KR20120117977A - Polypeptides that bind il-23r - Google Patents

Abstract

The present invention relates to a polypeptide that binds to IL-23R including a multimerization, eg, a polypeptide having a polypeptide sequence that binds to the trimerization domain and IL-23R. The multimerization domain can be derived from human tetranectin. IL-23R binding polypeptides inhibit the activation of IL-23R by natural IL-23, which can be used as a therapeutic for various immune related disorders and cancers. Methods of selecting polypeptides and methods of making multimeric complexes are described.

Description

Polypeptide which binds to IL-23R {POLYPEPTIDES THAT BIND IL-23R}

Before and after reference of related application

This application is partly filed in U.S. Patent Application No. 12 / 577,067, filed Oct. 9, 2009, partly filed in International Application PCT / US09 / 60271, filed Oct. 9, 2009, and Feb. 10, 2010. Partially filed in US Application 12 / 703,752, filed on May, each of which is incorporated herein by reference in its entirety.

Sequence Listing Description

The Sequence Listing has been submitted to this application in electronic format only, which is incorporated herein by reference. Sequence Listing Document File "10- .SequenceListing.txt " Generated by The byte size.

Field of invention

The present invention relates to the treatment of cancer as well as inflammatory and autoimmune diseases. In particular, the present invention relates to polypeptides that bind to the IL-23R subunit of the IL-23R heterodimeric receptor and block the interaction of IL-23 with its receptor.

BACKGROUND OF THE INVENTION

IL-23 is a cytokine essential for the development and survival of Th17 cells. From preclinical models and clinical trials, evidence continues to emerge that Th17 cells play an important role in the pathology of many autoimmune diseases, including rheumatoid arthritis, inflammatory growth disease, psoriasis, systemic lupus erythematosus (SLE) and multiple sclerosis. IL-23R is an important target in Th17 cells. The IL-23 heterodimeric receptor consists of two subunits of IL-23R and IL-12Rβ1, and IL-23R is the only subunit for the IL-23 pathway. IL-12Rβ1 is shared with the IL-12 receptor and thus with the IL-12 pathway. Similarly, the IL-23 cytokine consists of two subunits of p19 and p40, p19 is unique for IL-23, and p40 is shared with IL-12. Binding of IL-23 to the heterodimeric IL-23 receptor mediates activation of specific T cell subsets, NK cells and myeloid cells.

Importantly, genetic changes in IL-23R are associated with susceptibility to psoriasis and Crohn's disease, and also include ankylosing spondylitis, Bog-Koyagi-Harada disease, systemic sclerosis, Beliefs disease (BD), Primary Sjogren's syndrome, related to susceptibility to goodpasture disease. In addition, the importance of IL-23 in graft-versus-host disease and chronic ulcers has been proposed, and IL-23 is associated with tumorigenesis.

Blocking the IL-23 pathway is effective in many preclinical models of autoimmune disease. However, the characteristics of shared ligand and receptor subunits between IL-23 and IL-12 pathways result in more complex biology than previously recognized, and the separation of IL-23 blockade from IL-12 blockade is potent and safe. Seems to have an important therapeutic association with Blocking either or the other, or both, of IL-23 and IL-12 may be performed at the level of cytokine subunits or receptor subunits.

Antibodies targeting IL-23 / IL-12 cytokines are approved (e.g., p40-targeted Uste), along with IL-23 specific anti-p19 antibodies from Schering Plough in early clinical development Ustekinumab) or Abbott Laboratories, but there is a need for IL-23 specific blocking with good efficacy and better safety profiles for the following reasons:

The distribution of IL-23 heterodimeric receptors is relatively limited to IL-23 heterodimeric receptor expressing cells, which are mainly found in inflammatory / disease tissues. In contrast, IL-23 can be detected systemically and is more abundant.

Targeting receptors on the p19 subunit of IL-23 has been found to be beneficial in situations where cytokines are not cell bound and / or abundant, as evidenced in autoimmune tissues such as synovial membranes from rheumatoid arthritis patients.

Targeting receptors will block more effectively in patients with receptor variants that may be more sensitive to IL-23 signaling (ie, low threshold variants that require very few ligands for signaling).

In addition, if initially developed to block IL-12, preclinical efficacy of Ustekinumab is mediated through IL-12 blockade and blocking the IL-12 pathway may be detrimental based on the following observations. And clinical evidence exists:

In psoriasis trials with Ustekinumab, p19, an IL-23-specific cytokine subunit, was downregulated in plaque (but not p35, an IL-12-specific cytokine subunit). ).

P19 and p40 knockout mice were resistant to the induction of experimental autoimmune disease, whereas knockout of IL-12 specific subunit p35 exacerbated many experimental autoimmune diseases.

In addition to the potential for good efficacy, selective blocking of IL-23 relative to both IL-12 and IL-23 is particularly advantageous with regard to the safety associated with susceptibility to infection, which is the blocking of both cytokines. This has been shown to increase susceptibility to this Toxoplasma gondii, Cryptococcus neoformans, and M. tuberculosis, and similar other pathogens.

• Safety advantages may also be related to the potential for tumorigenicity. Preclinical data suggest that inhibiting IL-12 enhances tumor growth, while inhibiting IL-23 can reduce tumor growth. In contrast to IL-12p40, IL-23 is overexpressed in human tumors. In addition, murine validation studies demonstrate that IL-23 knockout mice or anti-IL-23 treated mice are resistant to tumor formation, while elevated IL-23 levels can increase tumor formation.

Thus, a molecule that selectively blocks IL-23 heterodimeric receptors by blocking IL-23R, a composition comprising the molecule, a method of screening the molecule, and the therapeutic treatment of a wide range of inflammatory and autoimmune diseases and cancers There is a need in the art for using molecules. These molecules show good target retention due to the binding effect and localize treatment to the inflammatory site associated with the disorder without significantly compromising systemic immunity.

Summary of the Invention

In one aspect, the invention relates to a polypeptide having a trimerizing domain and at least one polypeptide sequence that binds human IL-23R without activating the IL-23 heterodimeric receptor. In another embodiment, the polypeptides of the invention do not bind to at least one of human IL-12Rβ1 or human IL-12Rβ2 and compete with native human IL-23 for binding to human IL-23R. The trimerization domain is a human tetranectin trimerization domain having up to 5 amino acid substitutions at positions 26, 30, 33, 36, 37, 40, 41, 42, 45, 46, 47, 48, 49, 50 and 51 ( The polypeptide of SEQ ID NO: 108). Such polypeptides may form trimer complexes. Polypeptides may be trimerized to form trimeric complexes.

In addition, the polypeptides of the invention comprise at least one polypeptide that binds IL-23R and is linked to one of the N-terminus and C-terminus of the trimerization domain, and also to the rest of the N-terminus and C-terminus. Includes coordinators of located inflammation. Polypeptides of the invention may also have a polypeptide that binds to IL-23 linked to each of the N-terminus and C-terminus, wherein the N-terminal polypeptide is the same as or different from the C-terminal polypeptide. Polypeptides may also have therapeutic agents covalently attached to such polypeptides.

Further, the polypeptide of the present invention comprises a C-type lectin-like domain (CTLD), wherein one of loops 1, 2, 3 or 4 of loop segment A or loop segment B of CTLD binds to IL-23. Sequence. In various embodiments, the polypeptide sequence of CTLD is selected from the group consisting of SEQ ID NOs: 133, 134, 135, 167, 137, 138, 139, 140, and 141.

The present invention also relates to a method for preventing the activation of IL-23R by IL-23 in cells expressing IL-23R. The method comprises contacting the cell with the trimer complex of the present invention. In another embodiment, the present invention includes a pharmaceutical composition comprising a trimer complex and at least one pharmaceutically acceptable excipient. The composition can be administered to treat an immune disorder or cancer. The composition may also include a modulator of inflammation, a chemotherapeutic agent or a cytotoxic agent.

Further, the present invention relates to a method of producing a polypeptide of the present invention. The method comprises selecting a first polypeptide that binds IL-23R and fusing this first polypeptide with either the N-terminus or C-terminus of the multimerization domain. The method may also include selecting a second polypeptide sequence that is a mediator of inflammation and fusing this second polypeptide with the rest of the N-terminus or C-terminus of the multimerization domain. The first polypeptide may be selected to not bind to at least one of IL-12Rβ1 or IL-12Rβ2. The polypeptide can be used to prepare a trimer complex that prevents the activation of IL-23R in cells expressing IL-23R.

Further, the present invention relates to a polypeptide that competes with natural human IL-23 for binding to natural IL-23R, wherein the polypeptide does not activate human IL-23R and at least one of IL-12Rβ1 or IL-12Rβ2. Do not combine in one. The polypeptide can be a CTLD modified in one of loops 1, 2, 3 or 4 of loop segment A or loop segment B for binding to IL-23R, which is SEQ ID NO: 133, 134, 135, 167, 137, 138, 139, 140, and 141.

Description of Drawings

1A and 1B show human IL-23 (SEQ ID NO: 1), human IL-23R (SEQ ID NO: 5), human IL-12Rβ1 (SEQ ID NO: 6), human IL-12Rβ2 (SEQ ID NO: 7), polypeptides of human IL-12A (SEQ ID NO: 3), and human IL-12B (SEQ ID NO: 2) are shown.

2A, B, C and D show examples of tetranectin trimerization module variants for use with exemplary polypeptides of the invention.

3 shows the alignment of amino acid sequences of trimerized structural components of the tetranectin protein family. The amino acid sequence corresponding to residues V17 to K52 comprising exon 2 of human tetranectin (1-letter code) and the first three residues of exon 3 (SEQ ID NO: 99); Murine tetranectin (SEQ ID NO: 100) (Sorensen et al . , Gene, 152: 243-245, 1995); Tetranectin homologue protein (SEQ ID NO: 107) isolated from reefshark cartilage (Neame and Boynton, 1992, 1996); And tetranectin homologue protein (SEQ ID NO: 106) (Neame and Boynton, database accession number PATCHX: u22298) isolated from bovine cartilage. The residues at positions a and d in the heptad repeat are indicated in bold. The listed consensus sequence (SEQ ID NO: 108) of the tetranectin protein family trimerization structural component includes residues present at positions a and d in the heptad repeats shown in the figures, as well as other conserved residues in that region. . "*" Represents an aliphatic hydrophobic residue.

4 shows the alignment of amino acid sequences of ten CTLDs of known 3D-structure. The sequence positions of the major secondary structural components are indicated in each of the above sequences, which are labeled in successive numbered order with "αN" for α-helix number N and "βM" for β-stranded number M. . Four cysteine residues associated with the formation of two conserved disulfide bridges of CTLD are indicated and listed in the figures as "CI", "CII", "CIII" and "CIV", respectively. The two conserved disulfide bridges are CI-CIV and CII-CIII, respectively. Various loops 1-4 and LSB (loop 5) in the human tetranectin sequence are underlined. Ten C-type lectins include hTN: human tetranectin (SEQ ID NO: 109), MBP: mannose binding protein (SEQ ID NO: 110); SP-D: surfactant protein D (SEQ ID NO: 111); LY49A: NK receptor LY49A (SEQ ID NO: 112); H1-ASR: H1 subunit of asialo glycoprotein receptor (SEQ ID NO: 113); MMR-4: macrophage mannose receptor domain 4 (SEQ ID NO: 114); VIII-A (SEQ ID NO: 115) and VIII-B (SEQ ID NO: 116): coagulation factor VIII / VIII-binding protein domains A and B, respectively; Lit: ristostatin (SEQ ID NO: 117); TU14: Encapsulated C-type lectin (SEQ ID NO: 118). All of the above CTLDs except TU14 are derived from human proteins.

5 shows a human (Swissprot P05452) (SEQ ID NO: 119), a mouse (Swissprot P43025) (SEQ ID NO: 120), a chicken (Swissprot Q9DDD4) (SEQ ID NO: 121), a cow (Swissprot Q2KIS7) (SEQ ID NO: 122), Atlantic Salmon (Swissprot B5XCV4) (SEQ ID NO: 123), Frog (Swissprot Q5I0R9) (SEQ ID NO: 124), Zebrafish (GenBank XP_701303) (SEQ ID NO: 125) Amino acid sequence of tetranectin and related CTLD homologues isolated from cartilage of bovine (Swissprot u22298) (SEQ ID NO: 126) and shark (Swissprot p26258) (SEQ ID NO: 127).

6 shows a PCR method for generating randomized loops in CTLD.

FIG. 7 shows the DNA and amino acid sequences of human tetranectin CTLD modified to contain restriction sites for cloning showing Ca2 + binding sites. Restriction sites are indicated by underlined solid lines. The loop is indicated by a dashed underline. Calcium coordinating residues are indicated in bold italics, which are site 1: D 116, E 120, G 147, E 150, N 151; Site 2: includes Q 143, D 145, E 150, D 165. The CTLD domain starts at amino acid A45 in bold (ie ALQTVCL ...). Changes to the native tetranectin (TNCTLD) nucleotide sequence are shown in lowercase letters. Restriction sites were generated using silent mutations that do not alter the natural amino acid sequence.

8 depicts a number of sequences of polypeptides of the invention that bind to IL-23R. The sequence was generated according to the method of the present invention by selecting a polypeptide from a library of polypeptides having a scaffold structure of human tetranectin CTLD modified in one or more loop regions. The CTLD scaffold of this sequence starts at A45 of human tetranectin (SEQ ID NO: 119). Portions of the sequence representing the randomized loop region are underlined.

9 shows maturation of humans starting in the trimerization domain (SEQ ID NOS: 143 [nucleotide sequence] and 142 [amino acid sequence]) and murine tetranectin (SEQ ID NOS: 144 [nucleotide sequence] and 145 [amino acid sequence]). The alignment of the nucleotide and amino acid sequences of the coding region of the form is shown, and known secondary structural components are indicated.

10 shows the results of a competitive ELISA. Binding of human IL-23 to human IL-23R in the presence or absence of a polypeptide of the invention was evaluated.

FIG. 11 shows the results of an experiment comparing IL-23-induced IL-17 production in the presence of the ATRIMER ™ complex 4G8, natural human IL-23, and Ustekinumab of the present invention. Illustrated.

FIG. 12 shows the results of an experiment comparing IL-23-induced IL-17 production in the presence of the Atrimer ™ Complex 1A4 and Ustekinumab of the present invention.

FIG. 13 shows the results of an experiment comparing IL-12-induced IFNγ production in the presence of the Atrimer ™ Complex 4G8, natural human IL-23, and Ustekinumab of the present invention.

14 shows the results of experiments comparing Stat-3 phosphorylation in NKL cells in response to IL-23 and polypeptides of the invention.

FIG. 15 is a table showing experimental results associated with various Atrimer ™ polypeptide complexes of the present invention. FIG.

FIG. 16 shows the three-dimensional structure (ribbon format) for human tetranectin, which represents the secondary structural characteristics of the protein. The structure has been described in Ca ²⁺ -bonded form.

17A includes human mannose binding protein (MBP), rat mannose binding protein-C (MBP-C), human surfactant protein D, rat mannose binding protein-A (MBP-A), and rat surfactant protein A. Three-dimensional superposition of CTLD for human tetranectin (HTN) and various tetranectin homologues is shown. CTLD superimposition structures were generated using Swiss PDB Viewer Deep View v.4.0.1 for Macintosh using the three-dimensional structure of human tetranectin as a template. FIG. 17B shows the corresponding amino acid sequence of CTLDS for the human tetranectin and tetranectin analogs shown in FIG. 17A. In FIG. 17B, 1HUP is human mannose binding protein, 1BV4A is rat mannose binding protein, 2GGUA is human surfactant protein D, 1KX0A is rat mannose binding protein A, and 1R13 is rat surfactant protein A.

18A shows human pancreatitis-related protein, human dendritic cell-specific ICAM-3-grabbing non-integrin 2 (DC-SIGNR), rat agrecan, mouse scavenger receptor And three-dimensional overlapping structures of CTLDs for human tetranectin (HTN) and various tetranectin analogs, including human scavenger receptors. CTLD superimposition structures were generated using Swiss PDB Viewer Deep View v.4.0.1 for Macintosh using the three-dimensional structure of human tetranectin as a template. FIG. 18B shows the corresponding amino acid sequence of CTLDS for the human tetranectin and tetranectin analogs shown in FIG. 18A. In FIG. 18B, 1TDQB is rat aggrecan, 1UV0A is a human pancreatitis-related protein, 20X8A is a human scavenger receptor, 20X9A is a mouse scavenger receptor, and 1SL6A is a human DC-SIGNR.

DETAILED DESCRIPTION OF THE INVENTION

In various aspects, the invention relates to a polypeptide that binds to IL-23R and comprises a polypeptide sequence of a multimerization domain and one or more polypeptide sequences that bind to IL-23R. In one embodiment, the polypeptides of the invention act as IL-23R antagonists. Two, three or more polypeptides can be multimerized to form a multimer complex comprising a polypeptide that binds IL-23R. In one alternative embodiment, the polypeptide binds to IL-23R but not to IL-12β1 or IL-12β2. The invention also provides a method of treating an immune mediated disorder, cancer and other diseases in a subject by administering the polypeptide or a multimeric complex of polypeptides to a patient in need thereof.

Justice

Before defining the invention in more detail, a number of terms are defined. Unless specific definitions of terms are provided herein, the terms and phrases used throughout this specification should be interpreted to have the same meaning as commonly understood in the art. Also, the singular forms as used in the specification and the appended claims of the present invention include plural referents unless the context clearly dictates otherwise.

"IL-23" is a cytokine that acts as an innate and adaptive immunity, meaning a heterodimeric protein complex belonging to the IL-6 superfamily. Heterodimeric complexes are secreted by activated dendritic cells and phagocytes and keratinocytes. IL-23 is also expressed by cutaneous Langerhans cells. IL-23A, p19 subunit, also known as IL-B30, or simply “p19” is associated with IL-12B, p40 subunit to form IL-23 (p19 / p40). The amino acid sequences of IL-23A (p19) (SEQ ID NO: 1) and IL-12B (SEQ ID NO: 2) are shown in FIG. 1.

IL-23 is upregulated by a wide variety of pathogens and pathogen-products with self-signaling for risk or damage. IL-23 is upregulated in psoriasis skin tissue, dendritic cells of multiple sclerosis patients, and IL-23 has been found to be active in promoting tumor incidence and growth. In addition, IL-23 stimulates neutrophils and macrophage infiltration, as well as promotes angiogenesis and inflammatory mediators in the tumor microenvironment. IL-23 can cause down regulation of IL-12 and interferon γ, both of which are essential cytokines for cytotoxic immune responses, which are influx and activity of anti-tumor effector lymphocytes Adjust. IL-23 is indistinguishable from anti-tumor immunity and affects repurposing of adaptive cytotoxic effector responses close to the proinflammatory and proangiogenic effector pathways that feed tumors Proposed. As a result, IL-23 enables the persistence of recognized tumor cells with tumor-associated inflammation. This concept may explain tumor growth in the presence of large amounts of tumor-specific T cells.

The term “IL-23 heterodimeric receptor” refers to a heterodimeric polypeptide complex of IL-23R and IL-12Rβ1. This receptor binds to IL-23. Polypeptide sequences of IL-23R and IL-12Rβ1 are shown in FIG. 1.

The term "IL-23R" refers to a polypeptide capable of complexing with IL-12Rβ1 to form an IL-23 heterodimeric receptor. IL-23R is also referred to as IL-23R subunit.

The term “IL-12Rβ1” refers to a polypeptide complexed with IL-23R to form an IL-23 heterotrimeric receptor and separately and independently complexed with IL-12Rβ2 to form a heterodimeric IL-12 receptor. Polypeptide sequences of IL-12Rβ1 and IL-12Rβ2 are shown in FIG. 1.

"Inhibitor" and "antagonist" or "active agent" and "agonist" mean an inhibitory or activating molecule, respectively. An "inhibitor" can reduce, block, prevent, retard, inactivate, or desensitize a biological function or activity associated with, for example, a gene, protein, ligand, receptor, or cell, Down-regulating compounds. Active agents are, for example, genes, proteins, ligands, receptors, or compounds that increase, activate, promote, enhance activation, sensitize, or upregulate the biological function or activity of a cell. . An “agonist” is a compound that interacts with a target to cause or promote an increase in activation of the target. An "antagonist" is a compound that counters the action of an agonist. Antagonists prevent, reduce, inhibit or neutralize the activity of agonists. An agonist can also prevent, inhibit or reduce the constitutive activity of a target, eg, a target receptor, even in the absence of an agonist identified.

A "modulator" of a gene, receptor, ligand, or cell is a molecule that alters the activity of a gene, receptor, ligand, or cell when activity in regulatory properties can be activated, inhibited or altered. Modulators may act alone or may use cofactors such as proteins, metal ions, or small molecules.

The term “IL-23R antagonist” alone or in combination with IL-12Rβ1 blocks IL-23R's ability to bind and bind IL-23, blocks receptor heterodimer formation, changes in form or receptor internalization. By any molecule that blocks or attenuates receptor signaling through a variety of mechanisms that can block or induce changes that affect intracellular signaling, including.

As used herein, the term “binding member” refers to a member of a molecular pair having binding specificity for each other. Members of a binding pair may be naturally derived or synthetically produced in whole or in part. One member of a molecular pair binds to a particular spatial and polar configuration of the other member of the molecular pair and thus has regions or cavities on the surface that are complementary thereto. Thus, members of the pair have the property of binding specific to each other.

When referred to in a ligand / receptor, antibody / antigen, or other binding pair, “specific” or “selective” binding refers to a binding reaction that determines the presence of a member of a binding pair in the heterologous set of another member of the binding pair. Thus, under specified conditions, for example, the specified ligand binds to a specific receptor and does not bind to a significant amount of other proteins present in the sample.

As used herein, the term “multimerization domain” refers to an amino acid sequence that includes functionality that can be associated with other amino acid sequence (s) having a multimerization domain to form a multimer complex. In various embodiments of the present invention, the multimerization domain is a dimerization domain, trimerization domain, tetramerization domain, pentomerization domain, and the like. Such domains may form polypeptide complexes of two, three, four, five or more polypeptides of the invention. In one embodiment, the polypeptide contains an amino acid sequence of a “trimerization domain” that forms a trimeric complex with two other trimerization domains. The trimerization domain can be associated with another trimerization domain (homotrimer) of the same amino acid sequence, or with the trimerization domain (heterotrimer) of different amino acid sequence. This interaction can be caused by covalent bonds between components of the trimerization domain as well as by hydrogen bonding, hydrophobic bonding, van der Waals bonding and salt bridges.

The trimerization domain of the polypeptides of the invention can be derived from tetranectin as described in US Patent Application Publication No. 2007/0154901 (the '901 application), which is incorporated by reference in its entirety. The mature human tetranectin single chain polypeptide sequence is provided herein as SEQ ID NO: 142. Examples of tetranectin trimerization domains include amino acids 17-49, 17-50, 17-51, and 17-52 of SEQ ID NO: 99, the amino acids encoded by exon 2 of the human tetranectin gene, and optionally exon 3 of the gene. Contains the first 1, 2 or 3 amino acids encoded by. Other examples include amino acids 1 to 49, 1 to 50, 1 to 51 and 1 to 52, which are both exons 1 and 2, and optionally the first 1, 2 or 3 amino acids encoded by exon 3 of the gene. Alternatively, only a portion of the amino acid sequence encoded by exon 1 is included in the trimerization domain. In particular, the N-terminus of the trimerization domain is residues 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17 of SEQ ID NO: 99. May begin at any residue of In certain embodiments, the N-terminus is I10 or V17 and the C-terminus is Q47, T48, V49, C (S) 50, L51 or K52 (numbering according to SEQ ID NO: 99). 2A-2D also provide a number of potential truncation variants of the human tetranectin trimerization domain.

In one aspect of the invention, the trimerization domain is SEQ ID NO: 108 which is the consensus sequence of the tetranectin family trimerization structural component as described more fully in US 2007/00154901, which is incorporated herein by reference in its entirety. Tetranectin trimerization structural component ("TTSE") having the amino acid sequence of. As shown in FIG. 3, TTSE has any substantial degree of adverse effect on the ability of TTSE to form variants of naturally occurring members of the tetranectin family of proteins, especially alpha helical coiled coil trimers. Variants modified within the amino acid sequence without affecting. In various embodiments of the invention, the trimeric polypeptide according to the invention has at least 66% amino acid sequence identity with the consensus sequence of SEQ ID NO: 108, eg, at least 73% with the consensus sequence of SEQ ID NO: 108. And TTSE as a trimerization domain having sequence identity (calculating only defined (but not X) residues) of at least 80%, at least 86% or at least 92%. That is, at least one, at least two, at least three, at least four, or at least five of the defined amino acids of SEQ ID NO: 108 may be substituted.

In one specific embodiment, the cysteine (C50) at position 50 of SEQ ID NO: 142 is a serine, threonine, methionine or any other amino acid to avoid the formation of unwanted interchain disulfide bridges that may result in unwanted multimerization. It may be advantageously mutated with residues. Other known variants are amino acid residue numbers 6, 21, 22, 24, 25, 27, 28, 31, 32, 35, 39, 41, and 42 that may be substituted by amino acid residues that destroy any non-helix. At least one amino acid residue selected from (numbering according to SEQ ID NO: 142). These residues have not been found to be directly related to the intermolecular interactions that stabilize the trimer complex between the three TTSEs of the native tetranectin monomer. In one embodiment shown in FIG. 3, the TTSE has a repeated heptad having the formula abcdefg (N to C), wherein residues a and d (ie, positions 26, 30, 33, 37, 40, 44, 47, And 51) can be any hydrophobic amino acid (numbering according to SEQ ID NO: 99).

In further embodiments, the TTSE trimerization domain comprises a polyhistidine sequence and / or integration of a protease cleavage site, such as blood coagulation factor VIIa or Granzyme B (US 2005/0199251, incorporated herein by reference). And C-terminal KG or KGS sequences. In addition, to aid purification, the proline at position 2 may be substituted with glycine.

Certain non-limiting examples of TTSE truncations and variants are shown in FIGS. 2A-2D. In addition, a number of trimerization domains are known that have substantial homology (greater than 66%) with the trimerization domain of human tetranectin:

Table 1

Other human polypeptides known to be trimerized include:

Another example of the trimerization domain is disclosed in US Pat. No. 6,190,886, which is incorporated herein by reference in its entirety. Trimers can then be prepared under appropriate conditions using three polypeptides comprising the collector neck region amino acid sequence. A number of collectors have been identified, including:

Collector's neck area of human SP-D:

Collector's neck area of bovine SP-D:

Collector's neck area of rat SP-D:

Collector's neck area of bovine conglutinin:

Collector's neck area of bovine collector:

Neck area of human SP-D:

Other examples of MBP trimerization domains are described in PCT Application Serial No. US08 / 76266, published as WO 2009/036349, which is incorporated by reference in its entirety. Such trimerization domains can be further oligomerized and create higher regimen multimer complexes.

In the context of the present invention, a "trimerization domain" may interact with other similar or identical trimerization domains. This interaction is the type that produces the trimer protein or polypeptide. Such interactions can be caused by hydrogen bonding, hydrophobic bonding, van der Waals bonding, and salt bridges as well as covalent bonding between the components of the trimerization domain. The trimerization effect of the trimerization domain is caused by a coiled coil structure that interacts with the coiled coil structure of two different trimerization domains to form a triple alpha helical coiled coil trimer that is stable even at relatively high temperatures. In various embodiments, for example, in embodiments of trimerization domains based on tetranectin structural components, the complex is stable at least 60 ° C., eg, in some embodiments, at least 70 ° C.

The terms "C-type lectin-like protein" and "C-type lectin" are used to mean any protein that is present in or encoded in the genome of any eukaryotic species, which protein is one or more that binds to a carbohydrate ligand. Contain one or more domains belonging to a CTLD or a subgroup of CTLD. The above definitions refer to C-type lectin-like proteins and C-type lectin- and mutant C-type lectin-like proteins that are specifically lacking membrane attached C-type lectin-like proteins and C-type lectins, "soluble" C-type lectin-like proteins and functional membrane domains. And any product obtained by chemical modification of C-type lectin-like proteins and C-type lectins, as well as C-type lectins, wherein one or more amino acid residues have been modified in vivo by glycosylation or any other post-synthesis modification. Include.

CTLD consists of approximately 120 amino acid residues and contains two or three intrachain disulfide bridges as a feature. Although the similarity at the amino acid sequence level between CTLDs from different proteins is relatively low, the 3D-structure of many CTLDs is highly highly oriented with structural variations that are essentially limited to the so-called loop-regions defined by five or fewer loops. It turns out to be conservative. Many CTLDs contain one or two binding sites for calcium, with most of the side chains interacting with calcium located within the loop-regions.

Based on the CTLD where 3D structural information is available, the canonical CTLD is composed of seven major secondary structural components (i.e. five βs) that appear in succession in the order of β1, α1, α2, β2, β3, β4 and β5. -Strand and two α-helices) are inferred as structural features. 4 illustrates the alignment of CTLD of ten known C-type lectins. In all CTLDs with 3D structure determined, the β-strand is arranged in two antiparallel β-sheets, one consisting of β1 and β5 and the other consisting of β2, β3 and β4. An additional β-strand, β0, often precedes β1 in the sequence and, when present, forms an additional strand that is incorporated into β1, β5-sheet. In addition, two disulfide bridges linking α 1 and β 5 (C _I -C _IV ), one linking β 3, and polypeptide segments linking β 4 and β 5 (C _II -C _III ) so far It is found invariably in all characterized CTLDs. 5 also shows the alignment of CTLDs from human tetranectin and eight other tetranectin or tetranectin-like polypeptides.

In CTLD 3D-structures, these conserved secondary structure components form dense scaffolds for multiple loops collectively referred to as "loop-regions" protruding from the core in the context of the present invention. In the primary structure of the CTLD, this loop is organized into two segments, loop segment A, LSA, and loop segment B, LSB. LSAs are long polypeptide segments that link β2 and β3, which often lack regular secondary structure and contain no more than four loops. LSB is a polypeptide segment that connects β-strand β3 and β4. moiety of the LSA with a single residue in β4 is Ca ^{2 +} the number of CTLD comprising the CTLD of tetra nektin - It has been found that the specific binding site-binding sites and a ligand. For example, mutations induced with 1 or substitution of a few residues study binding specificity, Ca ^{2 +} - it has been found that the sensitivity and / or affinity can be provided by changing the CTLD domain. Non-limiting examples include tetranectin, ritstatin, mouse macrophage galactose lectin, cooper cell receptor, chicken neurocan, perlucin, asialo glycoprotein receptor, cartilage proteoglycan core protein, IgE Fc receptor, pancreatitis- Related proteins, mouse macrophage receptor, natural killer cell group, stem cell growth factor, factor VIII / VIII binding protein, mannose binding protein, bovine conglutinin, bovine CL43, collectin liver 1, surfactant protein A, surfactant protein D, e-selectin, capsular c-type lectin, CD94 NK receptor domain, LY49A NK receptor domain, chicken liver lectin, trout c-type lectin, HIV gp 120-binding c-type lectin, and dendritic cell immunoreceptors Many CTLDs are known. See, eg, US Patent Publication No. 2007/0275393, which is incorporated herein by reference in its entirety, and Essentials of Glycobiology, second edition. Edited by A. Varki, RD Cummings, JD Esko, HH. Freeze, P. Stanley, CR Bertozzi, GW Hart, ME Etzler. CHS Press].

"Atrimer ™ polypeptide complex" or "Atrimer ™ complex" means a trimer complex of three trimerization domains that also includes CTLD (Anaphore, Inc., San Diego, California).

The expression “effective amount” means the amount of a polypeptide of the present invention, optionally in combination with a therapeutic agent, effective to prevent, ameliorate, or treat the disease or condition whether administered simultaneously or sequentially. In certain embodiments, the effective amount reduces the effect of IL-23 on IL-23R expressing cells, affects other pathways for IL-23R expressing cells that synergize with IL-23R, or Affect other immune cells that work with -23R expressing cells, reduce the tendency of cells to proliferate or survive, or enhance or otherwise enhance the tendency (eg, synergistically) of cells that undergo apoptosis Amounts of polypeptides of the invention in combination, and therapeutic agents, such as cytotoxic or immunosuppressive agents, that are sufficient to increase, decrease tumor volume, or prolong survival of a mammal with cancer or an immune related disease. to be.

"Therapeutic agent" means a cytotoxic agent, chemotherapeutic agent, immunosuppressant, anti-inflammatory agent, immunostimulatory agent, and / or growth inhibitory agent.

As used herein for collateral therapy, the terms "immunosuppressant" and "modulator of inflammation" refer to substances that act to inhibit or conceal the immune system of the mammal being treated herein. These include substances that inhibit cytokine production, downregulate or inhibit self-antigen expression, inhibit the migration of immune cells to the site of chronic inflammation, or conceal MHC antigens. Examples of such agents include 2-amino-6-aryl-5-substituted pyrimidines (see US Pat. No. 4,665,077); Nonsteroidal anti-inflammatory drugs (NSAIDs); Azathioprine; Cyclophosphamide; Bromocryptine; Danazol; Dapsone; Glutaraldehyde (hiding MHC antigens as described in US Pat. No. 4,120,649); Anti-idiotype antibodies against MHC antigens and MHC fragments; Cyclosporin A; Steroids such as glucocorticosteroids such as prednisone, methylprednisolone, dexamethasone, and hydrocortisone; Methotrexate (oral or subcutaneous); Hydroxycloroquine; Sulfasalazine; Leflunomide; Cytokine or cytokine receptor antagonists such as anti-interferon-gamma (IFN-γ), -β, or -α antibodies, anti-tumor necrosis factor-α antibodies (eg, infliximab ), Adalimumab or azizia), anti-TNFα immunoadhesin (etanercept), anti-tumor necrosis factor-β antibody, anti-TGF-β antibody, anti- Interleukin-2 antibodies and anti-IL-2 receptor antibodies; Anti-IL-6 antibodies, anti-IL-6R antibodies, anti-LFA-1 antibodies, such as anti-CD11a and anti-CD18 antibodies; Anti-L3T4 antibodies; Heterologous anti-lymphocyte globulin; Pan-T antibodies, preferably anti-CD3 or anti-CD4 / CD4a antibodies; Soluble peptides containing LFA-3 binding domains (WO 90/08187 published Jul. 26, 1990); Streptokinase; TGF-β; Streptodomase; RNA or DNA from the host; FK506; RS-61443; Deoxyspergualin; Rapamycin; T-cell receptor (Cohen et al. , US Pat. No. 5,114,721); T-cell receptor fragments (Offner et al. , Science, 251: 430-432 (1991); WO 90/11294; Janeway, Nature, 341: 482 (1989); and WO 91/01133); And T-cell receptor antibodies (EP 340,109) such as T10B9, integrin inhibitors such as Tysabri, CCR9 or CCR6 antagonists, anti-TL1A antibodies or cytokines known to inhibit immune responses Such as, but not limited to, IL-10 or IL-27.

As used herein, the term “cytotoxic agent” means a substance that inhibits or prevents the function of a cell and / or causes cell destruction. The term refers to radioisotopes (eg, radioisotopes of At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² and Lu), chemotherapeutic agents, and toxins , Eg, small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof.

A "chemotherapeutic agent" is a chemical compound useful for the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; Alkyl sulfonates such as busulfan, improsulfan and piposulfan; Aziiridine such as benzodopa, carboquone, meturedopa, and uredopa; Ethyleneimine and methylamelamine, for example altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; Acetogenin (especially bullatacin and bullatacinone); Camptothecin (including the synthetic analog topotecan); Bryostatin; Calstatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); Cryptophycins (especially cryptophycin 1 and cryptophycin 8); Dolastatin; Duocarmycin (including the synthetic analogues KW-2189 and CB1-TM1); Elutherobin; Pancratistatin; Sarcodictyin; Spongestatin; Nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine Mechlorethamine oxide hydrochloride, melphalan, nomobichin, fenesterine, prednimustine, trofosfamide, uracil mustard; Nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; Antibiotics, for example, enediyne antibiotics (e.g. calicheamicin, in particular calicheamicin gamma 11 and calicheamicin omega 11 (e.g. Agnew, Chem Intl. Ed. Engl) 33: 183-186 (1994); dynemicin, for example dynemycin A; bisphosphonates, such as clodronate; esperamicin; Neocarzinostatin chromophore and related chromoprotein enantiin antibiotic chromophores, aclacinomysin, actinomycin, authramycin, azaserine, bleomycin (bleomycin), cactinomycin (cactinomycin), carabicin (carabicin), carminomycin (carminomycin), carzinophilin, chromomycinis, dactinomycin, daunorubicin daunorubicin, Detoru Detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy Doxorubicin), epirubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, for example mitomycin C, mycophenolic acid (mycophenolic acid), nogalamycin, nogalamycin, olivomycin, peplomycin, potpyromycin, potoromycin, puromycin, quelamycin, rodorubicin ), Streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; Anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); Folic acid analogs, for example denopterin, methotrexate, pteropterin, trimetrexate; Purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; Pyrimidine analogs, for example, ancitabine, azaciitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine ( dideoxyuridine, doxifluridine, enocitabine, floxuridine; Androgens such as calussterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; Anti-adrenal glands such as aminoglutethimide, mitotane, trilostane; Folic acid supplements such as frolinic acid; Aceglatone; Aldophosphamide glycoside; Aminolevulinic acid; Eniluracil; Amsacrine; Bestrabucil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquone; Elfornithine; Elliptinium acetate; Epothilone; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Lonidainine; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitrarine; Pentostatin; Phennamet; Pyrarubicin; Loxoxantrone; Podophyllinic acid; 2-ethylhydrazide; Procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2 ', 22 "-trichlorotriethylamine; trichothecene (especially T-2 toxin, verracurin A, roridin A and anguidine); Urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitobronitol; mitolactol; pipobroman; pipobroman; gacytosine; Arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids such as TAXOL® Paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ™ Cremophor-free, albumin-designed nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); Chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisp Tin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; norban Tronantrone; teniposide; edatrexate; daunomycin; aminopterin; gelloda; xeloda; ibandronate; CPT-11; Topoisomerase inhibitor RFS 2000; difluorometlhylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine; And pharmaceutically acceptable salts, acids or derivatives of any of the above. In addition, proteasome inhibitors such as bortezomib (Velcade), BCL-2 inhibitors, IAP antagonists (eg Smac mimics / xIAP and cIAP inhibitors such as Specific peptides, pyridine compounds, for example (S) -N- {6-benzo [1,3] dioxol-5-yl-1- [5- (4-fluoro-benzoyl) -pyridine-3 -Ylmethyl] -2-oxo-1,2-dihydro-pyridin-3-yl} -2-methylamino-propionamide, xIAP antisense), HDAC inhibitor (HDACI) and kinase inhibitor (Sorafenib) Is included in the above definition.

Also included are anti-tumor agents that act to modulate or inhibit hormonal action on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs) such as tamoxifen (NOLVADEX® tamoxifen). Raloxifene, drroloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON Toremifene; Aromatase inhibitors that inhibit the enzyme aromatase that modulates estrogen production in the adrenal glands, such as 4 (5) -imidazole, aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® Exemestane, formestanie, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastrozole; And anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; As well as troxacitabine (1,3-dioxolane nucleoside cytosine analogue); Antisense oligonucleotides, in particular antisense oligonucleotides that inhibit expression of genes in signaling pathways associated with abherant cell proliferation, such as PKC-alpha, Ralf and H-Ras; Ribozymes such as VEGF expression inhibitors (eg, ANGIOZYME® ribozymes) and HER2 expression inhibitors; Vaccines such as gene therapy vaccines such as ALLOVECTIN® vaccines, LEUVECTIN® vaccines, and VAXID® vaccines; PROLEUKIN® rIL-2; LURTOTECAN® topoisomerase 1 inhibitors; ABARELIX® rmRH; And pharmaceutically acceptable salts, acids or derivatives of any of the above.

As used herein, “growth inhibitor” refers to a compound or composition that inhibits the growth of cells in vitro or in vivo. Thus, a growth inhibitory agent is one that significantly reduces the percentage of cells that overexpress the gene in S phase. Examples of growth inhibitory agents include agents that block cell cycle progression (positions other than S phase), for example agents that induce G1 arrest and M-phase arrest. Classical M-stage blockers are vincas (vincristine and vinblastine), taxol, and topo II inhibitors such as doxorubicin, epirubicin ), Daunorubicin, etoposide, and bleomycin. Such agents that stop G1, such as DNA alkylating agents, for example tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5 Fluorouracil, and ara-C, also affects up to S-phase stop. Further information is provided in The Molecular Basis of Cancer, Mendelsohn and Israel, eds., Chapter 1, entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs" by Murakami et al . (WB Saunders: Philadelphia, 1995, pg. 13).

Agents that induce cellular stress, such as arginine depleting agents, such as arginase, are further included.

Further included are antibodies that affect B cells, such as Rituximab, anti-BAFF or anti-APRIL antibodies, and T cell depleted antibodies, such as Camppath. In addition, combinations of IL-23R antagonists with inhibitors of the aspirin and NFkB pathways may be beneficial.

As used herein, "synergistic activity", "synergy", "synergistic effect" or "synergistically effective amount" means that the effect observed when using a combination of an IL-23R antagonist and a therapeutic agent is (1) IL-23R Greater than the effect achieved when the antagonist or therapeutic agent is used alone (or separately), and (2) greater than the sum of the combined (added) effect on the IL-23R antagonist or therapeutic agent. This synergy or synergistic effect can be determined by various means known to those skilled in the art. For example, the synergistic effect of IL-23R antagonists and therapeutic agents may be used to test for cytokine release from immune cells, a reduction in the number or type of immune cells present, or, in the case of cancer, a decrease in tumor cell number or tumor size. It can be observed in an in vitro or in vivo assay format.

The terms "cancer", "cancerous" and "malignant" refer to or describe the physiological diseases of mammals that are typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, such as adenocarcinoma, lymphoma, blastoma, melanoma, sarcoma, and leukemia. More specific examples of such cancers include squamous cell cancer, small cell lung cancer, non-small cell lung cancer (NSCLC), gastrointestinal cancer, Hodgkin's and non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, For example, hepatocarcinoma and liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial carcinoma, myeloma (eg multiple myeloma), salivary gland carcinoma, kidney cancer, eg renal cell carcinoma and Wilms' tumor, Basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, and various types of head and neck cancers.

The term “immune related disease” means a disease or disorder in which a component of the mammal's immune system causes, mediates, or otherwise contributes to morbidity in a mammal. Also included are diseases in which the stimulation or interference of the immune response has an improved effect on disease progression. Autoimmune diseases, immune-mediated inflammatory diseases are included in the term. Examples of immune-related diseases and inflammatory diseases that can be treated according to the present invention (some of which are immune or T cell mediated) include systemic lupus erythematosus, rheumatoid arthritis, combustor chronic arthritis, spondyloarthritis, ankylosing spondylitis, systemic sclerosis (coccus) Subcutaneous), idiopathic inflammatory myopathy (skin myositis, polymyositis), primary Sjogren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia (immune thrombocytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune thrombocytopenia (idic hypoplatelet) Purple plague, immune-mediated hypothyroidism), thyroiditis (Grave's disease, Hashimoto's thyroiditis, combustive lymphocytic thyroiditis, atrophic thyroiditis), diabetes mellitus, immune-mediated nephropathy (tubulointerstitial nephritis), central nervous system And demyelinating diseases of the peripheral nervous system such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barré syndrome, Vogt-Goya Ki-Harada disease, goodpasture disease, and chronic inflammatory demyelinating polyneuropathy, hepatobiliary disease, such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatic viruses), autologous Immune Chronic Activity Hepatitis, Primary Gallbladder Liver Cirrhosis, Granuloma Hepatitis, and Sclerosing Gallbladder, Inflammatory Diseases, eg, Inflammatory Growth Disease (ulcerative colitis: Crohn's disease), Gluten-sensitive small bowel disease, Whiple disease, and fibrotic lung disease , Autoimmune or immune-mediated skin diseases, such as blister skin disease, polymorphic erythema and contact dermatitis, psoriasis, allergic diseases, for example asthma, allergic rhinitis, atopic dermatitis, food intolerance and urticaria, immune diseases of the lung Eosinophilic pneumonia, idiopathic fibrosis and irritable pneumonia, graft-related diseases such as graft rejection and graft-versus-host disease, immune-mediated or autoimmune ocular diseases such as uveitis, dry eye, billifs Disease (Beliefs disease, BD) .

Infectious diseases include AIDS (HIV infection), hepatitis A, B, C, D, and E, bacterial infections, fungal infections, protozoan infections, and parasitic infections.

"B-cell malignancies" are malignancies including B cells. Examples include Hodgkin's disease, such as lymphocyte predominant Hodgkin's disease (LPHD); Non-Hodgkin's lymphoma (NHL); Follicular central cell (FCC) lymphoma; Acute lymphocytic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hairy cell leukemia; Plasmacytoid lymphocytic lymphoma; Mantle cell lymphoma; AIDS or HIV-related lymphomas; Multiple myeloma; Central nervous system (CNS) lymphoma; Lymphocyte proliferative disease (PTLD) after transplantation; Waldenstrom's macroglobulinemia (lymphoblastic lymphoma); Mucosal associated lymphoid tissue (MALT) lymphoma; And limbic lymphoma / leukemia.

"Non-Hodgkin's lymphoma" (NHL) is low grade / vesicle NHL, recurrent or refractory NHL, foremost low grade NHL, stage III / IV NHL, chemotherapy resistant NHL, small lymphocyte (SL) NHL, intermediate grade / vesicle NHL, intermediate grade diffuse NHL, diffuse large cell lymphoma, attack NHL (including attack first NHL and attack recurrent NHL), NHL relapsed or refractory to autologous stem cell transplantation, high grade immunoblast NHL, high grade lymphocytic NHL, high grade bovine non-dividing cell NHL, bulky disease NHL, and the like.

A "tumor-associated antigen" (TAA) or a "tumor-specific antigen" (TSA) is a molecule produced in tumor cells that can trigger an immune response in a host. Tumor related antigens are found in both tumor and normal cells, but at differential expression levels, while tumor specific antigens are expressed only by tumor cells. TAAs or TSAs that appear on the surface of tumor cells are alpha-fetoprotein, cancer embryo antigen (CEA), CA-125, MUC-1, glypican-3, tumor-associated glycoprotein-72 (TAG-72) , Epithelial tumor antigen, tyrosinase, melanoma-associated antigen, MART-1, gp100, TRP-1, TRP-2, MSH-1, MAGE-1, -2, -3, -12, RAGE-1, GAGE 1- , -2, BAGE, NY-ESO-1, beta-catenin, CDCP-1, CDC-27, SART-1, EpCAM, CD20, CD23, CD33, EGFR, HER-2, breast tumor-associated antigen BTA-1 And BTA-2, RCAS1 (receptor-binding cancer antigen expressed in SiSo cells), placental-specific 1 (PLAC-1), syndecan, MN (gp250), in particular idiotype However, it is not limited thereto. Tumor-associated antigens also include blood group antigens, eg, Le ^a , Le ^b , LeX, LeY, H-2, B-1, B-2 antigens (see Table 19 below). Ideally, for the purposes of the present invention, TAA or TSA targets are not internalized upon binding.

A "non-natural amino acid" or "non-naturally occurring amino acid" means, for example, a modification of a naturally encoded amino acid (including, but not limited to, 20 conventional amino acids or pyrrolysine and selenocysteine) Eg, amino acids, caused by post-translational modifications, but not one of the 20 common amino acids, including amino acids that do not naturally integrate into the polypeptide chains growing by the translation complex. Examples of such non-naturally occurring amino acids include, but are not limited to, N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine, and O-phosphotyrosine.

"Conservatively modified variants" applies to both amino acid and nucleic acid sequences. In the context of a particular nucleic acid sequence, a conservatively modified variant refers to a nucleic acid that encodes the same or essentially the same amino acid sequence or, if the nucleic acid does not encode an amino acid sequence, to essentially the same nucleic acid sequence. Due to the degeneracy of the genetic code, a very large number of functionally identical nucleic acids can encode any given protein.

With respect to amino acid sequences, one of ordinary skill in the art would recognize that individual substitutions to nucleic acids, peptides, polypeptides, or protein sequences that substitute for a specific percentage of amino acids or amino acids in the sequence encoded relative to conserved amino acids are “conservatively modified variants”. will be. Conservative substitution tables that provide functionally similar amino acids are well known in the art.

An example of a conservative substitution is the exchange of an amino acid of one of the following groups with another amino acid of the same group (US Pat. No. 5,767,063 issued to Lee, et al; Kyte and Doolittle (1982) J. Mol. Biol. 157: 105 132): (1) hydrophobic: norleucine, Ile, Val, Leu, Phe, Cys, or Met; (2) neutral hydrophilic: Cys, Ser, Thr; (3) acidic: Asp, Glu; (4) basic: Asn, Gln, His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe; (7) small amino acids: Gly, Ala, Ser.

To investigate the degree of inhibition, for example, a sample or assay provided, eg, comprising a protein, gene, cell or organism, is treated with a potential active agent or inhibitor and compared to a control sample without inhibitor. Control samples, ie samples not treated with antagonists, are assigned a relative activity value of 100%. Activity values relative to the control are about 90% or less, typically 85% or less, more typically 80% or less, most typically 75% or less, generally 70% or less, more generally 65% or less, most typically 60% or less, typically 55% or less, generally 50% or less, more generally 45% or less, most generally 40% or less, preferably Preferably, inhibition is achieved when it is 35% or less, more preferably 30% or less, even more preferably 25% or less, and most preferably less than 25%. An activity value relative to the control is about 110%, generally at least 120%, more generally at least 140%, more generally at least 160%, often at least 180%, more often at least 2 times, most often at least 2.5 times, generally at least Activation is achieved when 5 times, more generally at least 10 times, preferably at least 20 times, more preferably at least 40 times, most preferably more than 40 times high.

The endpoint of activation or inhibition can be monitored as follows. Activation, inhibition, and response to, for example, treatment of cells, physiological fluids, tissues, organs, and animal or human subjects can be monitored by endpoints. The endpoint may include, for example, an amount or a percentage of the release of inflammation, carcinogenicity, or cellular degranulation or secretion, for example cytokine, toxic oxygen, or protease. The endpoint may be, for example, ion flow or transport; Cell migration; Cell adhesion; Cell proliferation; Metastatic potential; Cell differentiation; And a predetermined amount of change in phenotype, eg, change in expression of a gene associated with inflammation, apoptosis, transformation, cell cycle, or metastasis (eg, Knight (2000) Ann. Clin. Lab.Sci. 30: 145-158; Hood and Cheresh (2002) Nature Rev. Cancer 2: 91-100; Timme, et al. (2003) Curr.Drug Targets 4: 251-261; Robbins and Itzkowitz (2002) Med. Clin.North Am. 86: 1467-1495; Grady and Markowitz (2002) Annu. Rev. Genomics Hum. Genet. 3: 101-128; Bauer, et. al . (2001) Glia 36: 235-243; Stanimirovic and Satoh (2000) Brain Pathol. 10: 113-126).

The end point of inhibition is generally 75% or less of the control, preferably 50% or less of the control, more preferably 25% or less of the control, most preferably 10% or less of the control. In general, the end point of activation is at least 150% of the control group, preferably at least 2 times the control group, more preferably at least 4 times the control group, and most preferably at least 10 times the control group.

The "labeled" composition can be detected directly or indirectly by spectroscopic, photochemical, biochemical, immunochemical, isotope, or chemical methods. For example, useful labels include ³² P, ³³ P, ³⁵ S, ¹⁴ C, ³ H, ¹²⁵ I, stable isotopes, fluorescent dyes, electron-density reagents, substrates, epitope tags, or enzymes such as enzymes Enzymes used in enzyme-linked immunoassay, or fluorettes (see, eg, Rozinov and Nolan (1998) Chem. Biol. 5: 713-728).

Many of the unnatural amino acids suitable for use in the present invention are commercially available, for example, from Sigma (USA) or Aldrich (Milwaukee, Wis., USA). Non-commercial amino acids which are not commercially available are optionally synthesized as provided herein, as provided in various publications, or using standard methods known to those skilled in the art. For organic synthesis techniques, see, for example, Organic Chemistry by Fessendon and Fessendon, (1982, Second Edition, Willard Grant Press, Boston Mass.); Advanced Organic Chemistry by March (Third Edition, 1985, Wiley and Sons, New York); and Advanced Organic Chemistry by Carey and Sundberg (Third Edition, Parts A and B, 1990, Plenum Press, New York). Additional publications describing the synthesis of unnatural amino acids are described, for example, in WO 2002/085923 entitled "In vivo incorporation of Unnatural Amino Acids;" Matsoukas et al., (1995) J. Med. Chem., 38, 4660-4669; King, F.E. & Kidd, D.A.A. (1949) A New Synthesis of Glutamine and of .gamma. -Dipeptides of Glutamic Acid from Phthylated Intermediates. J. Chem. Soc, 3315-3319; Friedman, O. M. & Chatterrji, R. (1959) Synthesis of Derivatives of Glutamine as Model Substrates for Anti-Tumor Agents. J. Am. Chem. Soc. 81, 3750-3752; Craig, J.C. et al. (1988) Absolute Configuration of the Enantiomers of 7-Chloro-4 [[4- (diethylamino) -1-methylbutyl] amino] quinoline (Chloroquine). J. Org. Chem. 53, 1167-1170; Azoulay, M., Vilmont, M. & Frappier, F. (1991) Glutamine analogues as Potential Antimalarials, Eur. J. Med. Chem. 26, 201-5; Koskinen, A.M.P. & Rapoport, H. (1989) Synthesis of 4-Substituted Prolines as Conformationally Constrained Amino Acid Analogues. J. Org. Chem. 54, 1859-1866; Christie, B. D. & Rapoport, H. (1985) Synthesis of Optically Pure Pipecolates from L-Asparagine. Application to the Total Synthesis of (+)-Apovincamine through Amino Acid Decarbonylation and Iminium Ion Cyclization. J. Org. Chem. 1989: 1859-1866; Barton et al, (1987) Synthesis of Novel a-Amino-Acids and Derivatives Using Radical Chemistry: Synthesis of L-and D-a-Amino-Adipic Acids, L-a-aminopimelic Acid and Appropriate Unsaturated Derivatives. Tetrahedron Lett. 43: 4297-4308; and, Subasinghe et al, (1992) Quisqualic acid analogues: synthesis of beta-heterocyclic 2-aminopropanoic acid derivatives and their activity at a novel quisqualate-sensitized site. J. Med. Chem. 35: 4602-7. See also US 2004/0198637 and US 2005/0170404, each of which is incorporated herein by reference in its entirety.

