser Tyr
          1 5
           <![CDATA[ <210> 540]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 540]]>
          Ser Leu Ile Tyr Arg Ala Asn Arg Leu Val
          1 5 10
           <![CDATA[ <210> 541]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 541]]>
          Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val
          1 5 10
           <![CDATA[ <210> 542]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 542]]>
          Leu Gln Tyr Asp Glu Phe Pro Phe
          1 5
           <![CDATA[ <210> 543]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 543]]>
          Gly Gly Ser Ile Ser Ser Asp Tyr
          1 5
           <![CDATA[ <210> 544]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 544]]>
          Gly Gly Ser Ile Ser Ser Asp Tyr Ala Trp Asn
          1 5 10
           <![CDATA[ <210> 545]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 545]]>
          Ser Ser Asp Tyr Ala Trp Asn
          1 5
           <![CDATA[ <210> 546]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 546]]>
          Gly Gly Ser Ile Ser Ser Asp Tyr Ala
          1 5
           <![CDATA[ <210> 547]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 547]]>
          Ser Tyr Arg Gly Ser
          1 5
           <![CDATA[ <210> 548]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 548]]>
          Tyr Arg Ser Tyr Arg Gly Ser Thr Ser
          1 5
           <![CDATA[ <210> 549]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 549]]>
          Trp Ile Gly Tyr Arg Ser Tyr Arg Gly Ser Thr Ser
          1 5 10
           <![CDATA[ <210> 550]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 550]]>
          Arg Ser Tyr Arg Gly Ser Thr
          1 5
           <![CDATA[ <210> 551]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 551]]>
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp
          1 5 10 15
           <![CDATA[ <210> 552]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 552]]>
          Ala Arg Arg Gly Tyr Tyr Gly Ser Ser Ser His Trp Tyr Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 553]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 553]]>
          Tyr Ser Tyr Leu Ala Trp Tyr
          1 5
           <![CDATA[ <210> 554]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 554]]>
          Glu Asn Ile Tyr Ser Tyr
          1 5
           <![CDATA[ <210> 555]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 555]]>
          Leu Leu Ile Tyr Asn Ala Lys Thr Leu Ala
          1 5 10
           <![CDATA[ <210> 556]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 556]]>
          Gln His His Tyr Gly Thr Pro Leu
          1 5
           <![CDATA[ <210> 557]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 557]]>
          Ser Tyr Ser Gly Ser
          1 5
           <![CDATA[ <210> 558]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 558]]>
          Tyr Ile Ser Tyr Ser Gly Ser Thr Arg
          1 5
           <![CDATA[ <210> 559]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 559]]>
          Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg
          1 5 10
           <![CDATA[ <210> 560]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 560]]>
          Ile Ser Tyr Ser Gly Ser Thr
          1 5
           <![CDATA[ <210> 561]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 561]]>
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp
          1 5 10
           <![CDATA[ <210> 562]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 562]]>
          Ala Arg Arg Tyr Arg Tyr Asp Glu Gly Tyr Gly Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 563]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 563]]>
          Tyr Ser Asn Leu Ala Trp Tyr
          1 5
           <![CDATA[ <210> 564]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 564]]>
          Glu Asn Ile Tyr Ser Asn
          1 5
           <![CDATA[ <210> 565]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 565]]>
          Leu Leu Ile Tyr Ala Ala Thr Asn Leu Ala
          1 5 10
           <![CDATA[ <210> 566]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 566]]>
          Gln His Phe Trp Gly Thr Pro Pro Trp
          1 5
           <![CDATA[ <210> 567]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 567]]>
          Gly Tyr Thr Phe Thr Ser Tyr Trp Ile Asn
          1 5 10
           <![CDATA[ <210> 568]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 568]]>
          Thr Ser Tyr Trp Ile Asn
          1 5
           <![CDATA[ <210> 569]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 569]]>
          Gly Tyr Thr Phe Thr Ser Tyr Trp
          1 5
           <![CDATA[ <210> 570]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 570]]>
          Val Pro Gly Ser Gly Ser
          1 5
           <![CDATA[ <210> 571]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 571]]>
          Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr
          1 5 10
           <![CDATA[ <210> 572]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 572]]>
          Trp Met Gly Arg Ile Val Pro Gly Ser Gly Ser Thr Tyr
          1 5 10
           <![CDATA[ <210> 573]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 573]]>
          Ile Val Pro Gly Ser Gly Ser Thr
          1 5
           <![CDATA[ <210> 574]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 574]]>
          Ala Arg Lys Pro Asn Phe Asp
          1 5
           <![CDATA[ <210> 575]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 575]]>
          Ala Arg Lys Pro Asn Phe Asp Val
          1 5
           <![CDATA[ <210> 576]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 576]]>
          Gly Thr Asn Val Ala Trp Tyr
          1 5
           <![CDATA[ <210> 577]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 577]]>
          Gln Asn Val Gly Thr Asn
          1 5
           <![CDATA[ <210> 578]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 578]]>
          Ala Val Ile Tyr Ser Ala Ser Tyr Arg Phe
          1 5 10
           <![CDATA[ <210> 579]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 579]]>
          Gln Gln Tyr Asn Ser Tyr Pro Leu
          1 5
           <![CDATA[ <210> 580]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 580]]>
          Ser Phe Val Ile His
          1 5
           <![CDATA[ <210> 581]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 581]]>
          Asp Tyr Tyr Ile Asn
          1 5
           <![CDATA[ <210> 582]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 582]]>
          Asn Tyr Trp Ile Gly
          1 5
           <![CDATA[ <210> 583]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 583]]>
          Asp Tyr Tyr Met Asn
          1 5
           <![CDATA[ <210> 584]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 584]]>
          Thr Tyr Asp Ile Asn
          1 5
           <![CDATA[ <210> 585]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 585]]>
          Asp His Tyr Met Glu
          1 5
           <![CDATA[ <210> 586]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 586]]>
          Asp Tyr Tyr Met Asp
          1 5
           <![CDATA[ <210> 587]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 587]]>
          Tyr Ser Trp Ile His
          1 5
           <![CDATA[ <210> 588]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 588]]>
          Ser Tyr Trp Met His
          1 5
           <![CDATA[ <210> 589]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 589]]>
          Asp Tyr Gly Met Ala
          1 5
           <![CDATA[ <210> 590]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 590]]>
          Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
          1 5 10 15
           <![CDATA[ <210> 591]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 591]]>
          Tyr Ile Tyr Asn Glu Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
          1 5 10 15
           <![CDATA[ <210> 592]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 592]]>
          Tyr Ile Tyr Asn Gln Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
          1 5 10 15
           <![CDATA[ <210> 593]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 593]]>
          Tyr Ile Tyr Asn Ser Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
          1 5 10 15
           <![CDATA[ <210> 594]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 594]]>
          Tyr Ile Tyr Asn Asp Ala Thr Lys Tyr Asn Glu Arg Phe Arg Gly
          1 5 10 15
           <![CDATA[ <210> 595]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 595]]>
          Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 596]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 596]]>
          Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ser Gln Lys Phe Gln
          1 5 10 15
          Gly
           <![CDATA[ <210> 597]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 597]]>
          Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ala Gln Lys Phe Gln
          1 5 10 15
          Gly
           <![CDATA[ <210> 598]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 598]]>
          Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 599]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 599]]>
          Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe Arg
          1 5 10 15
          Gly
           <![CDATA[ <210> 600]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 600]]>
          Arg Val Ser Pro Ser Gln Gly Gly Thr Asn Tyr Asn Gln Lys Phe Arg
          1 5 10 15
          Gly
           <![CDATA[ <210> 601]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 601]]>
          Arg Val Ser Pro Ser Ser Gly Gly Thr Asn Tyr Asn Gln Lys Phe Arg
          1 5 10 15
          Gly
           <![CDATA[ <210> 602]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 602]]>
          Arg Val Ser Pro Ser Asn Ala Gly Thr Asn Tyr Asn Gln Lys Phe Arg
          1 5 10 15
          Gly
           <![CDATA[ <210> 603]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 603]]>
          Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Arg Gly
          1 5 10 15
           <![CDATA[ <210> 604]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 604]]>
          Trp Ile Phe Pro Gly Asp Val Thr Thr Lys Tyr Asn Glu Lys Phe Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 605]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 605]]>
          Trp Ile Tyr Pro Gly Ser Gly Asn Ser Lys Tyr Asn Glu Ile Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 606]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 606]]>
          Ser Ile Tyr Pro Asn His Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 607]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 607]]>
          Asp Ile His Pro Asn Thr Gly Gly Asn Ser Asn Asn Gln Lys Phe Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 608]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 608]]>
          Glu Ile Asn Pro Asn Asn Gly Phe Thr Asn Tyr Asn Glu Lys Phe Lys
          1 5 10 15
          Ser
           <![CDATA[ <210> 609]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 609]]>
          Glu Ile Asn Pro Gly Asn Gly Asp Thr Tyr Tyr Asn Glu Lys Phe Lys
          1 5 10 15
          Ser
           <![CDATA[ <210> 610]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 610]]>
          Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val Thr
          1 5 10 15
          Gly
           <![CDATA[ <210> 611]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 611]]>
          Asp Tyr Tyr Phe Asp Tyr
          1 5
           <![CDATA[ <210> 612]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 612]]>
          Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr
          1 5
           <![CDATA[ <210> 613]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 613]]>
          Ser Gly Gly Met Tyr Tyr Phe Asp Tyr
          1 5
           <![CDATA[ <210> 614]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 614]]>
          Ser Gly Gly Leu Tyr Tyr Phe Asp Tyr
          1 5
           <![CDATA[ <210> 615]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 615]]>
          Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 616]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 616]]>
          Asp Phe Tyr Phe Asp Tyr
          1 5
           <![CDATA[ <210> 617]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 617]]>
          Ala Gly Tyr Gly Tyr Val Arg Tyr Ser Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 618]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 618]]>
          Trp Asp Tyr Gly Ala Tyr Phe Pro Tyr
          1 5
           <![CDATA[ <210> 619]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 619]]>
          Gly Tyr Tyr Gly Tyr Asp Gly Phe Phe Asp Phe
          1 5 10
           <![CDATA[ <210> 620]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 620]]>
          Gly Tyr Tyr Gly Tyr Asp Gly Phe Phe Asp Tyr
          1 5 10
           <![CDATA[ <210> 621]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 621]]>
          Trp Gly Tyr Gly Ala Trp Phe Ala Tyr
          1 5
           <![CDATA[ <210> 622]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 622]]>
          Gly Ala Tyr Tyr Ala Met Asp Tyr
          1 5
           <![CDATA[ <210> 623]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 623]]>
          Trp Tyr Asp Asn Tyr Ile Asp Tyr
          1 5
           <![CDATA[ <210> 624]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 624]]>
          His Gly Tyr Tyr Gly Ser Ser Tyr Asp Tyr
          1 5 10
           <![CDATA[ <210> 625]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 625]]>
          Arg Ala Ser Glu Ser Val Asp Tyr Tyr Gly Ile Ser Phe Met Asn
          1 5 10 15
           <![CDATA[ <210> 626]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 626]]>
          Lys Ala Ser Gln Asn Val Gly Ile Asn Val Ala
          1 5 10
           <![CDATA[ <210> 627]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 627]]>
          Lys Ala Ser Gln Lys Val Gly Ile Lys Val Ala
          1 5 10
           <![CDATA[ <210> 628]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 628]]>
          Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu
          1 5 10 15
          Ala
           <![CDATA[ <210> 629]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 629]]>
          Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Leu Met Tyr
          1 5 10 15
           <![CDATA[ <210> 630]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 630]]>
          Arg Val Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Met His
          1 5 10 15
           <![CDATA[ <210> 631]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 631]]>
          Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala
          1 5 10
           <![CDATA[ <210> 632]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 632]]>
          Lys Ser Ser Gln Ser Leu Leu Tyr Ser Asn Gly Lys Thr Tyr Leu Asn
          1 5 10 15
           <![CDATA[ <210> 633]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 633]]>
          Lys Pro Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn
          1 5 10 15
           <![CDATA[ <210> 634]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 634]]>
          Lys Ala Ser Gln Asp Val Asn Thr Ala Val Ala
          1 5 10
           <![CDATA[ <210> 635]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 635]]>
          Lys Ser Ser Gln Ser Leu Leu Asn Ser Asp Gly Lys Thr Tyr Phe Asn
          1 5 10 15
           <![CDATA[ <210> 636]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 636]]>
          Ala Ala Ser Asn Gln Gly Ser
          1 5
           <![CDATA[ <210> 637]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 637]]>
          Ser Ala Ser Tyr Arg Ser Ser
          1 5
           <![CDATA[ <210> 638]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 638]]>
          Trp Ala Ser Thr Arg Glu Ser
          1 5
           <![CDATA[ <210> 639]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 639]]>
          Leu Ala Ser Asn Leu Glu Ser
          1 5
           <![CDATA[ <210> 640]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 640]]>
          Ser Ala Ser Tyr Arg Tyr Ser
          1 5
           <![CDATA[ <210> 641]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 641]]>
          Leu Val Ser Lys Leu Asp Ser
          1 5
           <![CDATA[ <210> 642]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 642]]>
          Trp Ala Ser Ser Arg His Thr
          1 5
           <![CDATA[ <210> 643]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 643]]>
          Gln Val Ser Lys Leu Asp Pro
          1 5
           <![CDATA[ <210> 644]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 644]]>
          Gln Gln Ser Lys Glu Val Pro Tyr Thr
          1 5
           <![CDATA[ <210> 645]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 645]]>
          Gln Gln Tyr Asn Ser Phe Pro Tyr Thr
          1 5
           <![CDATA[ <210> 646]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 646]]>
          Gln Gln Tyr Ser Ser Phe Pro Tyr Thr
          1 5
           <![CDATA[ <210> 647]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 647]]>
          Gln Gln Tyr Gln Ser Phe Pro Tyr Thr
          1 5
           <![CDATA[ <210> 648]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 648]]>
          Gln Gln Tyr Asn Ala Phe Pro Tyr Thr
          1 5
           <![CDATA[ <210> 649]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 649]]>
          Gln Gln Tyr Lys Ser Phe Pro Tyr Thr
          1 5
           <![CDATA[ <210> 650]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 650]]>
          Gln Gln Tyr Tyr Tyr Tyr Pro Leu Thr
          1 5
           <![CDATA[ <210> 651]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 651]]>
          Gln Gln Asn Asn Glu Asp Pro Leu Thr
          1 5
           <![CDATA[ <210> 652]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 652]]>
          Gln Gln Asn Asn Glu Asp Pro Trp Thr
          1 5
           <![CDATA[ <210> 653]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 653]]>
          His Gln Tyr Asn Ser Phe Pro Tyr Thr
          1 5
           <![CDATA[ <210> 654]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 654]]>
          Val Gln Gly Thr His Phe Pro Tyr Thr
          1 5
           <![CDATA[ <210> 655]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 655]]>
          Trp Gln Gly Thr His Phe Pro Arg Thr
          1 5
           <![CDATA[ <210> 656]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 656]]>
          His Gln Tyr Ser Thr Ser Pro Tyr Thr
          1 5
           <![CDATA[ <210> 657]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 657]]>
          Leu Gln Gly Thr Tyr Phe Pro His Thr
          1 5
           <![CDATA[ <210> 658]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (27)..(27)]]>
           <![CDATA[ <223> X is G or Y]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (28)..(28)]]>
           <![CDATA[ <223> X is T or S]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (30)..(30)]]>
           <![CDATA[ <223> X is S or T]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (56)..(56)]]>
           <![CDATA[ <223> X is G or A]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (67)..(67)]]>
           <![CDATA[ <223> X is R or K]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (68)..(68)]]>
           <![CDATA[ <223> X is V or A]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (70)..(70)]]>
           <![CDATA[ <223> X is I or L]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (72)..(72)]]>
           <![CDATA[ <223> X is A or V]]>
           <![CDATA[ <400> 658]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Xaa Xaa Phe Xaa Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Xaa Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Xaa Xaa Thr Xaa Thr Xaa Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 659]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (1)..(1)]]>
           <![CDATA[ <223> X is E or D]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> VARIANT]]>
           <![CDATA[ <222> (45)..(45)]]>
           <![CDATA[ <223> X is L or R]]>
           <![CDATA[ <400> 659]]>
          Xaa Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
                      20 25 30
          His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Xaa Leu Ile Tyr
                  35 40 45
          Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
              50 55 60
          Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
          65 70 75 80
          Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr
                          85 90 95
          Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 660]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 660]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Ala Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 661]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 661]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 662]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 662]]>
          Gly Tyr Thr Met Asn
          1 5
           <![CDATA[ <210> 663]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 663]]>
          Leu Ile Thr Pro Tyr Asn Ala Ala Ser Ser Tyr Asn Gln Lys Phe Arg
          1 5 10 15
          Gly
           <![CDATA[ <210> 664]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 664]]>
          Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe Arg
          1 5 10 15
          Gly
           <![CDATA[ <210> 665]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 665]]>
          Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr
          1 5 10
           <![CDATA[ <210> 666]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 666]]>
          Ser Ala Ser Ser Ser Ser Val Ser Tyr Met His
          1 5 10
           <![CDATA[ <210> 667]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 667]]>
          Asp Thr Ser Lys Leu Ala Ser
          1 5
           <![CDATA[ <210> 668]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 668]]>
          Gln Gln Trp Ser Lys His Pro Leu Thr
          1 5
           <![CDATA[ <210> 669]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 669]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 670]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 670]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 671]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 671]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 672]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 672]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 673]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 673]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 674]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 674]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Ala Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 675]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 675]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
                      20 25 30
          His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
                  35 40 45
          Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
              50 55 60
          Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
          65 70 75 80
          Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr
                          85 90 95
          Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 676]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 676]]>
          Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
                      20 25 30
          His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
                  35 40 45
          Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
              50 55 60
          Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
          65 70 75 80
          Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr
                          85 90 95
          Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 677]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 677]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
                      20 25 30
          His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Arg Leu Ile Tyr
                  35 40 45
          Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
              50 55 60
          Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
          65 70 75 80
          Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr
                          85 90 95
          Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 678]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 678]]>
          Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
                      20 25 30
          His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Arg Leu Ile Tyr
                  35 40 45
          Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
              50 55 60
          Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
          65 70 75 80
          Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr
                          85 90 95
          Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 679]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 679]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
                      20 25 30
          His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
                  35 40 45
          Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
              50 55 60
          Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
          65 70 75 80
          Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr
                          85 90 95
          Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 680]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 680]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Ser Gly
                      100 105 110
          Thr Pro Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 681]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 681]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
                      20 25 30
          Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Leu Ile Thr Pro Tyr Asn Ala Ala Ser Ser Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Ser Gly
                      100 105 110
          Thr Pro Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 682]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 682]]>
          Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
          1 5 10 15
          Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
                      20 25 30
          His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
                  35 40 45
          Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser
              50 55 60
          Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu
          65 70 75 80
          Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr
                          85 90 95
          Phe Gly Ser Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 683]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 683]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Lys Gln Met Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
          65 70 75 80
          Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 684]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 684]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Phe Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 685]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 685]]>
          Gln Val Gln Met Lys Glu Ser Gly Thr Glu Leu Val Arg Pro Gly Thr
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ala Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Lys Gln Arg Pro Gly His Gly Pro Glu Trp Ile
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Thr Ile Tyr Phe Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Leu Thr Val Ser Ser
                  115
           <![CDATA[ <210> 686]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 686]]>
          Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Leu Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Ser Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 687]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 687]]>
          Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Lys Gln Met Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ala Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
          65 70 75 80
          Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 688]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 688]]>
          Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val
          1 5 10 15
          Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr Asp Ile
                      20 25 30
          Asn Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Trp
                  35 40 45
          Ile Phe Pro Gly Asp Val Thr Thr Lys Tyr Asn Glu Lys Phe Lys Gly
              50 55 60
          Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met His
          65 70 75 80
          Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg
                          85 90 95
          Ala Gly Tyr Gly Tyr Val Arg Tyr Ser Met Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Ser Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 689]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 689]]>
          Gln Val Gln Met Lys Glu Ser Gly Pro Glu Leu Ala Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Ser Lys Tyr Asn Glu Ile Phe
              50 55 60
          Lys Asp Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Thr Lys Trp Asp Tyr Gly Ala Tyr Phe Pro Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 690]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 690]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Asp
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His
                      20 25 30
          Tyr Met Glu Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Ser Ile Tyr Pro Asn His Gly Gly Thr Ser Tyr Asn Gln Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
          65 70 75 80
          Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Tyr Tyr Gly Tyr Asp Gly Phe Phe Asp Phe Trp Gly Gln
                      100 105 110
          Gly Thr Thr Leu Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 691]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 691]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Asp
          1 5 10 15
          Ser Val Lys Met Ser Cys Glu Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Pro Glu Trp Ile
                  35 40 45
          Gly Asp Ile His Pro Asn Thr Gly Gly Asn Ser Asn Asn Gln Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Gly Thr Ala Tyr