The terms “amino acid modification (s)” and “modification (s)” refer to amino acid substitutions, deletions or insertions or any combination thereof in another amino acid sequence, eg, an amino acid sequence relative to a natural amino acid sequence. Substitution variants herein are substitution variants wherein at least one amino acid residue in the native CTLD sequence has been removed and a different amino acid inserted in its place at the same position. The substitution may be a single substitution when only one amino acid in the molecule is substituted, or it may be a plurality of substitutions when two or more amino acids are substituted in the same molecule. Specific reference to one or more amino acid substitutions in the CTLD means a number of substitutions where each individual amino acid substitution may occur at any amino acid position in the CTLD, including consecutive and discontinuous amino acid positions. Likewise, specific reference to one or more amino acid insertions or deletions in the CTLD refers to a number of insertions or deletions in which each individual amino acid insertion or deletion may occur at any amino acid position in the CTLD, including consecutive and discontinuous amino acid positions. .

The terms “nucleic acid molecule encoding”, “DNA sequence encoding”, and “DNA encoding” refer to the order or order of deoxyribonucleotides along the strand of deoxyribonucleic acid. The order of these deoxyribonucleotides determines the order of amino acids along the polypeptide chain. Thus, the DNA sequence encodes an amino acid sequence.

The terms “randomize,” “randomize,” and “randomized,” as used in any context to identify a randomized polypeptide or nucleic acid sequence, as well as any analogous terminology refer to the entirety of a polypeptide or nucleic acid sequence or segment ( ensemble, wherein the amino acid residues or nucleotides at one or more sequence positions can vary between various members of the polypeptide or nucleic acid, such that the nucleic acid residues or nucleotides occurring at each said sequence position are all possible amino acid residues or nucleotides or Belong to a set of amino acid residues or nucleotides that may include any restricted subset thereof. The term is often used to mean a total number of possible amino acid residues or nucleotides equal for each member of the total, but this also means that the number of possible amino acid residues or nucleotides of each member of the total is within an appropriate range of integers. Can be used to mean a total that can be an integer.

Turning now to the present invention in more detail, in one aspect, the present invention relates to a polypeptide having a multimerization domain and at least one polypeptide binding member that binds to IL-23R. According to the invention, the binding member can be linked to the multimerization domain, for example at the N-terminus or the C-terminus. Furthermore, in certain embodiments, a binding member that binds to IL-23R, or two different binding members, can be bound to IL-23R by linking to both the N-terminus and C-terminus of the multimerization domain of the monomer. It may be advantageous to provide multimeric polypeptide complexes comprising six binding members. In general, polypeptides of the invention are fusion proteins of non-natural polypeptides, eg, polypeptide sequences that bind to the multimerization domain and IL-23R. Non-natural polypeptides can also be natural polypeptides whose naturally occurring amino acid sequences have been altered by addition, deletion, or substitution of amino acids. Examples of such polypeptides include polypeptides in which at least one of the loop regions of the domain has a modified C-type lectin-like domain (CTLD) as described herein. In another aspect of the invention, a polypeptide that binds to IL-23R is a fragment or variant of a natural polypeptide that binds to a receptor, where the fusion domain is no longer natural when the naturally occurring polypeptide, variant or fragment is fused to a multimerization domain. It is not a developing polypeptide. Thus, the present invention does not exclude naturally occurring polypeptides, fragments or variants thereof from portions of the fusion proteins of the present invention.

In an embodiment of this aspect, the polypeptide is an IL-23R antagonist that binds IL-23R and prevents signaling through the IL-23 pathway. In one embodiment, the polypeptide binds to IL23-R (SEQ ID NO: 5) or variants thereof. Polypeptides of the invention that prevent binding of natural IL-23 ligands bind to one or more sites on IL-23R, thereby preventing activation of the receptor by the IL-23 ligand. In addition, the polypeptides of the present invention do not have agonist activity and do not activate IL-23 heterodimeric receptors.

In one specific embodiment, the polypeptide does not specifically bind IL-12Rβ1 or IL-12Rβ2. Thus, the use of the polypeptides of the invention in therapeutic compositions can avoid the consequences of undesirably blocking the activity of IL-12 for certain therapies.

In various embodiments, monomeric polypeptides of the invention comprise a multimerization domain capable of forming a multimer complex with another multimerization domain, and at least two segments of a polypeptide sequence that binds IL-23R. The sequence that binds IL-23R may be fused with a multimerization domain at the N-terminus, C-terminus, or both N-terminus and C-terminus of the domain. In one embodiment, the polypeptide that binds IL-23R at the N-terminus is different from the polypeptide that binds IL-23R at the C-terminus of the trimerization domain.

In one embodiment, the first polypeptide that binds IL-23R is fused to one of the N-terminus and C-terminus of the trimerization domain, and the second polypeptide that is a modulator of inflammation is the N-terminus or C- of the trimerization domain Fused to the rest of the terminus. Modulators other than polypeptides may be covalently or non-covalently linked to the trimerization domain, as will be understood by those skilled in the art. In addition to modulators of inflammation, other polypeptides and non-polypeptide therapeutics may be linked to the trimerization module.

For the treatment of cancer, it may be desirable to target the polypeptides of the invention to the tumor environment to more effectively prevent the tumor-promoting action of IL-23 on tumor cells. Thus, another aspect of the invention provides a polypeptide that binds to IL-23R on one terminus (either the N-terminus or C-terminus) of a domain, and on the other terminus (the rest of the N-terminus or C-terminus). And a multimerization domain having a polypeptide that binds to a tumor-associated (TAA) or tumor-specific antigen (TSA). The domain that binds TAA or TSA can be a peptide, eg, CTLD, single chain antibody, or any type of domain that specifically binds to the desired target.

In one particular method, the activity of the death receptor agonist induces the drug to the site of inflammation in the cancerous environment and allows for the clustering of the death receptor specific polypeptide on the second end of the trimerization domain. It can be improved by designing molecules with binding activity mediated through the IL-23R binding polypeptide at one end. In various embodiments, the polypeptide binds to the death receptor with a lower affinity than IL-23R. More particularly, polypeptides that bind to IL-23R have at least twice as much affinity as polypeptides that bind to death receptors, eg, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 15, 20, 50 And 100-fold greater affinity.

Indications of the trimeric complex with both IL-23R-binding polypeptide (s) and TAA or TSA targeting agent (s) include non-small cell lung cancer (NSCLC), colorectal cancer, ovarian cancer, kidney cancer, pancreatic cancer, sarcoma, non- Hodgkin's lymphoma (NHL), multiple myeloma, breast cancer, prostate cancer, melanoma, glioblastoma, neuroblastoma.

In another embodiment, a polypeptide that specifically binds to an IL-23 receptor is contained within the loop region of the CTLD. The polypeptide may be part of an IL-23 polypeptide or may be a sequence identified as provided herein. In this embodiment, the sequence is contained in the loop region of the CTLD and the CTLD is fused to the trimerization domain either at the N-terminus or C-terminus of the domain either directly or via an appropriate linker. In addition, the polypeptide of the invention may comprise a second CTLD domain fused to the N-terminus and the rest of the C-terminus, and the sequence of said CTLD and / or its affinity for IL-23R may be the same or different. have. In a variation of this embodiment, the polypeptide comprises a polypeptide that binds IL-23R at one of the termini of the trimerization domain, and a CTLD at the remainder of the terminus. One, two or three of the polypeptides may be part of a trimer complex containing up to six specific binding members for IL-23R.

A polypeptide sequence that binds IL-23R may have a binding affinity for IL-23R that is approximately equivalent to the binding affinity that native IL-23 has to IL-23R. In certain embodiments, polypeptides of the invention have a binding affinity for IL-23R that is greater or less than the binding affinity that native IL-23 has to the same IL-23R as above.

One or more amino acid mutations in a native IL-23 (p19) sequence, or random sequence, having a selective binding affinity for IL-23R, but no selective binding affinity for IL-12Rβ1 or IL-12Rβ2. It may include. For example, the binding affinity of the binding member to IL-23R is approximately equivalent (unchanged) or greater (increased) compared to native IL-23, and the binding to IL-12Rβ1 or IL-12Rβ2 Where a member's binding affinity is smaller or nearly lost compared to the native sequence IL-23, for purposes herein, the binding affinity of the member is considered to be "selective" for IL-23R. In another example, the affinity of the binding member for IL-23R is less than the affinity of IL-23 for the receptor, but the binding member is greater for IL-23R than the affinity for IL-12Rβ1 or IL-12Rβ2. The binding member is still selective for the receptor if it has affinity. Preferred IL-23R selective antagonists of the present invention will have a binding affinity of at least 5 times, preferably at least 10 times greater for IL-23R compared to IL-12Rβ1 or IL-12Rβ2, even more preferably, Will have at least 100-fold greater binding affinity for IL-23R compared to IL-12Rβ1 or IL-12Rβ2.

Each binding affinity of the antagonist can be compared and determined by the binding properties of native IL-23 or a portion thereof by ELISA, RIA, and / or BIAcore assays known in the art. Preferred IL-23R selective antagonists of the invention will not inhibit IL-12 signaling in at least one type of mammalian cell, and such signaling inhibition may be determined by methods known in the art, such as ELISA. Can be.

In one embodiment, the IL-23R antagonist comprises an antibody or antibody fragment. In the context of the present invention, the term “antibody” is used to describe an immunoglobulin whether it is natural or partially or wholly synthetically produced. As antibodies can be modified in many ways, the term “antibody” should be considered to include any specific binding member or substance having a binding domain with the necessary receptor specificity. Thus, the term includes antibody fragments, derivatives, functional equivalents and homologues of any antibody, including any polypeptide comprising an immunoglobulin binding domain, whether natural or wholly or partially synthetic. Thus, chimeric molecules comprising immunoglobulin binding domains or equivalents fused to another polypeptide are included. The term also includes any polypeptide or protein, eg, antibody mimic, that is an antibody binding domain or has a binding domain homologous to an antibody binding domain. They may be derived from natural sources or may be produced synthetically in part or in whole. Examples of antibodies include immunoglobulin isotypes and isotype subclasses thereof; Fragments comprising antigen binding domains such as Fab, Fab ', F (ab') ₂ , scFv, Fv, dAb, Fd; And diabody.

In another aspect, the invention relates to a multimer complex of three polypeptides, each comprising at least one polypeptide that binds to a multimerization domain and IL-23R. In one embodiment, the multimer complex is a polypeptide substantially homologous to a human tetranectin trimer structural component, or other human trimerized polypeptide, lectin neck region comprising a mannose binding protein (MBP) trimer domain. Polypeptides having a multimerization domain selected from polypeptides, and other polypeptides. The multimer complex may be composed of any of the polypeptides of the invention, wherein the polypeptides of the multimer complex comprise multimerization domains that can be associated with one another to form a multimer. Thus, in some embodiments, the multimer complex is a homomultimer complex consisting of polypeptides having the same amino acid sequence. In other embodiments, the multimer complex is a heteromultimer complex consisting of different amino acid sequences, eg, polypeptides having different multimerization domains, and / or different polypeptides that bind IL-23R. In addition, the heteromultimer complex may comprise a therapeutic agent and an IL-23R antagonist.

Further, in one aspect, the present invention relates to a method of preparing a polypeptide for preventing the activation of IL-23R in a cell expressing IL-23R. The method comprises (a) selecting a first polypeptide (s) that specifically binds IL-23R; (b) implanting the first polypeptide (s) into one or two loop regions of tetranectin CTLD to form a first binding determinant, or fusion of the polypeptide directly to a tetranectin trimerization domain; And (c) fusing either the N-terminus or C-terminus of the first CTLD with the tetranectin trimerization domain. In one specific embodiment of the method, the polypeptide that binds IL-23R does not bind IL-12Rβ1 or IL-12Rβ2.

Tetranectin CTLDs have up to 5 loop regions in which binding members for IL-23R can be inserted or identified by selection from a randomized library as described herein. Thus, if the polypeptide of the invention comprises CTLD, the polypeptide may have up to 5 binding members for IL-23R attached to the trimerization domain via CTLD. Each of the bonding members may be the same or different.

In another embodiment of the polypeptides of the invention, the receptor antagonist may be bound to one end of the trimerization domain and one or more therapeutic agents may be bound to the second end. The agent can be linked directly or via a suitable linker as would be understood by one skilled in the art. Such agents may act in the same pathway as antagonists or in different pathways for immune disorders, cancer and other diseases. In addition to binding to one of the ends of the polypeptide, the agent may be covalently linked to the trimerization domain via a peptide bound to the side chain in the trimerization domain or through binding to a cysteine residue. Other methods of covalently coupling an agent to a module can also be used, for example, as set forth in US Pat. No. 6,190,886, which is incorporated herein by reference.

Identification of Polypeptide Sequences Specific to IL-23R

In one aspect, specific binding members for IL-23R can be obtained from a random library of polypeptides by selection of members of a random library of polypeptides that specifically bind to a receptor. Many systems are known which present phenotypes with putative ligand binding sites. This is shown on phage display (eg, fibrous phage fd [Dunn (1996), Griffiths and Duncan (1998), Marks et al. (1992)), phage lambda [Mikawa et al. (1996)), eukaryotic virus viruses. Display (eg, baculovirus [Ernst et al. (2000)]), cell display (eg, bacterial cells [Benhar et al. (2000)], yeast cells [Boder and Wittrup (1997)] , And displays on mammalian cells (Whitehorn et al. (1995)), ribosome linked displays (Schaffitzel et al. (1999), and phagemid linked displays [Gates et al. (1996).

In addition, US2007 / 0275393, which is hereby incorporated by reference in its entirety, specifically describes the procedure for achieving a display system for the generation of CTLD libraries. The overall procedure is to (1) identify the location of the loop-region by referring to the 3D structure of the selected CTLD, if available, or the β2 and β3 consensus sequence components as disclosed above and β4-, if the information is not available. Identification of the sequence position of the β2, β3 and β4 strands by sequence alignment with known sequences, aided by further confirmation by identification of sequence elements corresponding to the strand feature; (2) subcloning of nucleic acid fragments encoding select CTLD into a protein display vector system with or without prior insertion of an endonuclease restriction site close to the sequences encoding β2, β3 and β4; And (3) a nucleic acid fragment that is randomly selected from a nucleic acid fragment encoding a portion or all of the loop-region of the selected CTLD, the nucleic acid fragment encoding the original loop-region polypeptide fragment after insertion into a nucleic acid environment encoding the receptive framework. Substitution of a randomly selected member of a total of a plurality of nucleic acid fragments for substitution by fragments. Each cloned nucleic acid fragment encoding a novel polypeptide that replaces the original loop-segment or the entire loop-region will be decoded within a translation frame determined within its novel sequence context.

Complexes that act as homotrimeric proteins that block native IL-23 from IL-23R binding and activation can be formed. However, peptides with IL-23R binding activity must first be identified. To achieve this, peptides with known binding activity can be used, or additional novel peptides identified by screening from the display library can be used. By way of non-limiting example, many different display systems are available, such as phage, ribosomal and yeast displays.

To select novel peptides with binding activity, libraries can be constructed and first screened for binding to IL-23R as individual peptides displayed on the surface of a single monomer CTLD domain, or phage. If a sequence with IL-23R binding activity is identified, this sequence will then be transplanted into the trimerization domain of human tetranectin, resulting in a potential protein therapeutic that can bind IL-23R.

Four main methods can be used to construct the phage display library and trimerized domain constructs. The first method is to construct and / or use random peptide phage display libraries. Random linear peptides and / or random peptides constructed as disulfide confinement loops are individually displayed on the surface of phage particles and selected for binding to the desired IL-23R via phage display “panning”. After obtaining peptide clones with IL-23R binding activity, these peptides are implanted into the trimerization domain or loop of CTLD domain of human tetranectin, and then onto the trimerization domain and screened for antagonist activity.

A second method for the construction of phage display libraries and trimerized domain constructs involves obtaining CTLD derived conjugates. Libraries can be constructed by randomizing one or more amino acids of five different loops in the CTLD scaffold of human tetranectin displayed on the phage surface. Binding to IL-23R can be selected via phage display panning. After obtaining CTLD clones with peptide loops exhibiting IL-23R binding activity, such CTLD clones can be transplanted into the trimerized domain of human tetranectin and screened for antagonist activity.

A third method for the construction of phage display libraries and trimerization domain constructs takes known sequences with binding capacity to IL-23R, transplants them directly into the trimerization domain of human tetranectin, and screens for binding activity It includes.

The fourth method involves using a peptide sequence with known binding capacity to IL-23R, which peptide sequence is first novel with randomized amino acids present on the peptide side and / or randomized selected internal amino acids within the peptide. After creating a library, binding is improved by selecting for improved binding via phage display. After obtaining a conjugate with improved affinity, the conjugate of this peptide can be implanted into the trimerization domain of human tetranectin and screened for antagonist efficacy. In this method, the original library can be constructed with free peptide displayed on the surface of the phage particles as in the first method (above), or with defined loops in the CTLD scaffold as in the second method discussed above. After obtaining the conjugates with improved affinity, screening for the antagonist activity and transplantation of such peptides into the trimerization domain of human tetranectin occurs.

Forms of trimerization domains with up to 16 residues removed at the N-terminus (V17) or with altered C-terminus can be used. C-terminal variants named Trip V [SEQ ID NO: 60], TripT [SEQ ID NO: 61], TripQ [SEQ ID NO: 62], and TripK [SEQ ID NO: 59] (see FIG. 2) are trimmed. Enables unique presentation of CTLD domains on embodied domains. TripV, TripT, TripQ are fusions of CTLD molecules directly into the trimerization module without any structural flexibility, but the CTLD molecules 1/3 rotated from TripV to TripT and TripT to TripQ. This is due to the fact that each of these amino acids is present in α-helical turn and 3.2 aa is required for complete rotation. The free peptide selected for binding in the first, third and fourth methods can be grafted into any of the above forms of the trimerization domain. The resulting fusions can then be screened to ensure that the combination of peptide and orientation provides for optimal activity. Peptides selected for defined binding within the loop of CTLD of netranectin can be implanted into the full length trimerization domain.

More particularly, four methods are described below. While this method focuses on phage display, other equivalent methods of identifying polypeptides can be used.

Method 1

Non-limiting examples include New England Biolabs Ph.D. Peptide display library kits, such as the Phage display Peptide Library Kit, are commercially available and can be purchased for use in the selection of new and novel peptides having IL-23R binding activity. Three types of New England Biolabs kits are available: Ph.D.-7 Peptide Library Kit, 7 containing a linear random peptide of 7 amino acids length, with a library size of 2.8x10 ⁹ independent clones. dog Ph.D.-C7C disulfide Constrained peptide library Kit , and 2.8x10 ⁹ independent clones containing the construct a peptide having a size of the random peptide library and 1.2x10 ⁹ independent clones of the amino acids in length, as defined disulfide loop Ph.D.-12 Peptide Library Kit containing a linear random peptide of 12 amino acids length with a library size.

Alternatively, a similar library can be constructed with peptides containing random amino acids similar to the kit. For construction, random nucleotides are generated using the NNK, or NNS method, where N is an equivalent mixture of four nucleic acid bases A, C, G and T. K is an equivalent mixture of G or T and S is an equivalent mixture of G or C. Such randomized positions can be cloned into gene III proteins in phage or phagemid display vector systems. Both NNK and NNS methods include all 20 possible amino acids and one stop codon at slightly different frequencies for the encoded amino acids. Due to the limitation of bacterial transformation efficiency, the library size generated for phage display is usually to the extent mentioned above, so that peptides containing up to seven randomized amino acid positions can be produced, which is also a theoretical combination of It includes the entire repertoire (20 ⁷ = 1.28x10 ⁹ ). Longer peptide libraries can be constructed using NNK or NNS methods, but the actual phage display library size is likely to not include all possible theoretical amino acid combinations with respect to this length due to the requirement for bacterial transformation.

Thus, ribosomal display libraries involving larger / longer random peptides may be beneficial. For disulfide defined libraries, similar NNK or NNS random nucleotide methods are used. However, these random positions are flanked by cysteine amino acid residues, allowing disulfide bridge formation. N-terminal cysteines are often preceded by additional amino acids such as alanine. In addition, a flexible linker consisting of, but not limited to, several glycine residues can serve as a spacer between the peptide and the gene III protein for any of the random peptide libraries.

Method 2

The human tetranectin CTLDs shown in FIGS. 4 and 5 contain five loops (one loop including four loops in the LSA and one LSB), which can be altered to provide binding of CTLD to various protein targets. Random amino acid sequences may be located in one or more of these loops to generate a library from which CTLD domains with the desired binding properties can be selected. Construction of the library containing random peptides defined within any or all of the five loops of human tetranectin CTLD can be achieved using, but not limited to, NNK or NNS described in Method 1 above. One example of how seven random peptides can be inserted into loop 1 of TN CTLD is as follows.

PCR can be accomplished using primers 1X for (SEQ ID NO :) and 1X rev2 (SEQ ID NO :) in a PCR reaction without template to generate fragment A, and separate without template to generate fragment B In the PCR reaction, primers BstX1for (SEQ ID NO :) and PstBssRevC (SEQ ID NO :) can be used. PCR can be performed using high accuracy polymerase or taq blends and standard PCR thermocycling conditions. These two overlapping fragments can then be purified and used with external primers Bglfor12 (SEQ ID NO: 5) and PstRev (SEQ ID NO: 6) to generate the desired DNA fragments by PCR. Cleavage with other suitable restriction enzymes when using restriction enzymes BglII and PstI, or other primers, allows for gel separation of fragments containing loops or portions of TN CTLD. This purified fragment is then lysed with a similarly cleaved phage display vector containing restriction modified CTLD fused to gene III, for example pPHCPAB (SEQ ID NO: 150) or pANA27 (SEQ ID NO: 164). May be published (see FIG. 6).

Modification of other loops by replacement with randomized amino acids can be performed similarly to that set forth above. Replacement of defined amino acids in a loop with randomized amino acids is not limited to any particular loop, nor to the original size of the loop. Similarly, no full replacement of the loop is required, and partial replacement is possible for any of the loops. In some cases, retention of some of the original amino acids in the loop, for example the calcium co-amino acids shown in FIG. 7, may be desired. In such cases, substitutions using randomized amino acids may occur for fewer amino acids in the loop to retain calcium cooperative amino acids, or additional randomized to increase the overall size of the loop while still retaining the calcium cooperative amino acids. Amino acids can be added to the loop. Very large peptides can be accepted and tested by combining loop regions such as loops 1 and 2 or loops 3 and 4 into one large replacement loop. In addition, other CTLD, non-limiting examples, MBL CTLD may be used in place of the CTLD of tetranectin. Transplantation of peptides into the CTLD can occur using methods similar to those described above.

In various exemplary embodiments of the invention, a polypeptide that binds to IL-23R can be identified using a combinatorial peptide library based on a CTLD backbone, and a library of nucleic acid sequences encoding the polypeptide of the library, wherein the CTLD of the polypeptide Is modified according to a number of exemplary plans labeled only as plans (a)-(h) for identification purposes:

In one aspect, the invention provides a combinatorial peptide library and a library of nucleic acid sequences encoding a polypeptide of the library, wherein the CTLD of the polypeptide is in a number of schemes labeled only as Schemes (a)-(j) for identification purposes. Is deformed accordingly. Each scheme is described in more detail herein, with variations at least as follows:

(a) amino acid modification in at least one of four loops in loop segment A (LSA) of CTLD, wherein the amino acid modification comprises insertion of at least one amino acid into loop 1 and random substitution of at least five amino acids in loop 1;

(b) amino acid modification in at least one of four loops in loop segment A (LSA) of CTLD, wherein the amino acid modification comprises random substitution of at least five amino acids in loop 1 and random substitution of at least three amino acids in loop 2 ;

(c) amino acid modification in at least one of the four loops in loop segment A (LSA) of CTLD, wherein the amino acid modification comprises random substitution of at least seven amino acids in loop 1 and insertion of at least one amino acid in loop 4;

(d) amino acid modification in at least one of the four loops in loop segment A (LSA) of CTLD, wherein the amino acid modification comprises at least one amino acid insertion in loop 3 and random substitution of at least three amino acids in loop 3;

(e) in at least one of the four loops in loop segment A (LSA) of CTLD, wherein the amino acid modification comprises a modification that combines the two loops into a single loop, wherein the two combined loops are loop 3 and loop 4 Amino acid modification of;

(f) amino acid modification in at least one of the four loops in loop segment A (LSA) of CTLD, wherein the amino acid modification comprises at least one amino acid insertion in loop 4 and random substitution of at least three amino acids in loop 4;

(g) five in loop segment A (LSA) and loop segment B (LSB) of CTLD, wherein the amino acid modification comprises random substitution of at least five amino acid residues in loop 3 and random substitution of at least three amino acids in loop 5 Amino acid modification in at least one of the loops;

(h) amino acid modification in at least one of the four loops in loop segment A (LSA) of CTLD, wherein the amino acid modification comprises random substitution of at least one amino acid and insertion of at least six amino acids in loop 3;

loop segment A of CTLD, wherein (i) the amino acid modification comprises (1) random substitution of at least 6 amino acids in loop 3 and (2) random substitution of at least 6 amino acids in loop 3 and at least one amino acid insertion Amino acid modification in at least one of the four loops in (LSA);

(j) loop segment A of CTLD, wherein the amino acid modification comprises at least one or more amino acid insertions in at least one of the four loops in loop segment A (LSA) of CTLD or loop 5 in loop segment B (LSB) Amino acid modification in at least one of the four loops in (LSA).

In connection with scheme (a), the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD is in four loops of LSA of CTLD. At least one or amino acid modification in the loop of the LSB, wherein the amino acid modification comprises at least one amino acid insertion in loop 1 and random substitution of at least 5 amino acids in loop 1.

In certain embodiments of this aspect of the combinatorial library, when the CTLD is derived from human tetranectin, the CTLD also has a random substitution of arginine-130. For CTLDs that are not CTLDs of human tetranectin, these peptides are located directly adjacent to the C-terminal peptide of loop 2 in the C-terminal direction. For example, in mouse tetranectin, this peptide is Gly-130. In certain embodiments of this aspect of the combinatorial library, when the CTLD is derived from human or mouse tetranectin, the CTLD comprises substitution of lysine-148 with alanine in loop 4.

In certain embodiments, where the combinatorial library has a modified CTLD of Scheme (a), the amino acid modification comprises two amino acid insertions in loop 1 and random substitution of at least five amino acids in loop 1. In another embodiment, where the combinatorial library has a modified CTLD of Scheme (a) and the CTLD is derived from human tetranectin, the amino acid modification is at least one amino acid insertion in loop 1, and at least 5 amino acids in loop 1 Random substitutions, and random substitutions of arginine 130. In one specific embodiment, where the combinatorial library has a modified CTLD of Scheme (a) and the CTLD is derived from human tetranecti, the amino acid modification is 2 amino acid insertions in loop 1, random substitution of 5 amino acids in loop 1 , And random substitutions of arginine 130. In one specific embodiment, where the combinatorial library has a modified CTLD of Scheme (a) and the CTLD is derived from mouse tetranectin, the amino acid modification is 2 amino acid insertions in loop 1, random substitution of 5 amino acids in loop 1 , And random substitution of leucine 130. In any of the embodiments of scheme (a), the amino acid modification may further comprise a substitution of lysine-148 with alanine. Thus, in one specific embodiment of this aspect of the combinatorial library, the CTLD comprises two amino acid insertions in loop 1, a random substitution of at least five amino acids in loop 1, adjacent to loop 2 outside of the arginine-130 or C-terminal direction. Random substitutions of other amino acids located therein and substitution of lysine-148 with alanine in loop 4.

In relation to scheme (b), the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD is in four loops within the LSA of CTLD. At least one amino acid modification, wherein the amino acid modification comprises a random substitution of at least 5 amino acids in loop 1 and a random substitution of at least 3 amino acids in loop 2.

In certain embodiments of this embodiment of the combinatorial library of scheme (b), where the CTLD is derived from tetranectin, the amino acid modification is at least 5 amino acids in loop 1, at least 3 amino acids in loop 2, And random substitution of another amino acid located adjacent to the outside of loop 2 in the arginine-130 or C-terminal direction. In certain embodiments, where the combinatorial library has a modified CTLD of Scheme (b) and the CTLD is derived from human tetranectin, the amino acid modification is random substitution of at least 5 amino acids in loop 1, at least 3 amino acids in loop 2 And a random substitution of Arginine 130. In one embodiment, where the combinatorial library has a modified CTLD of Scheme (b) and the CTLD is derived from human tetranectin, the amino acid modification is a random substitution of 5 amino acids in loop 1, a random of 3 amino acids in loop 2 Substitutions, and random substitutions of arginine 130. In certain other embodiments, where the combinatorial library has a modified CTLD of Scheme (b) and the CTLD is derived from mouse tetranectin, the amino acid modification is random substitution of at least 5 amino acids in loop 1, at least 3 in loop 2 Random substitutions of amino acids, and random substitutions of leucine 130. In one embodiment, where the combinatorial library has a modified CTLD of Scheme (b) and the CTLD is derived from mouse tetranectin, the amino acid modification is a random substitution of 5 amino acids in loop 1, a random of 3 amino acids in loop 2 Substitutions, and random substitutions of leucine 130. In any of the embodiments of scheme (b), the amino acid modification may further comprise a substitution of lysine-148 with alanine. Thus, in one specific embodiment, the amino acid modifications comprise a random substitution of at least 5 amino acids in loop 1, a random substitution of at least 3 amino acids in loop 2, and adjacent to outside of loop 2 in the arginine-130 or C-terminal direction. Random substitutions of the other amino acids positioned and substitution of lysine-148 with alanine in loop 4.

In relation to scheme (c), the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD is a loop segment A (LSA) of CTLD. At least one amino acid modification in at least one of the four loops in the amino acid modification, wherein the amino acid modification comprises random substitution of at least seven amino acids in loop 1 and at least one amino acid insertion in loop 4.

In certain embodiments of this aspect of the combinatorial library, the polypeptide member of the combinatorial library further comprises random substitution of at least two amino acids in loop 4. In certain other embodiments of the above embodiments, the amino acid modifications include three amino acid insertions within loop 4 and optionally further comprise random substitution of at least two amino acids. In one embodiment, the amino acid modification comprises random substitution of at least seven amino acids in loop 1, at least three amino acid insertions in loop 4, and random substitution of at least two amino acids in loop 4. In one particular embodiment, the amino acid modification comprises random substitution of seven amino acids in loop 1, three amino acid insertions in loop 4, and random substitution of two amino acids in loop 4.

In relation to scheme (d), the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD is a loop segment A (LSA) of CTLD. At least one amino acid modification in at least one of the four loops within, wherein the amino acid modification includes at least one amino acid insertion in loop 3 and random substitution of at least three amino acids in loop 3.

In certain embodiments, where the combinatorial library has a modified CTLD of Scheme (d), the amino acid modification may further comprise at least one amino acid insertion in loop 4, resulting in random substitution of at least three amino acids in loop 4 It may further comprise. In any of the embodiments described for scheme (d), the amino acid modification may comprise three amino acid insertions in loop 3. In any of the embodiments described for scheme (d), the amino acid modification may comprise three amino acid insertions in loop 4. Thus, in certain embodiments, amino acid modifications include random substitution of at least 3 amino acids in loop 3, random substitution of at least 3 amino acids in loop 4, at least one amino acid insertion in loop 3, and at least one amino acid insertion in loop 4 It includes. In certain embodiments, the amino acid modification comprises random substitution of at least 3 amino acids in loop 3, random substitution of at least 3 amino acids in loop 4, at least 3 amino acid insertions in loop 3 and at least 3 amino acid insertions in loop 4 . In one specific embodiment, the amino acid modification comprises random substitution of three amino acids in loop 3, random substitution of three amino acids in loop 4, three amino acid insertions in loop 3 and three amino acid insertions in loop 4. In any of the embodiments described, wherein the CTLD is tetranectin, the amino acid modification may further comprise random substitution of lysine-148 with alanine or random substitution in loop 4.

In connection with scheme (e), the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD is loop segment A (LSA) of CTLD. At least one of the four loops within includes amino acid modifications, wherein the amino acid modifications include modifications that combine the two loops into a single loop, wherein the two combined loops are loop 3 and loop 4. In certain embodiments, where a member of the combinatorial library has a modified CTLD of Scheme (e), the amino acid modification comprises random substitution of at least 6 amino acids in loop 3 and random substitution of at least 4 amino acids in loop 4. In one specific embodiment, the amino acid modification comprises random substitution of six amino acids in loop 3 and random substitution of four amino acids in loop 4. In any of embodiments of scheme (e), when the CTLD is derived from human tetranectin, the amino acid modification may further comprise random substitution of proline-144. In one specific embodiment, where the CTLD is derived from human tetranectin, the amino acid modification comprises random substitution of six amino acids in loop 3, random substitution of four amino acids in loop 4, and random substitution of proline 144, eg For example, it generates a combined loop 3 and loop 4 amino acid sequence comprising NWEXXXXXXX XGGXXXN (SEQ ID NO :), wherein X is any amino acid and the amino acid sequence of SEQ ID NO: forms a single loop region. . Thus, in one specific embodiment, the polypeptide member of the combinatorial library comprises the sequence NWEXXXXXXX XGGXXXN (SEQ ID NO :), wherein X is any amino acid and the amino acid sequence of SEQ ID NO: is combined and modified loop 3 And form a single loop from loop 4.

In relation to scheme (f), the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD is loop segment A (LSA) of CTLD. At least one amino acid modification in at least one of the four loops within, wherein the amino acid modification includes at least one amino acid insertion in loop 4 and randomized substitution of at least three amino acids in loop 4. In certain embodiments, the amino acid modifications comprise four amino acid insertions in loop 4. In one embodiment, the amino acid modification comprises at least four amino acid insertions in loop 4 and random substitution of at least three amino acids in loop 4. In one specific embodiment, the amino acid substitutions comprise four amino acid insertions into loop 4 and random substitution of three amino acids in loop 4.

In relation to scheme (g), the polypeptide members of the combinatorial library include modified loop 3 and modified loop 5, wherein the modified loop 3 comprises randomization of five amino acid residues, wherein the modified loop 5 is Randomization of three amino acid residues. In one embodiment, the polypeptide members of the combinatorial library include modified loop 3, modified loop 5, and modified loop 4, wherein the modification to loop 4 abolishes plasminogen binding. For example, if the combinatorial library has a modified CTLD of Scheme (g) and the CTLD is derived from human tetranectin, then the amino acid modification is one or more amino acid modifications in loop 4 that regulate the plasminogen binding affinity of the CTLD. For example, the substitution of lysine 148 with alanine may be further included. Thus, in certain embodiments, where the CTLD is derived from human tetranectin, the amino acid modification is random substitution of at least 5 amino acid residues in loop 3, random substitution of at least 3 amino acid residues in loop 5, and lysine in loop 4 Substitution of 148 for alanine. In one specific embodiment, the amino acid modification comprises random substitution of five amino acid residues in loop 3 and random substitution of three amino acid residues in loop 5, and in another embodiment, where CTLD is derived from human tetranectin, The amino acid modification further comprises substitution of lysine 148 with alanine in loop 4.

In relation to scheme (h), the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD is loop segment A (LSA) of CTLD. At least one amino acid modification in at least one of the four loops within the amino acid modification, wherein the amino acid modification comprises random substitution of at least one amino acid and at least six amino acid insertions. In certain embodiments, where the CTLD is derived from human tetranectin, the amino acid modifications result in one or more amino acid modifications in loop 4 that modulate the plasminogen binding affinity of the CTLD, eg, substitution of alanine for lysine 148. It may further comprise. In certain embodiments, where the CTLD is derived from human tetranectin, a member of the combinatorial library comprises random substitution of at least one amino acid and insertion of at least six amino acids in loop 3, and substitution of alanine for lysine 148 in loop 4 Has In one specific embodiment, the amino acid modification comprises random substitution of one amino acid and insertion of six amino acids in loop 3. In one specific embodiment, when the CTLD is derived from human tetranectin, a member of the combinatorial library is responsible for random substitution of one amino acid and insertion of six amino acids in loop 3, and substitution of alanine for lysine 148 in loop 4 Have In any of the above embodiments, when the CTLD is derived from human tetranectin, one of the substitutions is the substitution of isoleucine 140.

In relation to scheme (i), the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD is loop segment A (LSA) of CTLD. Amino acid modifications in at least one of the four loops within, wherein the amino acid modifications comprise a combination of random substitution of six amino acids in loop 3 and random substitution of six amino acids in loop 3 and insertion of one amino acid. In one embodiment, the mixing further comprises random substitution of six amino acids and insertion of two amino acids in loop 3. Thus, in one embodiment, the amino acid modification is random substitution of six amino acids in loop 3, random substitution of six amino acids in loop 3 and insertion of one amino acid, and random substitution of six amino acids in loop 3 and two amino acids Includes a mix of insertions. In any of embodiments of scheme (i), wherein the CTLD is derived from human tetranectin, the amino acid modification further comprises a substitution of lysine 148 with alanine in loop 4.

In relation to scheme (i), the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD is loop segment A (LSA) of CTLD. An amino acid modification in at least one of the four loops in the amino acid modification, wherein the amino acid modification is in at least one of the four loops in loop segment A (LSA) of CTLD, and wherein the amino acid modification is in loop segment A (LSA) of CTLD At least four or more amino acid insertions in at least one of the four loops or loop 5 in loop segment B (LSB).

In embodiments in which the combinatorial library comprises one or more amino acid modifications (either alone or in combination with modifications to other regions of the CTLD) for the loop 4 region, the particular modification (s) may maintain the metal ion-binding affinity of the CTLD or It is designed to be regulated or abolished. Such modifications affect the plasminogen-binding activity of CTLD (see, eg, Nielbo, et al., Biochemistry , 2004 , 43 (27), pp 8636-8643; or Graversen 1998).

Polypeptide members of the library may comprise one or more amino acid modifications (eg, by insertion, substitution, extension, or randomization) in any combination of the four LSA loops and the LSB loop (loop 5) of the CTLD. Thus, in any of the various embodiments described herein, the randomized CTLD is alone or a modification of one or more amino acids in any one, two, three, or four loops of the LSA loop region (loops 1-4) And one or more amino acid modifications in the loop of the LSB loop region (Loop 5) in combination with. In one aspect, the present invention provides a combinatorial polypeptide library comprising a member of a polypeptide having a randomized C-type lectin domain (CTLD), wherein the randomized CTLD comprises four loops of loop segment A (LSA) of CTLD. One or more amino acid modifications in at least one of and one or more amino acid modifications in a loop (loop 5) of loop segment B (LSB), wherein the one or more amino acid modifications comprise randomization of LSB amino acid residues.

According to various embodiments described herein, a polypeptide member of a combinatorial library may comprise one or more amino acid modifications (eg, two loops) in any two, three, four, or five loops within the loop regions (LSA and LSB) of the CTLD. , 3 loops, 4 loops, or any random combination of random amino acid modifications to all 5 loops). Polypeptide members of the combinatorial library may further comprise additional amino acid modifications within regions of the CTLD outside the loop regions (LSA and LSB), eg, α-helices or β-strands (eg, FIG. 1).

In a further embodiment of the invention, the CTLD loop region may extend beyond the exemplary constructs detailed in the following non-limiting examples.

In one aspect, the invention also provides a library of nucleic acid molecules encoding a polypeptide of a combination polypeptide library according to any one of the embodiments and embodiments described above. In one embodiment of this aspect, the invention provides a library of nucleic acid sequences encoding a polypeptide of a library, wherein the CTLD of the polypeptide is modified according to schemes (a)-(j).

As will be described more fully in the Examples below, modification schemes (a)-(h) comprising preferred polypeptides include, for example, SEQ ID NOS: 133-141 as shown in FIG. 8. It is confirmed by one or more of.

Method 3

In another method, known polypeptides that bind IL-23R can be cloned directly to the N or C terminal trimerization domain using cysteine as a free linear peptide or disulfide defined loop. Single chain antibodies or domain antibodies capable of binding to IL-23R can also be cloned at either end of the trimerization domain. In addition, peptides with known binding properties can be cloned directly into either of the loop regions of the TN CTLD. Peptides selected as disulfide-limited loops or complementarity determining regions of antibodies may be highly applicable to rearrangement of human tetranectin into the loop region of CTLD. For all such constructs, binding as a monomer as well as binding and blocking activity as trimer when fused with the trimerization domain can be tested later.

Method 4:

In some cases where direct cloning of peptides with binding activity may not be sufficient, further optimization and selection may be necessary. For example, peptides with known binding to IL-23R, including but not limited to those mentioned above, can be transplanted into CTLD of human tetranectin. In order to select the optimal presentation of the peptide for binding, phage display selection for binding can be performed after one or more of the amino acids present on the side are randomized. In addition, peptides that exhibit limited or weak binding alone are also implanted into one of the loops of the CTLD library containing randomization of another additional loop, followed by selection via phage display for increased binding and / or specificity. Can be. In addition, for peptides whose specific interaction / binding amino acids have been identified through known crystal structures, randomization of non-binding amino acids is investigated, followed by selection via phage display for increased binding and receptor specificity. Can be. Regions of the IL-23 ligand identified as responsible for binding can also be tested across species. While conserved amino acids are retained, randomization and selection for non-species conserved positions can be tested.

Processing method

Another aspect of the invention relates to a method of preventing the activation of IL-23R in cells expressing IL-23R. The method comprises contacting the cell with an IL-23R binding polypeptide of the invention comprising at least one polypeptide that specifically binds to the trimerization domain and IL-23R. In one embodiment of this aspect, the method comprises contacting said cell with the trimer complex of the invention. The IL-23R binding polypeptide may be an antagonist of IL-23R (or a heterodimeric receptor) or as described above to bind to IL-23R to present a tumor, site of inflammation, or other desired location presenting IL-23R. Local delivery of therapeutic agents associated with trimerization domains may be possible.

In another aspect, the invention provides an immunological disorder or tumor by administering to a subject a therapeutically effective amount of an IL-23R antagonist comprising a polypeptide having a trimerization domain and at least one polypeptide that specifically binds IL-23R. A method of treating a subject. In one embodiment of this aspect, the method comprises administering to the subject a trimer complex of the invention.

Another aspect of the invention relates to combination therapy. Formulations comprising an IL-23R antagonist and a therapeutic agent are also provided by the present invention. Such formulations are believed to be particularly suitable for storage as well as therapeutic administration. Such formulations may be prepared by known techniques. For example, formulations can be prepared by buffer exchange on a gel filtration column.

The IL-23R antagonists and therapeutic agents described herein can be used in a variety of therapeutic applications. One such application is a method of treating various cancers. IL-23R antagonists and therapeutic agents are known, for example, by intravenous administration as a bolus or continuous infusion over a period of time, intramuscular, intraperitoneal, intracerebral, subcutaneous, intra-articular, intramuscular, intramedullary It may be administered by the oral, topical or inhalation route. Optionally, administration can be performed via mini-pump infusion using various commercially available devices.

Effective doses and schedules for administering IL-23R antagonists can be determined empirically, and such determinations are within the skill of the art. Single or multiple dosages may be used. It is currently contemplated that the effective dose or effective amount of the antagonist used alone may range from about 1 μg to about 100 mg or more per kg of body weight per day. Interstitial sizing of the dosage can be performed in a manner known in the art, for example, as described in Mordenti et. al . , Pharmaceut. Res., 8: 1351 (1991).

When in vivo administration of an IL-23R antagonist is used, the general dosage is from about 10 ng to 100 mg or more, preferably from about 1 μg / kg / day to 10, per kg body weight of mammal per day, depending on the route of administration. May vary from mg / kg / day. Guidance as to particular dosages and methods of delivery is provided in the literature [eg, U.S. Pat. Pat. Nos. 4,657,760; 5,206,344; Or 5,225,212]. Those skilled in the art will appreciate that various formulations will be effective for a variety of therapeutic compounds and a variety of disorders, for example, administration targeted to one organ or tissue may require delivery in a manner different from that for another organ or tissue. It will be recognized. Those skilled in the art will appreciate that the dosage of the IL-23R antagonist to be administered will vary depending, for example, on the mammal to which the IL-23R antagonist will be administered, the route of administration, and other drugs or therapies administered to the mammal.

It is contemplated that other additional therapies may be used in the method. One or more other therapies include radiation therapy, cytokine (s), growth inhibitor (s), chemotherapeutic agent (s), cytotoxic agent (s), tyrosine kinase inhibitors, ras farnesyl transferase inhibitors, angiogenesis inhibitors, And administration of any other agent that enhances the sensitivity of cancer cells to death by cyclin-dependent kinase inhibitors or IL-23R antagonists known in the art.

Preparation and dosing schedules for chemotherapeutic agents may be used in accordance with the manufacturer's instructions or may be empirically determined by a skilled practitioner. Preparation and dosing schedules for such chemotherapeutic agents are also described in Chemotherapy Service Ed., M. C. Perry, Williams & Wilkins, Baltimore, Md. (1992). Chemotherapeutic agents may precede or follow administration of the Apo2L variant, or may be provided concurrently with the Apo2L variant.

The polypeptides and therapeutic agents (and one or more other therapies) of the invention may be administered simultaneously (in conjunction) or sequentially. In certain embodiments, non-natural polypeptides of the invention or multimers (eg, trimer) complexes thereof, and the therapeutic agent are administered simultaneously. In another embodiment, the polypeptide or trimer complex is administered prior to the administration of the therapeutic agent. In another embodiment, the therapeutic agent is administered before the polypeptide or trimer complex. After administration, the cells to be treated in vitro can be analyzed. When treated in vivo, the treated mammal can be monitored by a variety of methods well known to the skilled practitioner. For example, tumor tissue may be pathologically tested to assay for cell death, or serum may be analyzed for immune system response.

Pharmaceutical composition

In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a polypeptide of the invention in combination with a pharmaceutically acceptable carrier or excipient. As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. do. Examples of pharmaceutically acceptable carriers or excipients include water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable substances, such as wetting substances or small amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion, may also be included. Optionally, disintegrants such as crosslinked polyvinyl pyrrolidone, agar, alginic acid or salts thereof, such as sodium alginate and the like, may be included. In addition to excipients, the pharmaceutical composition may comprise carrier proteins such as one or more of serum albumin, buffers, binders, sweeteners and other flavoring agents, colorants and polyethylene glycols.

The composition includes, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (eg injection and infusion solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. It can exist in various forms. Preferred forms will depend on the intended route of administration and therapeutic application. In one embodiment, the composition is in the form of a composition similar to that used for passive immunization of a human with an injection or infusion solution, eg, an antibody. In one embodiment, the mode of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular) administration. In one embodiment, the polypeptide (or trimer complex) is administered by intravenous infusion or injection. In another embodiment, the polypeptide or trimer complex is administered by intramuscular or subcutaneous injection.

Other suitable routes of administration for the pharmaceutical compositions include, but are not limited to, rectal, transdermal, vaginal, transmucosal or intestinal administration.

Therapeutic compositions are typically sterile and stable under the conditions of manufacture and storage. The compositions may be formulated in solution, microemulsions, dispersions, liposomes, or other ordered structures suitable for high drug concentrations. Sterile injectable solutions can be prepared by incorporating the active compound (ie, a polypeptide or trimer complex) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterile filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze-drying to produce any additional desired ingredients together with the powder of the active ingredient from the presterile-filtered solution. Proper fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prolonged absorption of the injectable composition may occur by including an agent in the composition which delays absorption, for example, monostearate salt and gelatin.

Articles of manufacture, such as kits containing IL-23R antagonists and therapeutic agents useful for the treatment of the disorders described herein, include at least a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container may be formed from various materials, for example glass or plastic. Labels on or associated with the container indicate that the formulation is to be used to treat the disease of choice. The article of manufacture may further comprise a container comprising a pharmaceutically acceptable buffer such as phosphate buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desired from the commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. The article of manufacture may also include a container having another active agent as described above.

Typically, an appropriate amount of pharmaceutically acceptable salt is used in the formulation to render the formulation isotonic. Examples of pharmaceutically acceptable carriers include salts, Ringer's solution and dextrose solution. The pH of the formulation is preferably about 6 to about 9, more preferably about 7 to about 7.5. It will be apparent to those skilled in the art that particular carriers may be more desirable depending on, for example, the route of administration and the concentration of IL-23R antagonist and therapeutic agent.

Therapeutic compositions can be prepared by mixing the desired molecule with the appropriate degree of purity with any pharmaceutically acceptable carrier, excipient, or stabilizer in the form of a lyophilized formulation, aqueous solution or aqueous suspension (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980)). Acceptable carriers, excipients, or stabilizers are preferably nontoxic to recipients at the dosages and concentrations employed, including buffers such as Tris, HEPES, PIPES, phosphate, citrate, and other organic acids; Antioxidants such as ascorbic acid and methionine; Preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzetonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, for example methyl or propyl paraben; catechol; rezo Lecinol; cyclohexanol; 3-pentanol; and m-cresol); Low molecular weight (less than about 10 residues) polypeptides; Proteins such as serum albumin, gelatin, or immunoglobulins; Hydrophilic polymers such as polyvinylpyrrolidone; Amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; Monosaccharides, disaccharides, and other carbohydrates such as glucose, mannose, or dextrins; Sugars such as sucrose, mannitol, trehalose or sorbitol; Salt-forming counter-ions such as sodium; And / or non-ionic surfactants such as TWEEN ™, PLURONICS ™ or polyethylene glycol (PEG).

Further examples of such carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids. Partially glyceride mixtures, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, and cellulose based Contains substances. Carriers for topical or gel-based forms include polysaccharides such as sodium carboxymethylcellulose or methylcellulose, polyvinylpyrrolidone, polyacrylates, polyoxyethylene-polyoxypropylene-block polymers, polyethylene glycols, and wood waxes ( wood wax) alcohol. For all administrations, conventional depot forms are suitably used. Such forms include, for example, microcapsules, nano-capsules, liposomes, gypsum, inhaled forms, nasal sprays, sublingual tablets, and sustained-release preparations.

Formulations used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes before or after lyophilization and reconstitution. The formulations may be stored in lyophilized form or in solution when administered systemically. In lyophilized form, they are typically formulated in combination with other ingredients for reconstitution with an appropriate diluent in use. An example of a liquid formulation is a sterile clear colorless preservative unadded solution filled in single-dose vials for subcutaneous injection.

The therapeutic formulation is generally placed in a container with a sterile access port, for example an intravenous solution bag or vial with a stopper that can be penetrated by a hypodermic needle. The formulations are preferably administered in aerosol formulations suitable for repeated intravenous (i.v.), subcutaneous (s.c), intramuscular (i.m.) injections or infusions, or intranasal or pulmonary delivery (for pulmonary delivery, see EP 257,956).

The molecules disclosed herein may also be administered in the form of sustained-release preparations. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing protein, which matrices are in the form of shaped articles, eg, films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (eg, Langer et. al . , J. Biomed. Mater. Res., 15: 167-277 (1981) and Langer, Chem. Tech., 12: 98-105 (1982), poly (2-hydroxyethyl-methacrylate) or poly (vinyl alcohol)), polylactide (US Pat. No. 3,773,919, EP 58,481) , Copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al , Biopolymers, 22: 547-556 (1983)), non-degradable ethylene-vinyl acetate (Langer et al . , Above), degradable lactic acid-glycolic acid copolymers such as Lupron Depot (injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3- Hydroxybutyric acid (EP 133,988).

Generation of Polypeptides

Polypeptides of the invention can be expressed in any suitable standard protein expression system by culturing a host transformed with a vector encoding the polypeptide under conditions in which the polypeptide is expressed. Preferably, the expression system is a system in which the desired protein can be easily separated. As a general rule, prokaryotic expression systems are available because high yields of proteins and effective purification and refolding methods can be obtained. Thus, the selection of appropriate expression systems (including vectors and cell types) is within the knowledge of those skilled in the art. Similarly, once a primary amino acid sequence for a polypeptide of the invention is selected, those skilled in the art will recognize such factors as codon bias in the selected host, the need for secretory signal sequences in the host, the introduction of proteases in the signal sequence, and the like. In view of the above, suitable recombinant DNA constructs encoding the desired amino acid sequences can be readily designed.

In one embodiment, the isolated polynucleotides encode polypeptides and trimerization domains that specifically bind to IL-23R. In one embodiment, the isolated polynucleotide encodes a first polypeptide that specifically binds IL-23R, and a trimerization domain. In certain embodiments, polypeptides and trimerization domains that specifically bind to IL-23R are encoded into a single continuous polynucleotide sequence (genetic fusion). In other embodiments, polypeptides and trimerization domains that specifically bind to IL-23R are encoded by non-contiguous polynucleotide sequences. Thus, in some embodiments, at least one polypeptide and trimerization domain that specifically binds IL-23R are expressed as separate polypeptides, isolated, purified, and fused together to form polypeptides of the invention.

Such recombinant DNA constructs can be inserted in-frame into any of a number of expression vectors appropriate for the selected host. In certain embodiments, the expression vector comprises a strong promoter that regulates the expression of the recombinant polypeptide construct. When recombinant expression methods are used to produce the polypeptides of the invention, the resulting polypeptides can be isolated and purified using suitable standard procedures well known in the art and optionally subjected to further processing, eg, lyophilization. Can be applied.

Standard techniques can be used for the production of recombinant DNA molecules, proteins, and polypeptides as well as tissue culture and cell transformation. See, eg, Sambrook, et al . (To) or Current Protocols in Molecular Biology (Ausubel et al . , eds., Green Publishers Inc. and Wiley and Sons 1994). Purification techniques are typically performed according to the manufacturer's specifications, or are described in Sambrook et. al . (Molecular Cloning: A Laboratory Manual.Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989)) using conventional procedures as described or commonly performed in the art, or as described herein. If no specific definitions are provided, the nomenclature used in connection with the experimental procedures and techniques related to molecular biology, biochemistry, analytical chemistry, and pharmaceutical / formulation chemistry described herein are well known and commonly used in the art. Standard techniques can be used for biochemical synthesis, biochemical analysis, pharmaceutical preparations, formulations, and delivery, and treatment of patients.

It will be appreciated that a flexible molecular linker may optionally be inserted between a particular binding member and a trimerization domain to covalently link the member to the trimerization domain. In certain embodiments, the linker is a polypeptide sequence of about 1-20 amino acid residues. The linker may be less than 10 amino acids, most preferably 5, 4, 3, 2, or 1 amino acid. In certain cases, 9, 8, 7 or 6 amino acids may be suitable. In useful embodiments, the linker is essentially non-immunogenic, does not tend to proteolytically degrade, and does not comprise amino acid residues (eg, cysteine residues) known to interact with other residues.

The following description also relates to methods for generating polypeptide and trimer complexes covalently attached (hereinafter “conjugated”) to one or more chemical groups. Chemical groups suitable for use in the conjugates are preferably not significantly toxic or immunogenic. Chemical groups are optionally selected to produce conjugates that can be stored and used under conditions suitable for storage. Various exemplary chemical groups that can be conjugated to a polypeptide are known in the art and include, for example, carbohydrates, such as carbohydrates, polyglutamate, and non-proteinaceous polymers that occur naturally in glycoproteins, for example. For example, polyols (see, eg, US Pat. No. 6,245,901).

For example, polyols may be conjugated to a polypeptide of the invention at one or more amino acid residues comprising lysine residues as disclosed in WO 93/00109, supra. The polyol used may be any water soluble poly (alkylene oxide) polymer, which may have a straight or branched chain. Suitable polyols include those substituted at one or more hydroxyl positions with chemical groups, for example alkyl groups having from 1 to 4 carbons. Typically, the polyol is a poly (alkylene glycol), for example poly (ethylene glycol) (PEG), so for ease of substrate, the remainder of the discussion is that the polyol used is PEG and the polyol is conjugated to the polypeptide. The method of gating relates to an exemplary embodiment referred to as "pegylation." However, those skilled in the art recognize that other polyols, such as poly (propylene glycol) and polyethylene-polypropylene glycol copolymers, may be used using the techniques for conjugation described herein for PEG.

The average molecular weight of PEG used in the PEGylation of Apo-2L can vary, typically in the range of about 500 to about 30,000 Daltons (D). Preferably, the average molecular weight of PEG is about 1,000 to about 25,000 D, more preferably about 1,000 to about 5,000 D. In one embodiment, PEGylation is performed with PEG with an average molecular weight of about 1,000 D. Optionally, the PEG homopolymer is unsubstituted, but it may also be substituted at one end with an alkyl group. Preferably, the alkyl group is a C1-C4 alkyl group, most preferably a methyl group. PEG preparations are commercially available and typically suitable PEG preparations for use in the present invention are non-homogeneous preparations which are commercially available according to average molecular weight. Commercially available PEG (5000) preparations, for example, typically contain molecules that differ slightly in molecular weight, usually at ± 500 D. Polypeptides of the invention can be further modified using techniques known in the art, for example, conjugated to moisturized compounds (eg, chemotherapeutic agents); Conjugated to a signal molecule (eg, a fluorophore); Conjugated to a specific binding pair of molecules (eg biotin / streptavidin, antibody / antigen); Stabilization by glycosylation, PEGylation, or further fusion to stabilizing domains (eg, Fc domains).

Various methods of PEGylating proteins are known in the art. Particular methods for generating proteins conjugated to PEG include those described in US Pat. Nos. 4,179,337, 4,935,465, and 5,849,535. Typically, a protein is covalently bound to the terminal reactor of the polymer via one or more of the amino acid residues of the protein, primarily depending on reaction conditions, molecular weight of the polymer, and the like. Polymers with reactor (s) are described herein as activated polymers. The reactor selectively reacts with free amino groups or other reactors of the protein. PEG polymers can be coupled to amino groups or other reactors of a protein in a random or site specific manner. However, it will be understood that the type and amount of reactor selected as well as the type of polymer employed to obtain optimal results depend on the particular protein or protein variant used to avoid the reactor reacting with too many specific activators of the protein. will be. Since it may not be possible to avoid this completely, it is recommended to use about 0.1 to 1000 moles, preferably 2 to 200 moles of activated polymer per mole of protein, depending on the protein concentration. The final amount of activated polymer per mole of protein is a balance to maintain optimal activity, while at the same time an amount that optimizes the circulating half-life of the protein.

As used herein, the term "polyol" generally means a polyhydric alcohol compound. The polyol may be, for example, any water soluble poly (alkylene oxide) polymer and may have a straight or branched chain. Preferred polyols include polyols substituted at one or more hydroxyl positions with a chemical group, for example an alkyl group having from 1 to 4 carbons. Typically, the polyol is poly (alkylene glycol), preferably poly (ethylene glycol) (PEG). However, one of ordinary skill in the art recognizes that other polyols, such as poly (propylene glycol) and polyethylene-polypropylene glycol copolymers, may be used using the techniques for conjugation described herein for PEG. The polyols of the present invention include polyols well known in the art and publicly available polyols such as those from commercial suppliers.

In addition, other half-life extending molecules, including serum albumin-binding peptides, IgG-binding peptides or peptides that bind FcRn, can be attached to the N- or C-terminus of the trimerization domain.

It should be appreciated that section headings are used herein for organizational purposes only and should not be construed as limiting the subject matter described in any way. All references cited herein are hereby incorporated by reference in their entirety for all purposes.

The examples set forth below are merely illustrative of specific embodiments of the invention and should not be construed as limiting the invention as defined by the appended claims below.

Example

The vectors (pANA) discussed in the examples below are derived from the previously described vectors (see US 2007/0275393). Particular vector sequences are provided in the Sequence Listing, and one of ordinary skill in the art would be able to obtain the vectors if a description is provided herein. The pPhCPAB phage display vector (SEQ ID NO: 150) has a gIII signal peptide coding region fused to an hTN sequence encoding ALQT (etc.) using a linker. The C-terminus of the CTLD region is fused to the remaining gIII coding region via a linker. Within the CTLD region, a nucleotide mutation was generated that did not alter the coding sequence but resulted in a restriction site suitable for cloning the PCR fragment containing the altered loop region. The region of the loop region was removed between the restriction sites so that all library phages could express only the recombinant and not the wild type tetranectin. Murine TN CTLD phage display vectors were similarly designed. Another embodiment of this vector is pANA27 (SEQ ID NO: 164) wherein the gene III C-terminal region is truncated and the inhibitory stop codon at the end of the hTN coding sequence is modified to encode glutamine. Murine vector pANA28 (SEQ ID NO: 165) was constructed in a similar manner.

Example 1

Library Construction: Mutations and Extensions of Loop 1

The nucleotide and amino acid sequences of human tetranectin and the positions of loops 1, 2, 3, 4, and 5 (LSB) are shown in FIG. 9. For 1-2 extended libraries of human tetranectin C-type lectin binding domains (“human 1-2X”), the coding sequence for loop 1 was modified to encode the sequence set forth in Table 2, wherein the five amino acid AAEGT (SEQ ID NO :) is 7 encoded by the nucleotide NNK NNK NNK NNK NNK NNK NNK (SEQ ID NO :), where N represents A, C, G, or T; K represents G or T Were substituted with four random amino acids. The amino acid arginine present immediately after loop 2 was also sufficiently randomized using the nucleotide NNK in the coding strand. These amino acids were randomized because arginine may contact the amino acids of loop 1 and define the forms that can be achieved by loop 1 randomization. In addition, the coding sequence for loop 4 was altered to encode alanine (A) instead of lysine 148 (K) to discard plasminogen binding found to be dependent on loop 4 lysine (Graversen et al, 1998).

Table 2

Amino acids of loop regions from human tetranectin (TN).

Parentheses denote amino acids that are contiguous but not considered part of the loop.

X = any amino acid.

Human loop 1 extension libraries were generated using overlapping PCR in the following manner (primer sequences are shown in Table 3). Primers 1Xfor (SEQ ID NO :) and 1Xrev (SEQ ID NO :) are mixed and extended by PCR, primers BstX1for (SEQ ID NO :) and PstBssRevC (SEQ ID NO :) are mixed and extended by PCR I was. The resulting fragments were purified from the gel, mixed and extended by PCR in the presence of external primers Bglfor12 (SEQ ID NO :) and PstRev (SEQ ID NO :). The resulting fragments were gel purified, digested with BglII and PstI and cloned into phage display vector pPhCPAB or pANA27. Phage display vector pPhCPAB was derived from pCANTAB (Pharmacia), which contained a portion of human tetranectin CTLD fused to M13 gene III protein. The CTLD region is modified to include the BglII and PstI restriction enzyme sites present on the sides of loops 1-4, and the 1-4 regions are modified to include stop codons to allow functional gene III from the vector without ligation of the in-frame insert. The protein could not be produced. The pANA27 was derived from pPhCPAB by replacing the BamHI to ClaI regions with the BamHI to ClaI sequences of SEQ ID NO: 164 (pANA27). This replaces the amber inhibitory stop codon with glutamine codons and truncates the amino terminal region of gene III.

The ligated material is transformed with electrocompetent XL1-Blue E. coli (Stratagene), 4-8 liters of cells are grown overnight, and DNA is isolated to master library DNA for panning. Stock was created. A library size of 1.5 × 10 ⁸ was obtained and the clones tested showed various sequences in the targeted region.

TABLE 3

Sequence used for generation of phage displayed C-type lectin domain library.

M = A or C; N = A, C, G, or T; K = G or T; S = G or C; W = A or T.

Example 2

Library Construction: Mutations in Loops 1 and 2

For the loop 1-2 library of human tetranectin C-type lectin binding domains (“human 1-2”), the coding sequence for loop 1 was modified to encode the sequence set forth in Table 2, wherein the five amino acid AAEGT ( SEQ ID NO :; human) is encoded by the nucleotide NNK NNK NNK NNK NNK (SEQ ID NO :), where N represents A, C, G, or T; K represents G or T Replaced with random amino acids. In loop 2 (including neighboring arginine), the human 4 amino acid TGAR was replaced with 4 random amino acids encoded by the nucleotide NNK NNK NNK NNK (SEQ ID NO :). It was also modified to encode alanine (A) instead of lysine (K) in the loop to discard plasminogen binding found to be dependent on loop 4 lysine (Graversen et al, 1998).

Human 1-2 libraries were generated using overlapping PCR in the following manner (primer sequences are shown in Table 3). Primers 1-2 for (SEQ ID NO :) and 1-2 rev (SEQ ID NO :) were mixed and extended by PCR. The resulting fragment was purified from the gel, mixed and extended by PCR in the presence of the external primers Bglfor12 (SEQ ID NO :) and PstRev12 (SEQ ID NO :). The resulting fragments were gel purified, cleaved with BglII and PstI and cloned into cleaved phage display vectors pPhCPAB or pANA27 similar to those described above. A library size of 4.86 x 10 ⁸ was obtained and the clones tested showed various sequences in the targeted region.

Example 3

Library Construction: Mutations and Extensions of Loops 1 and 4

For the loop 1-4 library of human C-type lectin binding domains (“human 1-4”), the coding sequence for loop 1 was modified to encode the sequence set forth in Table 2, wherein the seven amino acid DMAAEGT for human (SEQ ID NO :) is expressed as nucleotides NNS NNS NNS NNS NNS NNS NNS (SEQ ID NO :), where N represents A, C, G, or T; S represents G or C Were substituted with four random amino acids. In addition, the coding sequence for loop 4 was modified and extended to encode the sequence shown in Table 1, wherein the two amino acids KT of loop 4 for humans were nucleotide NNS NNS NNS NNS NNS (SEQ ID NO :) for humans It was replaced by five random amino acids encoded by.

Human 1-4 libraries were generated using overlapping PCR in the following manner (primer sequences are shown in Table 3). Mix primers BglBssfor (SEQ ID NO :) and BssBglrev (SEQ ID NO :), extend by PCR, mix primers BssPstfor (SEQ ID NO :) and PstBssRev (SEQ ID NO :), extend by PCR I was. The resulting fragment was purified from the gel, mixed and extended by PCR in the presence of the external primers Bglfor (SEQ ID NO :) and PstRev (SEQ ID NO :). The resulting fragments were gel purified, digested with BglII and PstI restriction enzymes and cloned into the digested phage display vector pPhCPAB or pANA27 similar to that described above. A library size of 2 × 10 ⁹ was obtained and the 12 clones tested showed various sequences in the targeted region.

Example 4

Library Construction: Mutations and Extensions of Loops 3 and 4

For the loop 3-4 extension library ("human 3-4X") of the human C-type lectin binding domain, the coding sequence for loop 3 was modified to encode the sequence set forth in Table 2, wherein the three of human tetranectin 6 random encoded amino acids EIT by the nucleotide NNK NNK NNK NNK NNK NNK (SEQ ID NO :) of the coding strand, where N represents A, C, G, or T; K represents G or T Replaced with amino acids. In addition, in loop 4, three amino acids KTE in humans were replaced with six random amino acids encoded by the nucleotides NNK NNK NNK NNK NNK NNK (SEQ ID NO :).

Human 3-4 extension libraries were generated using overlapping PCR in the following manner (primer sequences are shown in Table 3). Primer H Loop 1-2-F (SEQ ID NO :) and H Loop 3-4 Ext-R (SEQ ID NO :) are mixed, extended by PCR, and primer H Loop 3-4 Ext-F (SEQ ID NO :) and H Loop 5-R (SEQ ID NO :) were mixed and extended by PCR. The resulting fragments were purified from the gel, mixed and extended by PCR in the presence of additional H Loop 1-2-F (SEQ ID NO :) and H Loop 5-R (SEQ ID NO :). The resulting fragments were gel purified, digested with BglII and PstI restriction enzymes and cloned into the digested phage display vector pPhCPAB or pANA27 similar to that described above. A library size of 7.9 × 10 ⁸ was obtained and the clones tested showed various sequences in the targeted region.

Example 5

Library Construction: Mutations in Loops 3 and 4 and PRO Between These Loops

For the loop 3-4 combo library ("human 3-4 combo") of the human tetranectin C-type lectin binding domain, the coding sequences for loops 3 and 4 and the proline between these two loops are shown in Table 2 Was modified to encode the sequence shown in which human sequence TEITAQPDGGKTE (SEQ ID NO :) was replaced with the 13 amino acid sequence XXXXXXXXGGXXX (SEQ ID NO :), where X is the sequence NNK (N is A, C, G, or T represents; K represents G or T).

Human 3-4 combo libraries were generated using overlapping PCR in the following manner (primer sequences are shown in Table 3). Primers H Loop 1-2-F (SEQ ID NO :) and H Loop 3-4 Combo-R (SEQ ID NO :) are mixed, extended by PCR, and the resulting fragments are purified from the gel, mixed and And extended by PCR in the presence of additional H Loop 1-2-F (SEQ ID NO :) and H Loop 5-R (SEQ ID NO :). The resulting fragments were gel purified, digested with BglII and PstI restriction enzymes and cloned into the digested phage display vector pPhCPAB or pANA27 similar to that described above. A library size of 4.95 × 10 ⁹ was obtained and the clones tested showed various sequences in the targeted region.

Example 6

Library Construction: Mutations and Extensions of Loop 4

For the loop 4 extension library ("human 4") of the human tetranectin C-type lectin binding domain, the coding sequence for loop 4 was modified to encode the sequence set forth in Table 2, wherein the three amino acid KTE of human tetranectin Was replaced with seven random amino acids encoded by nucleotides NNK NNK NNK NNK NNK NNK NNK (SEQ ID NO :), where N represents A, C, G, or T; K represents G or T .

Human 4 extension libraries were generated using overlapping PCR in the following manner (primer sequences are shown in Table 3). Primer H Loop 1-2-F (SEQ ID NO :) and H Loop 3-R (SEQ ID NO :) are mixed, extended by PCR, primer H Loop 4 Ext-F (SEQ ID NO :) and H Loop 5-R (SEQ ID NO :) was mixed and extended by PCR. The resulting fragments were purified from the gel, mixed and extended by PCR in the presence of additional H Loop 1-2-F (SEQ ID NO :) and H Loop 5-R (SEQ ID NO :). The resulting fragments were gel purified, digested with BglII and PstI restriction enzymes and cloned into the digested phage display vector pPhCPAB or pANA27 similar to that described above. A library size of 2.7 × 10 ⁹ was obtained and the clones tested showed various sequences in the targeted region.

Example 7

Library Construction: Mutations with Extension of Loop 3 and Mutations without Extension of Loop 3

For the loop 3 alteration library of human tetranectin C-type lectin binding domains, the coding sequence for loop 3 was modified to encode the sequence shown in Table 2, wherein the human 6 amino acid ETEITA (SEQ ID NO :) nucleotides NNK NNK NNK NNK NNK NNK (SEQ ID NO :), NNK NNK NNK NNK NNK NNK NNK (SEQ ID NO :), and NNK NNK NNK NNK NNK NNK NNK NNK (SEQ ID NO :), where N is A, C , G, or T; K represents G or T), and 6, 7, or 8 random amino acids encoded. In addition, in loop 4, human 3 amino acid KTE was replaced with 6 random amino acids encoded by nucleotides NNK NNK NNK NNK NNK NNK (SEQ ID NO :). In addition, the coding sequence for loop 4 was altered to encode alanine (A) instead of lysine (K) to discard plasminogen binding found to be dependent on loop 4 lysine (Graversen et al, 1998).

Human loop 3 altered libraries were generated using overlapping PCR in the following manner. Primers HLoop3F6, HLoop3F7, and HLoop3F8 (SEQ ID NOS :, respectively) were separately mixed with HLoop4R (SEQ ID NO :) and extended by PCR. The resulting fragments were purified from the gels, mixed and extended by PCR in the presence of oligo H Loop 1-2F (SEQ ID NO :), HuBglfor (SEQ ID NO :) and PstRev (SEQ ID NO :). The resulting fragments were gel purified, digested with BglI and PstI restriction enzymes and cloned into the digested phage display vector pPhCPAB or pANA27 similar to that described above. After library generation, three libraries were pooled for panning.

Alternative loop extension of loop 3

Human loop 3 loop libraries were generated using nested PCR in the following manner. Primer Loop3AF2 (SEQ ID NO :) and Loop3AR2 (SEQ ID NO :) are mixed and extended by PCR, primers Loop3BF (SEQ ID NO :) and Loop3BR (SEQ ID NO :) are mixed and extended by PCR I was. The resulting fragments were purified from the gel, mixed and subjected to PCR in the presence of primers Bgl for (SEQ ID NO :) and Loop30R (SEQ ID NO :). The product was cleaved with BglII and PstI restriction enzymes and the purified fragment was cloned into a phage display vector pPhCPAB or pANA27 similarly cleaved as described above. In addition, the coding sequence for loop 4 was altered to encode alanine (A) instead of lysine (K) to discard plasminogen binding found to be dependent on loop 4 lysine (Graversen et al, 1998).

Example 8

Mutations in loops 3 and 5

For the loop 3 and 5 altered libraries of human C-type lectin binding domains, the coding sequences for loops 3 and 5 were modified to encode the sequences shown in Table 2, wherein the human 5 amino acid TEITA was nucleotide NNK NNK NNK NNK The 5 amino acids encoded by NNK (SEQ ID NO :) were replaced, and the human 3 amino acids AAN were replaced by 3 amino acids encoded by the nucleotide NNK NNK NNK. In addition, the coding sequence for loop 4 was altered to encode alanine (A) instead of lysine (K) to discard plasminogen binding found to be dependent on loop 4 lysine (Graversen et al, 1998).

Human loop 3 and 5 altered libraries were generated using overlapping PCR in the following manner. Primers h3-5AF (SEQ ID NO :) and h3-5AR (SEQ ID NO :) are mixed, extended by PCR, primers h3-5BF (SEQ ID NO :) and h3-5 BR (SEQ ID NO: ) Were mixed and extended by PCR. The resulting fragments were purified from gels, mixed and extended by PCR in the presence of h3-5 OF (SEQ ID NO :) and PstRev (SEQ ID NO :). The resulting fragments were gel purified, digested with BglI and PstI restriction enzymes and cloned into the digested phage display vector pPhCPAB or pANA27 similar to that described above.

Example 9

Panning and Screening of Human Library 1-4

Phage generated from human libraries 1-4 were panned in recombinant human IL-23R / Fc chimera (R & D Systems). Screening of the binding panel after 3, 4, and / or 5 rounds of panning using an ELISA plate assay confirmed receptor-specific binding in all cases.

To generate phage for panning, the master library DNA was transformed by electroporation to bacterial strain TG1 (Stratagene). The cells were allowed to recover for 1 hour with shaking at 37 ° C. in SOC (Super-Optimal broth with Catabolite repression) medium and the volume increased 10-fold by adding super broth (SB) to 20% glucose and 20 A final concentration of μg / mL carbenicillin was made. After shaking at 37 ° C. for 1 hour, the carbenicillin concentration was increased to 50 μg / mL for another 1 hour and then with 2% glucose and 50 μg / mL carbenicillin with helper phage M13K07. 400 mL of SB was added at a final concentration of 5 × 10 ⁹ pfu / mL. Incubation was continued at 37 ° C. with shaking for 30 minutes and then shaken at 100-150 rpm for another 30 minutes. Cells were centrifuged at 3200 g at 4 ° C. for 20 minutes and then resuspended in 500 mL SB medium containing 50 μg / mL carbenicillin and 50 μg / mL kanamycin. Cells were grown overnight at room temperature (RT) with shaking at 150 rpm. Phage were separated by pelleting bacterial cells by centrifugation at 15,000 g and 4 ° C. for 20 minutes. The supernatant was incubated with 1/4 volume (usually 250 mL supernatant / bottle + 62.5 mL PEG solution) on 20% PEG / 2.5 M NaCl on ice for 30 minutes. Phage were pelleted by centrifugation at 15,000 g and 4 ° C. for 20 minutes. Phage pellets in 1% bovine serum in phosphate buffered saline (PBS) containing 0.1% sodium azide (BSA / PBS / azide) and fully mini-EDTA-free protease inhibitor (Roche) prepared according to manufacturer's instructions Resuspend in albumin (BSA). Alternatively, phages were resuspended in Buffer D containing 0.05% boiled casein, 0.025% Tween-20, and protease inhibitors. The material was filter sterilized using a 25 mm diameter Whatman Puradisc, 0.2 μm pore size filter.

Phage generated from human library 1-4 were panned in recombinant human IL-23R / Fc chimera (R & D Systems cat # 1686-MR). Library panning was performed using plate or bead format. For the plate format, 6-8 wells of 96-well Immulon HB2 ELISA plates were coated with carrier-free human IL-23R / Fc at 250-1000 ng / well in Dulbecco PBS. The material is incubated in the plate overnight, then the wells are washed three times with PBS and addition of blocking buffer (1% BSA / PBS / azide, or buffer C containing 0.05% boiled casein and 1% Tween-20). The wells were then incubated at 37 ° C. for at least 1 hour. Additional wells were also treated with blocking buffer at the same time for subsequent uptake of phage binding to blocking buffer.

Three dilutions of phage preparations of 1:10 and 1: 100 dilutions in blocking buffer with undiluted, protease inhibitors were used. In some rounds of panning, recombinant human IgG1 Fc was added to each dilution at a final concentration of 10 μg / mL. Blocking buffer was removed from the “Block Only” (pre-absorption for blocking) wells and various phage mixtures were incubated in the wells at 37 ° C. for another hour. Aliquots (50 μL) of each phage mixture were transferred to washed and blocked target wells and incubated at 37 ° C. for 2 hours. For the first round of panning, bound phages were washed once with 1 × PBS / 0.05% Tween or Buffer D and eluted using glycine buffer, pH 2.2 containing 1 mg / mL BSA. After neutralization with 2 M Tris base (pH 11.5), the eluted phages were 2-4 milliliters of TG1 (Stratagene) at an optical density of about 0.9 measured at 600 nm (OD ₆₀₀ ) in yeast extract-Tryptone (YT) medium. ), XL1-Blue (Stratagene), ER2738 (Lucigen or NEB), or SS320 (Lucigen) cells were incubated for 15 minutes. Phage was prepared from the infection using this protocol but reduced to about 20% (volume). Phage prepared from eluted phage was subjected to an additional round of panning. In each round, titers of input and production phage were determined by plating on agar with appropriate antibiotics, and colonies from these plates were subsequently used for screening of the conjugates by ELISA.

A further round of panning was performed as described above, except that the wash was increased to 5 × in the second round of panning and the wash was increased to 10 × in the subsequent rounds. Three to six rounds of panning were performed. For the last round of panning, no phage was generated after infection, but rather, infected bacteria were grown overnight and maxiprep (Qiagen kit) was prepared from DNA. Glycerol stock (15%) of the input phage was stored frozen (-80 ° C) from each round.

For the bead panning format, human IL-23R was biotinylated and purified using Sulfo-NHS Micro Biotinylation Kit (Thermo-Scientific) according to the manufacturer's instructions. Phage pellets were resuspended in casein buffer containing 0.025% Tween 20 in PBS with 0.5% boiled casein, added EDTA-free protease inhibitor (Roche), according to the above protocol. For panning from. Using a magnet, streptavidin magnetic beads (two tubes with 50 μL or 0.5 mg of Myone T1 Dynabeads (Invitrogen) each) were washed several times in 0.5% boiled casein, 1% Tween 20 to remove preservatives. A 150 μL aliquot of phage prep was preincubated at 37 ° C. for 30 minutes with beads of one tube to remove streptavidin conjugates. Phage prep was then removed from the beads, 1 μg of biotinylated IL-23R was added at 100 μg / mL with 10 μL of human Fc and incubated for 2 hours at 37 ° C. with rotation. This material was then added to the washed beads of the remaining tubes and incubated at 37 ° C. for 30 minutes. Using a magnetic stand, the beads were washed 5 times with PBS / 0.05% Tween. Phage were eluted with glycine, pH 2.0 and used to infect bacteria as described above. In subsequent rounds of panning, the bead-bound phages were washed 10 times before eluting. The titers of the input and production phages were determined as described above.

For ELISA screening, colonies from subsequent rounds of panning were grown overnight in YT medium with 2% glucose and antibiotics and then grown to an OD ₆₀₀ of 0.5 using each aliquot to start a new culture. Helper phage was added at 5 × 10 ⁹ pfu / mL, infected at 37 ° C. for 30 minutes, and then grown at 37 ° C. with shaking. The bacteria were centrifuged, resuspended in YT medium with carbenicillin and kanamycin and grown overnight for phage production. The bacteria were then pelleted, the medium was removed and mixed with 1/5 volume (1: 5 milk mixture: supernatant) 6X PBS, 18% milk. ELISA plates were prepared by incubating overnight at 4 ° C. with 50-100 μL of PBS containing 75-100 ng / well recombinant human IL-23R / Fc. Double plates coated with human IgG Fc (R & D Systems) were used as controls. Plates were washed three times with PBS, blocked with 3% milk in 1 × PBS for 1 hour at 37 ° C. and incubated for 1 hour with 100 uL / well of each milked phage mixture. Plates were washed once with PBS / 0.05% Tween 20, washed twice with PBS, incubated with HRP-conjugated anti-M13 antibody (GE Healthcare) for 1 hour, three times with PBS / Tween and PBS each Washed and incubated with TMB substrate (VWR). Sulfuric acid was added to stop the color reaction and the absorbance was read at 450 nm to identify the positive conjugate.

Binding to human IL-23R was identified from the third and fourth rounds of panning. Examples of sequences from randomized regions of loops 1 and 4 from phage-displayed CTLD conjugates for human IL-23R / Fc chimeras are provided in Table 4. Tests from this data indicated that for 31/36 of the conjugate, the motif was evident in the randomization region of loop 4: the second and fifth amino acids were always glycine and the fourth amino acid was always a cyclic amino acid such as tryptophan or It was one of the phenylalanines, implying that the first amino acid was hydrophobic, usually a cyclic amino acid such as phenylalanine, tyrosine, or tryptophan, and the third amino acid was hydrophobic and usually valine. Glycine and serine are mainly present in the first and second positions, and valine is often present in the seventh position, but the loop 1 region has less consensus. Five additional conjugates did not appear to have the consensus, but two of them would form another small group with MFGMG (SEQ ID NO :) or LFGRG (SEQ ID NO :) in the loop 4 region. Many conjugates were each represented by multiple clones.

Table 4

Sequences of human loop 1 and 4 conjugates to human IL-23R / Fc chimeras

ELISA assay showed that the conjugate did not cross react with human IgG1 Fc or recombinant mouse IL-23R. ELISA and Biacore binding assays showed that purified monomeric CTLD and full length trimers from candidate clones 001-69.4G8 and other clones competed with IL-23 for binding to human IL-23R. Competition candidates were found to have nanomolar affinity.

Example 10

Affinity Maturation of Conjugates to Human IL-23R

Since the loop 4 region of human IL-23R is found to be an appropriate motif, it preserves the diversity of loop 4 already obtained by panning, but shuffles to reclassify the loop 4 region with all possible loop 1 regions from the original naive library. A shuffling method was developed. To this end, DNA from round 4 panning of human IL-23R was cleaved with EcoRl and BssHII restriction enzymes that cleaved between loop 1 and loop 4 regions and separated about 1.4 kb of fragments containing loop 4 regions. Separately, the original human 1-4 library DNA was digested with the same enzyme and a fragment of about 3.5 kb containing the loop 1 region was isolated. These fragments were ligated together and a new h1-4 shuffle library was generated as described above. The library was loaded into the bead protocol (above), except that the amount of biotinylated recombinant human IL-23R / Fc in each round of panning was reduced by approximately 10-fold from 200 ng (20 ng, 2 ng) to 0.1 ng. Panning was used. Phage supernatants from colonies were screened by ELISA as described above, conjugates identified, and sequenced. Loop 1 and 4 sequences of affinity-matured affinity are shown in Table 5 (SEQ ID NOS :).

Table 5

Loop 1 and 4 sequences from affinity-matured human loop 1-4 conjugates to human IL-23R

The diversity of loop 1 regions obtained in the first panning round 4 was maintained, a limited selection of loop 4 options was used, and loop 3 generated a separate affinity maturation library randomized at 6 positions. This, together with primers Bglfor (SEQ ID NO :) and H1-3-4R (SEQ ID NO :), amplifies the loop 1 region using DNA from the original panning round 4 of the human loop 1-4 library as a template. Was achieved by generating primers. These primers encode the following amino acid sequences for loops 3 and 4:

Such sequences include alterations in the loop 3 region of CTLD as well as the primary alternative to loop 4. Other primers similar to the above but more specific for loop 4 region sequences were also generated and used to generate another library that was randomized in the loop 3 region. The remaining region of interest was generated by overlapping PCR with primers PstLoop4rev (SEQ ID NO :) and Pst Rev (SEQ ID NO :).

The affinity matured IL-23R binding sequence obtained from the library is provided in Table 6. Some of the conjugates obtained were altered by exchanging more preferred Loop 4 or Loop 1 sequences with other sequences to obtain additional affinity-matured conjugates, which are included in Table 6.

Table 6

Clone 101-80-5H3 had two other amino acid alterations (Gly 146, Gly 147 to Ala 146, Ala 147) in the loop 4 region immediately upstream of the amino acid deleted from the designed loop 4 and the altered region.

Table 7 shows some additional clones prepared using primers similar to H1-3-4R (SEQ ID NO :) but with coding sequences that result in the selection of loop modifications as follows.

Table 7

Loop 4 defines five amino acid sequences of FGVFG (SEQ ID NO :), WGVFG, FGYFG, WGYFG, and WGVWG (SEQ ID NOS :, respectively) while maintaining the GlySer found at the beginning of loop 1 of the IL-23R conjugate. Another affinity matured library was generated by diversifying the five subsequent amino acids of loop 1 using the NNK method. Primers GSXX (SEQ ID NO :) and 090827 BssBglrev (SEQ ID NO :) are mixed, extended using PCR, and primers FGVFGfor, FGYFGfor, WGVFGfor, WGYFGfor, and WGVWGfor (SEQ ID NOS: _ to _) are individually Mixed with primers Pst Loop 4 rev (SEQ ID NO :) and extended using PCR. The resulting fragments were gel purified, mixed and extended by PCR in the presence of primers Bgl for (SEQ ID NO :) and Pst rev (SEQ ID NO :). The resulting fragments were digested with BglII and PstI and inserted into vector pANA27 for phage display. Bead panning for serial target dilutions was used to select affinity-matured candidates from the library. The sequences of candidates obtained from this library are provided in Table 8.

Table 8

Further changes in the amino acid sequence and the surrounding sequence of the loop were generated by alanine scanning, ie replacement of specific amino acids with amino acid alanine by gene site specific mutagenesis known to those skilled in the art. Table 9 lists alanine substitutions made in the candidate 056-53.H4E sequences. Such substitution is not limited to these residues and can be made in any candidate backbone. Table 10 shows that many of these substitutions are advantageous for affinity and / or protein production.

Table 9

Sequence of alanine scan candidates that bind IL-23R.

Note that the numbering of * 056-53.H4E amino acids differs from the TN sequence numbering in the last four candidates listed above, due to the introduction of three additional amino acids in loop 4. Thus, for example, E153 in 056-53.H4E corresponds to E150 in human TN sequence [7, SEQ ID NO: 131].

Table 10

Affinity and Yield Levels in the E. coli Plasma Membrane of the 056-53.H4E Atrimer ™ Polypeptide Complex Produced by Alanine Scanning

Example 11

human IL For -23R CTLD  And Atrimer ™ of polypeptide complex conjugate Subcloning  And generate

DNA fragments encoding loop regions were obtained by restriction digestion with BglII and PstI (or MfeI) restriction enzymes, and ligated to bacterial CTLD expression vectors pANA1, pANA3, or pANA12 previously cleaved with BglII and PstI. pANA1 (SEQ ID NO: 151) is a T7 based expression vector designed to express C-terminal 6xHis-tagged human monomer CTLD. The pelB signal peptide directs the protein to the periplasm or growth medium. pANA3 (SEQ ID NO: 153) is the C-terminal HA-His-tagged form of pANA1. pANA12 (SEQ ID NO: 162) is the C-terminal HA-StrepII-tagged form of pANA1. For expression of the trimer protein, the loop region can be subcloned into the Atrimer ™ polypeptide complex expression vector pANA4 or pANA10, resulting in the Atrimer ™ polypeptide complex secreted by E. coli. pANA4 (SEQ ID NO: 154) is a pBAD based expression vector containing C-terminal His / Myc-tagged full-length human TN with ompA signal peptide that directs the protein to the periplasm or growth medium. pANA10 (SEQ ID NO: 160) is the C-terminal HA-StrepII-tagged form of pANA4.

The expression construct was transformed with E. coli strain BL21 (DE3). Star (for pANA1, pANA3 and pANA12; generating monomeric CTLD) or BL21 (DE3) (for pANA4 and pANA10; generating atrimer ™ polypeptide complex) was plated with LB / Agar plates with appropriate antibiotics. Single colonies on new plates were inoculated in SB with 1 L of 1% glucose and kanamycin (for pANA1 and pANA12 vectors) or 2 × YT (doubled enriched yeast tryptone) medium with ampicillin (for pANA4 and pANA10 vectors) I was. Cultures were incubated with an OD ₆₀₀ of 0.5 at 37 ° C. on a shaker at 200 rpm and then cooled to room temperature. IPTG was added at a final concentration of 0.05 mM for pANA1 and pANA12, and arabinosis was added at a final concentration of 0.002-0.02% for pANA4 and pANA10. Induction was performed overnight at room temperature with shaking at 120-150 rpm, after which the bacteria were harvested by centrifugation. Plasma membrane space proteins were extracted by osmotic shock or light sonication.

6 × His-tagged proteins were purified using Ni ⁺ -NTA affinity chromatography. Briefly, the plasma membrane space protein was reconstituted in His-binding buffer (100 mM HEPES, pH 8.0, 500 mM NaCl, 10 mM imidazole) and loaded onto a Ni ⁺ -NTA column previously equilibrated with His-binding buffer. The column was washed with 10 × volume of binding buffer. Bound proteins were eluted with elution buffer (100 mM HEPES, pH 8.0, 500 mM NaCl, 500 mM imidazole). Purified protein was dialyzed with IX PBS buffer and bacterial endotoxin was removed by anion exchange.

The strep II-tagged monomer CTLD and Atrimer ™ polypeptide complexes were purified by Strep-Tactin affinity chromatography. Briefly, plasma membrane space proteins were reconstituted in IX PBS buffer and loaded onto Strep-Tactin columns previously equilibrated with IX PBS buffer. The column was washed with 10 × volume of PBS buffer. Proteins were eluted with elution buffer (1 × PBS with 2.5 mM desthiobiotin). Purified protein was dialyzed with IX PBS buffer and bacterial endotoxin was removed by anion exchange.

For some cell assays, the Atrimer ™ polypeptide complex was generated by mammalian cells. The DNA fragment encoding the loop region was subcloned into the mammalian expression vector pANA2 or pANA11 to generate the Atrimer ™ polypeptide complex in the HEK293 transient expression system. pANA2 (SEQ ID NO: 152) is a modified pCEP4 vector containing a C-terminal His tag. pANA11 (SEQ ID NO: 161) is the C-terminal HA-StrepII-tagged form of pANA2. DNA fragments encoding loop regions were obtained by double digestion with BglII and MfeI and ligated into expression vectors pANA2 and pANA11 previously cleaved with BglII and MfeI. Expression plasmids were purified from bacteria using the Qiagen HiSpeed Plasmid Maxi Kit (Qiagene). For HEK293 adherent cells, transient transfection was performed using Qiagen SuperFect Reagent according to the manufacturer's protocol. The day after transfection, the medium was removed and exchanged with 293 Isopro serum-free medium (Irvine Scientific). After 2 days, glucose in 0.5 M HEPES buffer was added to the medium at a final concentration of 1%. Tissue culture supernatants were harvested 4-7 days after transfection for purification. For HEK 293F suspension cells, transient transfection was performed with 293Fectin from Invitrogen according to the manufacturer's protocol. The following day, 1 × volume of fresh medium was added to the culture. Tissue culture supernatants were harvested 4-7 days after transfection for purification.

His or Strep II-tagged Atrimer ™ polypeptide complex purification from mammalian tissue culture supernatants was performed as described for the E. coli produced Atrimer ™ polypeptide complex.

Example 12

Characterization of conjugates by ELISA and competitive ELISA

ELISA assays performed as described in Example 9 showed that none of the phage-displayed conjugates cross reacted with human IgG1 Fc or recombinant mouse IL-23R / FC (R & D Systems).

Competitive ELISA assays were performed using purified monomeric CTLD or Atrimer ™ polypeptide complexes generated as described above from positive human IL-23R (IL-23R) conjugates that block binding of human IL-23 to human IL-23R. Was performed. The assay was generally performed as follows. Individual wells in Immulon HB2 plates were incubated overnight at 4 ° C. using 100 μL PBS containing 100 ng of anti-human IgG Fc (R & D MAB 110 clone 97924). Plates were washed five times with PBS / 0.05% Tween 20 and wells were incubated for 1.5 hours at room temperature with 100 μL of each PBS containing 50 ng of recombinant human IL-23R / Fc. Plates were washed as above, blocked with 3% bovine serum albumin (Sigma) in 150 μL of PBS for 1 hour at room temperature, then plates were washed as described and wells were competitor (Atrimer ™ polypeptide copmlexor CTLD). Incubate for 1-2 hours at room temperature with 100 μL of PBS each containing IL-23 with or without competitor. IL-23-containing solution was prepared as follows. Human IL-23 (eBioscience) was added at a concentration of 100 ng / mL. Competitors were included at a final concentration of 1 μg / mL. After incubation, plates were washed as described and wells were incubated for 40 minutes at room temperature with 100 μL of PBS each containing a 1: 5000 dilution of Streptavidin-HRP conjugate (Pierce catalog no. 21130). After washing, the wells were incubated with 100 μL of TMB (BioFX Lab catalog no. TMBH-1000-0) each for up to 30 minutes at room temperature. The reaction was stopped with an equal volume of 0.2 M sulfuric acid.

An example of the results of a competition assay (inhibition of IL-23 / IL-23R interactions) using the Atrimer ™ polypeptide complex from initial panning is shown in FIG. 10. IL-23 for binding to the Atrimer ™ polypeptide complex with CTLDs from clones 59-3B5, 61-p4G3, 78-2E6 and 056-53.H4E from the affinity-matured panning procedure Used for competition assay used.

Multiple Atrimer ™ polypeptide complexes were tested in a competitive ELISA to determine IC50 values more widely. As shown in Table 11, the Atrimer ™ polypeptide complex showed a low subnanomolar IC50.

Table 11

The ability of the Atrimer ™ polypeptide complex to compete with IL-23 for binding to IL-23R.

Atrimer ™ Polypeptide Complex 056-53.H4E was chosen as a standard for comparison and further competition assays were performed using the affinity-matured Atrimer ™ Polypeptide Complex. Table 12 provides the ratio of IC50 to 056-53.H4E of IC50 of the tested Atrimer ™ polypeptide complex performed in the same assay to better compare the competition results in the assay.

Table 12

Comparison of Atrimer ™ polypeptide complex ability to compete with IL-23 for binding to IL-23R.

Example 13

Characterization of affinity of human IL-23R conjugate by Biacore

Apparent affinity of monomer and trimer conjugates from both native library panning and affinity matured library panning are provided in Tables 13, 14 and 15. Biacore 3000 biosensors (GE Healthcare) were used to assess the interaction of human IL-23R and receptor conjugates. Fixation of anti-human IgG Fc antibody (GE Healthcare) against CM5 chip (GE Healthcare) using standard amine coupling chemistry, and the modified surface was replaced with recombinant human IL-23R / Fc fusion protein (R & D Systems). Was used to capture. Low density receptor surfaces below 200 RU were used for all assays. Atrimer ™ polypeptide complex dilution (1-500 nM) was injected onto the IL-23R surface at 30 μl / min and reaction rate constants from sensorgram data using Biaevaluation software (version 3.1, GE Healthcare). kinetic constants were derived. Data collection was 3 minutes for association and 5 minutes for dissociation. Anti-human IgG surface was regenerated using a 30 s pulse of 3M magnesium chloride. All sensograms were double-referenced for buffer injection as well as activation and blocking flow-cells.

Table 13

Affinity of Monomer CTLD IL-23R Binders from H Loop 1-4 Library

Table 14

Affinity of the full-length Atrimer ™ polypeptide complex IL-23R conjugate from the original and original affinity-matured library. "4G8 TN m" means mammalian-cell generated material. All other substances were produced in E. coli.

Table 15

Additional affinity-matured library and affinity of the Atrimer ™ polypeptide complex IL-23R conjugate from alanine-scan candidates. All materials were produced in E. coli.

Example 14

Atrimer ™ complex binding to IL-23R does not recognize IL-12Rβ1 or IL-12Rβ2.

A Biacore 3000 biosensor (GE Healthcare) was used to assess the interaction of the IL-23R binding Atrimer ™ complex with human IL-12Rβ1 / Fc or IL-12Rβ2 / Fc. Fixation of anti-human IgG Fc antibody (GE Healthcare) against CM5 chip (GE Healthcare) was performed using standard amine coupling chemistry and recombinant human IL-12Rβ1 / Fc or IL-12Rβ2 / Fc fusion protein (R & D Systems). The modified surface was used to capture). Low-density receptor surfaces of less than 200 RU were used for all assays. Atrimer ™ complex diluent (100 nM) was injected on the IL-12R surface at 30 μl / min. Data collection was 3 minutes for association and 5 minutes for dissociation. Anti-human IgG surface was regenerated using 30s pulses of 3M magnesium chloride. All sensograms were double referenced for buffer injection as well as anti-human IgG Fc antibody surface. As shown in Table 16, the Atrimer ™ complex did not show any measurable binding to human IL-12Rβ1 / Fc or IL-12Rβ2 / Fc.

Table 16

Example 15

Competition assay of human IL-23 binding to IL-23R in the presence of IL-23R conjugate using Biacore

The IL-23R binding Atamer polymer polypeptide complex was amine-coupled to the CM5 chip (GE Healthcare) and then IL-23R (IL-23R) was injected onto the chip surface. After binding stabilization, the ability of human IL-23 (eBioscience) to interact with IL-23R was monitored. Further competition assays were performed by preforming the complexes between IL-23R and IL-23 or between IL-23R and Atrimer ™ polypeptide complexes for 30 minutes at room temperature. The complex was then injected onto the surface with the amine-coupled Atrimer ™ complex. The remaining binding of the IL-23R atrimer was determined as shown in Table 17 for Atrimer A5F and expressed as percent of binding in the absence of competitors (IL-23 or other atrimers).

Table 17

A5F competes with the binding of IL-23 to IL-23R

Example 16

Test Activity of Selected Atrimer ™ Polypeptide Complexes in Cell Based Assays

Human peripheral blood mononuclear cells (PBMC) from healthy donors (AllCells) were subjected to human recombinant IL- in the presence of IL-23R Atrimer ™ polypeptide complex or Ustekinumab in 10% FBS / Advanced RPMI medium (Invitrogen). Stimulation was performed at 1 × 10 ⁶ cells / mL using 23 (1 ng / mL, eBioscience) and PHA (1 μg / mL, Sigma). After 4 days of culture, cell supernatants were harvested and assayed by ELISA using IL-17 Quantikine kit (R & D Systems). In parallel cultures, PBMCs were treated with human recombinant IL-12 (1 ng / mL, R & D Systems) in the presence of IL-23R Atrimer ™ polypeptide complex or Ustekinumab for 4 days. Cell supernatants were assayed for IFNγ and IL-17 by Luminex (Procarta, Panomics) and analyzed in Bioplex system (BioRad). All treatments were performed in triplicate and the mean and standard error were plotted using GraphPad Prism software. As shown in FIGS. 11, 12 and 13, the IL-23 Atrimer ™ polypeptide complex blocked IL-23-induced IL-17 production, but did not inhibit IL-12-induced IFNγ production. As expected, Ustekinumab inhibited both IL-23 and IL-12 responses.

Table 18 shows the results for the affinity-matured Atomer ™ polypeptide complexes tested in the PBMC assay. The ability of the Atrimer ™ polypeptide complex to block IL-23-induced IL-17, IL-17F, and IL-22 production was measured against the Atrimer ™ polypeptide complex as indicated. The results are presented as the ratio of IC50 to Atrimer ™ polypeptide complex relative to IC50 to Ustekinumab using calculation means. The results of one or more assays are shown for some Atrimer ™ polypeptide complexes.

Table 18

Levels of production of indicated cytokines in the presence of each Atrimer ™ polypeptide complex over Ustekinumab in the same experiment.

Atrimer / Ustekinumab

Example 17

NKL  Agonist assay

Upon binding of the selected IL-23R Atrimer ™ complex to the natural killer cell line NKL expressing the heterodimeric IL-23 receptor to indicate a lack of agonist activity of the IL-23R Atrimer ™ polypeptide complex against IL-23R. STAT-3 phosphorylation was determined. IL-23 at 50 ng / mL as the Atrimer ™ complex or positive control at a concentration of 150 μg / mL was incubated at 37 ° C. with 140,000 NKL cells / well in 96-well plates. After 10 minutes, the cells were centrifuged at 1200 rpm for 5 minutes and washed twice with PBS. Cells were then lysed and treated according to the protocol provided in the Stat3 phosphorylation kit obtained from Cell Signaling Technology (PATH SCAN Phospho Stat3 Sandwich ELISA kit, Cat # 7300, Cell Signaling Technology, Inc., Danvers, MA). Stat-3 phosphorylation was measured by absorbance at 450 nM using a Molecular Devices ELISA plate reader. As shown in FIG. 14 for the complexes of 056-53.H4E and H4EP1E9, activation of the IL-23R receptor by the Atrimer ™ complex was not observed, and as expected, IL-23 is STAT-3 phosphorylated. Generated. Tests such as 101-51-1A4, 101-51-1A7, 105-08-1A8, 101-54-4B6, H4E E137A, 101-113-6C108 and 101-54-4B10 as summarized in FIGS. 15A and 15B Similar results were obtained for all other atrimers.

The embodiment does not limit the range of changes that can be made in the library. Other libraries can be generated that utilize a varying number of random or more targeted amino acids to replace existing amino acids, and various combinations of loops can be used. In addition, other mutations and methods for generating mutations, such as random PCR mutagenesis, can be used to provide a variety of libraries that can be applied to panning.

Table 19: TAS and TAA Sequence Information:

While various specific embodiments of the invention have been described herein, it is to be understood that the invention is not limited to the precise embodiments described above, and that various changes or modifications may be made by those skilled in the art without departing from the scope and spirit of the invention.

The examples provided above are illustrative only and are not to be understood as a comprehensive list of all possible embodiments, applications or variations of the present invention. Accordingly, various modifications and variations of the described methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Moreover, various modifications of the described modes for carrying out the invention which are apparent to those skilled in the art of molecular biology, immunology, chemistry, biochemistry or related fields are included in the scope of the appended claims.

It is to be understood that the present invention is not limited to the particular methods, protocols, reagents, and the like described herein, which can vary as one skilled in the art will recognize. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.

Embodiments of the present invention and various features and advantageous details thereof are more fully described with reference to non-limiting embodiments and / or illustrated in the accompanying drawings and detailed in the following description. It is to be noted that the features illustrated in the figures are not necessarily drawn to scale, and that the features of one embodiment may be used in other embodiments as those skilled in the art will recognize, even if not explicitly stated.

All numerical values referred to herein include all values from the lower limit to the upper limit in increments of one unit, even if there is at least two units of separation between any lower limit and any upper limit. For example, the concentration of a component or the value of a process variable, for example size, angular size, pressure, time, etc., is said to be, for example, 1 to 90, in particular 20 to 80, more particularly 30 to 70 In this case, values such as 15 to 85, 22 to 68, 43 to 51, 30 to 32 and the like are explicitly listed in the present specification. For values less than 1, 1 unit is considered to be 0.0001, 0.001, 0.01 or 0.1 where appropriate. This is merely an example of what is specifically intended, and all possible combinations of numerical values between the lowest value and the highest value enumerated, should be considered to be expressly stated in this application in a similar manner.