          65 70 75 80
          Met Glu Leu His Ser Val Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Tyr Tyr Gly Tyr Asp Gly Phe Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Thr Leu Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 692]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 692]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Thr Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Thr Lys Trp Gly Tyr Gly Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 693]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 693]]>
          Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Ser
                      20 25 30
          Trp Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Asn Pro Asn Asn Gly Phe Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ile Gly Ala Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 694]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 694]]>
          Glu Val Gln Leu Gln Gln Ser Gly Thr Lys Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Asn Pro Gly Asn Gly Asp Thr Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Ser
                          85 90 95
          Thr Ile Trp Tyr Asp Asn Tyr Ile Asp Tyr Trp Gly Gln Gly Thr Thr
                      100 105 110
          Leu Thr Val Ser Ser
                  115
           <![CDATA[ <210> 695]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 695]]>
          Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
          1 5 10 15
          Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ala Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
              50 55 60
          Thr Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
                          85 90 95
          Ala Arg His Gly Tyr Tyr Gly Ser Ser Tyr Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Leu Thr Val Ser Ser
                  115
           <![CDATA[ <210> 696]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 696]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 697]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 697]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 698]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 698]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 699]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 699]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 700]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 700]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Val Thr Met Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 701]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 701]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 702]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 702]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Glu Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 703]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 703]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Gln Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 704]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 704]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Ser Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 705]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 705]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Ala Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser
           <![CDATA[ <210> 706]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 706]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 707]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 707]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 708]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 708]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 709]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 709]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ser Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 710]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 710]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 711]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 711]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 712]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 712]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 713]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 713]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 714]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 714]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 715]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 715]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 716]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 716]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 717]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 717]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 718]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 718]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 719]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 719]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 720]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 720]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 721]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 721]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 722]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 722]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 723]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 723]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Gln Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 724]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 724]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Ser Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 725]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 725]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Ala Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 726]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 726]]>
          Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Tyr Tyr
                      20 25 30
          Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
          65 70 75 80
          Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
                          85 90 95
          Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 727]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 727]]>
          Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Asp Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
          65 70 75 80
          Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 728]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 728]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
          1 5 10 15
          Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
                      20 25 30
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
                  35 40 45
          Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
              50 55 60
          Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
          65 70 75 80
          Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
                          85 90 95
          Tyr Tyr Tyr Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
                      100 105 110
          Lys
           <![CDATA[ <210> 729]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 729]]>
          Asp Ile Val Met Thr Gln Ser Thr Ala Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
                      20 25 30
          Gly Asn Ser Leu Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Thr Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
          65 70 75 80
          Pro Val Glu Ala Asp Asp Ala Ala Ile Tyr Tyr Cys Gln Gln Asn Asn
                          85 90 95
          Glu Asp Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
                      100 105 110
           <![CDATA[ <210> 730]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 730]]>
          Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Gln Arg Ala Thr Ile Ser Cys Arg Val Ser Glu Ser Val Asp Ser Tyr
                      20 25 30
          Gly Asn Ser Phe Met His Trp Tyr Arg Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
          65 70 75 80
          Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
                          85 90 95
          Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 731]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 731]]>
          Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Asn Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Val Ser Asn Val Gln Ser
          65 70 75 80
          Glu Asp Leu Thr Glu Tyr Phe Cys His Gln Tyr Asn Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 732]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 732]]>
          Asp Ile Val Met Thr Gln Ser Thr Leu Thr Leu Ser Val Thr Leu Gly
          1 5 10 15
          Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
                      20 25 30
          Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
                  35 40 45
          Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Val Gln Gly
                          85 90 95
          Thr His Phe Pro Tyr Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 733]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 733]]>
          Asp Ile Val Leu Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
          1 5 10 15
          Gln Pro Ala Ser Ile Ser Cys Lys Pro Ser Gln Ser Leu Leu Asp Ser
                      20 25 30
          Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
                  35 40 45
          Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
                          85 90 95
          Thr His Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 734]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 734]]>
          Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn Thr Ala
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Gln Leu Ile
                  35 40 45
          Tyr Trp Ala Ser Ser Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
          65 70 75 80
          Glu Asp Leu Ala Asp Tyr Phe Cys His Gln Tyr Ser Thr Ser Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 735]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 735]]>
          Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Ile Gly
          1 5 10 15
          Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
                      20 25 30
          Asp Gly Lys Thr Tyr Phe Asn Trp Leu His Gln Arg Pro Gly Gln Ser
                  35 40 45
          Pro Lys Arg Leu Ile Phe Gln Val Ser Lys Leu Asp Pro Gly Ile Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Thr Glu Asp Leu Gly Val Tyr Tyr Cys Leu Gln Gly
                          85 90 95
          Thr Tyr Phe Pro His Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 736]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 736]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Tyr Tyr
                      20 25 30
          Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Asp
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
          65 70 75 80
          Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Lys
                          85 90 95
          Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 737]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 737]]>
          Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Tyr Tyr
                      20 25 30
          Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Asp
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
          65 70 75 80
          Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Lys
                          85 90 95
          Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 738]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 738]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 739]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 739]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 740]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 740]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 741]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 741]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ala Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 742]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 742]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Lys Val Gly Ile Lys
                      20 25 30
          Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 743]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 743]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
                      20 25 30
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
                  35 40 45
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
              50 55 60
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
          65 70 75 80
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
                          85 90 95
          Tyr Tyr Tyr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
                      100 105 110
          Lys
           <![CDATA[ <210> 744]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 744]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
                      20 25 30
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
                  35 40 45
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
              50 55 60
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
          65 70 75 80
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
                          85 90 95
          Tyr Tyr Tyr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
                      100 105 110
          Lys
           <![CDATA[ <210> 745]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 745]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
                      20 25 30
          Gly Asn Ser Leu Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
          65 70 75 80
          Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
                          85 90 95
          Glu Asp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 746]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 746]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
                      20 25 30
          Gly Asn Ser Leu Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
          65 70 75 80
          Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
                          85 90 95
          Glu Asp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 747]]>
           <![CDATA[ <211> 330]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 747]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                          325 330
           <![CDATA[ <210> 748]]>
           <![CDATA[ <211> 330]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 748]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                          325 330
           <![CDATA[ <210> 749]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 749]]>
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
          1 5 10 15
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
                      20 25 30
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
                  35 40 45
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
              50 55 60
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
          65 70 75 80
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                          85 90 95
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
                      100 105
           <![CDATA[ <210> 750]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 750]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Lys Gln Met Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
          65 70 75 80
          Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 751]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 751]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Phe Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 752]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 752]]>
          Gln Val Gln Met Lys Glu Ser Gly Thr Glu Leu Val Arg Pro Gly Thr
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ala Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Lys Gln Arg Pro Gly His Gly Pro Glu Trp Ile
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Thr Ile Tyr Phe Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 753]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 753]]>
          Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Leu Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 754]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 754]]>
          Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Lys Gln Met Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ala Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
          65 70 75 80
          Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 755]]>
           <![CDATA[ <211> 449]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 755]]>
          Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val
          1 5 10 15
          Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr Asp Ile
                      20 25 30
          Asn Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Trp
                  35 40 45
          Ile Phe Pro Gly Asp Val Thr Thr Lys Tyr Asn Glu Lys Phe Lys Gly
              50 55 60
          Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met His
          65 70 75 80
          Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg
                          85 90 95
          Ala Gly Tyr Gly Tyr Val Arg Tyr Ser Met Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
                  115 120 125
          Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
              130 135 140
          Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
          145 150 155 160
          Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
                          165 170 175
          Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
                      180 185 190
          Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
                  195 200 205
          Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
              210 215 220
          Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
          225 230 235 240
          Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
                          245 250 255
          Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
                      260 265 270
          Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
                  275 280 285
          Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
              290 295 300
          Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
          305 310 315 320
          Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
                          325 330 335
          Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
                      340 345 350
          Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
                  355 360 365
          Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
              370 375 380
          Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
          385 390 395 400
          Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
                          405 410 415
          Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
                      420 425 430
          Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
                  435 440 445
          Lys
           <![CDATA[ <210> 756]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 756]]>
          Gln Val Gln Met Lys Glu Ser Gly Pro Glu Leu Ala Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Ser Lys Tyr Asn Glu Ile Phe
              50 55 60
          Lys Asp Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Thr Lys Trp Asp Tyr Gly Ala Tyr Phe Pro Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 757]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 757]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Asp
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His
                      20 25 30
          Tyr Met Glu Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Ser Ile Tyr Pro Asn His Gly Gly Thr Ser Tyr Asn Gln Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
          65 70 75 80
          Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Tyr Tyr Gly Tyr Asp Gly Phe Phe Asp Phe Trp Gly Gln
                      100 105 110
          Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
                  115 120 125
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
              130 135 140
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
          145 150 155 160
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
                          165 170 175
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
                      180 185 190
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
                  195 200 205
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
              210 215 220
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
          225 230 235 240
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                          245 250 255
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
                      260 265 270
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
                  275 280 285
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
              290 295 300
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
          305 310 315 320
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
                          325 330 335
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                      340 345 350
          Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
                  355 360 365
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
              370 375 380
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
          385 390 395 400
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
                          405 410 415
          Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
                      420 425 430
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
                  435 440 445
          Gly Lys
              450
           <![CDATA[ <210> 758]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 758]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Asp
          1 5 10 15
          Ser Val Lys Met Ser Cys Glu Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Pro Glu Trp Ile
                  35 40 45
          Gly Asp Ile His Pro Asn Thr Gly Gly Asn Ser Asn Asn Gln Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Gly Thr Ala Tyr
          65 70 75 80
          Met Glu Leu His Ser Val Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Tyr Tyr Gly Tyr Asp Gly Phe Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
                  115 120 125
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
              130 135 140
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
          145 150 155 160
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
                          165 170 175
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
                      180 185 190
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
                  195 200 205
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
              210 215 220
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
          225 230 235 240
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                          245 250 255
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
                      260 265 270
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
                  275 280 285
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
              290 295 300
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
          305 310 315 320
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
                          325 330 335
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                      340 345 350
          Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
                  355 360 365
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
              370 375 380
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
          385 390 395 400
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
                          405 410 415
          Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
                      420 425 430
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
                  435 440 445
          Gly Lys
              450
           <![CDATA[ <210> 759]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 759]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Thr Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Thr Lys Trp Gly Tyr Gly Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 760]]>
           <![CDATA[ <211> 447]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 760]]>
          Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Ser
                      20 25 30
          Trp Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Asn Pro Asn Asn Gly Phe Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ile Gly Ala Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
                      100 105 110
          Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
                  115 120 125
          Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
              130 135 140
          Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
          145 150 155 160
          Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
                          165 170 175
          Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
                      180 185 190
          Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
                  195 200 205
          Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
              210 215 220
          Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
          225 230 235 240
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
                          245 250 255
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
                      260 265 270
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                  275 280 285
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
              290 295 300
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
          305 310 315 320
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
                          325 330 335
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                      340 345 350
          Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                  355 360 365
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
              370 375 380
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
          385 390 395 400
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
                          405 410 415
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                      420 425 430
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 761]]>
           <![CDATA[ <211> 447]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 761]]>
          Glu Val Gln Leu Gln Gln Ser Gly Thr Lys Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Asn Pro Gly Asn Gly Asp Thr Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Ser
                          85 90 95
          Thr Ile Trp Tyr Asp Asn Tyr Ile Asp Tyr Trp Gly Gln Gly Thr Thr
                      100 105 110
          Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
                  115 120 125
          Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
              130 135 140
          Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
          145 150 155 160
          Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
                          165 170 175
          Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
                      180 185 190
          Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
                  195 200 205
          Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
              210 215 220
          Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
          225 230 235 240
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
                          245 250 255
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
                      260 265 270
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                  275 280 285
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
              290 295 300
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
          305 310 315 320
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
                          325 330 335
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                      340 345 350
          Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                  355 360 365
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
              370 375 380
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
          385 390 395 400
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
                          405 410 415
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                      420 425 430
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 762]]>
           <![CDATA[ <211> 449]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 762]]>
          Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
          1 5 10 15
          Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ala Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
              50 55 60
          Thr Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
                          85 90 95
          Ala Arg His Gly Tyr Tyr Gly Ser Ser Tyr Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
                  115 120 125
          Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
              130 135 140
          Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
          145 150 155 160
          Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
                          165 170 175
          Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
                      180 185 190
          Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
                  195 200 205
          Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
              210 215 220
          Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
          225 230 235 240
          Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
                          245 250 255
          Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
                      260 265 270
          Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
                  275 280 285
          Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
              290 295 300
          Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
          305 310 315 320
          Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
                          325 330 335
          Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
                      340 345 350
          Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
                  355 360 365
          Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
              370 375 380
          Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
          385 390 395 400
          Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
                          405 410 415
          Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
                      420 425 430
          Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
                  435 440 445
          Lys
           <![CDATA[ <210> 763]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 763]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 764]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 764]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 765]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 765]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 766]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 766]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 767]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 767]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Val Thr Met Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 768]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 768]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 769]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 769]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Glu Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 770]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 770]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Gln Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 771]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 771]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Ser Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 772]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 772]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Ala Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 773]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 773]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 774]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 774]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 775]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 775]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 776]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 776]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ser Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 777]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 777]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 778]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 778]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 779]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 779]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 780]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 780]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 781]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 781]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 782]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 782]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 783]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 783]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 784]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 784]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 785]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 785]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 786]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 786]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 787]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 787]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 788]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 788]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 789]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 789]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 790]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 790]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Gln Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 791]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 791]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Ser Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 792]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 792]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Ala Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 793]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 793]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Lys Gln Met Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
          65 70 75 80
          Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 794]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 794]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Phe Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 795]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 795]]>
          Gln Val Gln Met Lys Glu Ser Gly Thr Glu Leu Val Arg Pro Gly Thr
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ala Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Lys Gln Arg Pro Gly His Gly Pro Glu Trp Ile
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Thr Ile Tyr Phe Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 796]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 796]]>
          Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Leu Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
          225 230 235 240
          Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 797]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 797]]>
          Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Lys Gln Met Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ala Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
          65 70 75 80
          Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 798]]>
           <![CDATA[ <211> 449]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 798]]>
          Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val
          1 5 10 15
          Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr Asp Ile
                      20 25 30
          Asn Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Trp
                  35 40 45
          Ile Phe Pro Gly Asp Val Thr Thr Lys Tyr Asn Glu Lys Phe Lys Gly
              50 55 60
          Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met His
          65 70 75 80
          Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg
                          85 90 95
          Ala Gly Tyr Gly Tyr Val Arg Tyr Ser Met Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
                  115 120 125
          Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
              130 135 140
          Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
          145 150 155 160
          Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
                          165 170 175
          Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
                      180 185 190
          Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
                  195 200 205
          Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
              210 215 220
          Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
          225 230 235 240
          Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
                          245 250 255
          Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
                      260 265 270
          Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
                  275 280 285
          Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
              290 295 300
          Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
          305 310 315 320
          Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
                          325 330 335
          Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
                      340 345 350
          Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
                  355 360 365
          Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
              370 375 380
          Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
          385 390 395 400
          Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
                          405 410 415
          Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
                      420 425 430
          Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
                  435 440 445
          Lys
           <![CDATA[ <210> 799]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 799]]>
          Gln Val Gln Met Lys Glu Ser Gly Pro Glu Leu Ala Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Ser Lys Tyr Asn Glu Ile Phe
              50 55 60
          Lys Asp Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Thr Lys Trp Asp Tyr Gly Ala Tyr Phe Pro Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 800]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 800]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Asp
          1 5 10 15
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His
                      20 25 30
          Tyr Met Glu Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
                  35 40 45
          Gly Ser Ile Tyr Pro Asn His Gly Gly Thr Ser Tyr Asn Gln Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
          65 70 75 80
          Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Tyr Tyr Gly Tyr Asp Gly Phe Phe Asp Phe Trp Gly Gln
                      100 105 110
          Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
                  115 120 125
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
              130 135 140
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
          145 150 155 160
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
                          165 170 175
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
                      180 185 190
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
                  195 200 205
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
              210 215 220
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
          225 230 235 240
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                          245 250 255
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
                      260 265 270
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
                  275 280 285
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
              290 295 300
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
          305 310 315 320
          Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
                          325 330 335
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                      340 345 350
          Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
                  355 360 365
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
              370 375 380
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
          385 390 395 400
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
                          405 410 415
          Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
                      420 425 430
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
                  435 440 445
          Gly Lys
              450
           <![CDATA[ <210> 801]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 801]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Asp
          1 5 10 15
          Ser Val Lys Met Ser Cys Glu Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Pro Glu Trp Ile
                  35 40 45
          Gly Asp Ile His Pro Asn Thr Gly Gly Asn Ser Asn Asn Gln Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Gly Thr Ala Tyr
          65 70 75 80
          Met Glu Leu His Ser Val Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Tyr Tyr Gly Tyr Asp Gly Phe Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
                  115 120 125
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
              130 135 140
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
          145 150 155 160
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
                          165 170 175
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
                      180 185 190
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
                  195 200 205
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
              210 215 220
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
          225 230 235 240
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                          245 250 255
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
                      260 265 270
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
                  275 280 285
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
              290 295 300
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
          305 310 315 320
          Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
                          325 330 335
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                      340 345 350
          Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
                  355 360 365
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
              370 375 380
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
          385 390 395 400
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
                          405 410 415
          Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
                      420 425 430
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
                  435 440 445
          Gly Lys
              450
           <![CDATA[ <210> 802]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 802]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Ala
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Thr Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Thr Lys Trp Gly Tyr Gly Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 803]]>
           <![CDATA[ <211> 447]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 803]]>
          Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Ser
                      20 25 30
          Trp Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Asn Pro Asn Asn Gly Phe Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Ile Gly Ala Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
                      100 105 110
          Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
                  115 120 125
          Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
              130 135 140
          Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
          145 150 155 160
          Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
                          165 170 175
          Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
                      180 185 190
          Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
                  195 200 205
          Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
              210 215 220
          Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val
          225 230 235 240
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
                          245 250 255
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
                      260 265 270
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                  275 280 285
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
              290 295 300
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
          305 310 315 320
          Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
                          325 330 335
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                      340 345 350
          Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                  355 360 365
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
              370 375 380
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
          385 390 395 400
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
                          405 410 415
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                      420 425 430
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 804]]>
           <![CDATA[ <211> 447]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 804]]>
          Glu Val Gln Leu Gln Gln Ser Gly Thr Lys Leu Val Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
                      20 25 30
          Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Asn Pro Gly Asn Gly Asp Thr Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Ser
                          85 90 95
          Thr Ile Trp Tyr Asp Asn Tyr Ile Asp Tyr Trp Gly Gln Gly Thr Thr
                      100 105 110
          Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
                  115 120 125
          Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
              130 135 140
          Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
          145 150 155 160
          Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
                          165 170 175
          Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
                      180 185 190
          Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
                  195 200 205
          Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
              210 215 220
          Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val
          225 230 235 240
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
                          245 250 255
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
                      260 265 270
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                  275 280 285
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
              290 295 300
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
          305 310 315 320
          Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
                          325 330 335
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                      340 345 350
          Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                  355 360 365
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
              370 375 380
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
          385 390 395 400
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
                          405 410 415
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                      420 425 430
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 805]]>
           <![CDATA[ <211> 449]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 805]]>
          Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
          1 5 10 15
          Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ala Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
              50 55 60
          Thr Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
                          85 90 95
          Ala Arg His Gly Tyr Tyr Gly Ser Ser Tyr Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
                  115 120 125
          Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
              130 135 140
          Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
          145 150 155 160
          Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
                          165 170 175
          Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
                      180 185 190
          Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
                  195 200 205
          Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
              210 215 220
          Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
          225 230 235 240
          Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
                          245 250 255
          Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
                      260 265 270
          Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
                  275 280 285
          Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
              290 295 300
          Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
          305 310 315 320
          Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
                          325 330 335
          Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
                      340 345 350
          Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
                  355 360 365
          Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
              370 375 380
          Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
          385 390 395 400
          Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
                          405 410 415
          Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
                      420 425 430
          Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
                  435 440 445
          Lys
           <![CDATA[ <210> 806]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 806]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 807]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 807]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Ser Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 808]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 808]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 809]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 809]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 810]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 810]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Val Thr Met Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 811]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 811]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 812]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 812]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Glu Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 813]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 813]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Gln Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 814]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 814]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Ser Gly Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 815]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 815]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
                      20 25 30
          Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Tyr Ile Tyr Asn Asp Ala Thr Lys Tyr Asn Glu Arg Phe Arg Gly
              50 55 60
          Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
          65 70 75 80
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
                          85 90 95
          Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
                  115 120 125
          Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
                      180 185 190
          Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
              210 215 220
          Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
          225 230 235 240
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          245 250 255
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
                      260 265 270
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  275 280 285
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              290 295 300
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
          305 310 315 320
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          325 330 335
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
                      340 345 350
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  355 360 365
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              370 375 380
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          385 390 395 400
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                          405 410 415
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      420 425 430
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 816]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 816]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 817]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 817]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 818]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 818]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 819]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 819]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ser Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 820]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 820]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 821]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 821]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Gly Tyr Gly Ala Tyr Phe Thr Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 822]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 822]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 823]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 823]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 824]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 824]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 825]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 825]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 826]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 826]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Met Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 827]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 827]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
                      20 25 30
          Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Asp Ile Tyr Pro Arg Ser Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
              50 55 60
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Ser Gly Gly Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
                  115 120 125
          Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
              130 135 140
          Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
          145 150 155 160
          Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
                      180 185 190
          Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
                  195 200 205
          Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
              210 215 220
          His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
          225 230 235 240
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
                          245 250 255
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
                      260 265 270
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
                  275 280 285
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
              290 295 300
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
          305 310 315 320
          Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
                          325 330 335
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
                      340 345 350
          Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
                  355 360 365
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
              370 375 380
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
          385 390 395 400
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
                          405 410 415
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
                      420 425 430
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440 445
           <![CDATA[ <210> 828]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 828]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
          225 230 235 240
          Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 829]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 829]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
          225 230 235 240
          Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 830]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 830]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
          225 230 235 240
          Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 831]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 831]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
          225 230 235 240
          Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 832]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 832]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
          225 230 235 240
          Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 833]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 833]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Gln Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
          225 230 235 240
          Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 834]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 834]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Ser Gly Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
          225 230 235 240
          Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 835]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 835]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
                      20 25 30
          Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
                  35 40 45
          Gly Arg Val Ser Pro Ser Asn Ala Gly Thr Asn Tyr Asn Gln Lys Phe