The disclosures of all references and publications cited herein are expressly incorporated by reference in their entirety to the same extent as if each is individually incorporated by reference.

references

                         SEQUENCE LISTING <110> Kretz-Rommel, Anke        Wild, Martha A.        Bowdish, Katherine        Chen, Elise        Oltean, Daniela        Gonzalez, Maria        Kapoor, Mili   <120> POLYPEPTIDES THAT BIND IL-23R <130> 10-090 <140> US 12/703757 <141> 2010-02-10 <150> PCT / US09 / 60271 <151> 2009-10-09 <150> US 12 / 577,067 <151> 2009-10-09 <160> 494 <170> PatentIn version 3.5 <210> 1 <211> 189 <212> PRT <213> Homo sapiens <400> 1 Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr 1 5 10 15 Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln             20 25 30 Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His         35 40 45 Pro Leu Val Gly His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr     50 55 60 Thr Asn Asp Val Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln 65 70 75 80 Gly Leu Arg Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly                 85 90 95 Leu Ile Phe Tyr Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu             100 105 110 Pro Ser Leu Leu Pro Asp Ser Pro Val Gly Gln Leu His Ala Ser Leu         115 120 125 Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr     130 135 140 Gln Gln Ile Pro Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu 145 150 155 160 Leu Arg Phe Lys Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala                 165 170 175 Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Ser Pro             180 185 <210> 2 <211> 357 <212> PRT <213> Homo sapiens <400> 2 Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu 1 5 10 15 Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val             20 25 30 Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu         35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln     50 55 60 Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val                 85 90 95 Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp             100 105 110 Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe         115 120 125 Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp     130 135 140 Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg 145 150 155 160 Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser                 165 170 175 Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu             180 185 190 Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile         195 200 205 Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr     210 215 220 Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn 225 230 235 240 Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp                 245 250 255 Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr             260 265 270 Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg         275 280 285 Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala     290 295 300 Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser 305 310 315 320 Glu Trp Ala Ser Val Pro Cys Ser Val Asn Glu Glu Leu Pro Ser Ile                 325 330 335 Asn Thr Tyr Phe Pro Gln Asn Ile Leu Glu Ser His Phe Asn Arg Ile             340 345 350 Ser Leu Leu Glu Lys         355 <210> 3 <211> 253 <212> PRT <213> Homo sapiens <400> 3 Met Trp Pro Pro Gly Ser Ala Ser Gln Pro Pro Pro Ser Pro Ala Ala 1 5 10 15 Ala Thr Gly Leu His Pro Ala Ala Arg Pro Val Ser Leu Gln Cys Arg             20 25 30 Leu Ser Met Cys Pro Ala Arg Ser Leu Leu Leu Val Ala Thr Leu Val         35 40 45 Leu Leu Asp His Leu Ser Leu Ala Arg Asn Leu Pro Val Ala Thr Pro     50 55 60 Asp Pro Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg 65 70 75 80 Ala Val Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr                 85 90 95 Pro Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys             100 105 110 Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu         115 120 125 Ser Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys     130 135 140 Leu Ala Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser 145 150 155 160 Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn                 165 170 175 Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn             180 185 190 Met Leu Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser         195 200 205 Glu Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys     210 215 220 Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala 225 230 235 240 Val Thr Ile Asp Arg Val Met Ser Tyr Leu Asn Ala Ser                 245 250 <210> 4 <211> 155 <212> PRT <213> Homo sapiens <400> 4 Met Thr Pro Gly Lys Thr Ser Leu Val Ser Leu Leu Leu Leu Leu Ser 1 5 10 15 Leu Glu Ala Ile Val Lys Ala Gly Ile Thr Ile Pro Arg Asn Pro Gly             20 25 30 Cys Pro Asn Ser Glu Asp Lys Asn Phe Pro Arg Thr Val Met Val Asn         35 40 45 Leu Asn Ile His Asn Arg Asn Thr Asn Thr Asn Pro Lys Arg Ser Ser     50 55 60 Asp Tyr Tyr Asn Arg Ser Thr Ser Pro Trp Asn Leu His Arg Asn Glu 65 70 75 80 Asp Pro Glu Arg Tyr Pro Ser Val Ile Trp Glu Ala Lys Cys Arg His                 85 90 95 Leu Gly Cys Ile Asn Ala Asp Gly Asn Val Asp Tyr His Met Asn Ser             100 105 110 Val Pro Ile Gln Gln Glu Ile Leu Val Leu Arg Arg Glu Pro Pro His         115 120 125 Cys Pro Asn Ser Phe Arg Leu Glu Lys Ile Leu Val Ser Val Gly Cys     130 135 140 Thr Cys Val Thr Pro Ile Val His His Val Ala 145 150 155 <210> 5 <211> 227 <212> PRT <213> Homo sapiens <400> 5 Met Lys Asn Ser Asn Val Val Lys Met Leu Gln Glu Asn Ser Glu Leu 1 5 10 15 Met Asn Asn Asn Ser Ser Glu Gln Val Leu Tyr Val Asp Pro Met Ile             20 25 30 Thr Glu Ile Lys Glu Ile Phe Ile Pro Glu His Lys Pro Thr Asp Tyr         35 40 45 Lys Lys Glu Asn Thr Gly Pro Leu Glu Thr Arg Asp Tyr Pro Gln Asn     50 55 60 Ser Leu Phe Asp Asn Thr Thr Val Val Tyr Ile Pro Asp Leu Asn Thr 65 70 75 80 Gly Tyr Lys Pro Gln Ile Ser Asn Phe Leu Pro Glu Gly Ser His Leu                 85 90 95 Ser Asn Asn Asn Glu Ile Thr Ser Leu Thr Leu Lys Pro Pro Val Asp             100 105 110 Ser Leu Asp Ser Gly Asn Asn Pro Arg Leu Gln Lys His Pro Asn Phe         115 120 125 Ala Phe Ser Val Ser Ser Val Asn Ser Leu Ser Asn Thr Ile Phe Leu     130 135 140 Gly Glu Leu Ser Leu Ile Leu Asn Gln Gly Glu Cys Ser Ser Pro Asp 145 150 155 160 Ile Gln Asn Ser Val Glu Glu Glu Thr Thr Met Leu Leu Glu Asn Asp                 165 170 175 Ser Pro Ser Glu Thr Ile Pro Glu Gln Thr Leu Leu Pro Asp Glu Phe             180 185 190 Val Ser Cys Leu Gly Ile Val Asn Glu Glu Leu Pro Ser Ile Asn Thr         195 200 205 Tyr Phe Pro Gln Asn Ile Leu Glu Ser His Phe Asn Arg Ile Ser Leu     210 215 220 Leu Glu Lys 225 <210> 6 <211> 660 <212> PRT <213> Homo sapiens <400> 6 Met Glu Pro Leu Val Thr Trp Val Val Pro Leu Leu Phe Leu Phe Leu 1 5 10 15 Leu Ser Arg Gln Gly Ala Ala Cys Arg Thr Ser Glu Cys Cys Phe Gln             20 25 30 Asp Pro Pro Tyr Pro Asp Ala Asp Ser Gly Ser Ala Ser Gly Pro Arg         35 40 45 Asp Leu Arg Cys Tyr Arg Ile Ser Ser Asp Arg Tyr Glu Cys Ser Trp     50 55 60 Gln Tyr Glu Gly Pro Thr Ala Gly Val Ser His Phe Leu Arg Cys Cys 65 70 75 80 Leu Ser Ser Gly Arg Cys Cys Tyr Phe Ala Ala Gly Ser Ala Thr Arg                 85 90 95 Leu Gln Phe Ser Asp Gln Ala Gly Val Ser Val Leu Tyr Thr Val Thr             100 105 110 Leu Trp Val Glu Ser Trp Ala Arg Asn Gln Thr Glu Lys Ser Pro Glu         115 120 125 Val Thr Leu Gln Leu Tyr Asn Ser Val Lys Tyr Glu Pro Pro Leu Gly     130 135 140 Asp Ile Lys Val Ser Lys Leu Ala Gly Gln Leu Arg Met Glu Trp Glu 145 150 155 160 Thr Pro Asp Gln Val Gly Ala Glu Val Gln Phe Arg His Arg Thr                 165 170 175 Pro Ser Ser Pro Trp Lys Leu Gly Asp Cys Gly Pro Gln Asp Asp Asp             180 185 190 Thr Glu Ser Cys Leu Cys Pro Leu Glu Met Asn Val Ala Gln Glu Phe         195 200 205 Gln Leu Arg Arg Arg Gln Leu Gly Ser Gln Gly Ser Ser Trp Ser Lys     210 215 220 Trp Ser Ser Pro Val Cys Val Pro Pro Glu Asn Pro Pro Gln Pro Gln 225 230 235 240 Val Arg Phe Ser Val Glu Gln Leu Gly Gln Asp Gly Arg Arg Arg Leu                 245 250 255 Thr Leu Lys Glu Gln Pro Thr Gln Leu Glu Leu Pro Glu Gly Cys Gln             260 265 270 Gly Leu Ala Pro Gly Thr Glu Val Thr Tyr Arg Leu Gln Leu His Met         275 280 285 Leu Ser Cys Pro Cys Lys Ala Lys Ala Thr Arg Thr Leu His Leu Gly     290 295 300 Lys Met Pro Tyr Leu Ser Gly Ala Ala Tyr Asn Val Ala Val Ile Ser 305 310 315 320 Ser Asn Gln Phe Gly Pro Gly Leu Asn Gln Thr Trp His Ile Pro Ala                 325 330 335 Asp Thr His Thr Glu Pro Val Ala Leu Asn Ile Ser Val Gly Thr Asn             340 345 350 Gly Thr Thr Met Tyr Trp Pro Ala Arg Ala Gln Ser Met Thr Tyr Cys         355 360 365 Ile Glu Trp Gln Pro Val Gly Gln Asp Gly Gly Leu Ala Thr Cys Ser     370 375 380 Leu Thr Ala Pro Gln Asp Pro Asp Pro Ala Gly Met Ala Thr Tyr Ser 385 390 395 400 Trp Ser Arg Glu Ser Gly Ala Met Gly Gln Glu Lys Cys Tyr Tyr Ile                 405 410 415 Thr Ile Phe Ala Ser Ala His Pro Glu Lys Leu Thr Leu Trp Ser Thr             420 425 430 Val Leu Ser Thr Tyr His Phe Gly Gly Asn Ala Ser Ala Ala Gly Thr         435 440 445 Pro His His Val Ser Val Lys Asn His Ser Leu Asp Ser Val Val Ser     450 455 460 Asp Trp Ala Pro Ser Leu Leu Ser Thr Cys Pro Gly Val Leu Lys Glu 465 470 475 480 Tyr Val Val Arg Cys Arg Asp Glu Asp Ser Lys Gln Val Ser Glu His                 485 490 495 Pro Val Gln Pro Thr Glu Thr Gln Val Thr Leu Ser Gly Leu Arg Ala             500 505 510 Gly Val Ala Tyr Thr Val Gln Val Arg Ala Asp Thr Ala Trp Leu Arg         515 520 525 Gly Val Trp Ser Gln Pro Gln Arg Phe Ser Ile Glu Val Gln Val Ser     530 535 540 Asp Trp Leu Ile Phe Phe Ala Ser Leu Gly Ser Phe Leu Ser Ile Leu 545 550 555 560 Leu Val Gly Val Leu Gly Tyr Leu Gly Leu Asn Arg Ala Ala Arg His                 565 570 575 Leu Cys Pro Pro Leu Pro Thr Pro Cys Ala Ser Ser Ala Ile Glu Phe             580 585 590 Pro Gly Gly Lys Glu Thr Trp Gln Trp Ile Asn Pro Val Asp Phe Gln         595 600 605 Glu Glu Ala Ser Leu Gln Glu Ala Leu Val Val Glu Met Ser Trp Asp     610 615 620 Lys Gly Glu Arg Thr Glu Pro Leu Glu Lys Thr Glu Leu Pro Glu Gly 625 630 635 640 Ala Pro Glu Leu Ala Leu Asp Thr Glu Leu Ser Leu Glu Asp Gly Asp                 645 650 655 Arg Cys Asp Arg             660 <210> 7 <211> 862 <212> PRT <213> Homo sapiens <400> 7 Met Ala His Thr Phe Arg Gly Cys Ser Leu Ala Phe Met Phe Ile Ile 1 5 10 15 Thr Trp Leu Leu Ile Lys Ala Lys Ile Asp Ala Cys Lys Arg Gly Asp             20 25 30 Val Thr Val Lys Pro Ser His Val Ile Leu Leu Gly Ser Thr Val Asn         35 40 45 Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys Phe His Tyr Ser Arg     50 55 60 Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg Arg Ile Asn Phe His 65 70 75 80 His Gly His Ser Leu Asn Ser Gln Val Thr Gly Leu Pro Leu Gly Thr                 85 90 95 Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn Ser Asp Glu Ile Gln             100 105 110 Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala Pro Glu Gln Pro Gln         115 120 125 Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly Thr Val Ala Cys Thr     130 135 140 Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr Glu Tyr Thr Leu Gln 145 150 155 160 Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys Gln Cys Lys Asp Ile                 165 170 175 Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu Thr Pro Glu Ser Pro             180 185 190 Glu Ser Asn Phe Thr Ala Lys Val Thr Ala Val Asn Ser Leu Gly Ser         195 200 205 Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu Asp Ile Val Arg Pro     210 215 220 Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe Gln Lys Ala Ser Val Ser 225 230 235 240 Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly Leu Val Leu Leu Asn Arg                 245 250 255 Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu Trp Asn Met Val Asn Val             260 265 270 Thr Lys Ala Lys Gly Arg His Asp Leu Leu Asp Leu Lys Pro Phe Thr         275 280 285 Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu His Leu Tyr Lys Gly Ser     290 295 300 Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala Gln Thr Pro Glu Glu Glu 305 310 315 320 Pro Thr Gly Met Leu Asp Val Trp Tyr Met Lys Arg His Ile Asp Tyr                 325 330 335 Ser Arg Gln Gln Ile Ser Leu Phe Trp Lys Asn Leu Ser Val Ser Glu             340 345 350 Ala Arg Gly Lys Ile Leu His Tyr Gln Val Thr Leu Gln Glu Leu Thr         355 360 365 Gly Gly Lys Ala Met Thr Gln Asn Ile Thr Gly His Thr Ser Trp Thr     370 375 380 Thr Val Ile Pro Arg Thr Gly Asn Trp Ala Val Ala Val Ser Ala Ala 385 390 395 400 Asn Ser Lys Gly Ser Ser Leu Pro Thr Arg Ile Asn Ile Met Asn Leu                 405 410 415 Cys Glu Ala Gly Leu Leu Ala Pro Arg His Val Ser Ala Asn Ser Glu             420 425 430 Gly Met Asp Asn Ile Leu Val Thr Trp Gln Pro Pro Arg Lys Asp Pro         435 440 445 Ser Ala Val Gln Glu Tyr Val Val Glu Trp Arg Glu Leu His Pro Gly     450 455 460 Gly Asp Thr Gln Val Pro Leu Asn Trp Leu Arg Ser Arg Pro Tyr Asn 465 470 475 480 Val Ser Ala Leu Ile Ser Glu Asn Ile Lys Ser Tyr Ile Cys Tyr Glu                 485 490 495 Ile Arg Val Tyr Ala Leu Ser Gly Asp Gln Gly Gly Cys Ser Ser Ile             500 505 510 Leu Gly Asn Ser Lys His Lys Ala Pro Leu Ser Gly Pro His Ile Asn         515 520 525 Ala Ile Thr Glu Glu Lys Gly Ser Ile Leu Ile Ser Trp Asn Ser Ile     530 535 540 Pro Val Gln Glu Gln Met Gly Cys Leu Leu His Tyr Arg Ile Tyr Trp 545 550 555 560 Lys Glu Arg Asp Ser Asn Ser Gln Pro Gln Leu Cys Glu Ile Pro Tyr                 565 570 575 Arg Val Ser Gln Asn Ser His Pro Ile Asn Ser Leu Gln Pro Arg Val             580 585 590 Thr Tyr Val Leu Trp Met Thr Ala Leu Thr Ala Ala Gly Glu Ser Ser         595 600 605 His Gly Asn Glu Arg Glu Phe Cys Leu Gln Gly Lys Ala Asn Trp Met     610 615 620 Ala Phe Val Ala Pro Ser Ile Cys Ile Ala Ile Ile Met Val Gly Ile 625 630 635 640 Phe Ser Thr His Tyr Phe Gln Gln Lys Val Phe Val Leu Leu Ala Ala                 645 650 655 Leu Arg Pro Gln Trp Cys Ser Arg Glu Ile Pro Asp Pro Ala Asn Ser             660 665 670 Thr Cys Ala Lys Lys Tyr Pro Ile Ala Glu Glu Lys Thr Gln Leu Pro         675 680 685 Leu Asp Arg Leu Leu Ile Asp Trp Pro Thr Pro Glu Asp Pro Glu Pro     690 695 700 Leu Val Ile Ser Glu Val Leu His Gln Val Thr Pro Val Phe Arg His 705 710 715 720 Pro Pro Cys Ser Asn Trp Pro Gln Arg Glu Lys Gly Ile Gln Gly His                 725 730 735 Gln Ala Ser Glu Lys Asp Met Met His Ser Ala Ser Ser Pro Pro Pro             740 745 750 Pro Arg Ala Leu Gln Ala Glu Ser Arg Gln Leu Val Asp Leu Tyr Lys         755 760 765 Val Leu Glu Ser Arg Gly Ser Asp Pro Lys Pro Glu Asn Pro Ala Cys     770 775 780 Pro Trp Thr Val Leu Pro Ala Gly Asp Leu Pro Thr His Asp Gly Tyr 785 790 795 800 Leu Pro Ser Asn Ile Asp Asp Leu Pro Ser His Glu Ala Pro Leu Ala                 805 810 815 Asp Ser Leu Glu Glu Leu Glu Pro Gln His Ile Ser Leu Ser Val Phe             820 825 830 Pro Ser Ser Ser Leu His Pro Leu Thr Phe Ser Cys Gly Asp Lys Leu         835 840 845 Thr Leu Asp Gln Leu Lys Met Arg Cys Asp Ser Leu Met Leu     850 855 860 <210> 8 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 8 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Cys Leu Lys     50 <210> 9 <211> 54 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 9 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr             20 25 30 Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser Leu Lys Gly Ser     50 <210> 10 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 10 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val      <210> 11 <211> 47 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 11 Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys 1 5 10 15 Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ser Gln Glu Val             20 25 30 Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys         35 40 45 <210> 12 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 12 Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu 1 5 10 15 Leu Lys Ser Arg Leu Asp Thr Leu Ser Gln Glu Val Ala Leu Leu Lys             20 25 30 Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys         35 40 <210> 13 <211> 37 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 13 Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp 1 5 10 15 Thr Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln             20 25 30 Thr Val Ser Leu Lys         35 <210> 14 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 14 Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ser Gln 1 5 10 15 Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu             20 25 30 Lys      <210> 15 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 15 Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ser Gln Glu Val Ala Leu 1 5 10 15 Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys             20 25 <210> 16 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 16 Ser Arg Leu Asp Thr Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln 1 5 10 15 Gln Ala Leu Gln Thr Val Ser Leu Lys             20 25 <210> 17 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 17 Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys 1 5 10 15 Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ser Gln Glu Val             20 25 30 Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 <210> 18 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 18 Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys 1 5 10 15 Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ser Gln Glu Val             20 25 30 Ala Leu Leu Lys Glu Gln Gln Ala Leu         35 40 <210> 19 <211> 38 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 19 Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys 1 5 10 15 Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ser Gln Glu Val             20 25 30 Ala Leu Leu Lys Glu Gln         35 <210> 20 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 20 Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys 1 5 10 15 Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ser Gln Glu Val             20 25 30 Ala leu          <210> 21 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 21 Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys 1 5 10 15 Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ser Gln Glu             20 25 30 <210> 22 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 22 Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu 1 5 10 15 Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys             20 25 30 Glu Gln Gln Ala Leu Gln Thr Val         35 40 <210> 23 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 23 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr 1 5 10 15 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr             20 25 30 Val      <210> 24 <211> 53 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 24 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser Leu Lys Gly     50 <210> 25 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 25 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser Leu Lys     50 <210> 26 <211> 51 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 26 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser Leu     50 <210> 27 <211> 50 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 27 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser     50 <210> 28 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 28 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val      <210> 29 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 29 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 <210> 30 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 30 Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val 1 5 10 15 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu             20 25 30 Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val         35 40 45 Ser Leu Lys Gly     50 <210> 31 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 31 Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val 1 5 10 15 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu             20 25 30 Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val         35 40 45 <210> 32 <211> 51 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 32 Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val 1 5 10 15 Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala             20 25 30 Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser         35 40 45 Leu Lys Gly     50 <210> 33 <211> 50 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 33 Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn 1 5 10 15 Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln             20 25 30 Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu         35 40 45 Lys Gly     50 <210> 34 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 34 Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr 1 5 10 15 Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu             20 25 30 Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys         35 40 45 Gly      <210> 35 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 35 Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys 1 5 10 15 Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val             20 25 30 Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 45 <210> 36 <211> 47 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 36 Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met 1 5 10 15 Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala             20 25 30 Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 45 <210> 37 <211> 46 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 37 Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe 1 5 10 15 Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu             20 25 30 Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 45 <210> 38 <211> 45 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 38 Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu 1 5 10 15 Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu             20 25 30 Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 45 <210> 39 <211> 44 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 39 Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu 1 5 10 15 Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys             20 25 30 Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 40 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 40 Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu 1 5 10 15 Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu             20 25 30 Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 41 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 41 Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys 1 5 10 15 Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln             20 25 30 Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 42 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 42 Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser 1 5 10 15 Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln             20 25 30 Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 43 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 43 Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg 1 5 10 15 Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala             20 25 30 Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 44 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 44 Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu 1 5 10 15 Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu             20 25 30 Gln Thr Val Ser Leu Lys Gly         35 <210> 45 <211> 37 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 45 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr 1 5 10 15 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr             20 25 30 Val Ser Leu Lys Gly         35 <210> 46 <211> 36 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 46 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu 1 5 10 15 Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val             20 25 30 Ser Leu Lys Gly         35 <210> 47 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 47 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu 1 5 10 15 Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val             20 25 30 Ser leu lys         35 <210> 48 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 48 Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala 1 5 10 15 Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser             20 25 30 Leu Lys          <210> 49 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 49 Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln 1 5 10 15 Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu             20 25 30 Lys      <210> 50 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 50 Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu 1 5 10 15 Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys             20 25 30 <210> 51 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 51 Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val 1 5 10 15 Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys             20 25 30 <210> 52 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 52 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr 1 5 10 15 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr             20 25 30 Val      <210> 53 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 53 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr 1 5 10 15 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr             20 25 30 <210> 54 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 54 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu 1 5 10 15 Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln             20 25 30 <210> 55 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 55 Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala 1 5 10 15 Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser             20 25 30 Leu Lys Gly         35 <210> 56 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 56 Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln 1 5 10 15 Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu             20 25 30 Lys Gly          <210> 57 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 57 Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu 1 5 10 15 Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys             20 25 30 Gly      <210> 58 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 58 Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val 1 5 10 15 Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly             20 25 30 <210> 59 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 59 Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser Leu Lys     50 <210> 60 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 60 Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val      <210> 61 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 61 Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 <210> 62 <211> 47 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 62 Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln         35 40 45 <210> 63 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 63 Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu 1 5 10 15 Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys             20 25 30 Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys         35 40 <210> 64 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 64 Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu 1 5 10 15 Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys             20 25 30 Glu Gln Gln Ala Leu Gln Thr Val         35 40 <210> 65 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 65 Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu 1 5 10 15 Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys             20 25 30 Glu Gln Gln Ala Leu Gln Thr         35 <210> 66 <211> 38 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 66 Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu 1 5 10 15 Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys             20 25 30 Glu Gln Gln Ala Leu Gln         35 <210> 67 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 67 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu 1 5 10 15 Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val             20 25 30 Ser leu lys         35 <210> 68 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 68 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu 1 5 10 15 Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val             20 25 30 <210> 69 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 69 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu 1 5 10 15 Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr             20 25 30 <210> 70 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 70 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu 1 5 10 15 Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln             20 25 30 <210> 71 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 71 Met Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu 1 5 10 15 Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu             20 25 30 Lys Glu Gln Gln Ala Leu Gln Thr         35 40 <210> 72 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 72 Met Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr 1 5 10 15 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr             20 25 30 <210> 73 <211> 53 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 73 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr             20 25 30 Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser Leu Lys Gly     50 <210> 74 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 74 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr             20 25 30 Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser Leu Lys     50 <210> 75 <211> 51 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 75 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr             20 25 30 Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser Leu     50 <210> 76 <211> 50 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 76 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr             20 25 30 Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Ser     50 <210> 77 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 77 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr             20 25 30 Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val      <210> 78 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 78 Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val 1 5 10 15 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu             20 25 30 Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val         35 40 45 Ser Leu Lys Gly     50 <210> 79 <211> 51 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 79 Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val 1 5 10 15 Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser             20 25 30 Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser         35 40 45 Leu Lys Gly     50 <210> 80 <211> 50 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 80 Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn 1 5 10 15 Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser Gln             20 25 30 Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu         35 40 45 Lys Gly     50 <210> 81 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 81 Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr 1 5 10 15 Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser Gln Glu             20 25 30 Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys         35 40 45 Gly      <210> 82 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 82 Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys 1 5 10 15 Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser Gln Glu Val             20 25 30 Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 45 <210> 83 <211> 47 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 83 Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met 1 5 10 15 Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser Gln Glu Val Ala             20 25 30 Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 45 <210> 84 <211> 46 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 84 Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe 1 5 10 15 Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser Gln Glu Val Ala Leu             20 25 30 Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 45 <210> 85 <211> 45 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 85 Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu 1 5 10 15 Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser Gln Glu Val Ala Leu Leu             20 25 30 Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 45 <210> 86 <211> 44 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 86 Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu 1 5 10 15 Leu Lys Ala Arg Leu Asp Thr Leu Ser Gln Glu Val Ala Leu Leu Lys             20 25 30 Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 87 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 87 Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu 1 5 10 15 Lys Ala Arg Leu Asp Thr Leu Ser Gln Glu Val Ala Leu Leu Lys Glu             20 25 30 Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 88 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 88 Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys 1 5 10 15 Ala Arg Leu Asp Thr Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln             20 25 30 Gln Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 89 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 89 Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala 1 5 10 15 Arg Leu Asp Thr Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln             20 25 30 Ala Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 90 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 90 Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg 1 5 10 15 Leu Asp Thr Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala             20 25 30 Leu Gln Thr Val Ser Leu Lys Gly         35 40 <210> 91 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 91 Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu 1 5 10 15 Asp Thr Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu             20 25 30 Gln Thr Val Ser Leu Lys Gly         35 <210> 92 <211> 37 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 92 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr 1 5 10 15 Leu Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr             20 25 30 Val Ser Leu Lys Gly         35 <210> 93 <211> 36 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 93 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu 1 5 10 15 Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val             20 25 30 Ser Leu Lys Gly         35 <210> 94 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 94 Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu 1 5 10 15 Ser Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val             20 25 30 Ser leu lys         35 <210> 95 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 95 Asn Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser 1 5 10 15 Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser             20 25 30 Leu Lys          <210> 96 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 96 Thr Lys Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser Gln 1 5 10 15 Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu             20 25 30 Lys      <210> 97 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 97 Met Phe Glu Glu Leu Lys Ala Arg Leu Asp Thr Leu Ser Gln Glu Val 1 5 10 15 Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys             20 25 30 <210> 98 <211> 71 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 98 Met Gly Ser His His His His His Gly Ser Ile Gln Gly Arg Ser Pro 1 5 10 15 Gly Thr Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys             20 25 30 Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu         35 40 45 Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu     50 55 60 Gln Thr Val Ser Leu Lys Gly 65 70 <210> 99 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 99 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Cys Leu Lys     50 <210> 100 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 100 Glu Ser Pro Thr Pro Lys Ala Lys Lys Ala Ala Asn Ala Lys Lys Asp 1 5 10 15 Leu Val Ser Ser Lys Met Phe Glu Glu Leu Lys Asn Arg Met Asp Val             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Lys Gln Ala Leu Gln Thr         35 40 45 Val Cys Leu Lys     50 <210> 101 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 101 Gln Gln Asn Gly Lys Gly Arg Gln Lys Pro Ala Ala Ser Lys Lys Asp 1 5 10 15 Gly Val Ser Leu Lys Met Ile Glu Asp Leu Lys Ala Met Ile Asp Asn             20 25 30 Ile Ser Gln Glu Val Ala Leu Leu Lys Glu Lys Gln Ala Leu Gln Thr         35 40 45 Val Cys Leu Lys     50 <210> 102 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 102 Glu Thr Pro Thr Pro Lys Ala Lys Lys Ala Ala Asn Ala Lys Lys Asp 1 5 10 15 Ala Val Ser Pro Lys Met Leu Glu Glu Leu Lys Thr Gln Leu Asp Ser             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Cys Leu Lys     50 <210> 103 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 103 Gln Gln Thr Ser Ser Lys Lys Lys Gly Gly Lys Lys Asp Ala Glu Asn 1 5 10 15 Asn Ala Ala Ile Glu Glu Leu Lys Lys Gln Ile Asp Asn Ile Val Leu             20 25 30 Glu Leu Asn Leu Leu Lys Glu Gln Gln Ala Leu Gln Ser Val Cys Leu         35 40 45 Lys      <210> 104 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 104 Gln Gln Asn Gly Lys Lys Asn Lys Gln Asn Asn Lys Asp Val Val Ser 1 5 10 15 Met Lys Met Tyr Glu Asp Leu Lys Lys Lys Val Gln Asn Ile Glu Glu             20 25 30 Asp Val Ile His Leu Lys Glu Gln Gln Ala Leu Gln Thr Ile Cys Leu         35 40 45 Lys      <210> 105 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 105 Glu Gln Ser Leu Thr Lys Arg Lys Asn Gly Lys Lys Glu Ser Asn Ser 1 5 10 15 Ala Ala Ile Glu Glu Leu Lys Lys Gln Ile Asp Gln Ile Ile Gln Asp             20 25 30 Leu Asn Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Cys Leu Lys         35 40 45 <210> 106 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 106 Gln Thr Ser Cys His Ala Ser Lys Phe Lys Ala Arg Lys His Ser Lys 1 5 10 15 Arg Arg Val Lys Glu Lys Asp Gly Asp Leu Lys Thr Gln Val Glu Lys             20 25 30 Leu Trp Arg Glu Val Asn Ala Leu Lys Glu Met Gln Ala Leu Gln Thr         35 40 45 Val Cys Leu Arg     50 <210> 107 <211> 38 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 107 Lys Pro Ser Lys Ser Gly Lys Gly Lys Asp Asp Leu Arg Asn Glu Ile 1 5 10 15 Asp Lys Leu Trp Arg Glu Val Asn Ser Leu Lys Glu Met Gln Ala Leu             20 25 30 Gln Thr Val Cys Leu Lys         35 <210> 108 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (1) .. (25) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (27) .. (29) <223> Xaa can be any naturally occurring amino acid <220> <221> MISC_FEATURE (222) (30) .. (30) <223> Xaa can be any hydrophobic naturally occurring amino acid <220> <221> misc_feature (222) (31) .. (32) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature &Lt; 222 > (34) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (38) .. (39) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature &Lt; 222 > (43) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (52). (52) <223> Xaa can be any naturally occurring amino acid <400> 108 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa             20 25 30 Leu Xaa Xaa Glu Val Xaa Xaa Leu Lys Glu Xaa Gln Ala Leu Gln Thr         35 40 45 Val Cys Leu Xaa     50 <210> 109 <211> 137 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 109 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Asp Met Ala Ala Glu Gly Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile                 85 90 95 Thr Ala Gln Pro Asp Gly Gly Lys Thr Glu Asn Cys Ala Val Leu Ser             100 105 110 Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg Asp Gln Leu         115 120 125 Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 <210> 110 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 110 Asn Lys Leu His Ala Gly Ser Met Gly Lys Lys Ser Gly Lys Lys Phe 1 5 10 15 Phe Val Thr Asn His Glu Arg Met Pro Phe Ser Lys Val Lys Ala Leu             20 25 30 Cys Ser Glu Leu Arg Gly Thr Val Ala Ile Pro Arg Asn Ala Glu Glu         35 40 45 Asn Lys Ala Ile Gln Glu Val Ala Lys Thr Ser Ala Phe Leu Gly Ile     50 55 60 Thr Asp Glu Val Thr Glu Gly Gln Phe Met Tyr Val Thr Gly Gly Arg 65 70 75 80 Leu Thr Tyr Ser Asn Trp Lys Lys Asp Glu Pro Asn Asp His Gly Ser                 85 90 95 Gly Glu Asp Cys Val Thr Ile Val Asp Asn Gly Leu Trp Asn Asp Ile             100 105 110 Ser Cys Gln Ala Ser His Thr Ala Val Cys Ser Phe Pro Ala         115 120 125 <210> 111 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 111 Lys Lys Val Glu Leu Phe Pro Asn Gly Gln Ser Val Gly Glu Lys Ile 1 5 10 15 Phe Lys Thr Ala Gly Phe Val Lys Pro Phe Thr Glu Ala Gln Leu Leu             20 25 30 Cys Thr Gln Ala Gly Gly Gln Leu Ala Ser Pro Arg Ser Ala Ala Glu         35 40 45 Asn Ala Ala Leu Gln Gln Leu Val Val Ala Lys Asn Glu Ala Ala Phe     50 55 60 Leu Ser Met Thr Asp Ser Lys Thr Glu Gly Lys Phe Thr Tyr Pro Thr 65 70 75 80 Gly Glu Ser Leu Val Tyr Ser Asn Trp Ala Pro Gly Glu Pro Asn Asp                 85 90 95 Asp Gly Gly Ser Glu Asp Cys Val Glu Ile Phe Thr Asn Gly Lys Trp             100 105 110 Asn Asp Arg Ala Cys Gly Glu Lys Arg Leu Val Val Cys Ala Phe         115 120 125 <210> 112 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 112 Lys Val Tyr Trp Phe Cys Tyr Gly Met Lys Cy Ts Tyr Tyr Phe Val Met 1 5 10 15 Asp Arg Lys Thr Trp Ser Gly Cys Lys Gln Thr Cys Gln Ser Ser Ser             20 25 30 Leu Ser Leu Leu Lys Ile Asp Asp Glu Asp Glu Leu Lys Phe Leu Gln         35 40 45 Leu Leu Val Val Pro Ser Asp Ser Cys Trp Val Gly Leu Ser Tyr Asp     50 55 60 Asn Lys Lys Asp Trp Ala Trp Ile Asp Asn Arg Pro Ser Lys Leu Ala 65 70 75 80 Leu Asn Thr Arg Lys Tyr Asn Ile Arg Asp Arg Gly Gly Cys Met Leu                 85 90 95 Leu Ser Lys Thr Arg Leu Asp Asn Gly Asn Cys Asp Gln Val Phe Ile             100 105 110 Cys Ile Cys Gly Lys Arg Leu Asp Lys Phe Pro         115 120 <210> 113 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 113 Cys Pro Val Asn Trp Val Glu His Glu Arg Ser Cys Tyr Trp Phe Ser 1 5 10 15 Arg Ser Gly Lys Ala Trp