              50 55 60
          Arg Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Arg Gly Ala Gly Tyr Ser Tyr Tyr Ala Met Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
          225 230 235 240
          Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 836]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 836]]>
          Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Tyr Tyr
                      20 25 30
          Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
          65 70 75 80
          Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
                          85 90 95
          Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys Arg
                      100 105 110
          Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
              130 135 140
          Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
          145 150 155 160
          Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
                          165 170 175
          Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
                      180 185 190
          His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
                  195 200 205
          Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 837]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 837]]>
          Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Asp Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
          65 70 75 80
          Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 838]]>
           <![CDATA[ <211> 220]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 838]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
          1 5 10 15
          Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
                      20 25 30
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
                  35 40 45
          Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
              50 55 60
          Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
          65 70 75 80
          Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
                          85 90 95
          Tyr Tyr Tyr Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
                      100 105 110
          Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
                  115 120 125
          Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
              130 135 140
          Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
          145 150 155 160
          Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
                          165 170 175
          Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
                      180 185 190
          Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
                  195 200 205
          Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215 220
           <![CDATA[ <210> 839]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 839]]>
          Asp Ile Val Met Thr Gln Ser Thr Ala Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
                      20 25 30
          Gly Asn Ser Leu Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Thr Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
          65 70 75 80
          Pro Val Glu Ala Asp Asp Ala Ala Ile Tyr Tyr Cys Gln Gln Asn Asn
                          85 90 95
          Glu Asp Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
                      100 105 110
          Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
              130 135 140
          Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
          145 150 155 160
          Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
                          165 170 175
          Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
                      180 185 190
          His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
                  195 200 205
          Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 840]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 840]]>
          Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Gln Arg Ala Thr Ile Ser Cys Arg Val Ser Glu Ser Val Asp Ser Tyr
                      20 25 30
          Gly Asn Ser Phe Met His Trp Tyr Arg Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
          65 70 75 80
          Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
                          85 90 95
          Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
                      100 105 110
          Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
              130 135 140
          Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
          145 150 155 160
          Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
                          165 170 175
          Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
                      180 185 190
          His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
                  195 200 205
          Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 841]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 841]]>
          Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Asn Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Val Ser Asn Val Gln Ser
          65 70 75 80
          Glu Asp Leu Thr Glu Tyr Phe Cys His Gln Tyr Asn Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 842]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 842]]>
          Asp Ile Val Met Thr Gln Ser Thr Leu Thr Leu Ser Val Thr Leu Gly
          1 5 10 15
          Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
                      20 25 30
          Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
                  35 40 45
          Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Val Gln Gly
                          85 90 95
          Thr His Phe Pro Tyr Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 843]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 843]]>
          Asp Ile Val Leu Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
          1 5 10 15
          Gln Pro Ala Ser Ile Ser Cys Lys Pro Ser Gln Ser Leu Leu Asp Ser
                      20 25 30
          Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
                  35 40 45
          Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
                          85 90 95
          Thr His Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 844]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 844]]>
          Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn Thr Ala
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Gln Leu Ile
                  35 40 45
          Tyr Trp Ala Ser Ser Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
          65 70 75 80
          Glu Asp Leu Ala Asp Tyr Phe Cys His Gln Tyr Ser Thr Ser Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 845]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 845]]>
          Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Ser Val Thr Ile Gly
          1 5 10 15
          Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
                      20 25 30
          Asp Gly Lys Thr Tyr Phe Asn Trp Leu His Gln Arg Pro Gly Gln Ser
                  35 40 45
          Pro Lys Arg Leu Ile Phe Gln Val Ser Lys Leu Asp Pro Gly Ile Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Thr Glu Asp Leu Gly Val Tyr Tyr Cys Leu Gln Gly
                          85 90 95
          Thr Tyr Phe Pro His Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 846]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 846]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Tyr Tyr
                      20 25 30
          Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Asp
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
          65 70 75 80
          Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Lys
                          85 90 95
          Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
                      100 105 110
          Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
              130 135 140
          Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
          145 150 155 160
          Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
                          165 170 175
          Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
                      180 185 190
          His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
                  195 200 205
          Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 847]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 847]]>
          Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Tyr Tyr
                      20 25 30
          Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Asp
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
          65 70 75 80
          Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Lys
                          85 90 95
          Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
                      100 105 110
          Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
              130 135 140
          Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
          145 150 155 160
          Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
                          165 170 175
          Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
                      180 185 190
          His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
                  195 200 205
          Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 848]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 848]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 849]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 849]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 850]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 850]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 851]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 851]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ala Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 852]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 852]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Lys Val Gly Ile Lys
                      20 25 30
          Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Tyr Arg Ser Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Phe Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 853]]>
           <![CDATA[ <211> 220]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 853]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
                      20 25 30
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
                  35 40 45
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
              50 55 60
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
          65 70 75 80
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
                          85 90 95
          Tyr Tyr Tyr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
                      100 105 110
          Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
                  115 120 125
          Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
              130 135 140
          Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
          145 150 155 160
          Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
                          165 170 175
          Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
                      180 185 190
          Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
                  195 200 205
          Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215 220
           <![CDATA[ <210> 854]]>
           <![CDATA[ <211> 220]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 854]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
                      20 25 30
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
                  35 40 45
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
              50 55 60
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
          65 70 75 80
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
                          85 90 95
          Tyr Tyr Tyr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
                      100 105 110
          Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
                  115 120 125
          Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
              130 135 140
          Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
          145 150 155 160
          Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
                          165 170 175
          Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
                      180 185 190
          Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
                  195 200 205
          Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215 220
           <![CDATA[ <210> 855]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 855]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
                      20 25 30
          Gly Asn Ser Leu Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
          65 70 75 80
          Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
                          85 90 95
          Glu Asp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
                      100 105 110
          Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
              130 135 140
          Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
          145 150 155 160
          Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
                          165 170 175
          Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
                      180 185 190
          His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
                  195 200 205
          Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 856]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 856]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
          1 5 10 15
          Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
                      20 25 30
          Gly Asn Ser Leu Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
                  35 40 45
          Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
              50 55 60
          Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
          65 70 75 80
          Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
                          85 90 95
          Glu Asp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
                      100 105 110
          Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
              130 135 140
          Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
          145 150 155 160
          Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
                          165 170 175
          Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
                      180 185 190
          His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
                  195 200 205
          Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 857]]>
           <![CDATA[ <211> 330]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 857]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
          1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
          225 230 235 240
          Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                          325 330
           <![CDATA[ <210> 858]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 858]]>
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
          1 5 10 15
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
                      20 25 30
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
                  35 40 45
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
              50 55 60
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
          65 70 75 80
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                          85 90 95
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
                      100 105
           <![CDATA[ <210> 859]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 859]]>
          Asn Tyr Asp Met Ser
          1 5
           <![CDATA[ <210> 860]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 860]]>
          Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Val Asp Ser Val Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 861]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 861]]>
          Gln Glu Leu Gly Ser Tyr Tyr Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 862]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 862]]>
          Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
          1 5 10 15
           <![CDATA[ <210> 863]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 863]]>
          Lys Val Ser Asn Arg Phe Ser
          1 5
           <![CDATA[ <210> 864]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 864]]>
          Phe Gln Gly Ser His Val Pro Tyr Thr
          1 5
           <![CDATA[ <210> 865]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 865]]>
          Glu Val Met Leu Val Glu Ser Gly Gly Ala Leu Val Lys Pro Gly Gly
          1 5 10 15
          Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
                      20 25 30
          Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
                  35 40 45
          Ala Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Val Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu His
          65 70 75 80
          Leu Gln Met Ser Ser Leu Arg Ser Lys Asp Thr Ala Met Tyr Tyr Cys
                          85 90 95
          Ala Arg Gln Glu Leu Gly Ser Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Ser Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 866]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 866]]>
          Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
          1 5 10 15
          Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 867]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 867]]>
          Glu Val Met Leu Val Glu Ser Gly Gly Ala Leu Val Lys Pro Gly Gly
          1 5 10 15
          Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
                      20 25 30
          Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
                  35 40 45
          Ala Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Val Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu His
          65 70 75 80
          Leu Gln Met Ser Ser Leu Arg Ser Lys Asp Thr Ala Met Tyr Tyr Cys
                          85 90 95
          Ala Arg Gln Glu Leu Gly Ser Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
                  115 120 125
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
              130 135 140
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
          145 150 155 160
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
                          165 170 175
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
                      180 185 190
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
                  195 200 205
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
              210 215 220
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
          225 230 235 240
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                          245 250 255
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
                      260 265 270
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
                  275 280 285
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
              290 295 300
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
          305 310 315 320
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
                          325 330 335
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                      340 345 350
          Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
                  355 360 365
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
              370 375 380
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
          385 390 395 400
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
                          405 410 415
          Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
                      420 425 430
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
                  435 440 445
          Gly Lys
              450
           <![CDATA[ <210> 868]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 868]]>
          Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
          1 5 10 15
          Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 869]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 869]]>
          Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Thr Tyr Leu Glu
          1 5 10 15
           <![CDATA[ <210> 870]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 870]]>
          Arg Ser Ser Gln Ser Ile Val His Ser Gln Gly Asn Thr Tyr Leu Glu
          1 5 10 15
           <![CDATA[ <210> 871]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 871]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
                      20 25 30
          Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Val Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gln Glu Leu Gly Ser Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 872]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 872]]>
          Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 873]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 873]]>
          Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 874]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 874]]>
          Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Ala Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 875]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 875]]>
          Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Gln Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 876]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 876]]>
          Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Gln Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 877]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 877]]>
          Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Ala Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 878]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 878]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
          1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
                      20 25 30
          Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Val Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gln Glu Leu Gly Ser Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
                  115 120 125
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
              130 135 140
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
          145 150 155 160
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
                          165 170 175
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
                      180 185 190
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
                  195 200 205
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
              210 215 220
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
          225 230 235 240
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                          245 250 255
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
                      260 265 270
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
                  275 280 285
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
              290 295 300
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
          305 310 315 320
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
                          325 330 335
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                      340 345 350
          Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
                  355 360 365
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
              370 375 380
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
          385 390 395 400
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
                          405 410 415
          Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
                      420 425 430
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
                  435 440 445
          Gly Lys
              450
           <![CDATA[ <210> 879]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 879]]>
          Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 880]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 880]]>
          Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 881]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 881]]>
          Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Ala Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 882]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 882]]>
          Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Gln Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 883]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 883]]>
          Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Gln Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 884]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 884]]>
          Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
          1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
                      20 25 30
          Asn Ala Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
                          85 90 95
          Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 885]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 885]]>
          Gly Phe Thr Phe Ser Asn Tyr
          1 5
           <![CDATA[ <210> 886]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 886]]>
          Ser Ser Gly Gly Ser Tyr
          1 5
           <![CDATA[ <210> 887]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 887]]>
          Gln Glu Leu Gly Ser Tyr Tyr Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 888]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 888]]>
          Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
          1 5 10 15
           <![CDATA[ <210> 889]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 889]]>
          Lys Val Ser Asn Arg Phe Ser
          1 5
           <![CDATA[ <210> 890]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 890]]>
          Phe Gln Gly Ser His Val Pro Tyr Thr
          1 5
           <![CDATA[ <210> 891]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 891]]>
          Gly Phe Thr Phe Ser Asn Tyr Asp Met Ser
          1 5 10
           <![CDATA[ <210> 892]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 892]]>
          Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr
          1 5 10
           <![CDATA[ <210> 893]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 893]]>
          Gln Glu Leu Gly Ser Tyr Tyr Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 894]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 894]]>
          Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
          1 5 10 15
           <![CDATA[ <210> 895]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 895]]>
          Lys Val Ser Asn Arg Phe Ser
          1 5
           <![CDATA[ <210> 896]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 896]]>
          Phe Gln Gly Ser His Val Pro Tyr Thr
          1 5
           <![CDATA[ <210> 897]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 897]]>
          Ser Asn Tyr Asp Met Ser
          1 5
           <![CDATA[ <210> 898]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 898]]>
          Trp Val Ala Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr
          1 5 10
           <![CDATA[ <210> 899]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 899]]>
          Ala Arg Gln Glu Leu Gly Ser Tyr Tyr Ala Met Asp
          1 5 10
           <![CDATA[ <210> 900]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 900]]>
          Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr
          1 5 10
           <![CDATA[ <210> 901]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 901]]>
          Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe
          1 5 10
           <![CDATA[ <210> 902]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 902]]>
          Phe Gln Gly Ser His Val Pro Tyr
          1 5
           <![CDATA[ <210> 903]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 903]]>
          Gly Phe Thr Phe Ser Asn Tyr Asp
          1 5
           <![CDATA[ <210> 904]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 904]]>
          Ile Ser Ser Gly Gly Ser Tyr Thr
          1 5
           <![CDATA[ <210> 905]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 905]]>
          Ala Arg Gln Glu Leu Gly Ser Tyr Tyr Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 906]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 906]]>
          Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr
          1 5 10
           <![CDATA[ <210> 907]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 907]]>
          Lys Val Ser
          1           
           <![CDATA[ <210> 908]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 908]]>
          Phe Gln Gly Ser His Val Pro Tyr Thr
          1 5
           <![CDATA[ <210> 909]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 909]]>
          Ser Gly Phe Thr Phe Ser Asn Tyr Asp Met
          1 5 10
           <![CDATA[ <210> 910]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 910]]>
          Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Val Asp Ser Val Lys Gly Arg
          1 5 10 15
          Phe
           <![CDATA[ <210> 911]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 911]]>
          Glu Leu Gly Ser Tyr Tyr Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 912]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 912]]>
          Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr
          1 5 10
           <![CDATA[ <210> 913]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 913]]>
          Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg
          1 5 10
           <![CDATA[ <210> 914]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthetic sequence]]>
           <![CDATA[ <400> 914]]>
          Gly Ser His Val Pro Tyr Thr Phe
          1 5
          