Ala Asp Ala Asp Asn Tyr Cys Arg Leu Glu             20 25 30 Asp Ala His Leu Val Val Val Thr Ser Trp Glu Glu Gln Leu Phe Val         35 40 45 Gln His His Ile Gly Pro Val Asn Thr Trp Met Gly Leu His Asp Gln     50 55 60 Asn Gly Pro Trp Lys Trp Val Asp Gly Thr Asp Tyr Glu Thr Gly Phe 65 70 75 80 Lys Asn Trp Arg Pro Glu Gln Pro Asp Asp Trp Tyr Gly His Gly Leu                 85 90 95 Gly Gly Gly Glu Asp Cys Ala His Phe Thr Asp Asp Gly Arg Trp Asn             100 105 110 Asp Asp Val Cys Gln Arg Pro Tyr Arg Trp Val Cys Ser Thr Glu Leu         115 120 125 <210> 114 <211> 147 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 114 Gly Ile Pro Lys Cys Pro Glu Asp Trp Gly Ala Ser Ser Arg Thr Ser 1 5 10 15 Leu Cys Phe Lys Leu Tyr Ala Lys Gly Lys His Glu Lys Lys Thr Trp             20 25 30 Phe Glu Ser Arg Asp Phe Cys Arg Ala Leu Gly Gly Asp Leu Ala Ser         35 40 45 Ile Asn Asn Lys Glu Glu Gln Gln Thr Ile Trp Arg Leu Ile Thr Ala     50 55 60 Ser Gly Ser Tyr His Lys Leu Phe Trp Leu Gly Leu Thr Tyr Gly Ser 65 70 75 80 Pro Ser Glu Gly Phe Thr Trp Ser Asp Gly Ser Pro Val Ser Tyr Glu                 85 90 95 Asn Trp Ala Tyr Gly Glu Pro Asn Asn Tyr Gln Asn Val Glu Tyr Cys             100 105 110 Gly Glu Leu Lys Gly Asp Pro Thr Met Ser Trp Asn Asp Ile Asn Cys         115 120 125 Glu His Leu Asn Asn Trp Ile Cys Gln Ile Gln Lys Gly Gln Thr Pro     130 135 140 Lys pro asp 145 <210> 115 <211> 129 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 115 Asp Cys Leu Ser Gly Trp Ser Ser Tyr Glu Gly His Cys Tyr Lys Ala 1 5 10 15 Phe Ser Lys Tyr Lys Thr Trp Glu Asp Ala Glu Arg Val Cys Thr Glu             20 25 30 Gln Ala Lys Gly Ala His Leu Val Ser Ile Glu Ser Ser Gly Glu Ala         35 40 45 Asp Phe Val Ala Gln Leu Val Thr Gln Asn Met Lys Arg Leu Asp Phe     50 55 60 Tyr Ile Trp Ile Gly Leu Arg Val Gln Gly Lys Val Lys Gln Cys Asn 65 70 75 80 Ser Glu Trp Ser Asp Gly Ser Ser Val Ser Tyr Glu Asn Trp Ile Glu                 85 90 95 Ala Glu Ser Lys Thr Cys Leu Gly Leu Glu Lys Glu Thr Asp Phe Arg             100 105 110 Lys Trp Val Asn Ile Tyr Cys Gly Gln Gln Asn Pro Phe Val Cys Glu         115 120 125 Ala      <210> 116 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 116 Asp Cys Pro Ser Asp Trp Ser Ser Tyr Glu Gly His Cys Tyr Lys Pro 1 5 10 15 Phe Ser Glu Pro Lys Asn Trp Ala Asp Ala Glu Asn Phe Cys Thr Gln             20 25 30 Gln His Ala Gly Gly His Leu Val Ser Phe Gln Ser Ser Glu Glu Ala         35 40 45 Asp Phe Val Val Lys Leu Ala Phe Gln Thr Phe His Ser Ile Phe Trp     50 55 60 Met Gly Leu Ser Asn Val Trp Asn Gln Cys Asn Trp Gln Trp Ser Asn 65 70 75 80 Ala Ala Met Leu Arg Tyr Lys Ala Trp Ala Glu Glu Ser Tyr Cys Val                 85 90 95 Tyr Phe Lys Ser Thr Asn Asn Lys Trp Arg Ser Arg Ala Cys Arg Met             100 105 110 Met Ala Gln Phe Val Cys Glu Phe Gln Ala         115 120 <210> 117 <211> 135 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 117 Ala Arg Ile Ser Cys Pro Glu Gly Thr Asn Ala Tyr Arg Ser Tyr Cys 1 5 10 15 Tyr Tyr Phe Asn Glu Asp Arg Glu Thr Trp Val Asp Ala Asp Leu Tyr             20 25 30 Cys Gln Asn Met Asn Ser Gly Asn Leu Val Ser Val Leu Thr Gln Ala         35 40 45 Glu Gly Ala Phe Val Ala Ser Leu Ile Lys Glu Ser Gly Thr Asp Asp     50 55 60 Phe Asn Val Trp Ile Gly Leu His Asp Pro Lys Lys Asn Arg Arg Trp 65 70 75 80 His Trp Ser Ser Gly Ser Leu Val Ser Tyr Lys Ser Trp Gly Ile Gly                 85 90 95 Ala Pro Ser Ser Val Asn Pro Gly Tyr Cys Val Ser Leu Thr Ser Ser             100 105 110 Thr Gly Phe Gly Lys Trp Lys Asp Val Pro Cys Glu Asp Lys Phe Ser         115 120 125 Phe Val Cys Lys Phe Lys Asn     130 135 <210> 118 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 118 Asp Tyr Glu Ile Leu Phe Ser Asp Glu Thr Met Asn Tyr Ala Asp Ala 1 5 10 15 Gly Thr Tyr Cys Gly Ser Arg Gly Met Ala Leu Val Ser Ser Ala Met             20 25 30 Arg Asp Ser Thr Met Val Lys Ala Ile Leu Ala Phe Thr Glu Val Lys         35 40 45 Gly His Asp Tyr Trp Val Gly Ala Asp Asn Leu Gln Asp Gly Ala Tyr     50 55 60 Asn Phe Asn Trp Asn Asp Gly Val Ser Leu Pro Thr Asp Ser Asp Leu 65 70 75 80 Trp Ser Pro Asn Glu Pro Ser Asn Pro Gln Ser Trp Gln Leu Cys Val                 85 90 95 Gln Ile Trp Ser Lys Tyr Asn Leu Leu Asp Asp Val Gly Cys Gly Gly             100 105 110 Ala Arg Arg Val Ile Cys Glu Lys Glu Leu Asp         115 120 <210> 119 <211> 202 <212> PRT <213> Homo sapiens <400> 119 Met Glu Leu Trp Gly Ala Tyr Leu Leu Leu Cys Leu Phe Ser Leu Leu 1 5 10 15 Thr Gln Val Thr Thr Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val             20 25 30 Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys         35 40 45 Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln     50 55 60 Gln Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys 65 70 75 80 Cys Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu                 85 90 95 Asp Cys Ile Ser Arg Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser             100 105 110 Glu Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu         115 120 125 Ala Glu Ile Trp Leu Gly Leu Asn Asp Met Ala Ala Glu Gly Thr Trp     130 135 140 Val Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Thr Glu 145 150 155 160 Ile Thr Ala Gln Pro Asp Gly Gly Lys Thr Glu Asn Cys Ala Val Leu                 165 170 175 Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg Asp Gln             180 185 190 Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val         195 200 <210> 120 <211> 202 <212> PRT <213> Mus musculus <400> 120 Met Gly Phe Trp Gly Thr Tyr Leu Leu Phe Cys Leu Phe Ser Phe Leu 1 5 10 15 Ser Gln Leu Thr Ala Glu Ser Pro Thr Pro Lys Ala Lys Lys Ala Ala             20 25 30 Asn Ala Lys Lys Asp Leu Val Ser Ser Lys Met Phe Glu Glu Leu Lys         35 40 45 Asn Arg Met Asp Val Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Lys     50 55 60 Gln Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val Asn Leu Lys 65 70 75 80 Cys Leu Leu Ala Phe Thr Gln Pro Lys Thr Phe His Glu Ala Ser Glu                 85 90 95 Asp Cys Ile Ser Gln Gly Gly Thr Leu Gly Thr Pro Gln Ser Glu Leu             100 105 110 Glu Asn Glu Ala Leu Phe Glu Tyr Ala Arg His Ser Val Gly Asn Asp         115 120 125 Ala Asn Ile Trp Leu Gly Leu Asn Asp Met Ala Ala Glu Gly Ala Trp     130 135 140 Val Asp Met Thr Gly Gly Leu Leu Ala Tyr Lys Asn Trp Glu Thr Glu 145 150 155 160 Ile Thr Thr Gln Pro Asp Gly Gly Lys Ala Glu Asn Cys Ala Ala Leu                 165 170 175 Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg Asp Gln             180 185 190 Leu Pro Tyr Ile Cys Gln Phe Ala Ile Val         195 200 <210> 121 <211> 201 <212> PRT <213> Gallus gallus <400> 121 Met Ala Leu Arg Gly Ala Cys Leu Leu Leu Cys Leu Val Ser Leu Ala 1 5 10 15 His Ile Ser Val Gln Gln Asn Gly Lys Gly Arg Gln Lys Pro Ala Ala             20 25 30 Ser Lys Lys Asp Gly Val Ser Leu Lys Met Ile Glu Asp Leu Lys Ala         35 40 45 Met Ile Asp Asn Ile Ser Gln Glu Val Ala Leu Leu Lys Glu Lys Gln     50 55 60 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Ile His Leu Lys Cys 65 70 75 80 Phe Leu Ala Phe Ser Glu Ser Lys Thr Tyr His Glu Ala Ser Glu His                 85 90 95 Cys Ile Ser Gln Gly Gly Thr Leu Gly Thr Pro Gln Gly Gly Glu Glu             100 105 110 Asn Asp Ala Leu Tyr Asp Tyr Met Arg Lys Ser Ile Gly Asn Glu Ala         115 120 125 Glu Ile Trp Leu Gly Leu Asn Asp Met Val Ala Glu Gly Lys Trp Val     130 135 140 Asp Met Thr Gly Ser Pro Ile Arg Tyr Lys Asn Trp Glu Thr Glu Ile 145 150 155 160 Thr Thr Gln Pro Asp Gly Gly Lys Leu Glu Asn Cys Ala Ala Leu Ser                 165 170 175 Gly Val Ala Val Gly Lys Trp Phe Asp Lys Arg Cys Lys Glu Gln Leu             180 185 190 Pro Tyr Val Cys Gln Phe Met Ile Val         195 200 <210> 122 <211> 202 <212> PRT <213> Bos taurus <400> 122 Met Glu Leu Trp Gly Pro Cys Val Leu Leu Cys Leu Phe Ser Leu Leu 1 5 10 15 Thr Gln Val Thr Ala Glu Thr Pro Thr Pro Lys Ala Lys Lys Ala Ala             20 25 30 Asn Ala Lys Lys Asp Ala Val Ser Pro Lys Met Leu Glu Glu Leu Lys         35 40 45 Thr Gln Leu Asp Ser Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln     50 55 60 Gln Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys 65 70 75 80 Cys Phe Leu Ala Phe Val Gln Ala Lys Thr Phe His Glu Ala Ser Glu                 85 90 95 Asp Cys Ile Ser Arg Gly Gly Thr Leu Gly Thr Pro Gln Thr Gly Ser             100 105 110 Glu Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Ser Glu         115 120 125 Ala Glu Val Trp Leu Gly Phe Asn Asp Met Ala Ser Glu Gly Ser Trp     130 135 140 Val Asp Met Thr Gly Gly His Ile Ala Tyr Lys Asn Trp Glu Thr Glu 145 150 155 160 Ile Thr Ala Gln Pro Asp Gly Gly Lys Val Glu Asn Cys Ala Thr Leu                 165 170 175 Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg Asp Lys             180 185 190 Leu Pro Tyr Val Cys Gln Phe Ala Ile Val         195 200 <210> 123 <211> 198 <212> PRT <213> Salmo salar <400> 123 Met Arg Val Ser Gly Val Arg Leu Leu Phe Cys Leu Leu Leu Leu Gly 1 5 10 15 Gln Ser Thr Phe Gln Gln Thr Ser Ser Lys Lys Lys Gly Gly Lys Lys             20 25 30 Asp Ala Glu Asn Asn Ala Ala Ile Glu Glu Leu Lys Lys Gln Ile Asp         35 40 45 Asn Ile Val Leu Glu Leu Asn Leu Leu Lys Glu Gln Gln Ala Leu Gln     50 55 60 Ser Val Cys Leu Lys Gly Ile Lys Ile Ile Gly Lys Cys Phe Leu Ala 65 70 75 80 Asp Thr Ala Lys Lys Ile Tyr His Thr Ala Tyr Asp Asp Cys Ile Ala                 85 90 95 Lys Gly Gly Thr Ile Ser Thr Pro Leu Thr Gly Asp Glu Asn Asp Gln             100 105 110 Leu Val Asp Tyr Val Arg Arg Ser Ile Gly Pro Glu Glu His Ile Trp         115 120 125 Leu Gly Ile Asn Asp Met Val Thr Glu Gly Glu Trp Leu Asp Gln Ala     130 135 140 Gly Thr Asn Leu Arg Phe Lys Asn Trp Glu Thr Asp Ile Thr Asn Gln 145 150 155 160 Pro Asp Gly Gly Arg Thr His Asn Cys Ala Ile Leu Ser Thr Thr Ala                 165 170 175 Asn Gly Lys Trp Phe Asp Glu Ser Cys Arg Val Glu Lys Ala Ser Val             180 185 190 Cys Glu Phe Asn Ile Val         195 <210> 124 <211> 198 <212> PRT <213> Silurana tropicalis <400> 124 Met Glu Tyr Arg Arg Ala Cys Ile Leu Leu Cys Leu Phe Cys Phe Val 1 5 10 15 Gln Val Thr Leu Gln Gln Asn Gly Lys Lys Asn Lys Gln Asn Asn Lys             20 25 30 Asp Val Val Ser Met Lys Met Tyr Glu Asp Leu Lys Lys Lys Val Gln         35 40 45 Asn Ile Glu Glu Asp Val Ile His Leu Lys Glu Gln Gln Ala Leu Gln     50 55 60 Thr Ile Cys Leu Lys Gly Met Lys Ile Tyr Asn Lys Cys Phe Leu Ala 65 70 75 80 Phe Asn Glu Leu Lys Thr Tyr His Gln Ala Ser Asp Val Cys Phe Ala                 85 90 95 Gln Gly Gly Thr Leu Ser Thr Pro Glu Thr Gly Asp Glu Asn Asp Ser             100 105 110 Leu Tyr Asp Tyr Val Arg Lys Ser Ile Gly Ser Ser Ala Glu Ile Trp         115 120 125 Ile Gly Ile Asn Asp Met Ala Thr Glu Gly Thr Trp Leu Asp Leu Thr     130 135 140 Gly Ser Pro Ile Ser Phe Lys His Trp Glu Thr Glu Ile Thr Thr Gln 145 150 155 160 Pro Asp Gly Gly Lys Gln Glu Asn Cys Ala Ala Leu Ser Ala Ser Ala                 165 170 175 Ile Gly Arg Trp Phe Asp Lys Asn Cys Lys Thr Glu Leu Pro Phe Val             180 185 190 Cys Gln Phe Ser Ile Val         195 <210> 125 <211> 223 <212> PRT <213> Danio rerio <400> 125 Met Arg Asp Asp Ser Asp Lys Val Pro Ser Leu Leu Thr Asp Tyr Ile 1 5 10 15 Leu Lys Gly Cys Thr Tyr Ala Glu Glu Lys Met Asp Leu Lys Ala Val             20 25 30 Lys Phe Leu Leu Cys Val Ile Cys Leu Val Lys Ser Ser Pro Glu Gln         35 40 45 Ser Leu Thr Lys Arg Lys Asn Gly Lys Lys Glu Ser Asn Ser Ala Ala     50 55 60 Ile Glu Glu Leu Lys Lys Lys Gln Ile Asp Gln Ile Ile Gln Asp Leu Asn 65 70 75 80 Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Cys Leu Lys Gly Phe                 85 90 95 Lys Ile Pro Gly Lys Cys Phe Leu Val Asp Thr Val Lys Lys Asp Phe             100 105 110 His Ser Ala Asn Asp Asp Cys Ile Ala Lys Gly Gly Ile Leu Ser Thr         115 120 125 Pro Met Ser Gly His Glu Asn Asp Gln Leu Gln Glu Tyr Val Gln Gln     130 135 140 Thr Val Gly Pro Glu Thr His Ile Trp Leu Gly Val Asn Asp Met Ile 145 150 155 160 Lys Glu Gly Glu Trp Ile Asp Leu Thr Gly Ser Pro Ile Arg Phe Lys                 165 170 175 Asn Trp Glu Ser Glu Ile Thr His Gln Pro Asp Gly Gly Arg Thr His             180 185 190 Asn Cys Ala Val Leu Ser Ser Thr Ala Asn Gly Lys Trp Phe Asp Glu         195 200 205 Asp Cys Arg Gly Glu Lys Ala Ser Val Cys Gln Phe Asn Ile Val     210 215 220 <210> 126 <211> 197 <212> PRT <213> Bos taurus <400> 126 Met Ala Lys Asn Gly Leu Val Ile Tyr Ile Leu Val Ile Thr Leu Leu 1 5 10 15 Leu Asp Gln Thr Ser Cys His Ala Ser Lys Phe Lys Ala Arg Lys His             20 25 30 Ser Lys Arg Arg Val Lys Glu Lys Asp Gly Asp Leu Lys Thr Gln Val         35 40 45 Glu Lys Leu Trp Arg Glu Val Asn Ala Leu Lys Glu Met Gln Ala Leu     50 55 60 Gln Thr Val Cys Leu Arg Gly Thr Lys Phe His Lys Lys Cys Tyr Leu 65 70 75 80 Ala Ala Glu Gly Leu Lys His Phe His Glu Ala Asn Glu Asp Cys Ile                 85 90 95 Ser Lys Gly Gly Thr Leu Val Val Pro Arg Ser Ala Asp Glu Ile Asn             100 105 110 Ala Leu Arg Asp Tyr Gly Lys Arg Ser Leu Pro Gly Val Asn Asp Phe         115 120 125 Trp Leu Gly Ile Asn Asp Met Val Ala Glu Gly Lys Phe Val Asp Ile     130 135 140 Asn Gly Leu Ala Ile Ser Phe Leu Asn Trp Asp Gln Ala Gln Pro Asn 145 150 155 160 Gly Gly Lys Arg Glu Asn Cys Ala Leu Phe Ser Gln Ser Ala Gln Gly                 165 170 175 Lys Trp Ser Asp Glu Ala Cys His Ser Ser Lys Arg Tyr Ile Cys Glu             180 185 190 Phe Thr Ile Pro Gln         195 <210> 127 <211> 166 <212> PRT <213> Carcharhinus springeri <400> 127 Ser Lys Pro Ser Lys Ser Gly Lys Gly Lys Asp Asp Leu Arg Asn Glu 1 5 10 15 Ile Asp Lys Leu Trp Arg Glu Val Asn Ser Leu Lys Glu Met Gln Ala             20 25 30 Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Ile His Lys Lys Cys Tyr         35 40 45 Leu Ala Ser Arg Gly Ser Lys Ser Tyr His Ala Ala Asn Glu Asp Cys     50 55 60 Ile Ala Gln Gly Gly Thr Leu Ser Ile Pro Arg Ser Ser Asp Glu Gly 65 70 75 80 Asn Ser Leu Arg Ser Tyr Ala Lys Lys Ser Leu Val Gly Ala Arg Asp                 85 90 95 Phe Trp Ile Gly Val Asn Asp Met Thr Thr Glu Gly Lys Phe Val Asp             100 105 110 Val Asn Gly Leu Pro Ile Thr Tyr Phe Asn Trp Asp Arg Ser Lys Pro         115 120 125 Val Gly Gly Thr Arg Glu Asn Cys Val Ala Ala Ser Thr Ser Gly Gln     130 135 140 Gly Lys Trp Ser Asp Asp Val Cys Arg Ser Glu Lys Arg Tyr Ile Cys 145 150 155 160 Glu Tyr Leu Ile Pro Val                 165 <210> 128 <211> 204 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (7) .. (8) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (15) .. (15) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature &Lt; 222 > (17) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature &Lt; 222 > (22) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature &Lt; 222 > (31) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (39) .. (39) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (42) .. (42) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (45). (45) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (50) .. (50) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (54) .. (54) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature &Lt; 222 > (60) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature &Lt; 222 > (80) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (89) .. (89) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (111) .. (111) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (119) .. (120) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (122) .. (122) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (124) .. (124) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (131) .. (131) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (136) .. (136) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (144) .. (144) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (152) .. (152) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (154) .. (154) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (164). (164) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <171> (171) .. (171) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (179) .. (180) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (189) .. (189) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (201). (201) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (204) (204) .. (204) <223> Xaa can be any naturally occurring amino acid <400> 128 Met Glu Leu Trp Gly Ala Xaa Xaa Leu Leu Cys Leu Phe Ser Xaa Leu 1 5 10 15 Xaa Gln Val Thr Ala Xaa Xaa Xaa Xaa Xaa Lys Ala Lys Lys Xaa Xaa             20 25 30 Xaa Xaa Xaa Lys Lys Asp Xaa Val Ser Xaa Lys Met Xaa Glu Glu Leu         35 40 45 Lys Xaa Gln Ile Asp Xaa Leu Ala Gln Glu Val Xaa Leu Leu Lys Glu     50 55 60 Gln Gln Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Ile His Xaa 65 70 75 80 Lys Cys Phe Leu Ala Phe Thr Gln Xaa Lys Thr Phe His Glu Ala Ser                 85 90 95 Glu Asp Cys Ile Ser Gln Gly Gly Thr Leu Ser Thr Pro Gln Xaa Gly             100 105 110 Asp Glu Asn Asp Ala Leu Xaa Xaa Tyr Xaa Arg Xaa Ser Val Gly Asn         115 120 125 Glu Ala Xaa Ile Trp Leu Gly Xaa Asn Asp Met Ala Ala Glu Gly Xaa     130 135 140 Trp Val Asp Met Thr Gly Ser Xaa Ile Xaa Tyr Lys Asn Trp Glu Thr 145 150 155 160 Glu Ile Thr Xaa Gln Pro Asp Gly Gly Lys Xaa Glu Asn Cys Ala Ala                 165 170 175 Leu Ser Xaa Xaa Ala Asn Gly Lys Trp Phe Asp Lys Xaa Cys Arg Asp             180 185 190 Glu Leu Pro Tyr Val Cys Gln Phe Xaa Ile Val Xaa         195 200 <210> 129 <211> 240 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature &Lt; 222 > (34) <223> n is a, c, g, or t <220> <221> misc_feature <222> (36) .. (36) <223> k is g or t <220> <221> misc_feature (222) (37) .. (38) <223> n is a, c, g, or t <220> <221> misc_feature (222) (39) .. (39) <223> k is g or t <220> <221> misc_feature (222) (40) .. (41) <223> n is a, c, g, or t <220> <221> misc_feature (222) (42) .. (42) <223> k is g or t <220> <221> misc_feature (222) (43) .. (44) <223> n is a, c, g, or t <220> <221> misc_feature (45). (45) <223> k is g or t <220> <221> misc_feature (222) (46) .. (47) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (48) <223> k is g or t <220> <221> misc_feature (222) (49) .. (50) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (51) <223> k is g or t <220> <221> misc_feature <222> (52) .. (53) <223> n is a, c, g, or t <220> <221> misc_feature <222> (54) .. (54) <223> k is g or t <400> 129 gaggccgaga tctggctggg cctgaacgac atgnnknnkn nknnknnknn knnktgggtg 60 gatatgactg gcgcccgcat cgcctacaag aactgggaaa ctgagatcac cgcccaacct 120 gatggcggcg caaccgagaa ctgcgcggtc ctgtctggcg ccgccaacgg caagtggttc 180 gacaagcgct gcagggatca attgccctac atctgccagt tcgggatcgt ggcggccgca 240 <210> 130 <211> 80 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (12) .. (18) <223> Xaa can be any naturally occurring amino acid <400> 130 Glu Ala Glu Ile Trp Leu Gly Leu Asn Asp Met Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Trp Val Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp             20 25 30 Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly Gly Ala Thr Glu Asn Cys         35 40 45 Ala Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys     50 55 60 Arg Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val Ala Ala Ala 65 70 75 80 <210> 131 <211> 137 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 131 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Asp Met Ala Ala Glu Gly Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile                 85 90 95 Thr Ala Gln Pro Asp Gly Gly Lys Thr Glu Asn Cys Ala Val Leu Ser             100 105 110 Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg Asp Gln Leu         115 120 125 Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 <210> 132 <211> 414 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 132 caggccctcc agacggtctg cctgaagggg accaaggtgc acatgaaatg ctttctggcc 60 ttcacccaga cgaagacctt ccacgaggcc agcgaggact gcatctcgcg cgggggcacc 120 ctgagcaccc ctcagactgg ctcggagaac gacgccctgt atgagtacct gcgccagagc 180 gtgggcaacg aggccgagat ctggctgggc ctcaacgaca tggcggccga gggcacctgg 240 gtggacatga ctggcgcgcg tatcgcctac aagaactggg agactgagat caccgcgcaa 300 cccgatggcg gcaagaccga gaactgcgcg gtcctgtcag gcgcggccaa cggcaagtgg 360 ttcgacaagc gctgcaggga tcaattgccc tacatctgcc agttcgggat cgtg 414 <210> 133 <211> 140 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 133 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Gly Ser Ala Leu Thr Asn Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Pro Pro Gly                 85 90 95 Pro His His Pro Met Gly Gly Phe Gly Val Phe Gly Glu Asn Cys Ala             100 105 110 Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg         115 120 125 Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 140 <210> 134 <211> 140 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 134 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Gly Ser Ala Leu Thr Asn Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Pro Pro Pro                 85 90 95 Pro His His Pro Met Gly Gly Phe Gly Val Phe Gly Glu Asn Cys Ala             100 105 110 Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg         115 120 125 Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 140 <210> 135 <211> 140 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 135 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Gly Ser Ala Leu Thr Asn Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Arg Pro Ala                 85 90 95 Leu Val Gln Pro Arg Gly Gly Phe Gly Val Phe Gly Glu Asn Cys Ala             100 105 110 Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg         115 120 125 Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 140 <210> 136 <211> 140 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 136 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Gly Ser Ala Leu Thr Asn Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Arg Pro Pro                 85 90 95 Leu Tyr Gln Pro Gly Gly Gly Trp Gly Val Phe Gly Glu Asn Cys Ala             100 105 110 Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg         115 120 125 Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 140 <210> 137 <211> 140 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 137 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Gly Ser Ala Leu Thr Asn Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Arg Thr Pro                 85 90 95 Pro Trp Gln Pro Glu Gly Gly Phe Gly Tyr Phe Gly Glu Asn Cys Ala             100 105 110 Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg         115 120 125 Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 140 <210> 138 <211> 140 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 138 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Gly Ser Leu Arg Thr Asp Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile                 85 90 95 Thr Ala Gln Pro Asp Gly Gly Phe Gly Val Phe Gly Glu Asn Cys Ala             100 105 110 Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg         115 120 125 Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 140 <210> 139 <211> 140 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 139 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Gly Ser Leu Arg Thr Asn Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile                 85 90 95 Thr Ala Gln Pro Asp Gly Gly Phe Gly Val Phe Gly Glu Asn Cys Ala             100 105 110 Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg         115 120 125 Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 140 <210> 140 <211> 140 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 140 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Gly Ser Ala Leu Thr Asn Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Arg Pro Pro                 85 90 95 Leu Tyr Gln Pro Gly Gly Gly Phe Gly Val Phe Gly Glu Asn Cys Ala             100 105 110 Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg         115 120 125 Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 140 <210> 141 <211> 140 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 141 Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys 1 5 10 15 Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp             20 25 30 Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu         35 40 45 Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala     50 55 60 Glu Ile Trp Leu Gly Leu Asn Gly Ser Ala Leu Thr Asn Thr Trp Val 65 70 75 80 Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Ala Thr Glu Ile                 85 90 95 Thr Ala Gln Pro Asp Gly Gly Phe Gly Val Phe Gly Glu Asn Cys Ala             100 105 110 Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg         115 120 125 Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val     130 135 140 <210> 142 <211> 181 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 142 Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp 1 5 10 15 Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr         35 40 45 Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys Phe Leu Ala Phe     50 55 60 Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp Cys Ile Ser Arg 65 70 75 80 Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu Asn Asp Ala Leu                 85 90 95 Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala Glu Ile Trp Leu             100 105 110 Gly Leu Asn Asp Met Ala Ala Glu Gly Thr Trp Val Asp Met Thr Gly         115 120 125 Ala Arg Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro     130 135 140 Asp Gly Gly Lys Thr Glu Asn Cys Ala Val Leu Ser Gly Ala Ala Asn 145 150 155 160 Gly Lys Trp Phe Asp Lys Arg Cys Arg Asp Gln Leu Pro Tyr Ile Cys                 165 170 175 Gln Phe Gly Ile Val             180 <210> 143 <211> 546 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 143 gagccaccaa cccagaagcc caagaagatt gtaaatgcca agaaagatgt tgtgaacaca 60 aagatgtttg aggagctcaa gagccgtctg gacaccctgg cccaggaggt ggccctgctg 120 aaggagcagc aggccctgca gacggtctgc ctgaagggga ccaaggtgca catgaaatgc 180 tttctggcct tcacccagac gaagaccttc cacgaggcca gcgaggactg catctcgcgc 240 gggggcaccc tgagcacccc tcagactggc tcggagaacg acgccctgta tgagtacctg 300 cgccagagcg tgggcaacga ggccgagatc tggctgggcc tcaacgacat ggcggccgag 360 ggcacctggg tggacatgac cggcgcccgc atcgcctaca agaactggga gactgagatc 420 accgcgcaac ccgatggcgg caagaccgag aactgcgcgg tcctgtcagg cgcggccaac 480 ggcaagtggt tcgacaagcg ctgccgcgat cagctgccct acatctgcca gttcgggatc 540 gtgtag 546 <210> 144 <211> 546 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 144 gagtcaccca ctcccaaggc caagaaggct gcaaatgcca agaaagattt ggtgagctca 60 aagatgttcg aggagctcaa gaacaggatg gatgtcctgg cccaggaggt ggccctgctg 120 aaggagaagc aggccttaca gactgtgtgc ctgaagggca ccaaggtgaa cttgaagtgc 180 ctcctggcct tcacccaacc gaagaccttc catgaggcga gcgaggactg catctcgcaa 240 gggggcacgc tgggcacccc gcagtcagag ctagagaacg aggcgctgtt cgagtacgcg 300 cgccacagcg tgggcaacga tgcgaacatc tggctgggcc tcaacgacat ggccgcggaa 360 ggcgcctggg tggacatgac cggcggcctc ctggcctaca agaactggga gacggagatc 420 acgacgcaac ccgacggcgg caaagccgag aactgcgccg ccctgtctgg cgcagccaac 480 ggcaagtggt tcgacaagcg atgccgcgat cagttgccct acatctgcca gtttgccatt 540 gtgtag 546 <210> 145 <211> 181 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 145 Glu Ser Pro Thr Pro Lys Ala Lys Lys Ala Ala Asn Ala Lys Lys Asp 1 5 10 15 Leu Val Ser Ser Lys Met Phe Glu Glu Leu Lys Asn Arg Met Asp Val             20 25 30 Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Lys Gln Ala Leu Gln Thr         35 40 45 Val Cys Leu Lys Gly Thr Lys Val Asn Leu Lys Cys Leu Leu Ala Phe     50 55 60 Thr Gln Pro Lys Thr Phe His Glu Ala Ser Glu Asp Cys Ile Ser Gln 65 70 75 80 Gly Gly Thr Leu Gly Thr Pro Gln Ser Glu Leu Glu Asn Glu Ala Leu                 85 90 95 Phe Glu Tyr Ala Arg His Ser Val Gly Asn Asp Ala Asn Ile Trp Leu             100 105 110 Gly Leu Asn Asp Met Ala Ala Glu Gly Ala Trp Val Asp Met Thr Gly         115 120 125 Gly Leu Leu Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Thr Gln Pro     130 135 140 Asp Gly Gly Lys Ala Glu Asn Cys Ala Ala Leu Ser Gly Ala Ala Asn 145 150 155 160 Gly Lys Trp Phe Asp Lys Arg Cys Arg Asp Gln Leu Pro Tyr Ile Cys                 165 170 175 Gln Phe Ala Ile Val             180 <210> 146 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 146 Lys Met Phe Glu Glu Leu Lys Ser Gln Leu Asp Ser Leu Ala Gln Glu 1 5 10 15 Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Cys Leu             20 25 30 <210> 147 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 147 Lys Met Phe Glu Glu Leu Lys Ser Gln Val Asp Ser Leu Ala Gln Glu 1 5 10 15 Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Cys Leu             20 25 30 <210> 148 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 148 Ser Lys Met Phe Glu Glu Leu Lys Asn Arg Met Asp Val Leu Ala Gln 1 5 10 15 Glu Val Ala Leu Leu Lys Glu Lys Gln Ala Leu Gln Thr Val Cys Leu             20 25 30 <210> 149 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 149 Lys Met Phe Glu Glu Leu Lys Asn Arg Leu Asp Val Leu Ala Gln Glu 1 5 10 15 Val Ala Leu Leu Lys Glu Lys Gln Ala Leu Gln Thr Val Cys Leu             20 25 30 <210> 150 <211> 4779 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 150 gacgaaaggg cctcgtgata cgcctatttt tataggttaa tgtcatgata ataatggttt 60 cttagacgtc aggtggcact tttcggggaa atgtgcgcgg aacccctatt tgtttatttt 120 tctaaataca ttcaaatatg tatccgctca tgagacaata accctgataa atgcttcaat 180 aatattgaaa aaggaagagt atgagtattc aacatttccg tgtcgccctt attccctttt 240 ttgcggcatt ttgccttcct gtttttgctc acccagaaac gctggtgaaa gtaaaagatg 300 ctgaagatca gttgggtgct cgagtgggtt acatcgaact ggatctcaac agcggtaaga 360 tccttgagag ttttcgcccc gaagaacgtt ttccaatgat gagcactttt aaagttctgc 420 tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga gcaactcggt cgccgcatac 480 actattctca gaatgacttg gttgagtact caccagtcac agaaaagcat cttacggatg 540 gcatgacagt aagagaatta tgcagtgctg ccataaccat gagtgataac actgcggcca 600 acttacttct gacaacgatc ggaggaccga aggagctaac cgcttttttg cacaacatgg 660 gggatcatgt aactcgcctt gatcgttggg aaccggagct gaatgaagcc ataccaaacg 720 acgagcgtga caccacgatg cctgtagcaa tggcaacaac gttgcgcaaa ctattaactg 780 gcgaactact tactctagct tcccggcaac aattaataga ctggatggag gcggataaag 840 ttgcaggacc acttctgcgc tcggcccttc cggctggctg gtttattgct gataaatctg 900 gagccggtga gcgtgggtct cgcggtatca ttgcagcact ggggccagat ggtaagccct 960 cccgtatcgt agttatctac acgacgggga gtcaggcaac tatggatgaa cgaaatagac 1020 agatcgctga gataggtgcc tcactgatta agcattggta actgtcagac caagtttact 1080 catatatact ttagattgat ttaaaacttc atttttaatt taaaaggatc taggtgaaga 1140 tcctttttga taatctcatg accaaaatcc cttaacgtga gttttcgttc cactgagcgt 1200 cagaccccgt agaaaagatc aaaggatctt cttgagatcc tttttttctg cgcgtaatct 1260 gctgcttgca aacaaaaaaa ccaccgctac cagcggtggt ttgtttgccg gatcaagagc 1320 taccaactct ttttccgaag gtaactggct tcagcagagc gcagatacca aatactgtcc 1380 ttctagtgta gccgtagtta ggccaccact tcaagaactc tgtagcaccg cctacatacc 1440 tcgctctgct aatcctgtta ccagtggctg ctgccagtgg cgataagtcg tgtcttaccg 1500 ggttggactc aagacgatag ttaccggata aggcgcagcg gtcgggctga acggggggtt 1560 cgtgcataca gcccagcttg gagcgaacga cctacaccga actgagatac ctacagcgtg 1620 agctatgaga aagcgccacg cttcccgaag ggagaaaggc ggacaggtat ccggtaagcg 1680 gcagggtcgg aacaggagag cgcacgaggg agcttccagg gggaaacgcc tggtatcttt 1740 atagtcctgt cgggtttcgc cacctctgac ttgagcgtcg atttttgtga tgctcgtcag 1800 gggggcggag cctatggaaa aacgccagca acgcggcctt tttacggttc ctggcctttt 1860 gctggccttt tgctcacatg ttctttcctg cgttatcccc tgattctgtg gataaccgta 1920 ttaccgcctt tgagtgagct gataccgctc gccgcagccg aacgaccgag cgcagcgagt 1980 cagtgagcga ggaagcggaa gagcgcccaa tacgcaaacc gcctctcccc gcgcgttggc 2040 cgattcatta atgcagctgg cacgacaggt ttcccgactg gaaagcgggc agtgagcgca 2100 acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc 2160 cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatg 2220 accatgatta cgccaagctt tggagccttt tttttggaga ttttcaacgt gaaaaaatta 2280 ttattcgcaa ttcctttagt tgttcctttc tatgcggccc agccggccat ggccgccctc 2340 cagacggtct gcctgaaggg gaccaaggtg cacatgaaat gctttctggc cttcacccag 2400 acgaagacct tccacgaggc cagcgaggac tgcatctcgc gcgggggcac cctgagcacc 2460 cctcagactg gctcggagaa cgacgccctg tatgagtacc tgcgccagag cgtgggcaac 2520 gaggccgaga tctaagtgac gatatcctga cctaaggtac ctaagtgacg atatcctgac 2580 ctaactgcag ggatcaattg ccctacatct gccagttcgg gatcgtggcg gccgcaggtg 2640 cgccggtgcc gtatccggat ccgctggaac cgcgtgccgc atagactgtt gaaagttgtt 2700 tagcaaaacc tcatacagaa aattcattta ctaacgtctg gaaagacgac aaaactttag 2760 atcgttacgc taactatgag ggctgtctgt ggaatgctac aggcgttgtg gtttgtactg 2820 gtgacgaaac tcagtgttac ggtacatggg ttcctattgg gcttgctatc cctgaaaatg 2880 agggtggtgg ctctgagggt ggcggttctg agggtggcgg ttctgagggt ggcggtacta 2940 aacctcctga gtacggtgat acacctattc cgggctatac ttatatcaac cctctcgacg 3000 gcacttatcc gcctggtact gagcaaaacc ccgctaatcc taatccttct cttgaggagt 3060 ctcagcctct taatactttc atgtttcaga ataataggtt ccgaaatagg cagggtgcat 3120 taactgttta tacgggcact gttactcaag gcactgaccc cgttaaaact tattaccagt 3180 acactcctgt atcatcaaaa gccatgtatg acgcttactg gaacggtaaa ttcagagact 3240 gcgctttcca ttctggcttt aatgaggatc cattcgtttg tgaatatcaa ggccaatcgt 3300 ctgacctgcc tcaacctcct gtcaatgctg gcggcggctc tggtggtggt tctggtggcg 3360 gctctgaggg tggcggctct gagggtggcg gttctgaggg tggcggctct gagggtggcg 3420 gttccggtgg cggctccggt tccggtgatt ttgattatga aaaaatggca aacgctaata 3480 agggggctat gaccgaaaat gccgatgaaa acgcgctaca gtctgacgct aaaggcaaac 3540 ttgattctgt cgctactgat tacggtgctg ctatcgatgg tttcattggt gacgtttccg 3600 gccttgctaa tggtaatggt gctactggtg attttgctgg ctctaattcc caaatggctc 3660 aagtcggtga cggtgataat tcacctttaa tgaataattt ccgtcaatat ttaccttctt 3720 tgcctcagtc ggttgaatgt cgcccttatg tctttggcgc tggtaaacca tatgaatttt 3780 ctattgattg tgacaaaata aacttattcc gtggtgtctt tgcgtttctt ttatatgttg 3840 ccacctttat gtatgtattt tcgacgtttg ctaacatact gcgtaataag gagtcttaat 3900 aagaattcac tggccgtcgt tttacaacgt cgtgactggg aaaaccctgg cgttacccaa 3960 cttaatcgcc ttgcagcaca tccccctttc gccagctggc gtaatagcga agaggcccgc 4020 accgatcgcc cttcccaaca gttgcgcagc ctgaatggcg aatggcgcct gatgcggtat 4080 tttctcctta cgcatctgtg cggtatttca caccgcatac gtcaaagcaa ccatagtacg 4140 cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc gtgaccgcta 4200 cacttgccag cgccctagcg cccgctcctt tcgctttctt cccttccttt ctcgccacgt 4260 tcgccggctt tccccgtcaa gctctaaatc gggggctccc tttagggttc cgatttagtg 4320 ctttacggca cctcgacccc aaaaaacttg atttgggtga tggttcacgt agtgggccat 4380 cgccctgata gacggttttt cgccctttga cgttggagtc cacgttcttt aatagtggac 4440 tcttgttcca aactggaaca acactcaacc ctatctcggg ctattctttt gatttataag 4500 ggattttgcc gatttcggcc tattggttaa aaaatgagct gatttaacaa aaatttaacg 4560 cgaattttaa caaaatatta acgtttacaa ttttatggtg cagtctcagt acaatctgct 4620 ctgatgccgc atagttaagc cagccccgac acccgccaac acccgctgac gcgccctgac 4680 gggcttgtct gctcccggca tccgcttaca gacaagctgt gaccgtctcc gggagctgca 4740 tgtgtcagag gttttcaccg tcatcaccga aacgcgcga 4779 <210> 151 <211> 5747 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 151 tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg 60 cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc 120 ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc tccctttagg 180 gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc 240 acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt 300 ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc 360 ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta 420 acaaaaattt aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt 480 tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta 540 tccgctcatg aattaattct tagaaaaact catcgagcat caaatgaaac tgcaatttat 600 tcatatcagg attatcaata ccatattttt gaaaaagccg tttctgtaat gaaggagaaa 660 actcaccgag gcagttccat aggatggcaa gatcctggta tcggtctgcg attccgactc 720 gtccaacatc aatacaacct attaatttcc cctcgtcaaa aataaggtta tcaagtgaga 780 aatcaccatg agtgacgact gaatccggtg agaatggcaa aagtttatgc atttctttcc 840 agacttgttc aacaggccag ccattacgct cgtcatcaaa atcactcgca tcaaccaaac 900 cgttattcat tcgtgattgc gcctgagcga gacgaaatac gcgatcgctg ttaaaaggac 960 aattacaaac aggaatcgaa tgcaaccggc gcaggaacac tgccagcgca tcaacaatat 1020 tttcacctga atcaggatat tcttctaata cctggaatgc tgttttcccg gggatcgcag 1080 tggtgagtaa ccatgcatca tcaggagtac ggataaaatg cttgatggtc ggaagaggca 1140 taaattccgt cagccagttt agtctgacca tctcatctgt aacatcattg gcaacgctac 1200 ctttgccatg tttcagaaac aactctggcg catcgggctt cccatacaat cgatagattg 1260 tcgcacctga ttgcccgaca ttatcgcgag cccatttata cccatataaa tcagcatcca 1320 tgttggaatt taatcgcggc ctagagcaag acgtttcccg ttgaatatgg ctcataacac 1380 cccttgtatt actgtttatg taagcagaca gttttattgt tcatgaccaa aatcccttaa 1440 cgtgagtttt cgttccactg agcgtcagac cccgtagaaa agatcaaagg atcttcttga 1500 gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg 1560 gtggtttgtt tgccggatca agagctacca actctttttc cgaaggtaac tggcttcagc 1620 agagcgcaga taccaaatac tgtccttcta gtgtagccgt agttaggcca ccacttcaag 1680 aactctgtag caccgcctac atacctcgct ctgctaatcc tgttaccagt ggctgctgcc 1740 agtggcgata agtcgtgtct taccgggttg gactcaagac gatagttacc ggataaggcg 1800 cagcggtcgg gctgaacggg gggttcgtgc acacagccca gcttggagcg aacgacctac 1860 accgaactga gatacctaca gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga 1920 aaggcggaca ggtatccggt aagcggcagg gtcggaacag gagagcgcac gagggagctt 1980 ccagggggaa acgcctggta tctttatagt cctgtcgggt ttcgccacct ctgacttgag 2040 cgtcgatttt tgtgatgctc gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg 2100 gcctttttac ggttcctggc cttttgctgg ccttttgctc acatgttctt tcctgcgtta 2160 tcccctgatt ctgtggataa ccgtattacc gcctttgagt gagctgatac cgctcgccgc 2220 agccgaacga ccgagcgcag cgagtcagtg agcgaggaag cggaagagcg cctgatgcgg 2280 tattttctcc ttacgcatct gtgcggtatt tcacaccgca tatatggtgc actctcagta 2340 caatctgctc tgatgccgca tagttaagcc agtatacact ccgctatcgc tacgtgactg 2400 ggtcatggct gcgccccgac acccgccaac acccgctgac gcgccctgac gggcttgtct 2460 gctcccggca tccgcttaca gacaagctgt gaccgtctcc gggagctgca tgtgtcagag 2520 gttttcaccg tcatcaccga aacgcgcgag gcagctgcgg taaagctcat cagcgtggtc 2580 gtgaagcgat tcacagatgt ctgcctgttc atccgcgtcc agctcgttga gtttctccag 2640 aagcgttaat gtctggcttc tgataaagcg ggccatgtta agggcggttt tttcctgttt 2700 ggtcactgat gcctccgtgt aagggggatt tctgttcatg ggggtaatga taccgatgaa 2760 acgagagagg atgctcacga tacgggttac tgatgatgaa catgcccggt tactggaacg 2820 ttgtgagggt aaacaactgg cggtatggat gcggcgggac cagagaaaaa tcactcaggg 2880 tcaatgccag cgcttcgtta atacagatgt aggtgttcca cagggtagcc agcagcatcc 2940 tgcgatgcag atccggaaca taatggtgca gggcgctgac ttccgcgttt ccagacttta 3000 cgaaacacgg aaaccgaaga ccattcatgt tgttgctcag gtcgcagacg ttttgcagca 3060 gcagtcgctt cacgttcgct cgcgtatcgg tgattcattc tgctaaccag taaggcaacc 3120 ccgccagcct agccgggtcc tcaacgacag gagcacgatc atgcgcaccc gtggggccgc 3180 catgccggcg ataatggcct gcttctcgcc gaaacgtttg gtggcgggac cagtgacgaa 3240 ggcttgagcg agggcgtgca agattccgaa taccgcaagc gacaggccga tcatcgtcgc 3300 gctccagcga aagcggtcct cgccgaaaat gacccagagc gctgccggca cctgtcctac 3360 gagttgcatg ataaagaaga cagtcataag tgcggcgacg atagtcatgc cccgcgccca 3420 ccggaaggag ctgactgggt tgaaggctct caagggcatc ggtcgagatc ccggtgccta 3480 atgagtgagc taacttacat taattgcgtt gcgctcactg cccgctttcc agtcgggaaa 3540 cctgtcgtgc cagctgcatt aatgaatcgg ccaacgcgcg gggagaggcg gtttgcgtat 3600 tgggcgccag ggtggttttt cttttcacca gtgagacggg caacagctga ttgcccttca 3660 ccgcctggcc ctgagagagt tgcagcaagc ggtccacgct ggtttgcccc agcaggcgaa 3720 aatcctgttt gatggtggtt aacggcggga tataacatga gctgtcttcg gtatcgtcgt 3780 atcccactac cgagatatcc gcaccaacgc gcagcccgga ctcggtaatg gcgcgcattg 3840 cgcccagcgc catctgatcg ttggcaacca gcatcgcagt gggaacgatg ccctcattca 3900 gcatttgcat ggtttgttga aaaccggaca tggcactcca gtcgccttcc cgttccgcta 3960 tcggctgaat ttgattgcga gtgagatatt tatgccagcc agccagacgc agacgcgccg 4020 agacagaact taatgggccc gctaacagcg cgatttgctg gtgacccaat gcgaccagat 4080 gctccacgcc cagtcgcgta ccgtcttcat gggagaaaat aatactgttg atgggtgtct 4140 ggtcagagac atcaagaaat aacgccggaa cattagtgca ggcagcttcc acagcaatgg 4200 catcctggtc atccagcgga tagttaatga tcagcccact gacgcgttgc gcgagaagat 4260 tgtgcaccgc cgctttacag gcttcgacgc cgcttcgttc taccatcgac accaccacgc 4320 tggcacccag ttgatcggcg cgagatttaa tcgccgcgac aatttgcgac ggcgcgtgca 4380 gggccagact ggaggtggca acgccaatca gcaacgactg tttgcccgcc agttgttgtg 4440 ccacgcggtt gggaatgtaa ttcagctccg ccatcgccgc ttccactttt tcccgcgttt 4500 tcgcagaaac gtggctggcc tggttcacca cgcgggaaac ggtctgataa gagacaccgg 4560 catactctgc gacatcgtat aacgttactg gtttcacatt caccaccctg aattgactct 4620 cttccgggcg ctatcatgcc ataccgcgaa aggttttgcg ccattcgatg gtgtccggga 4680 tctcgacgct ctcccttatg cgactcctgc attaggaagc agcccagtag taggttgagg 4740 ccgttgagca ccgccgccgc aaggaatggt gcatgcaagg agatggcgcc caacagtccc 4800 ccggccacgg ggcctgccac catacccacg ccgaaacaag cgctcatgag cccgaagtgg 4860 cgagcccgat cttccccatc ggtgatgtcg gcgatatagg cgccagcaac cgcacctgtg 4920 gcgccggtga tgccggccac gatgcgtccg gcgtagagga tcgggatctc gatcccgcga 4980 aattaatacg actcactata ggggaattgt gagcggataa caattcccct ctagaaataa 5040 ttttgtttaa ctttaagaag gagatataca tatgaaatac cttcttccga ctgctgctgc 5100 tggtctttta ctgctggctg ctcagccggc tatggctgct ggtggtggtt ctgccctcca 5160 gacggtctgc ctgaagggga ccaaggtgca catgaaatgc tttctggcct tcacccagac 5220 gaagaccttc cacgaggcca gcgaggactg catctcgcgc gggggcaccc tgagcacccc 5280 tcagactggc tcggagaacg acgccctgta tgagtacctg cgccagagcg tgggcaacga 5340 ggccgagatc tggctgggcc tcaacgacat ggcggccgag ggcacctggg tggacatgac 5400 cggtacccgc atcgcctaca agaactggga gactgagatc accgcgcaac ccgatggcgg 5460 caagaccgag aactgcgcgg tcctgtcagg cgcggccaac ggcaagtggt tcgacaagcg 5520 ctgcagggat caattgccct acatctgcca gttcgggatc gtgcaccacc accaccacca 5580 ctaactcgag caccaccacc accaccactg agatccggct gctaacaaag cccgaaagga 5640 agctgagttg gctgctgcca ccgctgagca ataactagca taaccccttg gggcctctaa 5700 acgggtcttg aggggttttt tgctgaaagg aggaactata tccggat 5747 <210> 152 <211> 10975 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 152 gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60 gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120 ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180 ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240 atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 300 cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 360 tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 420 agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480 tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 540 aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 600 gtcagatcac tagaagctgg gtaccagctg ctagcgttta aacttaagct tagcgcagag 660 gcttggggca gccgagcggc agccaggccc cggcccgggc ctcggttcca gaagggagag 720 gagcccgcca aggcgcgcaa gagagcgggc tgcctcgcag tccgagccgg agagggagcg 780 cgagccgcgc cggccccgga cggcctccga aaccatggag ctgtgggggg cctacctgct 840 gctgtgcctg ttctccctgc tgacccaggt gaccaccgag ccaccaaccc agaagcccaa 900 gaagattgta aatgccaaga aagatgttgt gaacacaaag atgtttgagg agctcaagag 960 ccgtctggac accctggccc aggaggtggc cctgctgaag gagcagcagg ccctccagac 1020 ggtctgcctg aaggggacca aggtgcacat gaaatgcttt ctggccttca cccagacgaa 1080 gaccttccac gaggccagcg aggactgcat ctcgcgcggg ggcaccctga gcacccctca 1140 gactggctcg gagaacgacg ccctgtatga gtacctgcgc cagagcgtgg gcaacgaggc 1200 cgagatctgg ctgggcctca acgacatggc ggccgagggc acctgggtgg acatgaccgg 1260 tacccgcatc gcctacaaga actgggagac tgagatcacc gcgcaacccg atggcggcaa 1320 gaccgagaac tgcgcggtcc tgtcaggcgc ggccaacggc aagtggttcg acaagcgctg 1380 cagggatcaa ttgccctaca tctgccagtt cgggatcgtg caccaccacc accaccacta 1440 actcgaggcc ggcaaggccg gatccagaca tgataagata cattgatgag tttggacaaa 1500 ccacaactag aatgcagtga aaaaaatgct ttatttgtga aatttgtgat gctattgctt 1560 tatttgtaac cattataagc tgcaataaac aagttaacaa caagaattgc attcatttta 1620 tgtttcaggt tcagggggag gtgtgggagg ttttttaaag caagtaaaac ctctacaaat 1680 gtggtatggc tgattatgat ccggctgcct cgcgcgtttc ggtgatgacg gtgaaaacct 1740 ctgacacatg cagctcccgg agacggtcac agcttgtctg taagcggatg ccgggagcag 1800 acaagcccgt caggcgtcag cgggtgttgg cgggtgtcgg ggcgcagcca tgaggtcgac 1860 tctagaggat cgatgccccg ccccggacga actaaacctg actacgacat ctctgcccct 1920 tcttcgcggg gcagtgcatg taatcccttc agttggttgg tacaacttgc caactgggcc 1980 ctgttccaca tgtgacacgg ggggggacca aacacaaagg ggttctctga ctgtagttga 2040 catccttata aatggatgtg cacatttgcc aacactgagt ggctttcatc ctggagcaga 2100 ctttgcagtc tgtggactgc aacacaacat tgcctttatg tgtaactctt ggctgaagct 2160 cttacaccaa tgctggggga catgtacctc ccaggggccc aggaagacta cgggaggcta 2220 caccaacgtc aatcagaggg gcctgtgtag ctaccgataa gcggaccctc aagagggcat 2280 tagcaatagt gtttataagg cccccttgtt aaccctaaac gggtagcata tgcttcccgg 2340 gtagtagtat atactatcca gactaaccct aattcaatag catatgttac ccaacgggaa 2400 gcatatgcta tcgaattagg gttagtaaaa gggtcctaag gaacagcgat atctcccacc 2460 ccatgagctg tcacggtttt atttacatgg ggtcaggatt ccacgagggt agtgaaccat 2520 tttagtcaca agggcagtgg ctgaagatca aggagcgggc agtgaactct cctgaatctt 2580 cgcctgcttc ttcattctcc ttcgtttagc taatagaata actgctgagt tgtgaacagt 2640 aaggtgtatg tgaggtgctc gaaaacaagg tttcaggtga cgcccccaga ataaaatttg 2700 gacggggggt tcagtggtgg cattgtgcta tgacaccaat ataaccctca caaacccctt 2760 gggcaataaa tactagtgta ggaatgaaac attctgaata tctttaacaa tagaaatcca 2820 tggggtgggg acaagccgta aagactggat gtccatctca cacgaattta tggctatggg 2880 caacacataa tcctagtgca atatgatact ggggttatta agatgtgtcc caggcaggga 2940 ccaagacagg tgaaccatgt tgttacactc tatttgtaac aaggggaaag agagtggacg 3000 ccgacagcag cggactccac tggttgtctc taacaccccc gaaaattaaa cggggctcca 3060 cgccaatggg gcccataaac aaagacaagt ggccactctt ttttttgaaa ttgtggagtg 3120 ggggcacgcg tcagccccca cacgccgccc tgcggttttg gactgtaaaa taagggtgta 3180 ataacttggc tgattgtaac cccgctaacc actgcggtca aaccacttgc ccacaaaacc 3240 actaatggca ccccggggaa tacctgcata agtaggtggg cgggccaaga taggggcgcg 3300 attgctgcga tctggaggac aaattacaca cacttgcgcc tgagcgccaa gcacagggtt 3360 gttggtcctc atattcacga ggtcgctgag agcacggtgg gctaatgttg ccatgggtag 3420 catatactac ccaaatatct ggatagcata tgctatccta atctatatct gggtagcata 3480 ggctatccta atctatatct gggtagcata tgctatccta atctatatct gggtagtata 3540 tgctatccta atttatatct gggtagcata ggctatccta atctatatct gggtagcata 3600 tgctatccta atctatatct gggtagtata tgctatccta atctgtatcc gggtagcata 3660 tgctatccta atagagatta gggtagtata tgctatccta atttatatct gggtagcata 3720 tactacccaa atatctggat agcatatgct atcctaatct atatctgggt agcatatgct 3780 atcctaatct atatctgggt agcataggct atcctaatct atatctgggt agcatatgct 3840 atcctaatct atatctgggt agtatatgct atcctaattt atatctgggt agcataggct 3900 atcctaatct atatctgggt agcatatgct atcctaatct atatctgggt agtatatgct 3960 atcctaatct gtatccgggt agcatatgct atcctcatgc atatacagtc agcatatgat 4020 acccagtagt agagtgggag tgctatcctt tgcatatgcc gccacctccc aagggggcgt 4080 gaattttcgc tgcttgtcct tttcctgctg gttgctccca ttcttaggtg aatttaagga 4140 ggccaggcta aagccgtcgc atgtctgatt gctcaccagg taaatgtcgc taatgttttc 4200 caacgcgaga aggtgttgag cgcggagctg agtgacgtga caacatgggt atgccgaatt 4260 gccccatgtt gggaggacga aaatggtgac aagacagatg gccagaaata caccaacagc 4320 acgcatgatg tctactgggg atttattctt tagtgcgggg gaatacacgg cttttaatac 4380 gattgagggc gtctcctaac aagttacatc actcctgccc ttcctcaccc tcatctccat 4440 cacctccttc atctccgtca tctccgtcat caccctccgc ggcagcccct tccaccatag 4500 gtggaaacca gggaggcaaa tctactccat cgtcaaagct gcacacagtc accctgatat 4560 tgcaggtagg agcgggcttt gtcataacaa ggtccttaat cgcatccttc aaaacctcag 4620 caaatatatg agtttgtaaa aagaccatga aataacagac aatggactcc cttagcgggc 4680 caggttgtgg gccgggtcca ggggccattc caaaggggag acgactcaat ggtgtaagac 4740 gacattgtgg aatagcaagg gcagttcctc gccttaggtt gtaaagggag gtcttactac 4800 ctccatatac gaacacaccg gcgacccaag ttccttcgtc ggtagtcctt tctacgtgac 4860 tcctagccag gagagctctt aaaccttctg caatgttctc aaatttcggg ttggaacctc 4920 cttgaccacg atgctttcca aaccaccctc cttttttgcg cctgcctcca tcaccctgac 4980 cccggggtcc agtgcttggg ccttctcctg ggtcatctgc ggggccctgc tctatcgctc 5040 ccgggggcac gtcaggctca ccatctgggc caccttcttg gtggtattca aaataatcgg 5100 cttcccctac agggtggaaa aatggccttc tacctggagg gggcctgcgc ggtggagacc 5160 cggatgatga tgactgacta ctgggactcc tgggcctctt ttctccacgt ccacgacctc 5220 tccccctggc tctttcacga cttccccccc tggctctttc acgtcctcta ccccggcggc 5280 ctccactacc tcctcgaccc cggcctccac tacctcctcg accccggcct ccactgcctc 5340 ctcgaccccg gcctccacct cctgctcctg cccctcctgc tcctgcccct cctcctgctc 5400 ctgcccctcc tgcccctcct gctcctgccc ctcctgcccc tcctgctcct gcccctcctg 5460 cccctcctgc tcctgcccct cctgcccctc ctcctgctcc tgcccctcct gcccctcctc 5520 ctgctcctgc ccctcctgcc cctcctgctc ctgcccctcc tgcccctcct gctcctgccc 5580 ctcctgcccc tcctgctcct gcccctcctg ctcctgcccc tcctgctcct gcccctcctg 5640 ctcctgcccc tcctgcccct cctgcccctc ctcctgctcc tgcccctcct gctcctgccc 5700 ctcctgcccc tcctgcccct cctgctcctg cccctcctcc tgctcctgcc cctcctgccc 5760 ctcctgcccc tcctcctgct cctgcccctc ctgcccctcc tcctgctcct gcccctcctc 5820 ctgctcctgc ccctcctgcc cctcctgccc ctcctcctgc tcctgcccct cctgcccctc 5880 ctcctgctcc tgcccctcct cctgctcctg cccctcctgc ccctcctgcc cctcctcctg 5940 ctcctgcccc tcctcctgct cctgcccctc ctgcccctcc tgcccctcct gcccctcctc 6000 ctgctcctgc ccctcctcct gctcctgccc ctcctgctcc tgcccctccc gctcctgctc 6060 ctgctcctgt tccaccgtgg gtccctttgc agccaatgca acttggacgt ttttggggtc 6120 tccggacacc atctctatgt cttggccctg atcctgagcc gcccggggct cctggtcttc 6180 cgcctcctcg tcctcgtcct cttccccgtc ctcgtccatg gttatcaccc cctcttcttt 6240 gaggtccact gccgccggag ccttctggtc cagatgtgtc tcccttctct cctaggccat 6300 ttccaggtcc tgtacctggc ccctcgtcag acatgattca cactaaaaga gatcaataga 6360 catctttatt agacgacgct cagtgaatac agggagtgca gactcctgcc ccctccaaca 6420 gcccccccac cctcatcccc ttcatggtcg ctgtcagaca gatccaggtc tgaaaattcc 6480 ccatcctccg aaccatcctc gtcctcatca ccaattactc gcagcccgga aaactcccgc 6540 tgaacatcct caagatttgc gtcctgagcc tcaagccagg cctcaaattc ctcgtccccc 6600 tttttgctgg acggtaggga tggggattct cgggacccct cctcttcctc ttcaaggtca 6660 ccagacagag atgctactgg ggcaacggaa gaaaagctgg gtgcggcctg tgaggatcag 6720 cttatcgatg ataagctgtc aaacatgaga attcttgaag acgaaagggc ctcgtgatac 6780 gcctattttt ataggttaat gtcatgataa taatggtttc ttagacgtca ggtggcactt 6840 ttcggggaaa tgtgcgcgga acccctattt gtttattttt ctaaatacat tcaaatatgt 6900 atccgctcat gagacaataa ccctgataaa tgcttcaata atattgaaaa aggaagagta 6960 tgagtattca acatttccgt gtcgccctta ttcccttttt tgcggcattt tgccttcctg 7020 tttttgctca cccagaaacg ctggtgaaag taaaagatgc tgaagatcag ttgggtgcac 7080 gagtgggtta catcgaactg gatctcaaca gcggtaagat ccttgagagt tttcgccccg 7140 aagaacgttt tccaatgatg agcactttta aagttctgct atgtggcgcg gtattatccc 7200 gtgttgacgc cgggcaagag caactcggtc gccgcataca ctattctcag aatgacttgg 7260 ttgagtactc accagtcaca gaaaagcatc ttacggatgg catgacagta agagaattat 7320 gcagtgctgc cataaccatg agtgataaca ctgcggccaa cttacttctg acaacgatcg 7380 gaggaccgaa ggagctaacc gcttttttgc acaacatggg ggatcatgta actcgccttg 7440 atcgttggga accggagctg aatgaagcca taccaaacga cgagcgtgac accacgatgc 7500 ctgcagcaat ggcaacaacg ttgcgcaaac tattaactgg cgaactactt actctagctt 7560 cccggcaaca attaatagac tggatggagg cggataaagt tgcaggacca cttctgcgct 7620 cggcccttcc ggctggctgg tttattgctg ataaatctgg agccggtgag cgtgggtctc 7680 gcggtatcat tgcagcactg gggccagatg gtaagccctc ccgtatcgta gttatctaca 7740 cgacggggag tcaggcaact atggatgaac gaaatagaca gatcgctgag ataggtgcct 7800 cactgattaa gcattggtaa ctgtcagacc aagtttactc atatatactt tagattgatt 7860 taaaacttca tttttaattt aaaaggatct aggtgaagat cctttttgat aatctcatga 7920 ccaaaatccc ttaacgtgag ttttcgttcc actgagcgtc agaccccgta gaaaagatca 7980 aaggatcttc ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac 8040 caccgctacc agcggtggtt tgtttgccgg atcaagagct accaactctt tttccgaagg 8100 taactggctt cagcagagcg cagataccaa atactgtcct tctagtgtag ccgtagttag 8160 gccaccactt caagaactct gtagcaccgc ctacatacct cgctctgcta atcctgttac 8220 cagtggctgc tgccagtggc gataagtcgt gtcttaccgg gttggactca agacgatagt 8280 taccggataa ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag cccagcttgg 8340 agcgaacgac ctacaccgaa ctgagatacc tacagcgtga gctatgagaa agcgccacgc 8400 ttcccgaagg gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga acaggagagc 8460 gcacgaggga gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc 8520 acctctgact tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa 8580 acgccagcaa cgcggccttt ttacggttcc tggccttttg ctggccttga agctgtccct 8640 gatggtcgtc atctacctgc ctggacagca tggcctgcaa cgcgggcatc ccgatgccgc 8700 cggaagcgag aagaatcata atggggaagg ccatccagcc tcgcgtcgcg aacgccagca 8760 agacgtagcc cagcgcgtcg gccccgagat gcgccgcgtg cggctgctgg agatggcgga 8820 cgcgatggat atgttctgcc aagggttggt ttgcgcattc acagttctcc gcaagaattg 8880 attggctcca attcttggag tggtgaatcc gttagcgagg tgccgccctg cttcatcccc 8940 gtggcccgtt gctcgcgttt gctggcggtg tccccggaag aaatatattt gcatgtcttt 9000 agttctatga tgacacaaac cccgcccagc gtcttgtcat tggcgaattc gaacacgcag 9060 atgcagtcgg ggcggcgcgg tccgaggtcc acttcgcata ttaaggtgac gcgtgtggcc 9120 tcgaacaccg agcgaccctg cagcgacccg cttaacagcg tcaacagcgt gccgcagatc 9180 ccggggggca atgagatatg aaaaagcctg aactcaccgc gacgtctgtc gagaagtttc 9240 tgatcgaaaa gttcgacagc gtctccgacc tgatgcagct ctcggagggc gaagaatctc 9300 gtgctttcag cttcgatgta ggagggcgtg gatatgtcct gcgggtaaat agctgcgccg 9360 atggtttcta caaagatcgt tatgtttatc ggcactttgc atcggccgcg ctcccgattc 9420 cggaagtgct tgacattggg gaattcagcg agagcctgac ctattgcatc tcccgccgtg 9480 cacagggtgt cacgttgcaa gacctgcctg aaaccgaact gcccgctgtt ctgcagccgg 9540 tcgcggaggc catggatgcg atcgctgcgg ccgatcttag ccagacgagc gggttcggcc 9600 cattcggacc gcaaggaatc ggtcaataca ctacatggcg tgatttcata tgcgcgattg 9660 ctgatcccca tgtgtatcac tggcaaactg tgatggacga caccgtcagt gcgtccgtcg 9720 cgcaggctct cgatgagctg atgctttggg ccgaggactg ccccgaagtc cggcacctcg 9780 tgcacgcgga tttcggctcc aacaatgtcc tgacggacaa tggccgcata acagcggtca 9840 ttgactggag cgaggcgatg ttcggggatt cccaatacga ggtcgccaac atcttcttct 9900 ggaggccgtg gttggcttgt atggagcagc agacgcgcta cttcgagcgg aggcatccgg 9960 agcttgcagg atcgccgcgg ctccgggcgt atatgctccg cattggtctt gaccaactct 10020 atcagagctt ggttgacggc aatttcgatg atgcagcttg ggcgcagggt cgatgcgacg 10080 caatcgtccg atccggagcc gggactgtcg ggcgtacaca aatcgcccgc agaagcgcgg 10140 ccgtctggac cgatggctgt gtagaagtac tcgccgatag tggaaaccga cgccccagca 10200 ctcgtccgga tcgggagatg ggggaggcta actgaaacac ggaaggagac aataccggaa 10260 ggaacccgcg ctatgacggc aataaaaaga cagaataaaa cgcacgggtg ttgggtcgtt 10320 tgttcataaa cgcggggttc ggtcccaggg ctggcactct gtcgataccc caccgagacc 10380 ccattggggc caatacgccc gcgtttcttc cttttcccca ccccaccccc caagttcggg 10440 tgaaggccca gggctcgcag ccaacgtcgg ggcggcaggc cctgccatag ccactggccc 10500 cgtgggttag ggacggggtc ccccatgggg aatggtttat ggttcgtggg ggttattatt 10560 ttgggcgttg cgtggggtca ggtccacgac tggactgagc agacagaccc atggtttttg 10620 gatggcctgg gcatggaccg catgtactgg cgcgacacga acaccgggcg tctgtggctg 10680 ccaaacaccc ccgaccccca aaaaccaccg cgcggatttc tggcgtgcca agctagtcga 10740 ccaattctca tgtttgacag cttatcatcg cagatccggg caacgttgtt gccattgctg 10800 caggcgcaga actggtaggt atggaagatc catacattga atcaatattg gcaattagcc 10860 atattagtca ttggttatat agcataaatc aatattggct attggccatt gcatacgttg 10920 tatctatatc ataatatgta catttatatt ggctcatgtc caatatgacc gccat 10975 <210> 153 <211> 5774 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 153 tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg 60 cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc 120 ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc tccctttagg 180 gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc 240 acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt 300 ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc 360 ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta 420 acaaaaattt aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt 480 tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta 540 tccgctcatg aattaattct tagaaaaact catcgagcat caaatgaaac tgcaatttat 600 tcatatcagg attatcaata ccatattttt gaaaaagccg tttctgtaat gaaggagaaa 660 actcaccgag gcagttccat aggatggcaa gatcctggta tcggtctgcg attccgactc 720 gtccaacatc aatacaacct attaatttcc cctcgtcaaa aataaggtta tcaagtgaga 780 aatcaccatg agtgacgact gaatccggtg agaatggcaa aagtttatgc atttctttcc 840 agacttgttc aacaggccag ccattacgct cgtcatcaaa atcactcgca tcaaccaaac 900 cgttattcat tcgtgattgc gcctgagcga gacgaaatac gcgatcgctg ttaaaaggac 960 aattacaaac aggaatcgaa tgcaaccggc gcaggaacac tgccagcgca tcaacaatat 1020 tttcacctga atcaggatat tcttctaata cctggaatgc tgttttcccg gggatcgcag 1080 tggtgagtaa ccatgcatca tcaggagtac ggataaaatg cttgatggtc ggaagaggca 1140 taaattccgt cagccagttt agtctgacca tctcatctgt aacatcattg gcaacgctac 1200 ctttgccatg tttcagaaac aactctggcg catcgggctt cccatacaat cgatagattg 1260 tcgcacctga ttgcccgaca ttatcgcgag cccatttata cccatataaa tcagcatcca 1320 tgttggaatt taatcgcggc ctagagcaag acgtttcccg ttgaatatgg ctcataacac 1380 cccttgtatt actgtttatg taagcagaca gttttattgt tcatgaccaa aatcccttaa 1440 cgtgagtttt cgttccactg agcgtcagac cccgtagaaa agatcaaagg atcttcttga 1500 gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg 1560 gtggtttgtt tgccggatca agagctacca actctttttc cgaaggtaac tggcttcagc 1620 agagcgcaga taccaaatac tgtccttcta gtgtagccgt agttaggcca ccacttcaag 1680 aactctgtag caccgcctac atacctcgct ctgctaatcc tgttaccagt ggctgctgcc 1740 agtggcgata agtcgtgtct taccgggttg gactcaagac gatagttacc ggataaggcg 1800 cagcggtcgg gctgaacggg gggttcgtgc acacagccca gcttggagcg aacgacctac 1860 accgaactga gatacctaca gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga 1920 aaggcggaca ggtatccggt aagcggcagg gtcggaacag gagagcgcac gagggagctt 1980 ccagggggaa acgcctggta tctttatagt cctgtcgggt ttcgccacct ctgacttgag 2040 cgtcgatttt tgtgatgctc gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg 2100 gcctttttac ggttcctggc cttttgctgg ccttttgctc acatgttctt tcctgcgtta 2160 tcccctgatt ctgtggataa ccgtattacc gcctttgagt gagctgatac cgctcgccgc 2220 agccgaacga ccgagcgcag cgagtcagtg agcgaggaag cggaagagcg cctgatgcgg 2280 tattttctcc ttacgcatct gtgcggtatt tcacaccgca tatatggtgc actctcagta 2340 caatctgctc tgatgccgca tagttaagcc agtatacact ccgctatcgc tacgtgactg 2400 ggtcatggct gcgccccgac acccgccaac acccgctgac gcgccctgac gggcttgtct 2460 gctcccggca tccgcttaca gacaagctgt gaccgtctcc gggagctgca tgtgtcagag 2520 gttttcaccg tcatcaccga aacgcgcgag gcagctgcgg taaagctcat cagcgtggtc 2580 gtgaagcgat tcacagatgt ctgcctgttc atccgcgtcc agctcgttga gtttctccag 2640 aagcgttaat gtctggcttc tgataaagcg ggccatgtta agggcggttt tttcctgttt 2700 ggtcactgat gcctccgtgt aagggggatt tctgttcatg ggggtaatga taccgatgaa 2760 acgagagagg atgctcacga tacgggttac tgatgatgaa catgcccggt tactggaacg 2820 ttgtgagggt aaacaactgg cggtatggat gcggcgggac cagagaaaaa tcactcaggg 2880 tcaatgccag cgcttcgtta atacagatgt aggtgttcca cagggtagcc agcagcatcc 2940 tgcgatgcag atccggaaca taatggtgca gggcgctgac ttccgcgttt ccagacttta 3000 cgaaacacgg aaaccgaaga ccattcatgt tgttgctcag gtcgcagacg ttttgcagca 3060 gcagtcgctt cacgttcgct cgcgtatcgg tgattcattc tgctaaccag taaggcaacc 3120 ccgccagcct agccgggtcc tcaacgacag gagcacgatc atgcgcaccc gtggggccgc 3180 catgccggcg ataatggcct gcttctcgcc gaaacgtttg gtggcgggac cagtgacgaa 3240 ggcttgagcg agggcgtgca agattccgaa taccgcaagc gacaggccga tcatcgtcgc 3300 gctccagcga aagcggtcct cgccgaaaat gacccagagc gctgccggca cctgtcctac 3360 gagttgcatg ataaagaaga cagtcataag tgcggcgacg atagtcatgc cccgcgccca 3420 ccggaaggag ctgactgggt tgaaggctct caagggcatc ggtcgagatc ccggtgccta 3480 atgagtgagc taacttacat taattgcgtt gcgctcactg cccgctttcc agtcgggaaa 3540 cctgtcgtgc cagctgcatt aatgaatcgg ccaacgcgcg gggagaggcg gtttgcgtat 3600 tgggcgccag ggtggttttt cttttcacca gtgagacggg caacagctga ttgcccttca 3660 ccgcctggcc ctgagagagt tgcagcaagc ggtccacgct ggtttgcccc agcaggcgaa 3720 aatcctgttt gatggtggtt aacggcggga tataacatga gctgtcttcg gtatcgtcgt 3780 atcccactac cgagatatcc gcaccaacgc gcagcccgga ctcggtaatg gcgcgcattg 3840 cgcccagcgc catctgatcg ttggcaacca gcatcgcagt gggaacgatg ccctcattca 3900 gcatttgcat ggtttgttga aaaccggaca tggcactcca gtcgccttcc cgttccgcta 3960 tcggctgaat ttgattgcga gtgagatatt tatgccagcc agccagacgc agacgcgccg 4020 agacagaact taatgggccc gctaacagcg cgatttgctg gtgacccaat gcgaccagat 4080 gctccacgcc cagtcgcgta ccgtcttcat gggagaaaat aatactgttg atgggtgtct 4140 ggtcagagac atcaagaaat aacgccggaa cattagtgca ggcagcttcc acagcaatgg 4200 catcctggtc atccagcgga tagttaatga tcagcccact gacgcgttgc gcgagaagat 4260 tgtgcaccgc cgctttacag gcttcgacgc cgcttcgttc taccatcgac accaccacgc 4320 tggcacccag ttgatcggcg cgagatttaa tcgccgcgac aatttgcgac ggcgcgtgca 4380 gggccagact ggaggtggca acgccaatca gcaacgactg tttgcccgcc agttgttgtg 4440 ccacgcggtt gggaatgtaa ttcagctccg ccatcgccgc ttccactttt tcccgcgttt 4500 tcgcagaaac gtggctggcc tggttcacca cgcgggaaac ggtctgataa gagacaccgg 4560 catactctgc gacatcgtat aacgttactg gtttcacatt caccaccctg aattgactct 4620 cttccgggcg ctatcatgcc ataccgcgaa aggttttgcg ccattcgatg gtgtccggga 4680 tctcgacgct ctcccttatg cgactcctgc attaggaagc agcccagtag taggttgagg 4740 ccgttgagca ccgccgccgc aaggaatggt gcatgcaagg agatggcgcc caacagtccc 4800 ccggccacgg ggcctgccac catacccacg ccgaaacaag cgctcatgag cccgaagtgg 4860 cgagcccgat cttccccatc ggtgatgtcg gcgatatagg cgccagcaac cgcacctgtg 4920 gcgccggtga tgccggccac gatgcgtccg gcgtagagga tcgggatctc gatcccgcga 4980 aattaatacg actcactata ggggaattgt gagcggataa caattcccct ctagaaataa 5040 ttttgtttaa ctttaagaag gagatataca tatgaaatac cttcttccga ctgctgctgc 5100 tggtctttta ctgctggctg ctcagccggc tatggctgct ggtggtggtt ctgccctcca 5160 gacggtctgc ctgaagggga ccaaggtgca catgaaatgc tttctggcct tcacccagac 5220 gaagaccttc cacgaggcca gcgaggactg catctcgcgc gggggcaccc tgagcacccc 5280 tcagactggc tcggagaacg acgccctgta tgagtacctg cgccagagcg tgggcaacga 5340 ggccgagatc tggctgggcc tcaacgacat ggcggccgag ggcacctggg tggacatgac 5400 cggtacccgc atcgcctaca agaactggga gactgagatc accgcgcaac ccgatggcgg 5460 caagaccgag aactgcgcgg tcctgtcagg cgcggccaac ggcaagtggt tcgacaagcg 5520 ctgcagggat caattgccct acatctgcca gttcgggatc gtgtacccct acgacgtgcc 5580 cgactacgcc caccaccacc accaccacta actcgagcac caccaccacc accactgaga 5640 tccggctgct aacaaagccc gaaaggaagc tgagttggct gctgccaccg ctgagcaata 5700 actagcataa ccccttgggg cctctaaacg ggtcttgagg ggttttttgc tgaaaggagg 5760 aactatatcc ggat 5774 <210> 154 <211> 4649 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 154 aagaaaccaa ttgtccatat tgcatcagac attgccgtca ctgcgtcttt tactggctct 60 tctcgctaac caaaccggta accccgctta ttaaaagcat tctgtaacaa agcgggacca 120 aagccatgac aaaaacgcgt aacaaaagtg tctataatca cggcagaaaa gtccacattg 180 attatttgca cggcgtcaca ctttgctatg ccatagcatt tttatccata agattagcgg 240 atcctacctg acgcttttta tcgcaactct ctactgtttc tccatacccg ttttttgggc 300 taacaggagg aattcaccat gaaaaagaca gctatcgcga ttgcagtggc actggctggt 360 ttcgctaccg ttgcgcaagc ttctgagcca ccaacccaga agcccaagaa gattgtaaat 420 gccaagaaag atgttgtgaa cacaaagatg tttgaggagc tcaagagccg tctggacacc 480 ctggcccagg aggtggccct gctgaaggag cagcaggccc tccagacggt ctgcctgaag 540 gggaccaagg tgcacatgaa atgctttctg gccttcaccc agacgaagac cttccacgag 600 gccagcgagg actgcatctc gcgcgggggc accctgagca cccctcagac tggctcggag 660 aacgacgccc tgtatgagta cctgcgccag agcgtgggca acgaggccga gatctggctg 720 ggcctcaacg acatggcggc cgagggcacc tgggtggaca tgaccggtac ccgcatcgcc 780 tacaagaact gggagactga gatcaccgcg caacccgatg gcggcaagac cgagaactgc 840 gcggtcctgt caggcgcggc caacggcaag tggttcgaca agcgctgcag ggatcaattg 900 ccctacatct gccagttcgg gatcgttcta gaacaaaaac tcatctcaga agaggatctg 960 aatagcgccg tcgaccatca tcatcatcat cattgagttt aaacggtctc cagcttggct 1020 gttttggcgg atgagagaag attttcagcc tgatacagat taaatcagaa cgcagaagcg 1080 gtctgataaa acagaatttg cctggcggca gtagcgcggt ggtcccacct gaccccatgc 1140 cgaactcaga agtgaaacgc cgtagcgccg atggtagtgt ggggtctccc catgcgagag 1200 tagggaactg ccaggcatca aataaaacga aaggctcagt cgaaagactg ggcctttcgt 1260 tttatctgtt gtttgtcggt gaacgctctc ctgagtagga caaatccgcc gggagcggat 1320 ttgaacgttg cgaagcaacg gcccggaggg tggcgggcag gacgcccgcc ataaactgcc 1380 aggcatcaaa ttaagcagaa ggccatcctg acggatggcc tttttgcgtt tctacaaact 1440 ctttttgttt atttttctaa atacattcaa atatgtatcc gctcatgaga caataaccct 1500 gataaatgct tcaataatat tgaaaaagga agagtatgag tattcaacat ttccgtgtcg 1560 cccttattcc cttttttgcg gcattttgcc ttcctgtttt tgctcaccca gaaacgctgg 1620 tgaaagtaaa agatgctgaa gatcagttgg gtgcacgagt gggttacatc gaactggatc 1680 tcaacagcgg taagatcctt gagagttttc gccccgaaga acgttttcca atgatgagca 1740 cttttaaagt tctgctatgt ggcgcggtat tatcccgtgt tgacgccggg caagagcaac 1800 tcggtcgccg catacactat tctcagaatg acttggttga gtactcacca gtcacagaaa 1860 agcatcttac ggatggcatg acagtaagag aattatgcag tgctgccata accatgagtg 1920 ataacactgc ggccaactta cttctgacaa cgatcggagg accgaaggag ctaaccgctt 1980 ttttgcacaa catgggggat catgtaactc gccttgatcg ttgggaaccg gagctgaatg 2040 aagccatacc aaacgacgag cgtgacacca cgatgcctgt agcaatggca acaacgttgc 2100 gcaaactatt aactggcgaa ctacttactc tagcttcccg gcaacaatta atagactgga 2160 tggaggcgga taaagttgca ggaccacttc tgcgctcggc ccttccggct ggctggttta 2220 ttgctgataa atctggagcc ggtgagcgtg ggtctcgcgg tatcattgca gcactggggc 2280 cagatggtaa gccctcccgt atcgtagtta tctacacgac ggggagtcag gcaactatgg 2340 atgaacgaaa tagacagatc gctgagatag gtgcctcact gattaagcat tggtaactgt 2400 cagaccaagt ttactcatat atactttaga ttgatttaaa acttcatttt taatttaaaa 2460 ggatctaggt gaagatcctt tttgataatc tcatgaccaa aatcccttaa cgtgagtttt 2520 cgttccactg agcgtcagac cccgtagaaa agatcaaagg atcttcttga gatccttttt 2580 ttctgcgcgt aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg gtggtttgtt 2640 tgccggatca agagctacca actctttttc cgaaggtaac tggcttcagc agagcgcaga 2700 taccaaatac tgtccttcta gtgtagccgt agttaggcca ccacttcaag aactctgtag 2760 caccgcctac atacctcgct ctgctaatcc tgttaccagt ggctgctgcc agtggcgata 2820 agtcgtgtct taccgggttg gactcaagac gatagttacc ggataaggcg cagcggtcgg 2880 gctgaacggg gggttcgtgc acacagccca gcttggagcg aacgacctac accgaactga 2940 gatacctaca gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga aaggcggaca 3000 ggtatccggt aagcggcagg gtcggaacag gagagcgcac gagggagctt ccagggggaa 3060 acgcctggta tctttatagt cctgtcgggt ttcgccacct ctgacttgag cgtcgatttt 3120 tgtgatgctc gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg gcctttttac 3180 ggttcctggc cttttgctgg ccttttgctc acatgttctt tcctgcgtta tcccctgatt 3240 ctgtggataa ccgtattacc gcctttgagt gagctgatac cgctcgccgc agccgaacga 3300 ccgagcgcag cgagtcagtg agcgaggaag cggaagagcg cctgatgcgg tattttctcc 3360 ttacgcatct gtgcggtatt tcacaccgca tatggtgcac tctcagtaca atctgctctg 3420 atgccgcata gttaagccag tatacactcc gctatcgcta cgtgactggg tcatggctgc 3480 gccccgacac ccgccaacac ccgctgacgc gccctgacgg gcttgtctgc tcccggcatc 3540 cgcttacaga caagctgtga ccgtctccgg gagctgcatg tgtcagaggt tttcaccgtc 3600 atcaccgaaa cgcgcgaggc agcagatcaa ttcgcgcgcg aaggcgaagc ggcatgcata 3660 atgtgcctgt caaatggacg aagcagggat tctgcaaacc ctatgctact ccgtcaagcc 3720 gtcaattgtc tgattcgtta ccaattatga caacttgacg gctacatcat tcactttttc 3780 ttcacaaccg gcacggaact cgctcgggct ggccccggtg cattttttaa atacccgcga 3840 gaaatagagt tgatcgtcaa aaccaacatt gcgaccgacg gtggcgatag gcatccgggt 3900 ggtgctcaaa agcagcttcg cctggctgat acgttggtcc tcgcgccagc ttaagacgct 3960 aatccctaac tgctggcgga aaagatgtga cagacgcgac ggcgacaagc aaacatgctg 4020 tgcgacgctg gcgatatcaa aattgctgtc tgccaggtga tcgctgatgt actgacaagc 4080 ctcgcgtacc cgattatcca tcggtggatg gagcgactcg ttaatcgctt ccatgcgccg 4140 cagtaacaat tgctcaagca gatttatcgc cagcagctcc gaatagcgcc cttccccttg 4200 cccggcgtta atgatttgcc caaacaggtc gctgaaatgc ggctggtgcg cttcatccgg 4260 gcgaaagaac cccgtattgg caaatattga cggccagtta agccattcat gccagtaggc 4320 gcgcggacga aagtaaaccc actggtgata ccattcgcga gcctccggat gacgaccgta 4380 gtgatgaatc tctcctggcg ggaacagcaa aatatcaccc ggtcggcaaa caaattctcg 4440 tccctgattt ttcaccaccc cctgaccgcg aatggtgaga ttgagaatat aacctttcat 4500 tcccagcggt cggtcgataa aaaaatcgag ataaccgttg gcctcaatcg gcgttaaacc 4560 cgccaccaga tgggcattaa acgagtatcc cggcagcagg ggatcatttt gcgcttcagc 4620 catacttttc atactcccgc cattcagag 4649 <210> 155 <211> 10972 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 155 gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60 gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120 ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180 ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240 atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 300 cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 360 tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 420 agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480 tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 540 aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 600 gtcagatcac tagaagctgg gtaccagctg ctagcgttta aacttaagct tagcgcagag 660 gcttggggca gccgagcggc agccaggccc cggcccgggc ctcggttcca gaagggagag 720 gagcccgcca aggcgcgcaa gagagcgggc tgcctcgcag tccgagccgg agagggagcg 780 cgagccgcgc cggccccgga cggcctccga aaccatggag ctgtgggggg cctacctgct 840 gctgtgcctg ttctccctgc tgacccaggt gaccaccgag ccaccaaccc agaagcccaa 900 gaagattgta aatgccaaga aagatgttgt gaacacaaag atgtttgagg agctcaagag 960 ccgtctggac accctggccc aggaggtggc cctgctgaag gagcagcagg ccctccagac 1020 gtgcctgaag gggaccaagg tgcacatgaa atgctttctg gccttcaccc agacgaagac 1080 cttccacgag gccagcgagg actgcatctc gcgcgggggc accctgagca cccctcagac 1140 tggctcggag aacgacgccc tgtatgagta cctgcgccag agcgtgggca acgaggccga 1200 gatctggctg ggcctcaacg acatggcggc cgagggcacc tgggtggaca tgaccggtac 1260 ccgcatcgcc tacaagaact gggagactga gatcaccgcg caacccgatg gcggcaagac 1320 cgagaactgc gcggtcctgt caggcgcggc caacggcaag tggttcgaca agcgctgcag 1380 ggatcaattg ccctacatct gccagttcgg gatcgtgcac caccaccacc accactaact 1440 cgaggccggc aaggccggat ccagacatga taagatacat tgatgagttt ggacaaacca 1500 caactagaat gcagtgaaaa aaatgcttta tttgtgaaat ttgtgatgct attgctttat 1560 ttgtaaccat tataagctgc aataaacaag ttaacaacaa gaattgcatt cattttatgt 1620 ttcaggttca gggggaggtg tgggaggttt tttaaagcaa gtaaaacctc tacaaatgtg 1680 gtatggctga ttatgatccg gctgcctcgc gcgtttcggt gatgacggtg aaaacctctg 1740 acacatgcag ctcccggaga cggtcacagc ttgtctgtaa gcggatgccg ggagcagaca 1800 agcccgtcag gcgtcagcgg gtgttggcgg gtgtcggggc gcagccatga ggtcgactct 1860 agaggatcga tgccccgccc cggacgaact aaacctgact acgacatctc tgccccttct 1920 tcgcggggca gtgcatgtaa tcccttcagt tggttggtac aacttgccaa ctgggccctg 1980 ttccacatgt gacacggggg gggaccaaac acaaaggggt tctctgactg tagttgacat 2040 ccttataaat ggatgtgcac atttgccaac actgagtggc tttcatcctg gagcagactt 2100 tgcagtctgt ggactgcaac acaacattgc ctttatgtgt aactcttggc tgaagctctt 2160 acaccaatgc tgggggacat gtacctccca ggggcccagg aagactacgg gaggctacac 2220 caacgtcaat cagaggggcc tgtgtagcta ccgataagcg gaccctcaag agggcattag 2280 caatagtgtt tataaggccc ccttgttaac cctaaacggg tagcatatgc ttcccgggta 2340 gtagtatata ctatccagac taaccctaat tcaatagcat atgttaccca acgggaagca 2400 tatgctatcg aattagggtt agtaaaaggg tcctaaggaa cagcgatatc tcccacccca 2460 tgagctgtca cggttttatt tacatggggt caggattcca cgagggtagt gaaccatttt 2520 agtcacaagg gcagtggctg aagatcaagg agcgggcagt gaactctcct gaatcttcgc 2580 ctgcttcttc attctccttc gtttagctaa tagaataact gctgagttgt gaacagtaag 2640 gtgtatgtga ggtgctcgaa aacaaggttt caggtgacgc ccccagaata aaatttggac 2700 ggggggttca gtggtggcat tgtgctatga caccaatata accctcacaa accccttggg 2760 caataaatac tagtgtagga atgaaacatt ctgaatatct ttaacaatag aaatccatgg 2820 ggtggggaca agccgtaaag actggatgtc catctcacac gaatttatgg ctatgggcaa 2880 cacataatcc tagtgcaata tgatactggg gttattaaga tgtgtcccag gcagggacca 2940 agacaggtga accatgttgt tacactctat ttgtaacaag gggaaagaga gtggacgccg 3000 acagcagcgg actccactgg ttgtctctaa cacccccgaa aattaaacgg ggctccacgc 3060 caatggggcc cataaacaaa gacaagtggc cactcttttt tttgaaattg tggagtgggg 3120 gcacgcgtca gcccccacac gccgccctgc ggttttggac tgtaaaataa gggtgtaata 3180 acttggctga ttgtaacccc gctaaccact gcggtcaaac cacttgccca caaaaccact 3240 aatggcaccc cggggaatac ctgcataagt aggtgggcgg gccaagatag gggcgcgatt 3300 gctgcgatct ggaggacaaa ttacacacac ttgcgcctga gcgccaagca cagggttgtt 3360 ggtcctcata ttcacgaggt cgctgagagc acggtgggct aatgttgcca tgggtagcat 3420 atactaccca aatatctgga tagcatatgc tatcctaatc tatatctggg tagcataggc 3480 tatcctaatc tatatctggg tagcatatgc tatcctaatc tatatctggg tagtatatgc 3540 tatcctaatt tatatctggg tagcataggc tatcctaatc tatatctggg tagcatatgc 3600 tatcctaatc tatatctggg tagtatatgc tatcctaatc tgtatccggg tagcatatgc 3660 tatcctaata gagattaggg tagtatatgc tatcctaatt tatatctggg tagcatatac 3720 tacccaaata tctggatagc atatgctatc ctaatctata tctgggtagc atatgctatc 3780 ctaatctata tctgggtagc ataggctatc ctaatctata tctgggtagc atatgctatc 3840 ctaatctata tctgggtagt atatgctatc ctaatttata tctgggtagc ataggctatc 3900 ctaatctata tctgggtagc atatgctatc ctaatctata tctgggtagt atatgctatc 3960 ctaatctgta tccgggtagc atatgctatc ctcatgcata tacagtcagc atatgatacc 4020 cagtagtaga gtgggagtgc tatcctttgc atatgccgcc acctcccaag ggggcgtgaa 4080 ttttcgctgc ttgtcctttt cctgctggtt gctcccattc ttaggtgaat ttaaggaggc 4140 caggctaaag ccgtcgcatg tctgattgct caccaggtaa atgtcgctaa tgttttccaa 4200 cgcgagaagg tgttgagcgc ggagctgagt gacgtgacaa catgggtatg ccgaattgcc 4260 ccatgttggg aggacgaaaa tggtgacaag acagatggcc agaaatacac caacagcacg 4320 catgatgtct actggggatt tattctttag tgcgggggaa tacacggctt ttaatacgat 4380 tgagggcgtc tcctaacaag ttacatcact cctgcccttc ctcaccctca tctccatcac 4440 ctccttcatc tccgtcatct ccgtcatcac cctccgcggc agccccttcc accataggtg 4500 gaaaccaggg aggcaaatct actccatcgt caaagctgca cacagtcacc ctgatattgc 4560 aggtaggagc gggctttgtc ataacaaggt ccttaatcgc atccttcaaa acctcagcaa 4620 atatatgagt ttgtaaaaag accatgaaat aacagacaat ggactccctt agcgggccag 4680 gttgtgggcc gggtccaggg gccattccaa aggggagacg actcaatggt gtaagacgac 4740 attgtggaat agcaagggca gttcctcgcc ttaggttgta aagggaggtc ttactacctc 4800 catatacgaa cacaccggcg acccaagttc cttcgtcggt agtcctttct acgtgactcc 4860 tagccaggag agctcttaaa ccttctgcaa tgttctcaaa tttcgggttg gaacctcctt 4920 gaccacgatg ctttccaaac caccctcctt ttttgcgcct gcctccatca ccctgacccc 4980 ggggtccagt gcttgggcct tctcctgggt catctgcggg gccctgctct atcgctcccg 5040 ggggcacgtc aggctcacca tctgggccac cttcttggtg gtattcaaaa taatcggctt 5100 cccctacagg gtggaaaaat ggccttctac ctggaggggg cctgcgcggt ggagacccgg 5160 atgatgatga ctgactactg ggactcctgg gcctcttttc tccacgtcca cgacctctcc 5220 ccctggctct ttcacgactt ccccccctct ctctttcacg tcctctaccc cggcggcctc 5280 cactacctcc tcgaccccgg cctccactac ctcctcgacc ccggcctcca ctgcctcctc 5340 gaccccggcc tccacctcct gctcctgccc ctcctgctcc tgcccctcct cctgctcctg 5400 cccctcctgc ccctcctgct cctgcccctc ctgcccctcc tgctcctgcc cctcctgccc 5460 ctcctgctcc tgcccctcct gcccctcctc ctgctcctgc ccctcctgcc cctcctcctg 5520 ctcctgcccc tcctgcccct cctgctcctg cccctcctgc ccctcctgct cctgcccctc 5580 ctgcccctcc tgctcctgcc cctcctgctc ctgcccctcc tgctcctgcc cctcctgctc 5640 ctgcccctcc tgcccctcct gcccctcctc ctgctcctgc ccctcctgct cctgcccctc 5700 ctgcccctcc tgcccctcct gctcctgccc ctcctcctgc tcctgcccct cctgcccctc 5760 ctgcccctcc tcctgctcct gcccctcctg cccctcctcc tgctcctgcc cctcctcctg 5820 ctcctgcccc tcctgcccct cctgcccctc ctcctgctcc tgcccctcct gcccctcctc 5880 ctgctcctgc ccctcctcct gctcctgccc ctcctgcccc tcctgcccct cctcctgctc 5940 ctgcccctcc tcctgctcct gcccctcctg cccctcctgc ccctcctgcc cctcctcctg 6000 ctcctgcccc tcctcctgct cctgcccctc ctgctcctgc ccctcccgct cctgctcctg 6060 ctcctgttcc accgtgggtc cctttgcagc caatgcaact tggacgtttt tggggtctcc 6120 ggacaccatc tctatgtctt ggccctgatc ctgagccgcc cggggctcct ggtcttccgc 6180 ctcctcgtcc tcgtcctctt ccccgtcctc gtccatggtt atcaccccct cttctttgag 6240 gtccactgcc gccggagcct tctggtccag atgtgtctcc cttctctcct aggccatttc 6300 caggtcctgt acctggcccc tcgtcagaca tgattcacac taaaagagat caatagacat 6360 ctttattaga cgacgctcag tgaatacagg gagtgcagac tcctgccccc tccaacagcc 6420 cccccaccct catccccttc atggtcgctg tcagacagat ccaggtctga aaattcccca 6480 tcctccgaac catcctcgtc ctcatcacca attactcgca gcccggaaaa ctcccgctga 6540 acatcctcaa gatttgcgtc ctgagcctca agccaggcct caaattcctc gtcccccttt 6600 ttgctggacg gtagggatgg ggattctcgg gacccctcct cttcctcttc aaggtcacca 6660 gacagagatg ctactggggc aacggaagaa aagctgggtg cggcctgtga ggatcagctt 6720 atcgatgata agctgtcaaa catgagaatt cttgaagacg aaagggcctc gtgatacgcc 6780 tatttttata ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc 6840 ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 6900 cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 6960 gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 7020 ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 7080 tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 7140 aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgtg 7200 ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 7260 agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 7320 gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 7380 gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 7440 gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg 7500 cagcaatggc aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc 7560 ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg 7620 cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg 7680 gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga 7740 cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac 7800 tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa 7860 aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca 7920 aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag 7980 gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac 8040 cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa 8100 ctggcttcag cagagcgcag ataccaaata ctgtccttct agtgtagccg tagttaggcc 8160 accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag 8220 tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac 8280 cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc 8340 gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc 8400 ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca 8460 cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc 8520 tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg 8580 ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttgaagc tgtccctgat 8640 ggtcgtcatc tacctgcctg gacagcatgg cctgcaacgc gggcatcccg atgccgccgg 8700 aagcgagaag aatcataatg gggaaggcca tccagcctcg cgtcgcgaac gccagcaaga 8760 cgtagcccag cgcgtcggcc ccgagatgcg ccgcgtgcgg ctgctggaga tggcggacgc 8820 gatggatatg ttctgccaag ggttggtttg cgcattcaca gttctccgca agaattgatt 8880 ggctccaatt cttggagtgg tgaatccgtt agcgaggtgc cgccctgctt catccccgtg 8940 gcccgttgct cgcgtttgct ggcggtgtcc ccggaagaaa tatatttgca tgtctttagt 9000 tctatgatga cacaaacccc gcccagcgtc ttgtcattgg cgaattcgaa cacgcagatg 9060 cagtcggggc ggcgcggtcc gaggtccact tcgcatatta aggtgacgcg tgtggcctcg 9120 aacaccgagc gaccctgcag cgacccgctt aacagcgtca acagcgtgcc gcagatcccg 9180 gggggcaatg agatatgaaa aagcctgaac tcaccgcgac gtctgtcgag aagtttctga 9240 tcgaaaagtt cgacagcgtc tccgacctga tgcagctctc ggagggcgaa gaatctcgtg 9300 ctttcagctt cgatgtagga gggcgtggat atgtcctgcg ggtaaatagc tgcgccgatg 9360 gtttctacaa agatcgttat gtttatcggc actttgcatc ggccgcgctc ccgattccgg 9420 aagtgcttga cattggggaa ttcagcgaga gcctgaccta ttgcatctcc cgccgtgcac 9480 agggtgtcac gttgcaagac ctgcctgaaa ccgaactgcc cgctgttctg cagccggtcg 9540 cggaggccat ggatgcgatc gctgcggccg atcttagcca gacgagcggg ttcggcccat 9600 tcggaccgca aggaatcggt caatacacta catggcgtga tttcatatgc gcgattgctg 9660 atccccatgt gtatcactgg caaactgtga tggacgacac cgtcagtgcg tccgtcgcgc 9720 aggctctcga tgagctgatg ctttgggccg aggactgccc cgaagtccgg cacctcgtgc 9780 acgcggattt cggctccaac aatgtcctga cggacaatgg ccgcataaca gcggtcattg 9840 actggagcga ggcgatgttc ggggattccc aatacgaggt cgccaacatc ttcttctgga 9900 ggccgtggtt ggcttgtatg gagcagcaga cgcgctactt cgagcggagg catccggagc 9960 ttgcaggatc gccgcggctc cgggcgtata tgctccgcat tggtcttgac caactctatc 10020 agagcttggt tgacggcaat ttcgatgatg cagcttgggc gcagggtcga tgcgacgcaa 10080 tcgtccgatc cggagccggg actgtcgggc gtacacaaat cgcccgcaga agcgcggccg 10140 tctggaccga tggctgtgta gaagtactcg ccgatagtgg aaaccgacgc cccagcactc 10200 gtccggatcg ggagatgggg gaggctaact gaaacacgga aggagacaat accggaagga 10260 acccgcgcta tgacggcaat aaaaagacag aataaaacgc acgggtgttg ggtcgtttgt 10320 tcataaacgc ggggttcggt cccagggctg gcactctgtc gataccccac cgagacccca 10380 ttggggccaa tacgcccgcg tttcttcctt ttccccaccc caccccccaa gttcgggtga 10440 aggcccaggg ctcgcagcca acgtcggggc ggcaggccct gccatagcca ctggccccgt 10500 gggttaggga cggggtcccc catggggaat ggtttatggt tcgtgggggt tattattttg 10560 ggcgttgcgt ggggtcaggt ccacgactgg actgagcaga cagacccatg gtttttggat 10620 ggcctgggca tggaccgcat gtactggcgc gacacgaaca ccgggcgtct gtggctgcca 10680 aacacccccg acccccaaaa accaccgcgc ggatttctgg cgtgccaagc tagtcgacca 10740 attctcatgt ttgacagctt atcatcgcag atccgggcaa cgttgttgcc attgctgcag 10800 gcgcagaact ggtaggtatg gaagatccat acattgaatc aatattggca attagccata 10860 ttagtcattg gttatatagc ataaatcaat attggctatt ggccattgca tacgttgtat 10920 ctatatcata atatgtacat ttatattggc tcatgtccaa tatgaccgcc at 10972 <210> 156 <211> 10972 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 156 gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60 gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120 ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180 ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240 atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 300 cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 360 tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 420 agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480 tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 540 aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 600 gtcagatcac tagaagctgg gtaccagctg ctagcgttta aacttaagct tagcgcagag 660 gcttggggca gccgagcggc agccaggccc cggcccgggc ctcggttcca gaagggagag 720 gagcccgcca aggcgcgcaa gagagcgggc tgcctcgcag tccgagccgg agagggagcg 780 cgagccgcgc cggccccgga cggcctccga aaccatggag ctgtgggggg cctacctgct 840 gctgtgcctg ttctccctgc tgacccaggt gaccaccgag ccaccaaccc agaagcccaa 900 gaagattgta aatgccaaga aagatgttgt gaacacaaag atgtttgagg agctcaagag 960 ccgtctggac accctggccc aggaggtggc cctgctgaag gagcagcagg ccctccaggt 1020 ctgcctgaag gggaccaagg tgcacatgaa atgctttctg gccttcaccc agacgaagac 1080 cttccacgag gccagcgagg actgcatctc gcgcgggggc accctgagca cccctcagac 1140 tggctcggag aacgacgccc tgtatgagta cctgcgccag agcgtgggca acgaggccga 1200 gatctggctg ggcctcaacg acatggcggc cgagggcacc tgggtggaca tgaccggtac 1260 ccgcatcgcc tacaagaact gggagactga gatcaccgcg caacccgatg gcggcaagac 1320 cgagaactgc gcggtcctgt caggcgcggc caacggcaag tggttcgaca agcgctgcag 1380 ggatcaattg ccctacatct gccagttcgg gatcgtgcac caccaccacc accactaact 1440 cgaggccggc aaggccggat ccagacatga taagatacat tgatgagttt ggacaaacca 1500 caactagaat gcagtgaaaa aaatgcttta tttgtgaaat ttgtgatgct attgctttat 1560 ttgtaaccat tataagctgc aataaacaag ttaacaacaa gaattgcatt cattttatgt 1620 ttcaggttca gggggaggtg tgggaggttt tttaaagcaa gtaaaacctc tacaaatgtg 1680 gtatggctga ttatgatccg gctgcctcgc gcgtttcggt gatgacggtg aaaacctctg 1740 acacatgcag ctcccggaga cggtcacagc ttgtctgtaa gcggatgccg ggagcagaca 1800 agcccgtcag gcgtcagcgg gtgttggcgg gtgtcggggc gcagccatga ggtcgactct 1860 agaggatcga tgccccgccc cggacgaact aaacctgact acgacatctc tgccccttct 1920 tcgcggggca gtgcatgtaa tcccttcagt tggttggtac aacttgccaa ctgggccctg 1980 ttccacatgt gacacggggg gggaccaaac acaaaggggt tctctgactg tagttgacat 2040 ccttataaat ggatgtgcac atttgccaac actgagtggc tttcatcctg gagcagactt 2100 tgcagtctgt ggactgcaac acaacattgc ctttatgtgt aactcttggc tgaagctctt 2160 acaccaatgc tgggggacat gtacctccca ggggcccagg aagactacgg gaggctacac 2220 caacgtcaat cagaggggcc tgtgtagcta ccgataagcg gaccctcaag agggcattag 2280 caatagtgtt tataaggccc ccttgttaac cctaaacggg tagcatatgc ttcccgggta 2340 gtagtatata ctatccagac taaccctaat tcaatagcat atgttaccca acgggaagca 2400 tatgctatcg aattagggtt agtaaaaggg tcctaaggaa cagcgatatc tcccacccca 2460 tgagctgtca cggttttatt tacatggggt caggattcca cgagggtagt gaaccatttt 2520 agtcacaagg gcagtggctg aagatcaagg agcgggcagt gaactctcct gaatcttcgc 2580 ctgcttcttc attctccttc gtttagctaa tagaataact gctgagttgt gaacagtaag 2640 gtgtatgtga ggtgctcgaa aacaaggttt caggtgacgc ccccagaata aaatttggac 2700 ggggggttca gtggtggcat tgtgctatga caccaatata accctcacaa accccttggg 2760 caataaatac tagtgtagga atgaaacatt ctgaatatct ttaacaatag aaatccatgg 2820 ggtggggaca agccgtaaag actggatgtc catctcacac gaatttatgg ctatgggcaa 2880 cacataatcc tagtgcaata tgatactggg gttattaaga tgtgtcccag gcagggacca 2940 agacaggtga accatgttgt tacactctat ttgtaacaag gggaaagaga gtggacgccg 3000 acagcagcgg actccactgg ttgtctctaa cacccccgaa aattaaacgg ggctccacgc 3060 caatggggcc cataaacaaa gacaagtggc cactcttttt tttgaaattg tggagtgggg 3120 gcacgcgtca gcccccacac gccgccctgc ggttttggac tgtaaaataa gggtgtaata 3180 acttggctga ttgtaacccc gctaaccact gcggtcaaac cacttgccca caaaaccact 3240 aatggcaccc cggggaatac ctgcataagt aggtgggcgg gccaagatag gggcgcgatt 3300 gctgcgatct ggaggacaaa ttacacacac ttgcgcctga gcgccaagca cagggttgtt 3360 ggtcctcata ttcacgaggt cgctgagagc acggtgggct aatgttgcca tgggtagcat 3420 atactaccca aatatctgga tagcatatgc tatcctaatc tatatctggg tagcataggc 3480 tatcctaatc tatatctggg tagcatatgc tatcctaatc tatatctggg tagtatatgc 3540 tatcctaatt tatatctggg tagcataggc tatcctaatc tatatctggg tagcatatgc 3600 tatcctaatc tatatctggg tagtatatgc tatcctaatc tgtatccggg tagcatatgc 3660 tatcctaata gagattaggg tagtatatgc tatcctaatt tatatctggg tagcatatac 3720 tacccaaata tctggatagc atatgctatc ctaatctata tctgggtagc atatgctatc 3780 ctaatctata tctgggtagc ataggctatc ctaatctata tctgggtagc atatgctatc 3840 ctaatctata tctgggtagt atatgctatc ctaatttata tctgggtagc ataggctatc 3900 ctaatctata tctgggtagc atatgctatc ctaatctata tctgggtagt atatgctatc 3960 ctaatctgta tccgggtagc atatgctatc ctcatgcata tacagtcagc atatgatacc 4020 cagtagtaga gtgggagtgc tatcctttgc atatgccgcc acctcccaag ggggcgtgaa 4080 ttttcgctgc ttgtcctttt cctgctggtt gctcccattc ttaggtgaat ttaaggaggc 4140 caggctaaag ccgtcgcatg tctgattgct caccaggtaa atgtcgctaa tgttttccaa 4200 cgcgagaagg tgttgagcgc ggagctgagt gacgtgacaa catgggtatg ccgaattgcc 4260 ccatgttggg aggacgaaaa tggtgacaag acagatggcc agaaatacac caacagcacg 4320 catgatgtct actggggatt tattctttag tgcgggggaa tacacggctt ttaatacgat 4380 tgagggcgtc tcctaacaag ttacatcact cctgcccttc ctcaccctca tctccatcac 4440 ctccttcatc tccgtcatct ccgtcatcac cctccgcggc agccccttcc accataggtg 4500 gaaaccaggg aggcaaatct actccatcgt caaagctgca cacagtcacc ctgatattgc 4560 aggtaggagc gggctttgtc ataacaaggt ccttaatcgc atccttcaaa acctcagcaa 4620 atatatgagt ttgtaaaaag accatgaaat aacagacaat ggactccctt agcgggccag 4680 gttgtgggcc gggtccaggg gccattccaa aggggagacg actcaatggt gtaagacgac 4740 attgtggaat agcaagggca gttcctcgcc ttaggttgta aagggaggtc ttactacctc 4800 catatacgaa cacaccggcg acccaagttc cttcgtcggt agtcctttct acgtgactcc 4860 tagccaggag agctcttaaa ccttctgcaa tgttctcaaa tttcgggttg gaacctcctt 4920 gaccacgatg ctttccaaac caccctcctt ttttgcgcct gcctccatca ccctgacccc 4980 ggggtccagt gcttgggcct tctcctgggt catctgcggg gccctgctct atcgctcccg 5040 ggggcacgtc aggctcacca tctgggccac cttcttggtg gtattcaaaa taatcggctt 5100 cccctacagg gtggaaaaat ggccttctac ctggaggggg cctgcgcggt ggagacccgg 5160 atgatgatga ctgactactg ggactcctgg gcctcttttc tccacgtcca cgacctctcc 5220 ccctggctct ttcacgactt ccccccctct ctctttcacg tcctctaccc cggcggcctc 5280 cactacctcc tcgaccccgg cctccactac ctcctcgacc ccggcctcca ctgcctcctc 