      

Claims (167)

A compound having the structure of formula (I'):

(I') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein: L is -[CR' ₂ ]p-L '-[CH ₂ ]q- L' is absent, -S-, -O-, or -NH-; A is absent, carbocyclic, or heterocyclic; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, halogen, C _1-3 alkyl, or C _1-3 haloalkyl ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halogen, C _{1- 3} alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; R ⁹ in each occurrence are independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N( R') ₂ , -N(R')C(O)R _{' ,} -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R' , -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P( O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is in each occurrence independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; n is 0-5; p is 1 -3; and q is 0-3. The compound of claim 1 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is C. The compound of claim 1 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is N. The compound of any one of claims 1-3 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein L' is not exist. The compound of any one of claims 1-3 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein L' is - S-. The compound of any one of claims 1-3 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein L' is - O-. The compound of any one of claims 1-3 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein L' is - NH-. The compound of any one of claims 1-7 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein p is 1. The compound of any one of claims 1-7 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein p is 2. The compound of any one of claims 1-7 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein p is 3. The compound of any one of claims 1-10 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein q is 0. The compound of any one of claims 1-10 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein q is 1. The compound of any one of claims 1-10 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein q is 2. The compound of any one of claims 1-10 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein q is 3. A compound having the structure of formula (II'):