5340 gaccccggcc tccacctcct gctcctgccc ctcctgctcc tgcccctcct cctgctcctg 5400 cccctcctgc ccctcctgct cctgcccctc ctgcccctcc tgctcctgcc cctcctgccc 5460 ctcctgctcc tgcccctcct gcccctcctc ctgctcctgc ccctcctgcc cctcctcctg 5520 ctcctgcccc tcctgcccct cctgctcctg cccctcctgc ccctcctgct cctgcccctc 5580 ctgcccctcc tgctcctgcc cctcctgctc ctgcccctcc tgctcctgcc cctcctgctc 5640 ctgcccctcc tgcccctcct gcccctcctc ctgctcctgc ccctcctgct cctgcccctc 5700 ctgcccctcc tgcccctcct gctcctgccc ctcctcctgc tcctgcccct cctgcccctc 5760 ctgcccctcc tcctgctcct gcccctcctg cccctcctcc tgctcctgcc cctcctcctg 5820 ctcctgcccc tcctgcccct cctgcccctc ctcctgctcc tgcccctcct gcccctcctc 5880 ctgctcctgc ccctcctcct gctcctgccc ctcctgcccc tcctgcccct cctcctgctc 5940 ctgcccctcc tcctgctcct gcccctcctg cccctcctgc ccctcctgcc cctcctcctg 6000 ctcctgcccc tcctcctgct cctgcccctc ctgctcctgc ccctcccgct cctgctcctg 6060 ctcctgttcc accgtgggtc cctttgcagc caatgcaact tggacgtttt tggggtctcc 6120 ggacaccatc tctatgtctt ggccctgatc ctgagccgcc cggggctcct ggtcttccgc 6180 ctcctcgtcc tcgtcctctt ccccgtcctc gtccatggtt atcaccccct cttctttgag 6240 gtccactgcc gccggagcct tctggtccag atgtgtctcc cttctctcct aggccatttc 6300 caggtcctgt acctggcccc tcgtcagaca tgattcacac taaaagagat caatagacat 6360 ctttattaga cgacgctcag tgaatacagg gagtgcagac tcctgccccc tccaacagcc 6420 cccccaccct catccccttc atggtcgctg tcagacagat ccaggtctga aaattcccca 6480 tcctccgaac catcctcgtc ctcatcacca attactcgca gcccggaaaa ctcccgctga 6540 acatcctcaa gatttgcgtc ctgagcctca agccaggcct caaattcctc gtcccccttt 6600 ttgctggacg gtagggatgg ggattctcgg gacccctcct cttcctcttc aaggtcacca 6660 gacagagatg ctactggggc aacggaagaa aagctgggtg cggcctgtga ggatcagctt 6720 atcgatgata agctgtcaaa catgagaatt cttgaagacg aaagggcctc gtgatacgcc 6780 tatttttata ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc 6840 ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 6900 cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 6960 gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 7020 ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 7080 tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 7140 aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgtg 7200 ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 7260 agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 7320 gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 7380 gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 7440 gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg 7500 cagcaatggc aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc 7560 ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg 7620 cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg 7680 gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga 7740 cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac 7800 tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa 7860 aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca 7920 aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag 7980 gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac 8040 cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa 8100 ctggcttcag cagagcgcag ataccaaata ctgtccttct agtgtagccg tagttaggcc 8160 accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag 8220 tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac 8280 cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc 8340 gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc 8400 ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca 8460 cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc 8520 tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg 8580 ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttgaagc tgtccctgat 8640 ggtcgtcatc tacctgcctg gacagcatgg cctgcaacgc gggcatcccg atgccgccgg 8700 aagcgagaag aatcataatg gggaaggcca tccagcctcg cgtcgcgaac gccagcaaga 8760 cgtagcccag cgcgtcggcc ccgagatgcg ccgcgtgcgg ctgctggaga tggcggacgc 8820 gatggatatg ttctgccaag ggttggtttg cgcattcaca gttctccgca agaattgatt 8880 ggctccaatt cttggagtgg tgaatccgtt agcgaggtgc cgccctgctt catccccgtg 8940 gcccgttgct cgcgtttgct ggcggtgtcc ccggaagaaa tatatttgca tgtctttagt 9000 tctatgatga cacaaacccc gcccagcgtc ttgtcattgg cgaattcgaa cacgcagatg 9060 cagtcggggc ggcgcggtcc gaggtccact tcgcatatta aggtgacgcg tgtggcctcg 9120 aacaccgagc gaccctgcag cgacccgctt aacagcgtca acagcgtgcc gcagatcccg 9180 gggggcaatg agatatgaaa aagcctgaac tcaccgcgac gtctgtcgag aagtttctga 9240 tcgaaaagtt cgacagcgtc tccgacctga tgcagctctc ggagggcgaa gaatctcgtg 9300 ctttcagctt cgatgtagga gggcgtggat atgtcctgcg ggtaaatagc tgcgccgatg 9360 gtttctacaa agatcgttat gtttatcggc actttgcatc ggccgcgctc ccgattccgg 9420 aagtgcttga cattggggaa ttcagcgaga gcctgaccta ttgcatctcc cgccgtgcac 9480 agggtgtcac gttgcaagac ctgcctgaaa ccgaactgcc cgctgttctg cagccggtcg 9540 cggaggccat ggatgcgatc gctgcggccg atcttagcca gacgagcggg ttcggcccat 9600 tcggaccgca aggaatcggt caatacacta catggcgtga tttcatatgc gcgattgctg 9660 atccccatgt gtatcactgg caaactgtga tggacgacac cgtcagtgcg tccgtcgcgc 9720 aggctctcga tgagctgatg ctttgggccg aggactgccc cgaagtccgg cacctcgtgc 9780 acgcggattt cggctccaac aatgtcctga cggacaatgg ccgcataaca gcggtcattg 9840 actggagcga ggcgatgttc ggggattccc aatacgaggt cgccaacatc ttcttctgga 9900 ggccgtggtt ggcttgtatg gagcagcaga cgcgctactt cgagcggagg catccggagc 9960 ttgcaggatc gccgcggctc cgggcgtata tgctccgcat tggtcttgac caactctatc 10020 agagcttggt tgacggcaat ttcgatgatg cagcttgggc gcagggtcga tgcgacgcaa 10080 tcgtccgatc cggagccggg actgtcgggc gtacacaaat cgcccgcaga agcgcggccg 10140 tctggaccga tggctgtgta gaagtactcg ccgatagtgg aaaccgacgc cccagcactc 10200 gtccggatcg ggagatgggg gaggctaact gaaacacgga aggagacaat accggaagga 10260 acccgcgcta tgacggcaat aaaaagacag aataaaacgc acgggtgttg ggtcgtttgt 10320 tcataaacgc ggggttcggt cccagggctg gcactctgtc gataccccac cgagacccca 10380 ttggggccaa tacgcccgcg tttcttcctt ttccccaccc caccccccaa gttcgggtga 10440 aggcccaggg ctcgcagcca acgtcggggc ggcaggccct gccatagcca ctggccccgt 10500 gggttaggga cggggtcccc catggggaat ggtttatggt tcgtgggggt tattattttg 10560 ggcgttgcgt ggggtcaggt ccacgactgg actgagcaga cagacccatg gtttttggat 10620 ggcctgggca tggaccgcat gtactggcgc gacacgaaca ccgggcgtct gtggctgcca 10680 aacacccccg acccccaaaa accaccgcgc ggatttctgg cgtgccaagc tagtcgacca 10740 attctcatgt ttgacagctt atcatcgcag atccgggcaa cgttgttgcc attgctgcag 10800 gcgcagaact ggtaggtatg gaagatccat acattgaatc aatattggca attagccata 10860 ttagtcattg gttatatagc ataaatcaat attggctatt ggccattgca tacgttgtat 10920 ctatatcata atatgtacat ttatattggc tcatgtccaa tatgaccgcc at 10972 <210> 157 <211> 10969 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 157 gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60 gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120 ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180 ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240 atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 300 cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 360 tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 420 agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480 tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 540 aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 600 gtcagatcac tagaagctgg gtaccagctg ctagcgttta aacttaagct tagcgcagag 660 gcttggggca gccgagcggc agccaggccc cggcccgggc ctcggttcca gaagggagag 720 gagcccgcca aggcgcgcaa gagagcgggc tgcctcgcag tccgagccgg agagggagcg 780 cgagccgcgc cggccccgga cggcctccga aaccatggag ctgtgggggg cctacctgct 840 gctgtgcctg ttctccctgc tgacccaggt gaccaccgag ccaccaaccc agaagcccaa 900 gaagattgta aatgccaaga aagatgttgt gaacacaaag atgtttgagg agctcaagag 960 ccgtctggac accctggccc aggaggtggc cctgctgaag gagcagcagg ccctccagtg 1020 cctgaagggg accaaggtgc acatgaaatg ctttctggcc ttcacccaga cgaagacctt 1080 ccacgaggcc agcgaggact gcatctcgcg cgggggcacc ctgagcaccc ctcagactgg 1140 ctcggagaac gacgccctgt atgagtacct gcgccagagc gtgggcaacg aggccgagat 1200 ctggctgggc ctcaacgaca tggcggccga gggcacctgg gtggacatga ccggtacccg 1260 catcgcctac aagaactggg agactgagat caccgcgcaa cccgatggcg gcaagaccga 1320 gaactgcgcg gtcctgtcag gcgcggccaa cggcaagtgg ttcgacaagc gctgcaggga 1380 tcaattgccc tacatctgcc agttcgggat cgtgcaccac caccaccacc actaactcga 1440 ggccggcaag gccggatcca gacatgataa gatacattga tgagtttgga caaaccacaa 1500 ctagaatgca gtgaaaaaaa tgctttattt gtgaaatttg tgatgctatt gctttatttg 1560 taaccattat aagctgcaat aaacaagtta acaacaagaa ttgcattcat tttatgtttc 1620 aggttcaggg ggaggtgtgg gaggtttttt aaagcaagta aaacctctac aaatgtggta 1680 tggctgatta tgatccggct gcctcgcgcg tttcggtgat gacggtgaaa acctctgaca 1740 catgcagctc ccggagacgg tcacagcttg tctgtaagcg gatgccggga gcagacaagc 1800 ccgtcaggcg tcagcgggtg ttggcgggtg tcggggcgca gccatgaggt cgactctaga 1860 ggatcgatgc cccgccccgg acgaactaaa cctgactacg acatctctgc cccttcttcg 1920 cggggcagtg catgtaatcc cttcagttgg ttggtacaac ttgccaactg ggccctgttc 1980 cacatgtgac acgggggggg accaaacaca aaggggttct ctgactgtag ttgacatcct 2040 tataaatgga tgtgcacatt tgccaacact gagtggcttt catcctggag cagactttgc 2100 agtctgtgga ctgcaacaca acattgcctt tatgtgtaac tcttggctga agctcttaca 2160 ccaatgctgg gggacatgta cctcccaggg gcccaggaag actacgggag gctacaccaa 2220 cgtcaatcag aggggcctgt gtagctaccg ataagcggac cctcaagagg gcattagcaa 2280 tagtgtttat aaggccccct tgttaaccct aaacgggtag catatgcttc ccgggtagta 2340 gtatatacta tccagactaa ccctaattca atagcatatg ttacccaacg ggaagcatat 2400 gctatcgaat tagggttagt aaaagggtcc taaggaacag cgatatctcc caccccatga 2460 gctgtcacgg ttttatttac atggggtcag gattccacga gggtagtgaa ccattttagt 2520 cacaagggca gtggctgaag atcaaggagc gggcagtgaa ctctcctgaa tcttcgcctg 2580 cttcttcatt ctccttcgtt tagctaatag aataactgct gagttgtgaa cagtaaggtg 2640 tatgtgaggt gctcgaaaac aaggtttcag gtgacgcccc cagaataaaa tttggacggg 2700 gggttcagtg gtggcattgt gctatgacac caatataacc ctcacaaacc ccttgggcaa 2760 taaatactag tgtaggaatg aaacattctg aatatcttta acaatagaaa tccatggggt 2820 ggggacaagc cgtaaagact ggatgtccat ctcacacgaa tttatggcta tgggcaacac 2880 ataatcctag tgcaatatga tactggggtt attaagatgt gtcccaggca gggaccaaga 2940 caggtgaacc atgttgttac actctatttg taacaagggg aaagagagtg gacgccgaca 3000 gcagcggact ccactggttg tctctaacac ccccgaaaat taaacggggc tccacgccaa 3060 tggggcccat aaacaaagac aagtggccac tctttttttt gaaattgtgg agtgggggca 3120 cgcgtcagcc cccacacgcc gccctgcggt tttggactgt aaaataaggg tgtaataact 3180 tggctgattg taaccccgct aaccactgcg gtcaaaccac ttgcccacaa aaccactaat 3240 ggcaccccgg ggaatacctg cataagtagg tgggcgggcc aagatagggg cgcgattgct 3300 gcgatctgga ggacaaatta cacacacttg cgcctgagcg ccaagcacag ggttgttggt 3360 cctcatattc acgaggtcgc tgagagcacg gtgggctaat gttgccatgg gtagcatata 3420 ctacccaaat atctggatag catatgctat cctaatctat atctgggtag cataggctat 3480 cctaatctat atctgggtag catatgctat cctaatctat atctgggtag tatatgctat 3540 cctaatttat atctgggtag cataggctat cctaatctat atctgggtag catatgctat 3600 cctaatctat atctgggtag tatatgctat cctaatctgt atccgggtag catatgctat 3660 cctaatagag attagggtag tatatgctat cctaatttat atctgggtag catatactac 3720 ccaaatatct ggatagcata tgctatccta atctatatct gggtagcata tgctatccta 3780 atctatatct gggtagcata ggctatccta atctatatct gggtagcata tgctatccta 3840 atctatatct gggtagtata tgctatccta atttatatct gggtagcata ggctatccta 3900 atctatatct gggtagcata tgctatccta atctatatct gggtagtata tgctatccta 3960 atctgtatcc gggtagcata tgctatcctc atgcatatac agtcagcata tgatacccag 4020 tagtagagtg ggagtgctat cctttgcata tgccgccacc tcccaagggg gcgtgaattt 4080 tcgctgcttg tccttttcct gctggttgct cccattctta ggtgaattta aggaggccag 4140 gctaaagccg tcgcatgtct gattgctcac caggtaaatg tcgctaatgt tttccaacgc 4200 gagaaggtgt tgagcgcgga gctgagtgac gtgacaacat gggtatgccg aattgcccca 4260 tgttgggagg acgaaaatgg tgacaagaca gatggccaga aatacaccaa cagcacgcat 4320 gatgtctact ggggatttat tctttagtgc gggggaatac acggctttta atacgattga 4380 gggcgtctcc taacaagtta catcactcct gcccttcctc accctcatct ccatcacctc 4440 cttcatctcc gtcatctccg tcatcaccct ccgcggcagc cccttccacc ataggtggaa 4500 accagggagg caaatctact ccatcgtcaa agctgcacac agtcaccctg atattgcagg 4560 taggagcggg ctttgtcata acaaggtcct taatcgcatc cttcaaaacc tcagcaaata 4620 tatgagtttg taaaaagacc atgaaataac agacaatgga ctcccttagc gggccaggtt 4680 gtgggccggg tccaggggcc attccaaagg ggagacgact caatggtgta agacgacatt 4740 gtggaatagc aagggcagtt cctcgcctta ggttgtaaag ggaggtctta ctacctccat 4800 atacgaacac accggcgacc caagttcctt cgtcggtagt cctttctacg tgactcctag 4860 ccaggagagc tcttaaacct tctgcaatgt tctcaaattt cgggttggaa cctccttgac 4920 cacgatgctt tccaaaccac cctccttttt tgcgcctgcc tccatcaccc tgaccccggg 4980 gtccagtgct tgggccttct cctgggtcat ctgcggggcc ctgctctatc gctcccgggg 5040 gcacgtcagg ctcaccatct gggccacctt cttggtggta ttcaaaataa tcggcttccc 5100 ctacagggtg gaaaaatggc cttctacctg gagggggcct gcgcggtgga gacccggatg 5160 atgatgactg actactggga ctcctgggcc tcttttctcc acgtccacga cctctccccc 5220 tggctctttc acgacttccc cccctggctc tttcacgtcc tctaccccgg cggcctccac 5280 tacctcctcg accccggcct ccactacctc ctcgaccccg gcctccactg cctcctcgac 5340 cccggcctcc acctcctgct cctgcccctc ctgctcctgc ccctcctcct gctcctgccc 5400 ctcctgcccc tcctgctcct gcccctcctg cccctcctgc tcctgcccct cctgcccctc 5460 ctgctcctgc ccctcctgcc cctcctcctg ctcctgcccc tcctgcccct cctcctgctc 5520 ctgcccctcc tgcccctcct gctcctgccc ctcctgcccc tcctgctcct gcccctcctg 5580 cccctcctgc tcctgcccct cctgctcctg cccctcctgc tcctgcccct cctgctcctg 5640 cccctcctgc ccctcctgcc cctcctcctg ctcctgcccc tcctgctcct gcccctcctg 5700 cccctcctgc ccctcctgct cctgcccctc ctcctgctcc tgcccctcct gcccctcctg 5760 cccctcctcc tgctcctgcc cctcctgccc ctcctcctgc tcctgcccct cctcctgctc 5820 ctgcccctcc tgcccctcct gcccctcctc ctgctcctgc ccctcctgcc cctcctcctg 5880 ctcctgcccc tcctcctgct cctgcccctc ctgcccctcc tgcccctcct cctgctcctg 5940 cccctcctcc tgctcctgcc cctcctgccc ctcctgcccc tcctgcccct cctcctgctc 6000 ctgcccctcc tcctgctcct gcccctcctg ctcctgcccc tcccgctcct gctcctgctc 6060 ctgttccacc gtgggtccct ttgcagccaa tgcaacttgg acgtttttgg ggtctccgga 6120 caccatctct atgtcttggc cctgatcctg agccgcccgg ggctcctggt cttccgcctc 6180 ctcgtcctcg tcctcttccc cgtcctcgtc catggttatc accccctctt ctttgaggtc 6240 cactgccgcc ggagccttct ggtccagatg tgtctccctt ctctcctagg ccatttccag 6300 gtcctgtacc tggcccctcg tcagacatga ttcacactaa aagagatcaa tagacatctt 6360 tattagacga cgctcagtga atacagggag tgcagactcc tgccccctcc aacagccccc 6420 ccaccctcat ccccttcatg gtcgctgtca gacagatcca ggtctgaaaa ttccccatcc 6480 tccgaaccat cctcgtcctc atcaccaatt actcgcagcc cggaaaactc ccgctgaaca 6540 tcctcaagat ttgcgtcctg agcctcaagc caggcctcaa attcctcgtc cccctttttg 6600 ctggacggta gggatgggga ttctcgggac ccctcctctt cctcttcaag gtcaccagac 6660 agagatgcta ctggggcaac ggaagaaaag ctgggtgcgg cctgtgagga tcagcttatc 6720 gatgataagc tgtcaaacat gagaattctt gaagacgaaa gggcctcgtg atacgcctat 6780 ttttataggt taatgtcatg ataataatgg tttcttagac gtcaggtggc acttttcggg 6840 gaaatgtgcg cggaacccct atttgtttat ttttctaaat acattcaaat atgtatccgc 6900 tcatgagaca ataaccctga taaatgcttc aataatattg aaaaaggaag agtatgagta 6960 ttcaacattt ccgtgtcgcc cttattccct tttttgcggc attttgcctt cctgtttttg 7020 ctcacccaga aacgctggtg aaagtaaaag atgctgaaga tcagttgggt gcacgagtgg 7080 gttacatcga actggatctc aacagcggta agatccttga gagttttcgc cccgaagaac 7140 gttttccaat gatgagcact tttaaagttc tgctatgtgg cgcggtatta tcccgtgttg 7200 acgccgggca agagcaactc ggtcgccgca tacactattc tcagaatgac ttggttgagt 7260 actcaccagt cacagaaaag catcttacgg atggcatgac agtaagagaa ttatgcagtg 7320 ctgccataac catgagtgat aacactgcgg ccaacttact tctgacaacg atcggaggac 7380 cgaaggagct aaccgctttt ttgcacaaca tgggggatca tgtaactcgc cttgatcgtt 7440 gggaaccgga gctgaatgaa gccataccaa acgacgagcg tgacaccacg atgcctgcag 7500 caatggcaac aacgttgcgc aaactattaa ctggcgaact acttactcta gcttcccggc 7560 aacaattaat agactggatg gaggcggata aagttgcagg accacttctg cgctcggccc 7620 ttccggctgg ctggtttatt gctgataaat ctggagccgg tgagcgtggg tctcgcggta 7680 tcattgcagc actggggcca gatggtaagc cctcccgtat cgtagttatc tacacgacgg 7740 ggagtcaggc aactatggat gaacgaaata gacagatcgc tgagataggt gcctcactga 7800 ttaagcattg gtaactgtca gaccaagttt actcatatat actttagatt gatttaaaac 7860 ttcattttta atttaaaagg atctaggtga agatcctttt tgataatctc atgaccaaaa 7920 tcccttaacg tgagttttcg ttccactgag cgtcagaccc cgtagaaaag atcaaaggat 7980 cttcttgaga tccttttttt ctgcgcgtaa tctgctgctt gcaaacaaaa aaaccaccgc 8040 taccagcggt ggtttgtttg ccggatcaag agctaccaac tctttttccg aaggtaactg 8100 gcttcagcag agcgcagata ccaaatactg tccttctagt gtagccgtag ttaggccacc 8160 acttcaagaa ctctgtagca ccgcctacat acctcgctct gctaatcctg ttaccagtgg 8220 ctgctgccag tggcgataag tcgtgtctta ccgggttgga ctcaagacga tagttaccgg 8280 ataaggcgca gcggtcgggc tgaacggggg gttcgtgcac acagcccagc ttggagcgaa 8340 cgacctacac cgaactgaga tacctacagc gtgagctatg agaaagcgcc acgcttcccg 8400 aagggagaaa ggcggacagg tatccggtaa gcggcagggt cggaacagga gagcgcacga 8460 gggagcttcc agggggaaac gcctggtatc tttatagtcc tgtcgggttt cgccacctct 8520 gacttgagcg tcgatttttg tgatgctcgt caggggggcg gagcctatgg aaaaacgcca 8580 gcaacgcggc ctttttacgg ttcctggcct tttgctggcc ttgaagctgt ccctgatggt 8640 cgtcatctac ctgcctggac agcatggcct gcaacgcggg catcccgatg ccgccggaag 8700 cgagaagaat cataatgggg aaggccatcc agcctcgcgt cgcgaacgcc agcaagacgt 8760 agcccagcgc gtcggccccg agatgcgccg cgtgcggctg ctggagatgg cggacgcgat 8820 ggatatgttc tgccaagggt tggtttgcgc attcacagtt ctccgcaaga attgattggc 8880 tccaattctt ggagtggtga atccgttagc gaggtgccgc cctgcttcat ccccgtggcc 8940 cgttgctcgc gtttgctggc ggtgtccccg gaagaaatat atttgcatgt ctttagttct 9000 atgatgacac aaaccccgcc cagcgtcttg tcattggcga attcgaacac gcagatgcag 9060 tcggggcggc gcggtccgag gtccacttcg catattaagg tgacgcgtgt ggcctcgaac 9120 accgagcgac cctgcagcga cccgcttaac agcgtcaaca gcgtgccgca gatcccgggg 9180 ggcaatgaga tatgaaaaag cctgaactca ccgcgacgtc tgtcgagaag tttctgatcg 9240 aaaagttcga cagcgtctcc gacctgatgc agctctcgga gggcgaagaa tctcgtgctt 9300 tcagcttcga tgtaggaggg cgtggatatg tcctgcgggt aaatagctgc gccgatggtt 9360 tctacaaaga tcgttatgtt tatcggcact ttgcatcggc cgcgctcccg attccggaag 9420 tgcttgacat tggggaattc agcgagagcc tgacctattg catctcccgc cgtgcacagg 9480 gtgtcacgtt gcaagacctg cctgaaaccg aactgcccgc tgttctgcag ccggtcgcgg 9540 aggccatgga tgcgatcgct gcggccgatc ttagccagac gagcgggttc ggcccattcg 9600 gaccgcaagg aatcggtcaa tacactacat ggcgtgattt catatgcgcg attgctgatc 9660 cccatgtgta tcactggcaa actgtgatgg acgacaccgt cagtgcgtcc gtcgcgcagg 9720 ctctcgatga gctgatgctt tgggccgagg actgccccga agtccggcac ctcgtgcacg 9780 cggatttcgg ctccaacaat gtcctgacgg acaatggccg cataacagcg gtcattgact 9840 ggagcgaggc gatgttcggg gattcccaat acgaggtcgc caacatcttc ttctggaggc 9900 cgtggttggc ttgtatggag cagcagacgc gctacttcga gcggaggcat ccggagcttg 9960 caggatcgcc gcggctccgg gcgtatatgc tccgcattgg tcttgaccaa ctctatcaga 10020 gcttggttga cggcaatttc gatgatgcag cttgggcgca gggtcgatgc gacgcaatcg 10080 tccgatccgg agccgggact gtcgggcgta cacaaatcgc ccgcagaagc gcggccgtct 10140 ggaccgatgg ctgtgtagaa gtactcgccg atagtggaaa ccgacgcccc agcactcgtc 10200 cggatcggga gatgggggag gctaactgaa acacggaagg agacaatacc ggaaggaacc 10260 cgcgctatga cggcaataaa aagacagaat aaaacgcacg ggtgttgggt cgtttgttca 10320 taaacgcggg gttcggtccc agggctggca ctctgtcgat accccaccga gaccccattg 10380 gggccaatac gcccgcgttt cttccttttc cccaccccac cccccaagtt cgggtgaagg 10440 cccagggctc gcagccaacg tcggggcggc aggccctgcc atagccactg gccccgtggg 10500 ttagggacgg ggtcccccat ggggaatggt ttatggttcg tgggggttat tattttgggc 10560 gttgcgtggg gtcaggtcca cgactggact gagcagacag acccatggtt tttggatggc 10620 ctgggcatgg accgcatgta ctggcgcgac acgaacaccg ggcgtctgtg gctgccaaac 10680 acccccgacc cccaaaaacc accgcgcgga tttctggcgt gccaagctag tcgaccaatt 10740 ctcatgtttg acagcttatc atcgcagatc cgggcaacgt tgttgccatt gctgcaggcg 10800 cagaactggt aggtatggaa gatccataca ttgaatcaat attggcaatt agccatatta 10860 gtcattggtt atatagcata aatcaatatt ggctattggc cattgcatac gttgtatcta 10920 tatcataata tgtacattta tattggctca tgtccaatat gaccgccat 10969 <210> 158 <211> 10975 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 158 gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60 gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120 ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180 ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240 atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 300 cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 360 tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 420 agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480 tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 540 aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 600 gtcagatcac tagaagctgg gtaccagctg ctagcgttta aacttaagct tagcgcagag 660 gcttggggca gccgagcggc agccaggccc cggcccgggc ctcggttcca gaagggagag 720 gagcccgcca aggcgcgcaa gagagcgggc tgcctcgcag tccgagccgg agagggagcg 780 cgagccgcgc cggccccgga cggcctccga aaccatggag ctgtgggggg cctacctgct 840 gctgtgcctg ttctccctgc tgacccaggt gaccaccgag ccaccaaccc agaagcccaa 900 gaagattgta aatgccaaga aagatgttgt gaacacaaag atgtttgagg agctcaagag 960 ccgtctggac accctggccc aggaggtggc cctgctgaag gagcagcagg ccctccagac 1020 ggtcagcctg aaggggacca aggtgcacat gaaaagcttt ctggccttca cccagacgaa 1080 gaccttccac gaggccagcg aggactgcat ctcgcgcggg ggcaccctga gcacccctca 1140 gactggctcg gagaacgacg ccctgtatga gtacctgcgc cagagcgtgg gcaacgaggc 1200 cgagatctgg ctgggcctca acgacatggc ggccgagggc acctgggtgg acatgaccgg 1260 tacccgcatc gcctacaaga actgggagac tgagatcacc gcgcaacccg atggcggcaa 1320 gaccgagaac tgcgcggtcc tgtcaggcgc ggccaacggc aagtggttcg acaagcgctg 1380 cagggatcaa ttgccctaca tctgccagtt cgggatcgtg caccaccacc accaccacta 1440 actcgaggcc ggcaaggccg gatccagaca tgataagata cattgatgag tttggacaaa 1500 ccacaactag aatgcagtga aaaaaatgct ttatttgtga aatttgtgat gctattgctt 1560 tatttgtaac cattataagc tgcaataaac aagttaacaa caagaattgc attcatttta 1620 tgtttcaggt tcagggggag gtgtgggagg ttttttaaag caagtaaaac ctctacaaat 1680 gtggtatggc tgattatgat ccggctgcct cgcgcgtttc ggtgatgacg gtgaaaacct 1740 ctgacacatg cagctcccgg agacggtcac agcttgtctg taagcggatg ccgggagcag 1800 acaagcccgt caggcgtcag cgggtgttgg cgggtgtcgg ggcgcagcca tgaggtcgac 1860 tctagaggat cgatgccccg ccccggacga actaaacctg actacgacat ctctgcccct 1920 tcttcgcggg gcagtgcatg taatcccttc agttggttgg tacaacttgc caactgggcc 1980 ctgttccaca tgtgacacgg ggggggacca aacacaaagg ggttctctga ctgtagttga 2040 catccttata aatggatgtg cacatttgcc aacactgagt ggctttcatc ctggagcaga 2100 ctttgcagtc tgtggactgc aacacaacat tgcctttatg tgtaactctt ggctgaagct 2160 cttacaccaa tgctggggga catgtacctc ccaggggccc aggaagacta cgggaggcta 2220 caccaacgtc aatcagaggg gcctgtgtag ctaccgataa gcggaccctc aagagggcat 2280 tagcaatagt gtttataagg cccccttgtt aaccctaaac gggtagcata tgcttcccgg 2340 gtagtagtat atactatcca gactaaccct aattcaatag catatgttac ccaacgggaa 2400 gcatatgcta tcgaattagg gttagtaaaa gggtcctaag gaacagcgat atctcccacc 2460 ccatgagctg tcacggtttt atttacatgg ggtcaggatt ccacgagggt agtgaaccat 2520 tttagtcaca agggcagtgg ctgaagatca aggagcgggc agtgaactct cctgaatctt 2580 cgcctgcttc ttcattctcc ttcgtttagc taatagaata actgctgagt tgtgaacagt 2640 aaggtgtatg tgaggtgctc gaaaacaagg tttcaggtga cgcccccaga ataaaatttg 2700 gacggggggt tcagtggtgg cattgtgcta tgacaccaat ataaccctca caaacccctt 2760 gggcaataaa tactagtgta ggaatgaaac attctgaata tctttaacaa tagaaatcca 2820 tggggtgggg acaagccgta aagactggat gtccatctca cacgaattta tggctatggg 2880 caacacataa tcctagtgca atatgatact ggggttatta agatgtgtcc caggcaggga 2940 ccaagacagg tgaaccatgt tgttacactc tatttgtaac aaggggaaag agagtggacg 3000 ccgacagcag cggactccac tggttgtctc taacaccccc gaaaattaaa cggggctcca 3060 cgccaatggg gcccataaac aaagacaagt ggccactctt ttttttgaaa ttgtggagtg 3120 ggggcacgcg tcagccccca cacgccgccc tgcggttttg gactgtaaaa taagggtgta 3180 ataacttggc tgattgtaac cccgctaacc actgcggtca aaccacttgc ccacaaaacc 3240 actaatggca ccccggggaa tacctgcata agtaggtggg cgggccaaga taggggcgcg 3300 attgctgcga tctggaggac aaattacaca cacttgcgcc tgagcgccaa gcacagggtt 3360 gttggtcctc atattcacga ggtcgctgag agcacggtgg gctaatgttg ccatgggtag 3420 catatactac ccaaatatct ggatagcata tgctatccta atctatatct gggtagcata 3480 ggctatccta atctatatct gggtagcata tgctatccta atctatatct gggtagtata 3540 tgctatccta atttatatct gggtagcata ggctatccta atctatatct gggtagcata 3600 tgctatccta atctatatct gggtagtata tgctatccta atctgtatcc gggtagcata 3660 tgctatccta atagagatta gggtagtata tgctatccta atttatatct gggtagcata 3720 tactacccaa atatctggat agcatatgct atcctaatct atatctgggt agcatatgct 3780 atcctaatct atatctgggt agcataggct atcctaatct atatctgggt agcatatgct 3840 atcctaatct atatctgggt agtatatgct atcctaattt atatctgggt agcataggct 3900 atcctaatct atatctgggt agcatatgct atcctaatct atatctgggt agtatatgct 3960 atcctaatct gtatccgggt agcatatgct atcctcatgc atatacagtc agcatatgat 4020 acccagtagt agagtgggag tgctatcctt tgcatatgcc gccacctccc aagggggcgt 4080 gaattttcgc tgcttgtcct tttcctgctg gttgctccca ttcttaggtg aatttaagga 4140 ggccaggcta aagccgtcgc atgtctgatt gctcaccagg taaatgtcgc taatgttttc 4200 caacgcgaga aggtgttgag cgcggagctg agtgacgtga caacatgggt atgccgaatt 4260 gccccatgtt gggaggacga aaatggtgac aagacagatg gccagaaata caccaacagc 4320 acgcatgatg tctactgggg atttattctt tagtgcgggg gaatacacgg cttttaatac 4380 gattgagggc gtctcctaac aagttacatc actcctgccc ttcctcaccc tcatctccat 4440 cacctccttc atctccgtca tctccgtcat caccctccgc ggcagcccct tccaccatag 4500 gtggaaacca gggaggcaaa tctactccat cgtcaaagct gcacacagtc accctgatat 4560 tgcaggtagg agcgggcttt gtcataacaa ggtccttaat cgcatccttc aaaacctcag 4620 caaatatatg agtttgtaaa aagaccatga aataacagac aatggactcc cttagcgggc 4680 caggttgtgg gccgggtcca ggggccattc caaaggggag acgactcaat ggtgtaagac 4740 gacattgtgg aatagcaagg gcagttcctc gccttaggtt gtaaagggag gtcttactac 4800 ctccatatac gaacacaccg gcgacccaag ttccttcgtc ggtagtcctt tctacgtgac 4860 tcctagccag gagagctctt aaaccttctg caatgttctc aaatttcggg ttggaacctc 4920 cttgaccacg atgctttcca aaccaccctc cttttttgcg cctgcctcca tcaccctgac 4980 cccggggtcc agtgcttggg ccttctcctg ggtcatctgc ggggccctgc tctatcgctc 5040 ccgggggcac gtcaggctca ccatctgggc caccttcttg gtggtattca aaataatcgg 5100 cttcccctac agggtggaaa aatggccttc tacctggagg gggcctgcgc ggtggagacc 5160 cggatgatga tgactgacta ctgggactcc tgggcctctt ttctccacgt ccacgacctc 5220 tccccctggc tctttcacga cttccccccc tggctctttc acgtcctcta ccccggcggc 5280 ctccactacc tcctcgaccc cggcctccac tacctcctcg accccggcct ccactgcctc 5340 ctcgaccccg gcctccacct cctgctcctg cccctcctgc tcctgcccct cctcctgctc 5400 ctgcccctcc tgcccctcct gctcctgccc ctcctgcccc tcctgctcct gcccctcctg 5460 cccctcctgc tcctgcccct cctgcccctc ctcctgctcc tgcccctcct gcccctcctc 5520 ctgctcctgc ccctcctgcc cctcctgctc ctgcccctcc tgcccctcct gctcctgccc 5580 ctcctgcccc tcctgctcct gcccctcctg ctcctgcccc tcctgctcct gcccctcctg 5640 ctcctgcccc tcctgcccct cctgcccctc ctcctgctcc tgcccctcct gctcctgccc 5700 ctcctgcccc tcctgcccct cctgctcctg cccctcctcc tgctcctgcc cctcctgccc 5760 ctcctgcccc tcctcctgct cctgcccctc ctgcccctcc tcctgctcct gcccctcctc 5820 ctgctcctgc ccctcctgcc cctcctgccc ctcctcctgc tcctgcccct cctgcccctc 5880 ctcctgctcc tgcccctcct cctgctcctg cccctcctgc ccctcctgcc cctcctcctg 5940 ctcctgcccc tcctcctgct cctgcccctc ctgcccctcc tgcccctcct gcccctcctc 6000 ctgctcctgc ccctcctcct gctcctgccc ctcctgctcc tgcccctccc gctcctgctc 6060 ctgctcctgt tccaccgtgg gtccctttgc agccaatgca acttggacgt ttttggggtc 6120 tccggacacc atctctatgt cttggccctg atcctgagcc gcccggggct cctggtcttc 6180 cgcctcctcg tcctcgtcct cttccccgtc ctcgtccatg gttatcaccc cctcttcttt 6240 gaggtccact gccgccggag ccttctggtc cagatgtgtc tcccttctct cctaggccat 6300 ttccaggtcc tgtacctggc ccctcgtcag acatgattca cactaaaaga gatcaataga 6360 catctttatt agacgacgct cagtgaatac agggagtgca gactcctgcc ccctccaaca 6420 gcccccccac cctcatcccc ttcatggtcg ctgtcagaca gatccaggtc tgaaaattcc 6480 ccatcctccg aaccatcctc gtcctcatca ccaattactc gcagcccgga aaactcccgc 6540 tgaacatcct caagatttgc gtcctgagcc tcaagccagg cctcaaattc ctcgtccccc 6600 tttttgctgg acggtaggga tggggattct cgggacccct cctcttcctc ttcaaggtca 6660 ccagacagag atgctactgg ggcaacggaa gaaaagctgg gtgcggcctg tgaggatcag 6720 cttatcgatg ataagctgtc aaacatgaga attcttgaag acgaaagggc ctcgtgatac 6780 gcctattttt ataggttaat gtcatgataa taatggtttc ttagacgtca ggtggcactt 6840 ttcggggaaa tgtgcgcgga acccctattt gtttattttt ctaaatacat tcaaatatgt 6900 atccgctcat gagacaataa ccctgataaa tgcttcaata atattgaaaa aggaagagta 6960 tgagtattca acatttccgt gtcgccctta ttcccttttt tgcggcattt tgccttcctg 7020 tttttgctca cccagaaacg ctggtgaaag taaaagatgc tgaagatcag ttgggtgcac 7080 gagtgggtta catcgaactg gatctcaaca gcggtaagat ccttgagagt tttcgccccg 7140 aagaacgttt tccaatgatg agcactttta aagttctgct atgtggcgcg gtattatccc 7200 gtgttgacgc cgggcaagag caactcggtc gccgcataca ctattctcag aatgacttgg 7260 ttgagtactc accagtcaca gaaaagcatc ttacggatgg catgacagta agagaattat 7320 gcagtgctgc cataaccatg agtgataaca ctgcggccaa cttacttctg acaacgatcg 7380 gaggaccgaa ggagctaacc gcttttttgc acaacatggg ggatcatgta actcgccttg 7440 atcgttggga accggagctg aatgaagcca taccaaacga cgagcgtgac accacgatgc 7500 ctgcagcaat ggcaacaacg ttgcgcaaac tattaactgg cgaactactt actctagctt 7560 cccggcaaca attaatagac tggatggagg cggataaagt tgcaggacca cttctgcgct 7620 cggcccttcc ggctggctgg tttattgctg ataaatctgg agccggtgag cgtgggtctc 7680 gcggtatcat tgcagcactg gggccagatg gtaagccctc ccgtatcgta gttatctaca 7740 cgacggggag tcaggcaact atggatgaac gaaatagaca gatcgctgag ataggtgcct 7800 cactgattaa gcattggtaa ctgtcagacc aagtttactc atatatactt tagattgatt 7860 taaaacttca tttttaattt aaaaggatct aggtgaagat cctttttgat aatctcatga 7920 ccaaaatccc ttaacgtgag ttttcgttcc actgagcgtc agaccccgta gaaaagatca 7980 aaggatcttc ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac 8040 caccgctacc agcggtggtt tgtttgccgg atcaagagct accaactctt tttccgaagg 8100 taactggctt cagcagagcg cagataccaa atactgtcct tctagtgtag ccgtagttag 8160 gccaccactt caagaactct gtagcaccgc ctacatacct cgctctgcta atcctgttac 8220 cagtggctgc tgccagtggc gataagtcgt gtcttaccgg gttggactca agacgatagt 8280 taccggataa ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag cccagcttgg 8340 agcgaacgac ctacaccgaa ctgagatacc tacagcgtga gctatgagaa agcgccacgc 8400 ttcccgaagg gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga acaggagagc 8460 gcacgaggga gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc 8520 acctctgact tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa 8580 acgccagcaa cgcggccttt ttacggttcc tggccttttg ctggccttga agctgtccct 8640 gatggtcgtc atctacctgc ctggacagca tggcctgcaa cgcgggcatc ccgatgccgc 8700 cggaagcgag aagaatcata atggggaagg ccatccagcc tcgcgtcgcg aacgccagca 8760 agacgtagcc cagcgcgtcg gccccgagat gcgccgcgtg cggctgctgg agatggcgga 8820 cgcgatggat atgttctgcc aagggttggt ttgcgcattc acagttctcc gcaagaattg 8880 attggctcca attcttggag tggtgaatcc gttagcgagg tgccgccctg cttcatcccc 8940 gtggcccgtt gctcgcgttt gctggcggtg tccccggaag aaatatattt gcatgtcttt 9000 agttctatga tgacacaaac cccgcccagc gtcttgtcat tggcgaattc gaacacgcag 9060 atgcagtcgg ggcggcgcgg tccgaggtcc acttcgcata ttaaggtgac gcgtgtggcc 9120 tcgaacaccg agcgaccctg cagcgacccg cttaacagcg tcaacagcgt gccgcagatc 9180 ccggggggca atgagatatg aaaaagcctg aactcaccgc gacgtctgtc gagaagtttc 9240 tgatcgaaaa gttcgacagc gtctccgacc tgatgcagct ctcggagggc gaagaatctc 9300 gtgctttcag cttcgatgta ggagggcgtg gatatgtcct gcgggtaaat agctgcgccg 9360 atggtttcta caaagatcgt tatgtttatc ggcactttgc atcggccgcg ctcccgattc 9420 cggaagtgct tgacattggg gaattcagcg agagcctgac ctattgcatc tcccgccgtg 9480 cacagggtgt cacgttgcaa gacctgcctg aaaccgaact gcccgctgtt ctgcagccgg 9540 tcgcggaggc catggatgcg atcgctgcgg ccgatcttag ccagacgagc gggttcggcc 9600 cattcggacc gcaaggaatc ggtcaataca ctacatggcg tgatttcata tgcgcgattg 9660 ctgatcccca tgtgtatcac tggcaaactg tgatggacga caccgtcagt gcgtccgtcg 9720 cgcaggctct cgatgagctg atgctttggg ccgaggactg ccccgaagtc cggcacctcg 9780 tgcacgcgga tttcggctcc aacaatgtcc tgacggacaa tggccgcata acagcggtca 9840 ttgactggag cgaggcgatg ttcggggatt cccaatacga ggtcgccaac atcttcttct 9900 ggaggccgtg gttggcttgt atggagcagc agacgcgcta cttcgagcgg aggcatccgg 9960 agcttgcagg atcgccgcgg ctccgggcgt atatgctccg cattggtctt gaccaactct 10020 atcagagctt ggttgacggc aatttcgatg atgcagcttg ggcgcagggt cgatgcgacg 10080 caatcgtccg atccggagcc gggactgtcg ggcgtacaca aatcgcccgc agaagcgcgg 10140 ccgtctggac cgatggctgt gtagaagtac tcgccgatag tggaaaccga cgccccagca 10200 ctcgtccgga tcgggagatg ggggaggcta actgaaacac ggaaggagac aataccggaa 10260 ggaacccgcg ctatgacggc aataaaaaga cagaataaaa cgcacgggtg ttgggtcgtt 10320 tgttcataaa cgcggggttc ggtcccaggg ctggcactct gtcgataccc caccgagacc 10380 ccattggggc caatacgccc gcgtttcttc cttttcccca ccccaccccc caagttcggg 10440 tgaaggccca gggctcgcag ccaacgtcgg ggcggcaggc cctgccatag ccactggccc 10500 cgtgggttag ggacggggtc ccccatgggg aatggtttat ggttcgtggg ggttattatt 10560 ttgggcgttg cgtggggtca ggtccacgac tggactgagc agacagaccc atggtttttg 10620 gatggcctgg gcatggaccg catgtactgg cgcgacacga acaccgggcg tctgtggctg 10680 ccaaacaccc ccgaccccca aaaaccaccg cgcggatttc tggcgtgcca agctagtcga 10740 ccaattctca tgtttgacag cttatcatcg cagatccggg caacgttgtt gccattgctg 10800 caggcgcaga actggtaggt atggaagatc catacattga atcaatattg gcaattagcc 10860 atattagtca ttggttatat agcataaatc aatattggct attggccatt gcatacgttg 10920 tatctatatc ataatatgta catttatatt ggctcatgtc caatatgacc gccat 10975 <210> 159 <211> 10927 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 159 gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60 gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120 ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180 ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240 atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 300 cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 360 tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 420 agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480 tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 540 aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 600 gtcagatcac tagaagctgg gtaccagctg ctagcgttta aacttaagct tagcgcagag 660 gcttggggca gccgagcggc agccaggccc cggcccgggc ctcggttcca gaagggagag 720 gagcccgcca aggcgcgcaa gagagcgggc tgcctcgcag tccgagccgg agagggagcg 780 cgagccgcgc cggccccgga cggcctccga aaccatggag ctgtgggggg cctacctgct 840 gctgtgcctg ttctccctgc tgacccaggt gaccaccgtt gtgaacacaa agatgtttga 900 ggagctcaag agccgtctgg acaccctggc ccaggaggtg gccctgctga aggagcagca 960 ggccctccag acggtctgcc tgaaggggac caaggtgcac atgaaatgct ttctggcctt 1020 cacccagacg aagaccttcc acgaggccag cgaggactgc atctcgcgcg ggggcaccct 1080 gagcacccct cagactggct cggagaacga cgccctgtat gagtacctgc gccagagcgt 1140 gggcaacgag gccgagatct ggctgggcct caacgacatg gcggccgagg gcacctgggt 1200 ggacatgacc ggtacccgca tcgcctacaa gaactgggag actgagatca ccgcgcaacc 1260 cgatggcggc aagaccgaga actgcgcggt cctgtcaggc gcggccaacg gcaagtggtt 1320 cgacaagcgc tgcagggatc aattgcccta catctgccag ttcgggatcg tgcaccacca 1380 ccaccaccac taactcgagg ccggcaaggc cggatccaga catgataaga tacattgatg 1440 agtttggaca aaccacaact agaatgcagt gaaaaaaatg ctttatttgt gaaatttgtg 1500 atgctattgc tttatttgta accattataa gctgcaataa acaagttaac aacaagaatt 1560 gcattcattt tatgtttcag gttcaggggg aggtgtggga ggttttttaa agcaagtaaa 1620 acctctacaa atgtggtatg gctgattatg atccggctgc ctcgcgcgtt tcggtgatga 1680 cggtgaaaac ctctgacaca tgcagctccc ggagacggtc acagcttgtc tgtaagcgga 1740 tgccgggagc agacaagccc gtcaggcgtc agcgggtgtt ggcgggtgtc ggggcgcagc 1800 catgaggtcg actctagagg atcgatgccc cgccccggac gaactaaacc tgactacgac 1860 atctctgccc cttcttcgcg gggcagtgca tgtaatccct tcagttggtt ggtacaactt 1920 gccaactggg ccctgttcca catgtgacac ggggggggac caaacacaaa ggggttctct 1980 gactgtagtt gacatcctta taaatggatg tgcacatttg ccaacactga gtggctttca 2040 tcctggagca gactttgcag tctgtggact gcaacacaac attgccttta tgtgtaactc 2100 ttggctgaag ctcttacacc aatgctgggg gacatgtacc tcccaggggc ccaggaagac 2160 tacgggaggc tacaccaacg tcaatcagag gggcctgtgt agctaccgat aagcggaccc 2220 tcaagagggc attagcaata gtgtttataa ggcccccttg ttaaccctaa acgggtagca 2280 tatgcttccc gggtagtagt atatactatc cagactaacc ctaattcaat agcatatgtt 2340 acccaacggg aagcatatgc tatcgaatta gggttagtaa aagggtccta aggaacagcg 2400 atatctccca ccccatgagc tgtcacggtt ttatttacat ggggtcagga ttccacgagg 2460 gtagtgaacc attttagtca caagggcagt ggctgaagat caaggagcgg gcagtgaact 2520 ctcctgaatc ttcgcctgct tcttcattct ccttcgttta gctaatagaa taactgctga 2580 gttgtgaaca gtaaggtgta tgtgaggtgc tcgaaaacaa ggtttcaggt gacgccccca 2640 gaataaaatt tggacggggg gttcagtggt ggcattgtgc tatgacacca atataaccct 2700 cacaaacccc ttgggcaata aatactagtg taggaatgaa acattctgaa tatctttaac 2760 aatagaaatc catggggtgg ggacaagccg taaagactgg atgtccatct cacacgaatt 2820 tatggctatg ggcaacacat aatcctagtg caatatgata ctggggttat taagatgtgt 2880 cccaggcagg gaccaagaca ggtgaaccat gttgttacac tctatttgta acaaggggaa 2940 agagagtgga cgccgacagc agcggactcc actggttgtc tctaacaccc ccgaaaatta 3000 aacggggctc cacgccaatg gggcccataa acaaagacaa gtggccactc ttttttttga 3060 aattgtggag tgggggcacg cgtcagcccc cacacgccgc cctgcggttt tggactgtaa 3120 aataagggtg taataacttg gctgattgta accccgctaa ccactgcggt caaaccactt 3180 gcccacaaaa ccactaatgg caccccgggg aatacctgca taagtaggtg ggcgggccaa 3240 gataggggcg cgattgctgc gatctggagg acaaattaca cacacttgcg cctgagcgcc 3300 aagcacaggg ttgttggtcc tcatattcac gaggtcgctg agagcacggt gggctaatgt 3360 tgccatgggt agcatatact acccaaatat ctggatagca tatgctatcc taatctatat 3420 ctgggtagca taggctatcc taatctatat ctgggtagca tatgctatcc taatctatat 3480 ctgggtagta tatgctatcc taatttatat ctgggtagca taggctatcc taatctatat 3540 ctgggtagca tatgctatcc taatctatat ctgggtagta tatgctatcc taatctgtat 3600 ccgggtagca tatgctatcc taatagagat tagggtagta tatgctatcc taatttatat 3660 ctgggtagca tatactaccc aaatatctgg atagcatatg ctatcctaat ctatatctgg 3720 gtagcatatg ctatcctaat ctatatctgg gtagcatagg ctatcctaat ctatatctgg 3780 gtagcatatg ctatcctaat ctatatctgg gtagtatatg ctatcctaat ttatatctgg 3840 gtagcatagg ctatcctaat ctatatctgg gtagcatatg ctatcctaat ctatatctgg 3900 gtagtatatg ctatcctaat ctgtatccgg gtagcatatg ctatcctcat gcatatacag 3960 tcagcatatg atacccagta gtagagtggg agtgctatcc tttgcatatg ccgccacctc 4020 ccaagggggc gtgaattttc gctgcttgtc cttttcctgc tggttgctcc cattcttagg 4080 tgaatttaag gaggccaggc taaagccgtc gcatgtctga ttgctcacca ggtaaatgtc 4140 gctaatgttt tccaacgcga gaaggtgttg agcgcggagc tgagtgacgt gacaacatgg 4200 gtatgccgaa ttgccccatg ttgggaggac gaaaatggtg acaagacaga tggccagaaa 4260 tacaccaaca gcacgcatga tgtctactgg ggatttattc tttagtgcgg gggaatacac 4320 ggcttttaat acgattgagg gcgtctccta acaagttaca tcactcctgc ccttcctcac 4380 cctcatctcc atcacctcct tcatctccgt catctccgtc atcaccctcc gcggcagccc 4440 cttccaccat aggtggaaac cagggaggca aatctactcc atcgtcaaag ctgcacacag 4500 tcaccctgat attgcaggta ggagcgggct ttgtcataac aaggtcctta atcgcatcct 4560 tcaaaacctc agcaaatata tgagtttgta aaaagaccat gaaataacag acaatggact 4620 cccttagcgg gccaggttgt gggccgggtc caggggccat tccaaagggg agacgactca 4680 atggtgtaag acgacattgt ggaatagcaa gggcagttcc tcgccttagg ttgtaaaggg 4740 aggtcttact acctccatat acgaacacac cggcgaccca agttccttcg tcggtagtcc 4800 tttctacgtg actcctagcc aggagagctc ttaaaccttc tgcaatgttc tcaaatttcg 4860 ggttggaacc tccttgacca cgatgctttc caaaccaccc tccttttttg cgcctgcctc 4920 catcaccctg accccggggt ccagtgcttg ggccttctcc tgggtcatct gcggggccct 4980 gctctatcgc tcccgggggc acgtcaggct caccatctgg gccaccttct tggtggtatt 5040 caaaataatc ggcttcccct acagggtgga aaaatggcct tctacctgga gggggcctgc 5100 gcggtggaga cccggatgat gatgactgac tactgggact cctgggcctc ttttctccac 5160 gtccacgacc tctccccctg gctctttcac gacttccccc cctggctctt tcacgtcctc 5220 taccccggcg gcctccacta cctcctcgac cccggcctcc actacctcct cgaccccggc 5280 ctccactgcc tcctcgaccc cggcctccac ctcctgctcc tgcccctcct gctcctgccc 5340 ctcctcctgc tcctgcccct cctgcccctc ctgctcctgc ccctcctgcc cctcctgctc 5400 ctgcccctcc tgcccctcct gctcctgccc ctcctgcccc tcctcctgct cctgcccctc 5460 ctgcccctcc tcctgctcct gcccctcctg cccctcctgc tcctgcccct cctgcccctc 5520 ctgctcctgc ccctcctgcc cctcctgctc ctgcccctcc tgctcctgcc cctcctgctc 5580 ctgcccctcc tgctcctgcc cctcctgccc ctcctgcccc tcctcctgct cctgcccctc 5640 ctgctcctgc ccctcctgcc cctcctgccc ctcctgctcc tgcccctcct cctgctcctg 5700 cccctcctgc ccctcctgcc cctcctcctg ctcctgcccc tcctgcccct cctcctgctc 5760 ctgcccctcc tcctgctcct gcccctcctg cccctcctgc ccctcctcct gctcctgccc 5820 ctcctgcccc tcctcctgct cctgcccctc ctcctgctcc tgcccctcct gcccctcctg 5880 cccctcctcc tgctcctgcc cctcctcctg ctcctgcccc tcctgcccct cctgcccctc 5940 ctgcccctcc tcctgctcct gcccctcctc ctgctcctgc ccctcctgct cctgcccctc 6000 ccgctcctgc tcctgctcct gttccaccgt gggtcccttt gcagccaatg caacttggac 6060 gtttttgggg tctccggaca ccatctctat gtcttggccc tgatcctgag ccgcccgggg 6120 ctcctggtct tccgcctcct cgtcctcgtc ctcttccccg tcctcgtcca tggttatcac 6180 cccctcttct ttgaggtcca ctgccgccgg agccttctgg tccagatgtg tctcccttct 6240 ctcctaggcc atttccaggt cctgtacctg gcccctcgtc agacatgatt cacactaaaa 6300 gagatcaata gacatcttta ttagacgacg ctcagtgaat acagggagtg cagactcctg 6360 ccccctccaa cagccccccc accctcatcc ccttcatggt cgctgtcaga cagatccagg 6420 tctgaaaatt ccccatcctc cgaaccatcc tcgtcctcat caccaattac tcgcagcccg 6480 gaaaactccc gctgaacatc ctcaagattt gcgtcctgag cctcaagcca ggcctcaaat 6540 tcctcgtccc cctttttgct ggacggtagg gatggggatt ctcgggaccc ctcctcttcc 6600 tcttcaaggt caccagacag agatgctact ggggcaacgg aagaaaagct gggtgcggcc 6660 tgtgaggatc agcttatcga tgataagctg tcaaacatga gaattcttga agacgaaagg 6720 gcctcgtgat acgcctattt ttataggtta atgtcatgat aataatggtt tcttagacgt 6780 caggtggcac ttttcgggga aatgtgcgcg gaacccctat ttgtttattt ttctaaatac 6840 attcaaatat gtatccgctc atgagacaat aaccctgata aatgcttcaa taatattgaa 6900 aaaggaagag tatgagtatt caacatttcc gtgtcgccct tattcccttt tttgcggcat 6960 tttgccttcc tgtttttgct cacccagaaa cgctggtgaa agtaaaagat gctgaagatc 7020 agttgggtgc acgagtgggt tacatcgaac tggatctcaa cagcggtaag atccttgaga 7080 gttttcgccc cgaagaacgt tttccaatga tgagcacttt taaagttctg ctatgtggcg 7140 cggtattatc ccgtgttgac gccgggcaag agcaactcgg tcgccgcata cactattctc 7200 agaatgactt ggttgagtac tcaccagtca cagaaaagca tcttacggat ggcatgacag 7260 taagagaatt atgcagtgct gccataacca tgagtgataa cactgcggcc aacttacttc 7320 tgacaacgat cggaggaccg aaggagctaa ccgctttttt gcacaacatg ggggatcatg 7380 taactcgcct tgatcgttgg gaaccggagc tgaatgaagc cataccaaac gacgagcgtg 7440 acaccacgat gcctgcagca atggcaacaa cgttgcgcaa actattaact ggcgaactac 7500 ttactctagc ttcccggcaa caattaatag actggatgga ggcggataaa gttgcaggac 7560 cacttctgcg ctcggccctt ccggctggct ggtttattgc tgataaatct ggagccggtg 7620 agcgtgggtc tcgcggtatc attgcagcac tggggccaga tggtaagccc tcccgtatcg 7680 tagttatcta cacgacgggg agtcaggcaa ctatggatga acgaaataga cagatcgctg 7740 agataggtgc ctcactgatt aagcattggt aactgtcaga ccaagtttac tcatatatac 7800 tttagattga tttaaaactt catttttaat ttaaaaggat ctaggtgaag atcctttttg 7860 ataatctcat gaccaaaatc ccttaacgtg agttttcgtt ccactgagcg tcagaccccg 7920 tagaaaagat caaaggatct tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc 7980 aaacaaaaaa accaccgcta ccagcggtgg tttgtttgcc ggatcaagag ctaccaactc 8040 tttttccgaa ggtaactggc ttcagcagag cgcagatacc aaatactgtc cttctagtgt 8100 agccgtagtt aggccaccac ttcaagaact ctgtagcacc gcctacatac ctcgctctgc 8160 taatcctgtt accagtggct gctgccagtg gcgataagtc gtgtcttacc gggttggact 8220 caagacgata gttaccggat aaggcgcagc ggtcgggctg aacggggggt tcgtgcacac 8280 agcccagctt ggagcgaacg acctacaccg aactgagata cctacagcgt gagctatgag 8340 aaagcgccac gcttcccgaa gggagaaagg cggacaggta tccggtaagc ggcagggtcg 8400 gaacaggaga gcgcacgagg gagcttccag ggggaaacgc ctggtatctt tatagtcctg 8460 tcgggtttcg ccacctctga cttgagcgtc gatttttgtg atgctcgtca ggggggcgga 8520 gcctatggaa aaacgccagc aacgcggcct ttttacggtt cctggccttt tgctggcctt 8580 gaagctgtcc ctgatggtcg tcatctacct gcctggacag catggcctgc aacgcgggca 8640 tcccgatgcc gccggaagcg agaagaatca taatggggaa ggccatccag cctcgcgtcg 8700 cgaacgccag caagacgtag cccagcgcgt cggccccgag atgcgccgcg tgcggctgct 8760 ggagatggcg gacgcgatgg atatgttctg ccaagggttg gtttgcgcat tcacagttct 8820 ccgcaagaat tgattggctc caattcttgg agtggtgaat ccgttagcga ggtgccgccc 8880 tgcttcatcc ccgtggcccg ttgctcgcgt ttgctggcgg tgtccccgga