(II') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkane group, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl , or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy _; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _1-6 hydroxyalkyl, - C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S (O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 ring Alkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' independently at each occurrence hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, or _C1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of claim 15 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is C. The compound of claim 15 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is N. The compound of any one of claims 1-2 or 4-16, which has the structure of formula (II''-A):

(II''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N(R')C(O)R', -C(O) OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _{1 -6} alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independent at each occurrence is C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1, 3-15, or 17, having the structure of formula (II-A):

(II-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR' , -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 Alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon ring, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2 or 4-16, which has the structure of formula (II''-B):

(II''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in Each occurrence is independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _{1-6hydroxyalkyl} , -C( O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O ) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl , -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _{2- 5} alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0- 3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1, 3-15, or 17, which has the structure of formula (II-B):

(II-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in each When they appear, they are all independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)OC _{1-6hydroxyalkyl} , -C(O) N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, - P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkyne group, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each with 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane group, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2 or 4-16, which has the structure of formula (II''-C):

(II''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N(R')C(O)R', -C(O) OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _{1 -6} alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy at each occurrence or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 halo alkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1, 3-15, or 17, having the structure of formula (II-C):

(II-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)OC _1-6 hydroxyalkyl, -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR' , -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -C(O)NHS(O) ₂ -C _1-6 Alkyl, -C(O)NHS(O) ₂ -C _3-8 cycloalkyl, -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl ; m is 0-3; and n is 0-5. A compound having the structure of formula (III'):

(III') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkane group, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl , or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N (R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' independently at each occurrence hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, or _C1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of claim 24 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is C. The compound of claim 24 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is N. The compound of any one of claims 1-2, 4-14, or 24-25, which has the structure of formula (III''-A):

(III''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independent at each occurrence is C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, 24, or 26, which has the structure of formula (III-A):

(III-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon ring, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, or 24-25, which has the structure of formula (III''-B):

(III''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in Halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R at each occurrence independently ')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR' , -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _{2- 5} alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0- 3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, 24, or 26, which has the structure of formula (III-B):

(III-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in each Occurs independently as halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R') C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', - P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkyne group, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each with 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane group, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, or 24-25, which has the structure of formula (III''-C):

(III''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy at each occurrence or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 halo alkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, 24, or 26, which has the structure of formula (III-C):

(III-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl ; m is 0-3; and n is 0-5. A compound having the structure of formula (IV'):

(IV') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkane group, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl , or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H, halo, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N (R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' independently at each occurrence hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, or _C1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of claim 33 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is C. The compound of claim 33, its pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt, wherein Q ⁷ is N. The compound of any one of claims 1-2, 4-14, and 33-34, which has the structure of formula (IV''-A):

(IV''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independent at each occurrence is C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, 33, or 35, which has the structure of formula (IV-A):

(IV-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon ring, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, or 33-34, which has the structure of formula (IV''-B):

(IV''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in Halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R at each occurrence independently ')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR' , -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _{2- 5} alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0- 3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, 33, or 35, which has the structure of formula (IV-B):

(IV-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in each Occurs independently as halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R') C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', - P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkyne group, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each with 0-3 R ¹⁰ substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkane group, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, or 33-34, which has the structure of formula (IV''-C):

(IV''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , - C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S (O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl , carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy at each occurrence or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 halo alkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, 33, or 35, which has the structure of formula (IV-C):

(IV-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _{1 -3} alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ^10s ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is capable of A reactive moiety linked to a linker or reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C( O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O )R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O , -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbon Ring, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl ; m is 0-3; and n is 0-5. A compound having the structure of formula (V _a ʹ):

(V _a ') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; Q ³ is N or CR ³ Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 halogen Alkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkane group, or C _1-3 haloalkoxy; R ³ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _{1- 3} alkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; ^R9 is at each occurrence independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , - N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R ' is independently at each occurrence hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n 0-5. The compound of claim 42 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is C. The compound of claim 42 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is N. The compound of any one of claims 1-2, 4-14, or 42-43, which has the structure of formula (V _a ''-A):

(V _a ''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen , C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; R ⁹ is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', - S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkyne wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, 42, or 44, which has the structure of formula (V _a -A):

(V _a -A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is A reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C (O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S( O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , = O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, Carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkane base; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, or 42-43, which has the structure of formula (V _a ''-B):

(V _a ''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen , C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ Halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N( R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR ', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _{2 -5} alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0 -3 R ¹⁰ substitutions; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, 42, or 44, which has the structure of formula (V _a -B):

(V _a -B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is in each Each occurrence is independently halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R',-C(O)OR',-OC(O)R',-S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 Alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each represented by 0-3 R ¹⁰ is substituted; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' is independently hydrogen, C _1-6 at every occurrence alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, or 42-43, which has the structure of formula (V _a ''-C):

(V _a ''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen , C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; R ⁹ is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', - S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkyne wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound 1-2, 4-14, 42, or 44 of any one of the claims, which has the structure of formula (V _a -C):

(V _a -C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocyclic or heterocyclic ring; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is A reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C (O)R', -C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S( O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , = O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, Carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkane base; m is 0-3; and n is 0-5. A compound having the structure of formula (VI'):

(VI') or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q ³ is N or CR ³ ; Q ⁴ is N or CR ⁴ ; Q ⁵ is N or CR ⁵ ; Q ⁶ is N or CR ⁶ ; Q ⁷ is C or N; R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is 0 -3 R ¹⁰ substitutions; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkane oxy; R ³ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁴ is H, halogen, C _1-3 alkyl, C _{1 -3} haloalkyl, or C _1-3 alkoxy; R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or C _1-3 alkoxy; R ⁶ is H , halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independent at each occurrence Halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O) R', -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O) (OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _{1 -4} haloalkyl, _C2-5 haloalkenyl, _C2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁹ series are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy in each occurrence; R' is independently in each occurrence is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of claim 51 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is C. The compound of claim 51 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Q ⁷ is N. The compound of any one of claims 1-2, 4-14, or 51-52, which has the structure of formula (VI''-A):

(VI''-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reaction capable of connecting with a linker A reactive moiety or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', - C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S (O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _{1 -4} alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy at each occurrence base; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3 ; and n is 0-5. The compound of any one of claims 1-2, 4-14, 51, or 53, which has the structure of formula (VI-A):

(VI-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _{1 -3} haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C( O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O ) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy at each occurrence; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, or 51-52, which has the structure of formula (VI''-B):

(VI''-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety capable of being linked to a linker or a reactive moiety capable of being linked to an antibody; R ⁹ is independently at each occurrence Halogen, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R' , -C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR ') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ at each occurrence independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' at each occurrence independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, 51, or 53, which has the structure of formula (VI-B):

(VI-B) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _{1 -3} haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} haloalkyl, or C _1-3 haloalkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety that can be linked to an antibody; R ⁹ is independently halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C(O)N(R') ₂ , -N(R')C(O)R', - C(O)OR', -OC(O)R', -S(O)R', -S(O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkane group, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is in each Each occurrence is independently C _1-3 alkoxy or C _1-3 haloalkoxy; R' is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl at each occurrence , C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-2, 4-14, or 51-52, which has the structure of formula (VI''-C):

(VI''-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _1-3 haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reaction capable of connecting with a linker A reactive moiety or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', - C(O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S (O) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _{1 -4} alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy at each occurrence base; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3 ; and n is 0-5. The compound of any one of claims 1-2, 4-14, 51, or 53, which has the structure of formula (VI-C):

(VI-C) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R ¹ is hydrogen, C _1-3 alkyl, or C _{1 -3} haloalkyl, wherein R ¹ is substituted with 0-3 R ¹⁰ ; R ² at each occurrence is independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} haloalkyl, or C _1-3 haloalkoxy; R ⁶ is H, halogen, C _1-3 alkyl, or C _1-3 alkoxy; R ⁷ is a reactive moiety that can be linked to a linker or a reactive moiety capable of being linked to an antibody; ^R9 is independently at each occurrence halo, -OR', -SR', -N(R') ₂ , -C(O)R', -C( O)N(R') ₂ , -N(R')C(O)R', -C(O)OR', -OC(O)R', -S(O)R', -S(O ) ₂ R', -S(O) ₂ OR', -P(O)(OR') ₂ , -OP(O)(OR') ₂ , -NO ₂ , =O, -CN, C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 haloalkyl, C _2-5 haloalkenyl, C _2-5 haloalkynyl, carbocycle, or heterocycle; wherein R ¹ , R ² , R ⁶ , and R ⁹ are each substituted with 0-3 R ¹⁰ ; R ¹⁰ is independently C _1-3 alkoxy or C _1-3 haloalkoxy at each occurrence; R' at each occurrence is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _1-6 haloalkyl; m is 0-3; and n is 0-5. The compound of any one of claims 1-59 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is hydrogen. The compound of any one of claims 1-59 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is halogen. Compound 61 as claimed, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is Cl. The compound of any one of claims 1-59 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is unsubstituted C _{1 -3} alkyl. The compound of claim 63 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is methyl. The compound of any one of claims 1-59 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is 1-3 R ¹⁰ -substituted C _1-3 alkyl. The compound of claim 65 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is -CH ₂ OCH ₃ . The compound of any one of claims 1-59 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is unsubstituted C _{1 -3} haloalkyl. The compound of claim 67 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is -CF ₃ . The compound of claim 67 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is -CHF ₂ . The compound of any one of claims 1-69 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0. The compound of any one of claims 1-69 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1-3. The compound of claim 71 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1. The compound of any one of claims 1-69 or 71-72 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ² is halogen. The compound of claim 73 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ² is F. The compound of any one of claims 1-50 or 60-74 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A is a heterocycle. The compound of claim 75 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A is pyridyl. The compound of claim 75 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A is pyrimidinyl. The compound of any one of claims 1-50 or 60-74 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A is a carbocycle. Compound 78 as claimed, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A is phenyl. The compound of any one of claims 1-79 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 0. The compound of any one of claims 1-79 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1-5. The compound of any one of claims 1-79 or 81 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1 or 2. The compound of any one of claims 1-79 or 81-82 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is halogen. The compound of claim 83 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is F, Cl, or Br. The compound of any one of claims 1-79 or 81-84 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -OR'. The compound of claim 85 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R' of at least one -OR' is C _1-6 alkyl . The compound of any one of claims 1-79 or 81-86 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is C _1-4 alkyl. The compound of claim 87 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is methyl. The compound of any one of claims 1-79 or 81-88 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -CN. The compound of any one of claims 1-79 or 81-89 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)N(R') ₂ . The compound of claim 90 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)N(CH ₃ ) ₂ . The compound of claim 90 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)NH ₂ . The compound of any one of claims 1-79 or 81-92 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -N(R') ₂ . The compound of claim 93 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -N(CH ₃ ) ₂ . The compound of any one of claims 1-79 or 81-94 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -NO ₂ . The compound of any one of claims 1-79 or 81-95 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)ORʹ. The compound of claim 96 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)OCH ₃ . The compound of claim 96 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)OH. The compound of any one of claims 1-79 or 81-98 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)OC _1-6 hydroxyalkyl. The compound of claim 99 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)OCH ₂ CH ₂ OH . The compound of any one of claims 1-79 or 81-100 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)NHS(O) ₂ -C _1-6 alkyl. The compound of claim 101 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is

,

,or

. The compound of any one of claims 1-79 or 81-102 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is -C(O)NHS(O) ₂ - _{C3-8cycloalkyl} . The compound of claim 103 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R ⁹ is

. The compound of any one of claims 1-104 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁶ is H. The compound of any one of claims 1-104 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁶ is halo. The compound of claim 106 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁶ is F or Cl. The compound of any one of claims 1-104 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁶ is C _1-3 alkyl . The compound of claim 108 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁶ is methyl. The compound of any one of claims 1-104 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁶ is C _1-3 alkoxy base. The compound of claim 110 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁶ is -OCH ₃ . The compound of any one of claims 1-111 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the reactive moiety capable of being attached to the linker Or the reactive moiety that can be linked to the antibody is -Y-(CR ¹¹ R ¹² ) _p -NHR ¹³ , -Y-(CR ¹¹ R ¹² ) _p -C(O)OR ¹³ , -Y-(CR ¹¹ R ¹² ) _p -C(O)NHR ¹³ , or -Y-(CR ¹¹ R ¹² ) _p -O-phenyl-C(O)-C _1-3 alkyl, wherein: Y is absent, -O-, -C(O)-, -C(O)O-, -CH ₂ -, -OCH ₂ CH ₂ -, -OCH ₂ CH ₂ O-, -C(O)NR ¹³ -, -OCH ₂ CH ₂ NR ¹³ (C)O-, -OCH ₂ CH ₂ NR ¹³ C(O)CH ₂ CH ₂ CH ₂ C(O)NR ¹³ -, -OCH ₂ CH ₂ CH ₂ NR ¹³ C(O)CH ₂ CH ₂ CH ₂ C(O)NR ¹³ -, or -OCH ₂ CH ₂ NR ¹⁴ -; R ¹¹ at each occurrence is independently H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or R ¹⁵ ; R ¹² at each occurrence is independently H, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or R ¹⁵ ; R ¹³ is H or C _1-3 alkyl; or R ¹¹ at each occurrence and R ¹² at each occurrence, together with the atom to which it is attached, forms a ring; or R ¹¹ at each occurrence forms a ring with R ¹³ ; R ¹⁴ is H, halogen, C _1-3 alkyl, or C _1-3 haloalkyl; R ¹⁵ is -C _0-3 alkyl-C(O)OR ¹³ ; and p is 0-5. The compound of claim 112 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ is -Y-(CR ¹¹ R ¹² ) _p -NHR ¹³ . The compound of claim 112 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ is -Y-(CR ¹¹ R ¹² ) _p -C (O)OR ¹³ . The compound of claim 112 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ is -Y-(CR ¹¹ R ¹² ) _p -O -Phenyl-C(O)-C _1-3 alkyl. The compound of any one of claims 112-115, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is absent. The compound of any one of claims 112-115 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -O-. The compound of any one of claims 112-115, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is _-CH2- . The compound of any one of claims 112-115, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -OCH ₂ CH ₂ -. The compound of any one of claims 112-115 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -OCH ₂ CH ₂ NR ¹⁴ -. The compound of any one of claims 112-115 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -C(O)-. The compound of any one of claims 112-115 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -C(O)O- . The compound of any one of claims 112-115 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -OCH ₂ CH ₂ O- . The compound of any one of claims 112-115 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -C(O)NR ¹³ -. The compound of any one of claims 112-115 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -OCH ₂ CH ₂ NR ¹³ (C) O-. The compound of any one of claims 112-115 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -OCH ₂ CH ₂ NR ¹³ C(O) _{CH2CH2CH2C (} ^O ) _NR13- . The compound of any one of claims 112-115 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -OCH ₂ CH ₂ CH ₂ ^NR13C (O) _{CH2CH2CH2C (} ^O ) _NR13- . The compound of claim 112 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ is:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,or

,

,

,

,

,

,

,

,

,

,

,

,

,

,or

. The compound having the structure of any one of the compounds listed in Table 1 according to claim 1 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. The compound of any one of claims 1-129 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compound is covalent with the linker L combine. The compound of any one of claims 1-129 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compound is combined with an antibody, an antibody construct , or the target moiety is covalently bound. The compound of claim 131 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compound is linked to an antibody, antibody construct, or The target moiety is covalently bound. The compound of claim 130 or 132 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L is a non-cleavable linker. The compound of claim 130 or 132 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L is an enzyme-cleavable linker. The compound of claim 130 or 132 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L is cleavable by lysosomal enzymes. The compound of claim 130 or 132 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L comprises the linker shown in Tables 2-7. The compound of claim 131 or 132 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the antibody, antibody construct, or target moiety comprises a specific Antigen-binding domains that bind sexually to tumor antigens or antigens associated with fibrosis pathogenicity. The compound of claim 137 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the antigen binding domain specifically binds to T cells, B cells, Antigens on astrocytes, endothelial cells, tumor cells, APCs, fibroblasts, fibroblasts, or cells associated with the pathogenicity of fibrosis. The compound of claim 137 or 138, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the antigen binding domain specifically binds to a compound comprising CLTA4, PD -1, OX40, LAG-3, GITR, GARP, CD25, CD27, PD-L1, TNFR2, ICOS, 41BB, CD70, CD73, CD38, or VTCN1 antigen. The compound of claim 137 or 138, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the antigen binding domain specifically binds to a compound comprising PDGFRβ, integrating Antigens of integrin αvβ1, integrin αvβ3, integrin αvβ6, integrin αvβ8, endosialin, FAP, ADAM12, LRRC15, MMP14, PDPN, CDH11, or F2RL2. The compound of claim 137 or 138, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the antigen binding domain specifically binds to the LRRC15 antigen. The compound of claim 137 or 138 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the antibody, antibody construct, or target moiety comprises a specific The antigen-binding domain of an antigen that binds sexually to hepatocytes. The compound of claim 142, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the antigen binding domain specifically binds to an antigen comprising ASGR1 or ASGR2 . A conjugate having the structure of:

, wherein A' is an antibody, an antibody construct, or a target moiety, L is a linker, D is a compound according to any one of claims 1-82 or a pharmaceutically acceptable isomer, racemate thereof , hydrate, solvate, isotope, or salt, and z is 1 to 20. The conjugate of claim 144, wherein A' is an antibody. The conjugate of claim 145, wherein the antibody is a monoclonal antibody. The conjugate of any of claims 144-146, wherein A' comprises a wild-type Fc domain. The conjugate of any of claims 144-146, wherein A' comprises a null Fc domain. The conjugate of claim 144, wherein the antibody, antibody construct, or target moiety comprises an antigen binding domain that specifically binds to a tumor antigen or an antigen associated with fibrosis pathogenicity. The conjugate of claim 149, wherein the antigen binding domain specifically binds to T cells, B cells, astrocytes, endothelial cells, tumor cells, APCs, fibroblasts, fibroblasts, or is pathogenic to fibrosis Antigens on Sexually Associated Cells. The conjugate of claim 149 or 150, wherein the antigen binding domain specifically binds to a compound comprising CLTA4, PD-1, OX40, LAG-3, GITR, GARP, CD25, CD27, PD-L1, TNFR2, ICOS, Antigens of 41BB, CD70, CD73, CD38, or VTCN1. The conjugate of claim 149 or 150, wherein the antigen binding domain specifically binds to a compound comprising PDGFRβ, integrin αvβ1, integrin αvβ3, integrin αvβ6, integrin αvβ8, endosialin, FAP, ADAM12, LRRC15 , MMP14, PDPN, CDH11, or an antigen of F2RL2. The conjugate of claim 149 or 150, wherein the antigen binding domain specifically binds to the LRRC15 antigen. The conjugate of claim 144, wherein the antibody, antibody construct, or targeting moiety comprises an antigen binding domain that specifically binds to an antigen on hepatocytes. The conjugate of claim 154, wherein the antigen binding domain specifically binds to an antigen comprising ASGR1 or ASGR2. The conjugate of claim 155, wherein the antigen-binding domain is an anti-ASGR1 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (i) the VH comprises a CDR1 containing the amino acid sequence of SEQ ID NO:1 (VH-CDR1), a VH-CDR2 containing the amino acid sequence selected from SEQ ID NO:8, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:8 The VH-CDR3 of the amino acid sequence of NO:13; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO:18, a CDR1 comprising any one of the amino acid sequences selected from SEQ ID NO:23 The VL-CDR2 of the amino acid sequence of one, and the VL-CDR3 of the amino acid sequence of SEQ ID NO: 33; (ii) the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1, a VH-CDR2 comprising the amino acid sequence selected from SEQ ID NO: 6, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a The VH-CDR3 of the amino acid sequence of NO:13; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO:18, a CDR1 comprising any one of the amino acid sequences selected from SEQ ID NO:23 The VL-CDR2 of the amino acid sequence of one, and the VL-CDR3 of the amino acid sequence of SEQ ID NO: 33; (iii) the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:2, a VH-CDR2 comprising the amino acid sequence selected from SEQ ID NO:9, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:9 The VH-CDR3 of the amino acid sequence of NO:14; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO:19, a CDR1 comprising any one of the amino acid sequences selected from SEQ ID NO:26 The VL-CDR2 of the amino acid sequence of one, and the VL-CDR3 of the amino acid sequence of SEQ ID NO: 34; (iv) the VH comprises a CDR1 (VH-CDR1) containing the amino acid sequence of SEQ ID NO: 1, a VH- containing the amino acid sequence selected from any one of SEQ ID NOS: 6-8 CDR2, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprising a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 18, a VH-CDR1 comprising the amino acid sequence selected from SEQ ID NO: 18 VL-CDR2 of the amino acid sequence of any one of NOS: 23-25, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 33; (v) the VH comprises a CDR1 containing the amino acid sequence of SEQ ID NO:2 (VH-CDR1), a VH-CDR2 containing the amino acid sequence of SEQ ID NO:9, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:14 and the VL comprises a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 19, an amino group containing SEQ ID NO: 26 or SEQ ID NO: 27 VL-CDR2 of the amino acid sequence, and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 34; (vi) the VH comprises a CDR1 containing the amino acid sequence of SEQ ID NO:5 (VH-CDR1), a VH-CDR2 containing the amino acid sequence of SEQ ID NO:12, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:17 and the VL comprises a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 22, a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 32 , and a VL-CDR3 containing the amino acid sequence of SEQ ID NO: 37; (vii) the VH comprises a CDR1 containing the amino acid sequence of SEQ ID NO:3 (VH-CDR1), a VH-CDR2 containing the amino acid sequence of SEQ ID NO:10, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:15 and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 20, a CDR1 comprising the amino acid sequence of VL-CDR2 of the amino acid sequence of SEQ ID NO: 35, and a VL-CDR3 of the amino acid sequence of SEQ ID NO: 35; or (viii) the VH comprises a CDR1 containing the amino acid sequence of SEQ ID NO:4 (VH-CDR1), a VH-CDR2 containing the amino acid sequence of SEQ ID NO:11, a VH-CDR2 containing the amino acid sequence of SEQ ID NO:16 and the VL comprises a CDR1 (VL-CDR1) containing the amino acid sequence of SEQ ID NO: 21, a VL-CDR2 containing the amino acid sequence of SEQ ID NO: 31 , and a VL-CDR3 containing the amino acid sequence of SEQ ID NO:36. The conjugate of claim 155, wherein the antigen-binding domain is an anti-ASGR1 antibody or an antigen-binding fragment thereof, comprising: (a) a VH containing an amino acid sequence that is at least 90% identical to an amino acid sequence selected from any one of SEQ ID NOS: 354, 353, 43-88, 352, and 355-357, and a VL containing an amino acid sequence that is at least 90% identical to an amino acid sequence selected from any one of SEQ ID NOS: 361, 131-133, 358-360, 362, and 363, provided that The amino acid sequences of VH-CDRs and VL-CDRs are unchanged; or (b) a VH containing an amino acid sequence that is at least 90% identical to an amino acid sequence selected from any one of SEQ ID NOS:354, and a VH containing an amino acid sequence selected from SEQ ID NOS:361 The amino acid sequence of any one has at least 90% identity to the VL of the amino acid sequence, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged; or (c) a VH containing an amino acid sequence that is at least 90% identical to an amino acid sequence selected from any one of SEQ ID NOS:353, and a VH containing an amino acid sequence selected from SEQ ID NOS:361 The amino acid sequence of any one has at least 90% identity to the VL of the amino acid sequence, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged; or (d) a VH containing an amino acid sequence that is at least 90% identical to an amino acid sequence selected from any one of SEQ ID NOS:354, and a VH containing an amino acid sequence selected from SEQ ID NOS:362 The amino acid sequence of any one has at least 90% identity to the VL of the amino acid sequence, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged; or (e) a VH containing an amino acid sequence that is at least 90% identical to an amino acid sequence selected from any one of SEQ ID NOS:353, and a VH containing an amino acid sequence selected from SEQ ID NOS:362 The amino acid sequence of any one has at least 90% identity to the VL of the amino acid sequence, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged; or (f) a VH containing an amino acid sequence selected from any one of SEQ ID NOS:354, 353, 43-88, 352, and 355-357, and a VH containing an amino acid sequence selected from SEQ ID NOS:361, the VL of the amino acid sequence of any one of 131-133, 358-360, 362, and 363; or (g) a VH containing an amino acid sequence selected from any one of SEQ ID NOS:354, and a VL containing an amino acid sequence selected from any one of SEQ ID NOS:361; or (h) a VH containing an amino acid sequence selected from any one of SEQ ID NOS:353, and a VL containing an amino acid sequence selected from any one of SEQ ID NOS:361; or (i) a VH containing an amino acid sequence selected from any one of SEQ ID NOS:354, and a VL containing an amino acid sequence selected from any one of SEQ ID NOS:362; or (j) a VH containing an amino acid sequence selected from any one of SEQ ID NOS:353, and a VL containing an amino acid sequence selected from any one of SEQ ID NOS:362. The conjugate of claim 155, wherein the antigen-binding domain is an anti-ASGR1 antibody, or an antigen-binding fragment thereof, comprising: (a) a VH containing an amino acid sequence that is at least 90% identical to an amino acid sequence selected from any one of SEQ ID NOS: 89-93, and a VH containing an amino acid sequence selected from SEQ ID NOS: The amino acid sequence of any one of 134-137 has at least 90% identity to the VL of the amino acid sequence, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged; or (b) a VH containing an amino acid sequence that is at least 90% identical to an amino acid sequence selected from any one of SEQ ID NOS:89, and a VH containing an amino acid sequence selected from SEQ ID NOS:134 The amino acid sequence of any one has at least 90% identity to the VL of the amino acid sequence, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged; or (c) a VH containing an amino acid sequence that is at least 90% identical to an amino acid sequence selected from any one of SEQ ID NOS:89, and a VH containing an amino acid sequence selected from SEQ ID NOS:136 The amino acid sequence of any one has at least 90% identity to the VL of the amino acid sequence, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged; or (d) a VH containing an amino acid sequence selected from any one of SEQ ID NOS: 89-93, and a VH containing an amino acid sequence selected from any one of SEQ ID NOS: 134-137 VL; or (e) a VH containing an amino acid sequence selected from any one of SEQ ID NOS:89, and a VL containing an amino acid sequence selected from any one of SEQ ID NOS:134; or (f) a VH containing an amino acid sequence selected from any one of SEQ ID NOS:89, and a VL containing an amino acid sequence selected from any one of SEQ ID NOS:136. A pharmaceutical composition comprising the compound of any one of claims 1-143 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and at least one pharmaceutically acceptable excipients. A pharmaceutical composition comprising the conjugate of any one of claims 144-158, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of claim 160, wherein the conjugate has an average DAR of about 1 to about 8, or about 1 to about 3, or about 3 to about 5. The pharmaceutical composition of claim 160, wherein the conjugate has an average DAR of from about 4 to about 8. The pharmaceutical composition of claim 161, wherein the conjugate has an average DAR of about 6 to about 8. A method of killing tumor cells in vivo, comprising in the presence of immune cells with an effective amount of a compound of any one of claims 1-143, a conjugate of any one of claims 144-158, or The pharmaceutical composition of any of claims 159-163 contacts a tumor cell population. A method of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-143, a conjugate of any one of claims 144-158, or a The pharmaceutical composition of any of claims 159-163. A method of treating or ameliorating fibrotic disease, comprising administering to a subject with fibrotic disease an effective amount of a compound according to any one of claims 1-143, such as any one of claims 144-158 A conjugate, or a pharmaceutical composition as claimed in any one of claims 159-163. A method for reducing myofibroblastic cells comprising administering to a subject at risk of developing or having a fibrotic disease an effective amount of a compound according to any one of claims 1-143, such as claims 144-158 The conjugate of any one, or the pharmaceutical composition of any one of claims 159-163.

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