agaaatatat 8940 ttgcatgtct ttagttctat gatgacacaa accccgccca gcgtcttgtc attggcgaat 9000 tcgaacacgc agatgcagtc ggggcggcgc ggtccgaggt ccacttcgca tattaaggtg 9060 acgcgtgtgg cctcgaacac cgagcgaccc tgcagcgacc cgcttaacag cgtcaacagc 9120 gtgccgcaga tcccgggggg caatgagata tgaaaaagcc tgaactcacc gcgacgtctg 9180 tcgagaagtt tctgatcgaa aagttcgaca gcgtctccga cctgatgcag ctctcggagg 9240 gcgaagaatc tcgtgctttc agcttcgatg taggagggcg tggatatgtc ctgcgggtaa 9300 atagctgcgc cgatggtttc tacaaagatc gttatgttta tcggcacttt gcatcggccg 9360 cgctcccgat tccggaagtg cttgacattg gggaattcag cgagagcctg acctattgca 9420 tctcccgccg tgcacagggt gtcacgttgc aagacctgcc tgaaaccgaa ctgcccgctg 9480 ttctgcagcc ggtcgcggag gccatggatg cgatcgctgc ggccgatctt agccagacga 9540 gcgggttcgg cccattcgga ccgcaaggaa tcggtcaata cactacatgg cgtgatttca 9600 tatgcgcgat tgctgatccc catgtgtatc actggcaaac tgtgatggac gacaccgtca 9660 gtgcgtccgt cgcgcaggct ctcgatgagc tgatgctttg ggccgaggac tgccccgaag 9720 tccggcacct cgtgcacgcg gatttcggct ccaacaatgt cctgacggac aatggccgca 9780 taacagcggt cattgactgg agcgaggcga tgttcgggga ttcccaatac gaggtcgcca 9840 acatcttctt ctggaggccg tggttggctt gtatggagca gcagacgcgc tacttcgagc 9900 ggaggcatcc ggagcttgca ggatcgccgc ggctccgggc gtatatgctc cgcattggtc 9960 ttgaccaact ctatcagagc ttggttgacg gcaatttcga tgatgcagct tgggcgcagg 10020 gtcgatgcga cgcaatcgtc cgatccggag ccgggactgt cgggcgtaca caaatcgccc 10080 gcagaagcgc ggccgtctgg accgatggct gtgtagaagt actcgccgat agtggaaacc 10140 gacgccccag cactcgtccg gatcgggaga tgggggaggc taactgaaac acggaaggag 10200 acaataccgg aaggaacccg cgctatgacg gcaataaaaa gacagaataa aacgcacggg 10260 tgttgggtcg tttgttcata aacgcggggt tcggtcccag ggctggcact ctgtcgatac 10320 cccaccgaga ccccattggg gccaatacgc ccgcgtttct tccttttccc caccccaccc 10380 cccaagttcg ggtgaaggcc cagggctcgc agccaacgtc ggggcggcag gccctgccat 10440 agccactggc cccgtgggtt agggacgggg tcccccatgg ggaatggttt atggttcgtg 10500 ggggttatta ttttgggcgt tgcgtggggt caggtccacg actggactga gcagacagac 10560 ccatggtttt tggatggcct gggcatggac cgcatgtact ggcgcgacac gaacaccggg 10620 cgtctgtggc tgccaaacac ccccgacccc caaaaaccac cgcgcggatt tctggcgtgc 10680 caagctagtc gaccaattct catgtttgac agcttatcat cgcagatccg ggcaacgttg 10740 ttgccattgc tgcaggcgca gaactggtag gtatggaaga tccatacatt gaatcaatat 10800 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 10860 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 10920 ccgccat 10927 <210> 160 <211> 4641 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 160 aagaaaccaa ttgtccatat tgcatcagac attgccgtca ctgcgtcttt tactggctct 60 tctcgctaac caaaccggta accccgctta ttaaaagcat tctgtaacaa agcgggacca 120 aagccatgac aaaaacgcgt aacaaaagtg tctataatca cggcagaaaa gtccacattg 180 attatttgca cggcgtcaca ctttgctatg ccatagcatt tttatccata agattagcgg 240 atcctacctg acgcttttta tcgcaactct ctactgtttc tccatacccg ttttttgggc 300 taacaggagg aattcaccat gaaaaagaca gctatcgcga ttgcagtggc actggctggt 360 ttcgctaccg ttgcgcaagc ttctgagcca ccaacccaga agcccaagaa gattgtaaat 420 gccaagaaag atgttgtgaa cacaaagatg tttgaggagc tcaagagccg tctggacacc 480 ctggcccagg aggtggccct gctgaaggag cagcaggccc tccagacggt ctgcctgaag 540 gggaccaagg tgcacatgaa atgctttctg gccttcaccc agacgaagac cttccacgag 600 gccagcgagg actgcatctc gcgcgggggc accctgagca cccctcagac tggctcggag 660 aacgacgccc tgtatgagta cctgcgccag agcgtgggca acgaggccga gatctggctg 720 ggcctcaacg acatggcggc cgagggcacc tgggtggaca tgaccggtac ccgcatcgcc 780 tacaagaact gggagactga gatcaccgcg caacccgatg gcggcaagac cgagaactgc 840 gcggtcctgt caggcgcggc caacggcaag tggttcgaca agcgctgcag ggatcaattg 900 ccctacatct gccagttcgg gatcgtgtac ccctacgacg tgcccgacta cgccggttgg 960 agccacccgc agttcgaaaa ataactcgag ataaacggtc tccagcttgg ctgttttggc 1020 ggatgagaga agattttcag cctgatacag attaaatcag aacgcagaag cggtctgata 1080 aaacagaatt tgcctggcgg cagtagcgcg gtggtcccac ctgaccccat gccgaactca 1140 gaagtgaaac gccgtagcgc cgatggtagt gtggggtctc cccatgcgag agtagggaac 1200 tgccaggcat caaataaaac gaaaggctca gtcgaaagac tgggcctttc gttttatctg 1260 ttgtttgtcg gtgaacgctc tcctgagtag gacaaatccg ccgggagcgg atttgaacgt 1320 tgcgaagcaa cggcccggag ggtggcgggc aggacgcccg ccataaactg ccaggcatca 1380 aattaagcag aaggccatcc tgacggatgg cctttttgcg tttctacaaa ctctttttgt 1440 ttatttttct aaatacattc aaatatgtat ccgctcatga gacaataacc ctgataaatg 1500 cttcaataat attgaaaaag gaagagtatg agtattcaac atttccgtgt cgcccttatt 1560 cccttttttg cggcattttg ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta 1620 aaagatgctg aagatcagtt gggtgcacga gtgggttaca tcgaactgga tctcaacagc 1680 ggtaagatcc ttgagagttt tcgccccgaa gaacgttttc caatgatgag cacttttaaa 1740 gttctgctat gtggcgcggt attatcccgt gttgacgccg ggcaagagca actcggtcgc 1800 cgcatacact attctcagaa tgacttggtt gagtactcac cagtcacaga aaagcatctt 1860 acggatggca tgacagtaag agaattatgc agtgctgcca taaccatgag tgataacact 1920 gcggccaact tacttctgac aacgatcgga ggaccgaagg agctaaccgc ttttttgcac 1980 aacatggggg atcatgtaac tcgccttgat cgttgggaac cggagctgaa tgaagccata 2040 ccaaacgacg agcgtgacac cacgatgcct gtagcaatgg caacaacgtt gcgcaaacta 2100 ttaactggcg aactacttac tctagcttcc cggcaacaat taatagactg gatggaggcg 2160 gataaagttg caggaccact tctgcgctcg gcccttccgg ctggctggtt tattgctgat 2220 aaatctggag ccggtgagcg tgggtctcgc ggtatcattg cagcactggg gccagatggt 2280 aagccctccc gtatcgtagt tatctacacg acggggagtc aggcaactat ggatgaacga 2340 aatagacaga tcgctgagat aggtgcctca ctgattaagc attggtaact gtcagaccaa 2400 gtttactcat atatacttta gattgattta aaacttcatt tttaatttaa aaggatctag 2460 gtgaagatcc tttttgataa tctcatgacc aaaatccctt aacgtgagtt ttcgttccac 2520 tgagcgtcag accccgtaga aaagatcaaa ggatcttctt gagatccttt ttttctgcgc 2580 gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag cggtggtttg tttgccggat 2640 caagagctac caactctttt tccgaaggta actggcttca gcagagcgca gataccaaat 2700 actgtccttc tagtgtagcc gtagttaggc caccacttca agaactctgt agcaccgcct 2760 acatacctcg ctctgctaat cctgttacca gtggctgctg ccagtggcga taagtcgtgt 2820 cttaccgggt tggactcaag acgatagtta ccggataagg cgcagcggtc gggctgaacg 2880 gggggttcgt gcacacagcc cagcttggag cgaacgacct acaccgaact gagataccta 2940 cagcgtgagc tatgagaaag cgccacgctt cccgaaggga gaaaggcgga caggtatccg 3000 gtaagcggca gggtcggaac aggagagcgc acgagggagc ttccaggggg aaacgcctgg 3060 tatctttata gtcctgtcgg gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc 3120 tcgtcagggg ggcggagcct atggaaaaac gccagcaacg cggccttttt acggttcctg 3180 gccttttgct ggccttttgc tcacatgttc tttcctgcgt tatcccctga ttctgtggat 3240 aaccgtatta ccgcctttga gtgagctgat accgctcgcc gcagccgaac gaccgagcgc 3300 agcgagtcag tgagcgagga agcggaagag cgcctgatgc ggtattttct ccttacgcat 3360 ctgtgcggta tttcacaccg catatggtgc actctcagta caatctgctc tgatgccgca 3420 tagttaagcc agtatacact ccgctatcgc tacgtgactg ggtcatggct gcgccccgac 3480 acccgccaac acccgctgac gcgccctgac gggcttgtct gctcccggca tccgcttaca 3540 gacaagctgt gaccgtctcc gggagctgca tgtgtcagag gttttcaccg tcatcaccga 3600 aacgcgcgag gcagcagatc aattcgcgcg cgaaggcgaa gcggcatgca taatgtgcct 3660 gtcaaatgga cgaagcaggg attctgcaaa ccctatgcta ctccgtcaag ccgtcaattg 3720 tctgattcgt taccaattat gacaacttga cggctacatc attcactttt tcttcacaac 3780 cggcacggaa ctcgctcggg ctggccccgg tgcatttttt aaatacccgc gagaaataga 3840 gttgatcgtc aaaaccaaca ttgcgaccga cggtggcgat aggcatccgg gtggtgctca 3900 aaagcagctt cgcctggctg atacgttggt cctcgcgcca gcttaagacg ctaatcccta 3960 actgctggcg gaaaagatgt gacagacgcg acggcgacaa gcaaacatgc tgtgcgacgc 4020 tggcgatatc aaaattgctg tctgccaggt gatcgctgat gtactgacaa gcctcgcgta 4080 cccgattatc catcggtgga tggagcgact cgttaatcgc ttccatgcgc cgcagtaaca 4140 attgctcaag cagatttatc gccagcagct ccgaatagcg cccttcccct tgcccggcgt 4200 taatgatttg cccaaacagg tcgctgaaat gcggctggtg cgcttcatcc gggcgaaaga 4260 accccgtatt ggcaaatatt gacggccagt taagccattc atgccagtag gcgcgcggac 4320 gaaagtaaac ccactggtga taccattcgc gagcctccgg atgacgaccg tagtgatgaa 4380 tctctcctgg cgggaacagc aaaatatcac ccggtcggca aacaaattct cgtccctgat 4440 ttttcaccac cccctgaccg cgaatggtga gattgagaat ataacctttc attcccagcg 4500 gtcggtcgat aaaaaaatcg agataaccgt tggcctcaat cggcgttaaa cccgccacca 4560 gatgggcatt aaacgagtat cccggcagca ggggatcatt ttgcgcttca gccatacttt 4620 tcatactccc gccattcaga g 4641 <210> 161 <211> 11011 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 161 gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60 gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120 ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180 ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240 atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 300 cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 360 tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 420 agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480 tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 540 aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 600 gtcagatcac tagaagctgg gtaccagctg ctagcgttta aacttaagct tagcgcagag 660 gcttggggca gccgagcggc agccaggccc cggcccgggc ctcggttcca gaagggagag 720 gagcccgcca aggcgcgcaa gagagcgggc tgcctcgcag tccgagccgg agagggagcg 780 cgagccgcgc cggccccgga cggcctccga aaccatggag ctgtgggggg cctacctgct 840 gctgtgcctg ttctccctgc tgacccaggt gaccaccgag ccaccaaccc agaagcccaa 900 gaagattgta aatgccaaga aagatgttgt gaacacaaag atgtttgagg agctcaagag 960 ccgtctggac accctggccc aggaggtggc cctgctgaag gagcagcagg ccctccagac 1020 ggtctgcctg aaggggacca aggtgcacat gaaatgcttt ctggccttca cccagacgaa 1080 gaccttccac gaggccagcg aggactgcat ctcgcgcggg ggcaccctga gcacccctca 1140 gactggctcg gagaacgacg ccctgtatga gtacctgcgc cagagcgtgg gcaacgaggc 1200 cgagatctgg ctgggcctca acgacatggc ggccgagggc acctgggtgg acatgaccgg 1260 tacccgcatc gcctacaaga actgggagac tgagatcacc gcgcaacccg atggcggcaa 1320 gaccgagaac tgcgcggtcc tgtcaggcgc ggccaacggc aagtggttcg acaagcgctg 1380 cagggatcaa ttgccctaca tctgccagtt cgggatcgtg tacccctacg acgtgcccga 1440 ctacgccggt tggagccacc cccagttcga gaagtgactc gaggccggca aggccggatc 1500 cagacatgat aagatacatt gatgagtttg gacaaaccac aactagaatg cagtgaaaaa 1560 aatgctttat ttgtgaaatt tgtgatgcta ttgctttatt tgtaaccatt ataagctgca 1620 ataaacaagt taacaacaag aattgcattc attttatgtt tcaggttcag ggggaggtgt 1680 gggaggtttt ttaaagcaag taaaacctct acaaatgtgg tatggctgat tatgatccgg 1740 ctgcctcgcg cgtttcggtg atgacggtga aaacctctga cacatgcagc tcccggagac 1800 ggtcacagct tgtctgtaag cggatgccgg gagcagacaa gcccgtcagg cgtcagcggg 1860 tgttggcggg tgtcggggcg cagccatgag gtcgactcta gaggatcgat gccccgcccc 1920 ggacgaacta aacctgacta cgacatctct gccccttctt cgcggggcag tgcatgtaat 1980 cccttcagtt ggttggtaca acttgccaac tgggccctgt tccacatgtg acacgggggg 2040 ggaccaaaca caaaggggtt ctctgactgt agttgacatc cttataaatg gatgtgcaca 2100 tttgccaaca ctgagtggct ttcatcctgg agcagacttt gcagtctgtg gactgcaaca 2160 caacattgcc tttatgtgta actcttggct gaagctctta caccaatgct gggggacatg 2220 tacctcccag gggcccagga agactacggg aggctacacc aacgtcaatc agaggggcct 2280 gtgtagctac cgataagcgg accctcaaga gggcattagc aatagtgttt ataaggcccc 2340 cttgttaacc ctaaacgggt agcatatgct tcccgggtag tagtatatac tatccagact 2400 aaccctaatt caatagcata tgttacccaa cgggaagcat atgctatcga attagggtta 2460 gtaaaagggt cctaaggaac agcgatatct cccaccccat gagctgtcac ggttttattt 2520 acatggggtc aggattccac gagggtagtg aaccatttta gtcacaaggg cagtggctga 2580 agatcaagga gcgggcagtg aactctcctg aatcttcgcc tgcttcttca ttctccttcg 2640 tttagctaat agaataactg ctgagttgtg aacagtaagg tgtatgtgag gtgctcgaaa 2700 acaaggtttc aggtgacgcc cccagaataa aatttggacg gggggttcag tggtggcatt 2760 gtgctatgac accaatataa ccctcacaaa ccccttgggc aataaatact agtgtaggaa 2820 tgaaacattc tgaatatctt taacaataga aatccatggg gtggggacaa gccgtaaaga 2880 ctggatgtcc atctcacacg aatttatggc tatgggcaac acataatcct agtgcaatat 2940 gatactgggg ttattaagat gtgtcccagg cagggaccaa gacaggtgaa ccatgttgtt 3000 acactctatt tgtaacaagg ggaaagagag tggacgccga cagcagcgga ctccactggt 3060 tgtctctaac acccccgaaa attaaacggg gctccacgcc aatggggccc ataaacaaag 3120 acaagtggcc actctttttt ttgaaattgt ggagtggggg cacgcgtcag cccccacacg 3180 ccgccctgcg gttttggact gtaaaataag ggtgtaataa cttggctgat tgtaaccccg 3240 ctaaccactg cggtcaaacc acttgcccac aaaaccacta atggcacccc ggggaatacc 3300 tgcataagta ggtgggcggg ccaagatagg ggcgcgattg ctgcgatctg gaggacaaat 3360 tacacacact tgcgcctgag cgccaagcac agggttgttg gtcctcatat tcacgaggtc 3420 gctgagagca cggtgggcta atgttgccat gggtagcata tactacccaa atatctggat 3480 agcatatgct atcctaatct atatctgggt agcataggct atcctaatct atatctgggt 3540 agcatatgct atcctaatct atatctgggt agtatatgct atcctaattt atatctgggt 3600 agcataggct atcctaatct atatctgggt agcatatgct atcctaatct atatctgggt 3660 agtatatgct atcctaatct gtatccgggt agcatatgct atcctaatag agattagggt 3720 agtatatgct atcctaattt atatctgggt agcatatact acccaaatat ctggatagca 3780 tatgctatcc taatctatat ctgggtagca tatgctatcc taatctatat ctgggtagca 3840 taggctatcc taatctatat ctgggtagca tatgctatcc taatctatat ctgggtagta 3900 tatgctatcc taatttatat ctgggtagca taggctatcc taatctatat ctgggtagca 3960 tatgctatcc taatctatat ctgggtagta tatgctatcc taatctgtat ccgggtagca 4020 tatgctatcc tcatgcatat acagtcagca tatgataccc agtagtagag tgggagtgct 4080 atcctttgca tatgccgcca cctcccaagg gggcgtgaat tttcgctgct tgtccttttc 4140 ctgctggttg ctcccattct taggtgaatt taaggaggcc aggctaaagc cgtcgcatgt 4200 ctgattgctc accaggtaaa tgtcgctaat gttttccaac gcgagaaggt gttgagcgcg 4260 gagctgagtg acgtgacaac atgggtatgc cgaattgccc catgttggga ggacgaaaat 4320 ggtgacaaga cagatggcca gaaatacacc aacagcacgc atgatgtcta ctggggattt 4380 attctttagt gcgggggaat acacggcttt taatacgatt gagggcgtct cctaacaagt 4440 tacatcactc ctgcccttcc tcaccctcat ctccatcacc tccttcatct ccgtcatctc 4500 cgtcatcacc ctccgcggca gccccttcca ccataggtgg aaaccaggga ggcaaatcta 4560 ctccatcgtc aaagctgcac acagtcaccc tgatattgca ggtaggagcg ggctttgtca 4620 taacaaggtc cttaatcgca tccttcaaaa cctcagcaaa tatatgagtt tgtaaaaaga 4680 ccatgaaata acagacaatg gactccctta gcgggccagg ttgtgggccg ggtccagggg 4740 ccattccaaa ggggagacga ctcaatggtg taagacgaca ttgtggaata gcaagggcag 4800 ttcctcgcct taggttgtaa agggaggtct tactacctcc atatacgaac acaccggcga 4860 cccaagttcc ttcgtcggta gtcctttcta cgtgactcct agccaggaga gctcttaaac 4920 cttctgcaat gttctcaaat ttcgggttgg aacctccttg accacgatgc tttccaaacc 4980 accctccttt tttgcgcctg cctccatcac cctgaccccg gggtccagtg cttgggcctt 5040 ctcctgggtc atctgcgggg ccctgctcta tcgctcccgg gggcacgtca ggctcaccat 5100 ctgggccacc ttcttggtgg tattcaaaat aatcggcttc ccctacaggg tggaaaaatg 5160 gccttctacc tggagggggc ctgcgcggtg gagacccgga tgatgatgac tgactactgg 5220 gactcctggg cctcttttct ccacgtccac gacctctccc cctggctctt tcacgacttc 5280 cccccctggc tctttcacgt cctctacccc ggcggcctcc actacctcct cgaccccggc 5340 ctccactacc tcctcgaccc cggcctccac tgcctcctcg accccggcct ccacctcctg 5400 ctcctgcccc tcctgctcct gcccctcctc ctgctcctgc ccctcctgcc cctcctgctc 5460 ctgcccctcc tgcccctcct gctcctgccc ctcctgcccc tcctgctcct gcccctcctg 5520 cccctcctcc tgctcctgcc cctcctgccc ctcctcctgc tcctgcccct cctgcccctc 5580 ctgctcctgc ccctcctgcc cctcctgctc ctgcccctcc tgcccctcct gctcctgccc 5640 ctcctgctcc tgcccctcct gctcctgccc ctcctgctcc tgcccctcct gcccctcctg 5700 cccctcctcc tgctcctgcc cctcctgctc ctgcccctcc tgcccctcct gcccctcctg 5760 ctcctgcccc tcctcctgct cctgcccctc ctgcccctcc tgcccctcct cctgctcctg 5820 cccctcctgc ccctcctcct gctcctgccc ctcctcctgc tcctgcccct cctgcccctc 5880 ctgcccctcc tcctgctcct gcccctcctg cccctcctcc tgctcctgcc cctcctcctg 5940 ctcctgcccc tcctgcccct cctgcccctc ctcctgctcc tgcccctcct cctgctcctg 6000 cccctcctgc ccctcctgcc cctcctgccc ctcctcctgc tcctgcccct cctcctgctc 6060 ctgcccctcc tgctcctgcc cctcccgctc ctgctcctgc tcctgttcca ccgtgggtcc 6120 ctttgcagcc aatgcaactt ggacgttttt ggggtctccg gacaccatct ctatgtcttg 6180 gccctgatcc tgagccgccc ggggctcctg gtcttccgcc tcctcgtcct cgtcctcttc 6240 cccgtcctcg tccatggtta tcaccccctc ttctttgagg tccactgccg ccggagcctt 6300 ctggtccaga tgtgtctccc ttctctccta ggccatttcc aggtcctgta cctggcccct 6360 cgtcagacat gattcacact aaaagagatc aatagacatc tttattagac gacgctcagt 6420 gaatacaggg agtgcagact cctgccccct ccaacagccc ccccaccctc atccccttca 6480 tggtcgctgt cagacagatc caggtctgaa aattccccat cctccgaacc atcctcgtcc 6540 tcatcaccaa ttactcgcag cccggaaaac tcccgctgaa catcctcaag atttgcgtcc 6600 tgagcctcaa gccaggcctc aaattcctcg tccccctttt tgctggacgg tagggatggg 6660 gattctcggg acccctcctc ttcctcttca aggtcaccag acagagatgc tactggggca 6720 acggaagaaa agctgggtgc ggcctgtgag gatcagctta tcgatgataa gctgtcaaac 6780 atgagaattc ttgaagacga aagggcctcg tgatacgcct atttttatag gttaatgtca 6840 tgataataat ggtttcttag acgtcaggtg gcacttttcg gggaaatgtg cgcggaaccc 6900 ctatttgttt atttttctaa atacattcaa atatgtatcc gctcatgaga caataaccct 6960 gataaatgct tcaataatat tgaaaaagga agagtatgag tattcaacat ttccgtgtcg 7020 cccttattcc cttttttgcg gcattttgcc ttcctgtttt tgctcaccca gaaacgctgg 7080 tgaaagtaaa agatgctgaa gatcagttgg gtgcacgagt gggttacatc gaactggatc 7140 tcaacagcgg taagatcctt gagagttttc gccccgaaga acgttttcca atgatgagca 7200 cttttaaagt tctgctatgt ggcgcggtat tatcccgtgt tgacgccggg caagagcaac 7260 tcggtcgccg catacactat tctcagaatg acttggttga gtactcacca gtcacagaaa 7320 agcatcttac ggatggcatg acagtaagag aattatgcag tgctgccata accatgagtg 7380 ataacactgc ggccaactta cttctgacaa cgatcggagg accgaaggag ctaaccgctt 7440 ttttgcacaa catgggggat catgtaactc gccttgatcg ttgggaaccg gagctgaatg 7500 aagccatacc aaacgacgag cgtgacacca cgatgcctgc agcaatggca acaacgttgc 7560 gcaaactatt aactggcgaa ctacttactc tagcttcccg gcaacaatta atagactgga 7620 tggaggcgga taaagttgca ggaccacttc tgcgctcggc ccttccggct ggctggttta 7680 ttgctgataa atctggagcc ggtgagcgtg ggtctcgcgg tatcattgca gcactggggc 7740 cagatggtaa gccctcccgt atcgtagtta tctacacgac ggggagtcag gcaactatgg 7800 atgaacgaaa tagacagatc gctgagatag gtgcctcact gattaagcat tggtaactgt 7860 cagaccaagt ttactcatat atactttaga ttgatttaaa acttcatttt taatttaaaa 7920 ggatctaggt gaagatcctt tttgataatc tcatgaccaa aatcccttaa cgtgagtttt 7980 cgttccactg agcgtcagac cccgtagaaa agatcaaagg atcttcttga gatccttttt 8040 ttctgcgcgt aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg gtggtttgtt 8100 tgccggatca agagctacca actctttttc cgaaggtaac tggcttcagc agagcgcaga 8160 taccaaatac tgtccttcta gtgtagccgt agttaggcca ccacttcaag aactctgtag 8220 caccgcctac atacctcgct ctgctaatcc tgttaccagt ggctgctgcc agtggcgata 8280 agtcgtgtct taccgggttg gactcaagac gatagttacc ggataaggcg cagcggtcgg 8340 gctgaacggg gggttcgtgc acacagccca gcttggagcg aacgacctac accgaactga 8400 gatacctaca gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga aaggcggaca 8460 ggtatccggt aagcggcagg gtcggaacag gagagcgcac gagggagctt ccagggggaa 8520 acgcctggta tctttatagt cctgtcgggt ttcgccacct ctgacttgag cgtcgatttt 8580 tgtgatgctc gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg gcctttttac 8640 ggttcctggc cttttgctgg ccttgaagct gtccctgatg gtcgtcatct acctgcctgg 8700 acagcatggc ctgcaacgcg ggcatcccga tgccgccgga agcgagaaga atcataatgg 8760 ggaaggccat ccagcctcgc gtcgcgaacg ccagcaagac gtagcccagc gcgtcggccc 8820 cgagatgcgc cgcgtgcggc tgctggagat ggcggacgcg atggatatgt tctgccaagg 8880 gttggtttgc gcattcacag ttctccgcaa gaattgattg gctccaattc ttggagtggt 8940 gaatccgtta gcgaggtgcc gccctgcttc atccccgtgg cccgttgctc gcgtttgctg 9000 gcggtgtccc cggaagaaat atatttgcat gtctttagtt ctatgatgac acaaaccccg 9060 cccagcgtct tgtcattggc gaattcgaac acgcagatgc agtcggggcg gcgcggtccg 9120 aggtccactt cgcatattaa ggtgacgcgt gtggcctcga acaccgagcg accctgcagc 9180 gacccgctta acagcgtcaa cagcgtgccg cagatcccgg ggggcaatga gatatgaaaa 9240 agcctgaact caccgcgacg tctgtcgaga agtttctgat cgaaaagttc gacagcgtct 9300 ccgacctgat gcagctctcg gagggcgaag aatctcgtgc tttcagcttc gatgtaggag 9360 ggcgtggata tgtcctgcgg gtaaatagct gcgccgatgg tttctacaaa gatcgttatg 9420 tttatcggca ctttgcatcg gccgcgctcc cgattccgga agtgcttgac attggggaat 9480 tcagcgagag cctgacctat tgcatctccc gccgtgcaca gggtgtcacg ttgcaagacc 9540 tgcctgaaac cgaactgccc gctgttctgc agccggtcgc ggaggccatg gatgcgatcg 9600 ctgcggccga tcttagccag acgagcgggt tcggcccatt cggaccgcaa ggaatcggtc 9660 aatacactac atggcgtgat ttcatatgcg cgattgctga tccccatgtg tatcactggc 9720 aaactgtgat ggacgacacc gtcagtgcgt ccgtcgcgca ggctctcgat gagctgatgc 9780 tttgggccga ggactgcccc gaagtccggc acctcgtgca cgcggatttc ggctccaaca 9840 atgtcctgac ggacaatggc cgcataacag cggtcattga ctggagcgag gcgatgttcg 9900 gggattccca atacgaggtc gccaacatct tcttctggag gccgtggttg gcttgtatgg 9960 agcagcagac gcgctacttc gagcggaggc atccggagct tgcaggatcg ccgcggctcc 10020 gggcgtatat gctccgcatt ggtcttgacc aactctatca gagcttggtt gacggcaatt 10080 tcgatgatgc agcttgggcg cagggtcgat gcgacgcaat cgtccgatcc ggagccggga 10140 ctgtcgggcg tacacaaatc gcccgcagaa gcgcggccgt ctggaccgat ggctgtgtag 10200 aagtactcgc cgatagtgga aaccgacgcc ccagcactcg tccggatcgg gagatggggg 10260 aggctaactg aaacacggaa ggagacaata ccggaaggaa cccgcgctat gacggcaata 10320 aaaagacaga ataaaacgca cgggtgttgg gtcgtttgtt cataaacgcg gggttcggtc 10380 ccagggctgg cactctgtcg ataccccacc gagaccccat tggggccaat acgcccgcgt 10440 ttcttccttt tccccacccc accccccaag ttcgggtgaa ggcccagggc tcgcagccaa 10500 cgtcggggcg gcaggccctg ccatagccac tggccccgtg ggttagggac ggggtccccc 10560 atggggaatg gtttatggtt cgtgggggtt attattttgg gcgttgcgtg gggtcaggtc 10620 cacgactgga ctgagcagac agacccatgg tttttggatg gcctgggcat ggaccgcatg 10680 tactggcgcg acacgaacac cgggcgtctg tggctgccaa acacccccga cccccaaaaa 10740 ccaccgcgcg gatttctggc gtgccaagct agtcgaccaa ttctcatgtt tgacagctta 10800 tcatcgcaga tccgggcaac gttgttgcca ttgctgcagg cgcagaactg gtaggtatgg 10860 aagatccata cattgaatca atattggcaa ttagccatat tagtcattgg ttatatagca 10920 taaatcaata ttggctattg gccattgcat acgttgtatc tatatcataa tatgtacatt 10980 tatattggct catgtccaat atgaccgcca t 11011 <210> 162 <211> 5783 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 162 tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg 60 cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc 120 ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc tccctttagg 180 gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc 240 acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt 300 ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc 360 ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta 420 acaaaaattt aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt 480 tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta 540 tccgctcatg aattaattct tagaaaaact catcgagcat caaatgaaac tgcaatttat 600 tcatatcagg attatcaata ccatattttt gaaaaagccg tttctgtaat gaaggagaaa 660 actcaccgag gcagttccat aggatggcaa gatcctggta tcggtctgcg attccgactc 720 gtccaacatc aatacaacct attaatttcc cctcgtcaaa aataaggtta tcaagtgaga 780 aatcaccatg agtgacgact gaatccggtg agaatggcaa aagtttatgc atttctttcc 840 agacttgttc aacaggccag ccattacgct cgtcatcaaa atcactcgca tcaaccaaac 900 cgttattcat tcgtgattgc gcctgagcga gacgaaatac gcgatcgctg ttaaaaggac 960 aattacaaac aggaatcgaa tgcaaccggc gcaggaacac tgccagcgca tcaacaatat 1020 tttcacctga atcaggatat tcttctaata cctggaatgc tgttttcccg gggatcgcag 1080 tggtgagtaa ccatgcatca tcaggagtac ggataaaatg cttgatggtc ggaagaggca 1140 taaattccgt cagccagttt agtctgacca tctcatctgt aacatcattg gcaacgctac 1200 ctttgccatg tttcagaaac aactctggcg catcgggctt cccatacaat cgatagattg 1260 tcgcacctga ttgcccgaca ttatcgcgag cccatttata cccatataaa tcagcatcca 1320 tgttggaatt taatcgcggc ctagagcaag acgtttcccg ttgaatatgg ctcataacac 1380 cccttgtatt actgtttatg taagcagaca gttttattgt tcatgaccaa aatcccttaa 1440 cgtgagtttt cgttccactg agcgtcagac cccgtagaaa agatcaaagg atcttcttga 1500 gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg 1560 gtggtttgtt tgccggatca agagctacca actctttttc cgaaggtaac tggcttcagc 1620 agagcgcaga taccaaatac tgtccttcta gtgtagccgt agttaggcca ccacttcaag 1680 aactctgtag caccgcctac atacctcgct ctgctaatcc tgttaccagt ggctgctgcc 1740 agtggcgata agtcgtgtct taccgggttg gactcaagac gatagttacc ggataaggcg 1800 cagcggtcgg gctgaacggg gggttcgtgc acacagccca gcttggagcg aacgacctac 1860 accgaactga gatacctaca gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga 1920 aaggcggaca ggtatccggt aagcggcagg gtcggaacag gagagcgcac gagggagctt 1980 ccagggggaa acgcctggta tctttatagt cctgtcgggt ttcgccacct ctgacttgag 2040 cgtcgatttt tgtgatgctc gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg 2100 gcctttttac ggttcctggc cttttgctgg ccttttgctc acatgttctt tcctgcgtta 2160 tcccctgatt ctgtggataa ccgtattacc gcctttgagt gagctgatac cgctcgccgc 2220 agccgaacga ccgagcgcag cgagtcagtg agcgaggaag cggaagagcg cctgatgcgg 2280 tattttctcc ttacgcatct gtgcggtatt tcacaccgca tatatggtgc actctcagta 2340 caatctgctc tgatgccgca tagttaagcc agtatacact ccgctatcgc tacgtgactg 2400 ggtcatggct gcgccccgac acccgccaac acccgctgac gcgccctgac gggcttgtct 2460 gctcccggca tccgcttaca gacaagctgt gaccgtctcc gggagctgca tgtgtcagag 2520 gttttcaccg tcatcaccga aacgcgcgag gcagctgcgg taaagctcat cagcgtggtc 2580 gtgaagcgat tcacagatgt ctgcctgttc atccgcgtcc agctcgttga gtttctccag 2640 aagcgttaat gtctggcttc tgataaagcg ggccatgtta agggcggttt tttcctgttt 2700 ggtcactgat gcctccgtgt aagggggatt tctgttcatg ggggtaatga taccgatgaa 2760 acgagagagg atgctcacga tacgggttac tgatgatgaa catgcccggt tactggaacg 2820 ttgtgagggt aaacaactgg cggtatggat gcggcgggac cagagaaaaa tcactcaggg 2880 tcaatgccag cgcttcgtta atacagatgt aggtgttcca cagggtagcc agcagcatcc 2940 tgcgatgcag atccggaaca taatggtgca gggcgctgac ttccgcgttt ccagacttta 3000 cgaaacacgg aaaccgaaga ccattcatgt tgttgctcag gtcgcagacg ttttgcagca 3060 gcagtcgctt cacgttcgct cgcgtatcgg tgattcattc tgctaaccag taaggcaacc 3120 ccgccagcct agccgggtcc tcaacgacag gagcacgatc atgcgcaccc gtggggccgc 3180 catgccggcg ataatggcct gcttctcgcc gaaacgtttg gtggcgggac cagtgacgaa 3240 ggcttgagcg agggcgtgca agattccgaa taccgcaagc gacaggccga tcatcgtcgc 3300 gctccagcga aagcggtcct cgccgaaaat gacccagagc gctgccggca cctgtcctac 3360 gagttgcatg ataaagaaga cagtcataag tgcggcgacg atagtcatgc cccgcgccca 3420 ccggaaggag ctgactgggt tgaaggctct caagggcatc ggtcgagatc ccggtgccta 3480 atgagtgagc taacttacat taattgcgtt gcgctcactg cccgctttcc agtcgggaaa 3540 cctgtcgtgc cagctgcatt aatgaatcgg ccaacgcgcg gggagaggcg gtttgcgtat 3600 tgggcgccag ggtggttttt cttttcacca gtgagacggg caacagctga ttgcccttca 3660 ccgcctggcc ctgagagagt tgcagcaagc ggtccacgct ggtttgcccc agcaggcgaa 3720 aatcctgttt gatggtggtt aacggcggga tataacatga gctgtcttcg gtatcgtcgt 3780 atcccactac cgagatatcc gcaccaacgc gcagcccgga ctcggtaatg gcgcgcattg 3840 cgcccagcgc catctgatcg ttggcaacca gcatcgcagt gggaacgatg ccctcattca 3900 gcatttgcat ggtttgttga aaaccggaca tggcactcca gtcgccttcc cgttccgcta 3960 tcggctgaat ttgattgcga gtgagatatt tatgccagcc agccagacgc agacgcgccg 4020 agacagaact taatgggccc gctaacagcg cgatttgctg gtgacccaat gcgaccagat 4080 gctccacgcc cagtcgcgta ccgtcttcat gggagaaaat aatactgttg atgggtgtct 4140 ggtcagagac atcaagaaat aacgccggaa cattagtgca ggcagcttcc acagcaatgg 4200 catcctggtc atccagcgga tagttaatga tcagcccact gacgcgttgc gcgagaagat 4260 tgtgcaccgc cgctttacag gcttcgacgc cgcttcgttc taccatcgac accaccacgc 4320 tggcacccag ttgatcggcg cgagatttaa tcgccgcgac aatttgcgac ggcgcgtgca 4380 gggccagact ggaggtggca acgccaatca gcaacgactg tttgcccgcc agttgttgtg 4440 ccacgcggtt gggaatgtaa ttcagctccg ccatcgccgc ttccactttt tcccgcgttt 4500 tcgcagaaac gtggctggcc tggttcacca cgcgggaaac ggtctgataa gagacaccgg 4560 catactctgc gacatcgtat aacgttactg gtttcacatt caccaccctg aattgactct 4620 cttccgggcg ctatcatgcc ataccgcgaa aggttttgcg ccattcgatg gtgtccggga 4680 tctcgacgct ctcccttatg cgactcctgc attaggaagc agcccagtag taggttgagg 4740 ccgttgagca ccgccgccgc aaggaatggt gcatgcaagg agatggcgcc caacagtccc 4800 ccggccacgg ggcctgccac catacccacg ccgaaacaag cgctcatgag cccgaagtgg 4860 cgagcccgat cttccccatc ggtgatgtcg gcgatatagg cgccagcaac cgcacctgtg 4920 gcgccggtga tgccggccac gatgcgtccg gcgtagagga tcgggatctc gatcccgcga 4980 aattaatacg actcactata ggggaattgt gagcggataa caattcccct ctagaaataa 5040 ttttgtttaa ctttaagaag gagatataca tatgaaatac cttcttccga ctgctgctgc 5100 tggtctttta ctgctggctg ctcagccggc tatggctgct ggtggtggtt ctgccctcca 5160 gacggtctgc ctgaagggga ccaaggtgca catgaaatgc tttctggcct tcacccagac 5220 gaagaccttc cacgaggcca gcgaggactg catctcgcgc gggggcaccc tgagcacccc 5280 tcagactggc tcggagaacg acgccctgta tgagtacctg cgccagagcg tgggcaacga 5340 ggccgagatc tggctgggcc tcaacgacat ggcggccgag ggcacctggg tggacatgac 5400 cggtacccgc atcgcctaca agaactggga gactgagatc accgcgcaac ccgatggcgg 5460 caagaccgag aactgcgcgg tcctgtcagg cgcggccaac ggcaagtggt tcgacaagcg 5520 ctgcagggat caattgccct acatctgcca gttcgggatc gtgtacccct acgacgtgcc 5580 cgactacgcc ggttggagcc acccgcagtt cgaaaaataa ctcgagcacc accaccacca 5640 ccactgagat ccggctgcta acaaagcccg aaaggaagct gagttggctg ctgccaccgc 5700 tgagcaataa ctagcataac cccttggggc ctctaaacgg gtcttgaggg gttttttgct 5760 gaaaggagga actatatccg gat 5783 <210> 163 <211> 4792 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 163 gacgaaaggg cctcgtgata cgcctatttt tataggttaa tgtcatgata ataatggttt 60 cttagacgtc aggtggcact tttcggggaa atgtgcgcgg aacccctatt tgtttatttt 120 tctaaataca ttcaaatatg tatccgctca tgagacaata accctgataa atgcttcaat 180 aatattgaaa aaggaagagt atgagtattc aacatttccg tgtcgccctt attccctttt 240 ttgcggcatt ttgccttcct gtttttgctc acccagaaac gctggtgaaa gtaaaagatg 300 ctgaagatca gttgggtgct cgagtgggtt acatcgaact ggatctcaac agcggtaaga 360 tccttgagag ttttcgcccc gaagaacgtt ttccaatgat gagcactttt aaagttctgc 420 tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga gcaactcggt cgccgcatac 480 actattctca gaatgacttg gttgagtact caccagtcac agaaaagcat cttacggatg 540 gcatgacagt aagagaatta tgcagtgctg ccataaccat gagtgataac actgcggcca 600 acttacttct gacaacgatc ggaggaccga aggagctaac cgcttttttg cacaacatgg 660 gggatcatgt aactcgcctt gatcgttggg aaccggagct gaatgaagcc ataccaaacg 720 acgagcgtga caccacgatg cctgtagcaa tggcaacaac gttgcgcaaa ctattaactg 780 gcgaactact tactctagct tcccggcaac aattaataga ctggatggag gcggataaag 840 ttgcaggacc acttctgcgc tcggcccttc cggctggctg gtttattgct gataaatctg 900 gagccggtga gcgtgggtct cgcggtatca ttgcagcact ggggccagat ggtaagccct 960 cccgtatcgt agttatctac acgacgggga gtcaggcaac tatggatgaa cgaaatagac 1020 agatcgctga gataggtgcc tcactgatta agcattggta actgtcagac caagtttact 1080 catatatact ttagattgat ttaaaacttc atttttaatt taaaaggatc taggtgaaga 1140 tcctttttga taatctcatg accaaaatcc cttaacgtga gttttcgttc cactgagcgt 1200 cagaccccgt agaaaagatc aaaggatctt cttgagatcc tttttttctg cgcgtaatct 1260 gctgcttgca aacaaaaaaa ccaccgctac cagcggtggt ttgtttgccg gatcaagagc 1320 taccaactct ttttccgaag gtaactggct tcagcagagc gcagatacca aatactgtcc 1380 ttctagtgta gccgtagtta ggccaccact tcaagaactc tgtagcaccg cctacatacc 1440 tcgctctgct aatcctgtta ccagtggctg ctgccagtgg cgataagtcg tgtcttaccg 1500 ggttggactc aagacgatag ttaccggata aggcgcagcg gtcgggctga acggggggtt 1560 cgtgcataca gcccagcttg gagcgaacga cctacaccga actgagatac ctacagcgtg 1620 agctatgaga aagcgccacg cttcccgaag ggagaaaggc ggacaggtat ccggtaagcg 1680 gcagggtcgg aacaggagag cgcacgaggg agcttccagg gggaaacgcc tggtatcttt 1740 atagtcctgt cgggtttcgc cacctctgac ttgagcgtcg atttttgtga tgctcgtcag 1800 gggggcggag cctatggaaa aacgccagca acgcggcctt tttacggttc ctggcctttt 1860 gctggccttt tgctcacatg ttctttcctg cgttatcccc tgattctgtg gataaccgta 1920 ttaccgcctt tgagtgagct gataccgctc gccgcagccg aacgaccgag cgcagcgagt 1980 cagtgagcga ggaagcggaa gagcgcccaa tacgcaaacc gcctctcccc gcgcgttggc 2040 cgattcatta atgcagctgg cacgacaggt ttcccgactg gaaagcgggc agtgagcgca 2100 acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc 2160 cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatg 2220 accatgatta cgccaagctt tggagccttt tttttggaga ttttcaacgt gaaaaaatta 2280 ttattcgcaa ttcctttagt tgttcctttc tatgcggccc agccggccat ggccgcctta 2340 cagactgtgt gcctgaaggg caccaaggtg aacttgaagt gcctcctggc cttcacccaa 2400 ccgaagacct tccatgaggc gagcgaggac tgcatctcgc aagggggcac gctgggtacc 2460 ccgcagtcag agctggagaa cgaggcgctg ttcgaatacg cgcgccacag cgtgggcaac 2520 gatgcgaaca tctggctggg cctcaacgac atggccgcgg aaggcgcctg ggtcgactaa 2580 gtgatatcct gacctaactg cagagatcag ttgccctaca tctgccagtt tgccattgtg 2640 gcggccgcag gtgcgccggt gccgtatccg gatccgctgg aaccgcgtgc cgcatagact 2700 gttgaaagtt gtttagcaaa acctcataca gaaaattcat ttactaacgt ctggaaagac 2760 gacaaaactt tagatcgtta cgctaactat gagggctgtc tgtggaatgc tacaggcgtt 2820 gtggtttgta ctggtgacga aactcagtgt tacggtacat gggttcctat tgggcttgct 2880 atccctgaaa atgagggtgg tggctctgag ggtggcggtt ctgagggtgg cggttctgag 2940 ggtggcggta ctaaacctcc tgagtacggt gatacaccta ttccgggcta tacttatatc 3000 aaccctctcg acggcactta tccgcctggt actgagcaaa accccgctaa tcctaatcct 3060 tctcttgagg agtctcagcc tcttaatact ttcatgtttc agaataatag gttccgaaat 3120 aggcagggtg cattaactgt ttatacgggc actgttactc aaggcactga ccccgttaaa 3180 acttattacc agtacactcc tgtatcatca aaagccatgt atgacgctta ctggaacggt 3240 aaattcagag actgcgcttt ccattctggc tttaatgagg atccattcgt ttgtgaatat 3300 caaggccaat cgtctgacct gcctcaacct cctgtcaatg ctggcggcgg ctctggtggt 3360 ggttctggtg gcggctctga gggtggcggc tctgagggtg gcggttctga gggtggcggc 3420 tctgagggtg gcggttccgg tggcggctcc ggttccggtg attttgatta tgaaaaaatg 3480 gcaaacgcta ataagggggc tatgaccgaa aatgccgatg aaaacgcgct acagtctgac 3540 gctaaaggca aacttgattc tgtcgctact gattacggtg ctgctatcga tggtttcatt 3600 ggtgacgttt ccggccttgc taatggtaat ggtgctactg gtgattttgc tggctctaat 3660 tcccaaatgg ctcaagtcgg tgacggtgat aattcacctt taatgaataa tttccgtcaa 3720 tatttacctt ctttgcctca gtcggttgaa tgtcgccctt atgtctttgg cgctggtaaa 3780 ccatatgaat tttctattga ttgtgacaaa ataaacttat tccgtggtgt ctttgcgttt 3840 cttttatatg ttgccacctt tatgtatgta ttttcgacgt ttgctaacat actgcgtaat 3900 aaggagtctt aataagaatt cactggccgt cgttttacaa cgtcgtgact gggaaaaccc 3960 tggcgttacc caacttaatc gccttgcagc acatccccct ttcgccagct ggcgtaatag 4020 cgaagaggcc cgcaccgatc gcccttccca acagttgcgc agcctgaatg gcgaatggcg 4080 cctgatgcgg tattttctcc ttacgcatct gtgcggtatt tcacaccgca tacgtcaaag 4140 caaccatagt acgcgccctg tagcggcgca ttaagcgcgg cgggtgtggt ggttacgcgc 4200 agcgtgaccg ctacacttgc cagcgcccta gcgcccgctc ctttcgcttt cttcccttcc 4260 tttctcgcca cgttcgccgg ctttccccgt caagctctaa atcgggggct ccctttaggg 4320 ttccgattta gtgctttacg gcacctcgac cccaaaaaac ttgatttggg tgatggttca 4380 cgtagtgggc catcgccctg atagacggtt tttcgccctt tgacgttgga gtccacgttc 4440 tttaatagtg gactcttgtt ccaaactgga acaacactca accctatctc gggctattct 4500 tttgatttat aagggatttt gccgatttcg gcctattggt taaaaaatga gctgatttaa 4560 caaaaattta acgcgaattt taacaaaata ttaacgttta caattttatg gtgcagtctc 4620 agtacaatct gctctgatgc cgcatagtta agccagcccc gacacccgcc aacacccgct 4680 gacgcgccct gacgggcttg tctgctcccg gcatccgctt acagacaagc tgtgaccgtc 4740 tccgggagct gcatgtgtca gaggttttca ccgtcatcac cgaaacgcgc ga 4792 <210> 164 <211> 4101 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 164 gacgaaaggg cctcgtgata cgcctatttt tataggttaa tgtcatgata ataatggttt 60 cttagacgtc aggtggcact tttcggggaa atgtgcgcgg aacccctatt tgtttatttt 120 tctaaataca ttcaaatatg tatccgctca tgagacaata accctgataa atgcttcaat 180 aatattgaaa aaggaagagt atgagtattc aacatttccg tgtcgccctt attccctttt 240 ttgcggcatt ttgccttcct gtttttgctc acccagaaac gctggtgaaa gtaaaagatg 300 ctgaagatca gttgggtgct cgagtgggtt acatcgaact ggatctcaac agcggtaaga 360 tccttgagag ttttcgcccc gaagaacgtt ttccaatgat gagcactttt aaagttctgc 420 tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga gcaactcggt cgccgcatac 480 actattctca gaatgacttg gttgagtact caccagtcac agaaaagcat cttacggatg 540 gcatgacagt aagagaatta tgcagtgctg ccataaccat gagtgataac actgcggcca 600 acttacttct gacaacgatc ggaggaccga aggagctaac cgcttttttg cacaacatgg 660 gggatcatgt aactcgcctt gatcgttggg aaccggagct gaatgaagcc ataccaaacg 720 acgagcgtga caccacgatg cctgtagcaa tggcaacaac gttgcgcaaa ctattaactg 780 gcgaactact tactctagct tcccggcaac aattaataga ctggatggag gcggataaag 840 ttgcaggacc acttctgcgc tcggcccttc cggctggctg gtttattgct gataaatctg 900 gagccggtga gcgtgggtct cgcggtatca ttgcagcact ggggccagat ggtaagccct 960 cccgtatcgt agttatctac acgacgggga gtcaggcaac tatggatgaa cgaaatagac 1020 agatcgctga gataggtgcc tcactgatta agcattggta actgtcagac caagtttact 1080 catatatact ttagattgat ttaaaacttc atttttaatt taaaaggatc taggtgaaga 1140 tcctttttga taatctcatg accaaaatcc cttaacgtga gttttcgttc cactgagcgt 1200 cagaccccgt agaaaagatc aaaggatctt cttgagatcc tttttttctg cgcgtaatct 1260 gctgcttgca aacaaaaaaa ccaccgctac cagcggtggt ttgtttgccg gatcaagagc 1320 taccaactct ttttccgaag gtaactggct tcagcagagc gcagatacca aatactgtcc 1380 ttctagtgta gccgtagtta ggccaccact tcaagaactc tgtagcaccg cctacatacc 1440 tcgctctgct aatcctgtta ccagtggctg ctgccagtgg cgataagtcg tgtcttaccg 1500 ggttggactc aagacgatag ttaccggata aggcgcagcg gtcgggctga acggggggtt 1560 cgtgcataca gcccagcttg gagcgaacga cctacaccga actgagatac ctacagcgtg 1620 agctatgaga aagcgccacg cttcccgaag ggagaaaggc ggacaggtat ccggtaagcg 1680 gcagggtcgg aacaggagag cgcacgaggg agcttccagg gggaaacgcc tggtatcttt 1740 atagtcctgt cgggtttcgc cacctctgac ttgagcgtcg atttttgtga tgctcgtcag 1800 gggggcggag cctatggaaa aacgccagca acgcggcctt tttacggttc ctggcctttt 1860 gctggccttt tgctcacatg ttctttcctg cgttatcccc tgattctgtg gataaccgta 1920 ttaccgcctt tgagtgagct gataccgctc gccgcagccg aacgaccgag cgcagcgagt 1980 cagtgagcga ggaagcggaa gagcgcccaa tacgcaaacc gcctctcccc gcgcgttggc 2040 cgattcatta atgcagctgg cacgacaggt ttcccgactg gaaagcgggc agtgagcgca 2100 acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc 2160 cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatg 2220 accatgatta cgccaagctt tggagccttt tttttggaga ttttcaacgt gaaaaaatta 2280 ttattcgcaa ttcctttagt tgttcctttc tatgcggccc agccggccat ggccgccctc 2340 cagacggtct gcctgaaggg gaccaaggtg cacatgaaat gctttctggc cttcacccag 2400 acgaagacct tccacgaggc cagcgaggac tgcatctcgc gcgggggcac cctgagcacc 2460 cctcagactg gctcggagaa cgacgccctg tatgagtacc tgcgccagag cgtgggcaac 2520 gaggccgaga tctaagtgac gatatcctga cctaaggtac ctaagtgacg atatcctgac 2580 ctaactgcag ggatcaattg ccctacatct gccagttcgg gatcgtggcg gccgcaggtg 2640 cgccggtgcc gtatccggat ccgctggaac cgcgtgccgc acaggctgag ggtggcggct 2700 ctgagggtgg cggttctgag ggtggcggct ctgagggtgg cggttccggt ggcggctccg 2760 gttccggtga ttttgattat gaaaaaatgg caaacgctaa taagggggct atgaccgaaa 2820 atgccgatga aaacgcgcta cagtctgacg ctaaaggcaa acttgattct gtcgctactg 2880 attacggtgc tgctatcgat ggtttcattg gtgacgtttc cggccttgct aatggtaatg 2940 gtgctactgg tgattttgct ggctctaatt cccaaatggc tcaagtcggt gacggtgata 3000 attcaccttt aatgaataat ttccgtcaat atttaccttc tttgcctcag tcggttgaat 3060 gtcgccctta tgtctttggc gctggtaaac catatgaatt ttctattgat tgtgacaaaa 3120 taaacttatt ccgtggtgtc tttgcgtttc ttttatatgt tgccaccttt atgtatgtat 3180 tttcgacgtt tgctaacata ctgcgtaata aggagtctta ataagaattc actggccgtc 3240 gttttacaac gtcgtgactg ggaaaaccct ggcgttaccc aacttaatcg ccttgcagca 3300 catccccctt tcgccagctg gcgtaatagc gaagaggccc gcaccgatcg cccttcccaa 3360 cagttgcgca gcctgaatgg cgaatggcgc ctgatgcggt attttctcct tacgcatctg 3420 tgcggtattt cacaccgcat acgtcaaagc aaccatagta cgcgccctgt agcggcgcat 3480 taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag 3540 cgcccgctcc tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc 3600 aagctctaaa tcgggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc 3660 ccaaaaaact tgatttgggt gatggttcac gtagtgggcc atcgccctga tagacggttt 3720 ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa 3780 caacactcaa ccctatctcg ggctattctt ttgatttata agggattttg ccgatttcgg 3840 cctattggtt aaaaaatgag ctgatttaac aaaaatttaa cgcgaatttt aacaaaatat 3900 taacgtttac aattttatgg tgcagtctca gtacaatctg ctctgatgcc gcatagttaa 3960 gccagccccg acacccgcca acacccgctg acgcgccctg acgggcttgt ctgctcccgg 4020 catccgctta cagacaagct gtgaccgtct ccgggagctg catgtgtcag aggttttcac 4080 cgtcatcacc gaaacgcgcg a 4101 <210> 165 <211> 4114 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 165 gacgaaaggg cctcgtgata cgcctatttt tataggttaa tgtcatgata ataatggttt 60 cttagacgtc aggtggcact tttcggggaa atgtgcgcgg aacccctatt tgtttatttt 120 tctaaataca ttcaaatatg tatccgctca tgagacaata accctgataa atgcttcaat 180 aatattgaaa aaggaagagt atgagtattc aacatttccg tgtcgccctt attccctttt 240 ttgcggcatt ttgccttcct gtttttgctc acccagaaac gctggtgaaa gtaaaagatg 300 ctgaagatca gttgggtgct cgagtgggtt acatcgaact ggatctcaac agcggtaaga 360 tccttgagag ttttcgcccc gaagaacgtt ttccaatgat gagcactttt aaagttctgc 420 tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga gcaactcggt cgccgcatac 480 actattctca gaatgacttg gttgagtact caccagtcac agaaaagcat cttacggatg 540 gcatgacagt aagagaatta tgcagtgctg ccataaccat gagtgataac actgcggcca 600 acttacttct gacaacgatc ggaggaccga aggagctaac cgcttttttg cacaacatgg 660 gggatcatgt aactcgcctt gatcgttggg aaccggagct gaatgaagcc ataccaaacg 720 acgagcgtga caccacgatg cctgtagcaa tggcaacaac gttgcgcaaa ctattaactg 780 gcgaactact tactctagct tcccggcaac aattaataga ctggatggag gcggataaag 840 ttgcaggacc acttctgcgc tcggcccttc cggctggctg gtttattgct gataaatctg 900 gagccggtga gcgtgggtct cgcggtatca ttgcagcact ggggccagat ggtaagccct 960 cccgtatcgt agttatctac acgacgggga gtcaggcaac tatggatgaa cgaaatagac 1020 agatcgctga gataggtgcc tcactgatta agcattggta actgtcagac caagtttact 1080 catatatact ttagattgat ttaaaacttc atttttaatt taaaaggatc taggtgaaga 1140 tcctttttga taatctcatg accaaaatcc cttaacgtga gttttcgttc cactgagcgt 1200 cagaccccgt agaaaagatc aaaggatctt cttgagatcc tttttttctg cgcgtaatct 1260 gctgcttgca aacaaaaaaa ccaccgctac cagcggtggt ttgtttgccg gatcaagagc 1320 taccaactct ttttccgaag gtaactggct tcagcagagc gcagatacca aatactgtcc 1380 ttctagtgta gccgtagtta ggccaccact tcaagaactc tgtagcaccg cctacatacc 1440 tcgctctgct aatcctgtta ccagtggctg ctgccagtgg cgataagtcg tgtcttaccg 1500 ggttggactc aagacgatag ttaccggata aggcgcagcg gtcgggctga acggggggtt 1560 cgtgcataca gcccagcttg gagcgaacga cctacaccga actgagatac ctacagcgtg 1620 agctatgaga aagcgccacg cttcccgaag ggagaaaggc ggacaggtat ccggtaagcg 1680 gcagggtcgg aacaggagag cgcacgaggg agcttccagg gggaaacgcc tggtatcttt 1740 atagtcctgt cgggtttcgc cacctctgac ttgagcgtcg atttttgtga tgctcgtcag 1800 gggggcggag cctatggaaa aacgccagca acgcggcctt tttacggttc ctggcctttt 1860 gctggccttt tgctcacatg ttctttcctg cgttatcccc tgattctgtg gataaccgta 1920 ttaccgcctt tgagtgagct gataccgctc gccgcagccg aacgaccgag cgcagcgagt 1980 cagtgagcga ggaagcggaa gagcgcccaa tacgcaaacc gcctctcccc gcgcgttggc 2040 cgattcatta atgcagctgg cacgacaggt ttcccgactg gaaagcgggc agtgagcgca 2100 acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc 2160 cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatg 2220 accatgatta cgccaagctt tggagccttt tttttggaga ttttcaacgt gaaaaaatta 2280 ttattcgcaa ttcctttagt tgttcctttc tatgcggccc agccggccat ggccgcctta 2340 cagactgtgt gcctgaaggg caccaaggtg aacttgaagt gcctcctggc cttcacccaa 2400 ccgaagacct tccatgaggc gagcgaggac tgcatctcgc aagggggcac gctgggtacc 2460 ccgcagtcag agctggagaa cgaggcgctg ttcgaatacg cgcgccacag cgtgggcaac 2520 gatgcgaaca tctggctggg cctcaacgac atggccgcgg aaggcgcctg ggtcgactaa 2580 gtgatatcct gacctaactg cagagatcag ttgccctaca tctgccagtt tgccattgtg 2640 gcggccgcag gtgcgccggt gccgtatccg gatccgctgg aaccgcgtgc cgcacaggct 2700 gagggtggcg gctctgaggg tggcggttct gagggtggcg gctctgaggg tggcggttcc 2760 ggtggcggct ccggttccgg tgattttgat tatgaaaaaa tggcaaacgc taataagggg 2820 gctatgaccg aaaatgccga tgaaaacgcg ctacagtctg acgctaaagg caaacttgat 2880 tctgtcgcta ctgattacgg tgctgctatc gatggtttca ttggtgacgt ttccggcctt 2940 gctaatggta atggtgctac tggtgatttt gctggctcta attcccaaat ggctcaagtc 3000 ggtgacggtg ataattcacc tttaatgaat aatttccgtc aatatttacc ttctttgcct 3060 cagtcggttg aatgtcgccc ttatgtcttt ggcgctggta aaccatatga attttctatt 3120 gattgtgaca aaataaactt attccgtggt gtctttgcgt ttcttttata tgttgccacc 3180 tttatgtatg tattttcgac gtttgctaac atactgcgta ataaggagtc ttaataagaa 3240 ttcactggcc gtcgttttac aacgtcgtga ctgggaaaac cctggcgtta cccaacttaa 3300 tcgccttgca gcacatcccc ctttcgccag ctggcgtaat agcgaagagg cccgcaccga 3360 tcgcccttcc caacagttgc gcagcctgaa tggcgaatgg cgcctgatgc ggtattttct 3420 ccttacgcat ctgtgcggta tttcacaccg catacgtcaa agcaaccata gtacgcgccc 3480 tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc gcagcgtgac cgctacactt 3540 gccagcgccc tagcgcccgc tcctttcgct ttcttccctt cctttctcgc cacgttcgcc 3600 ggctttcccc gtcaagctct aaatcggggg ctccctttag ggttccgatt tagtgcttta 3660 cggcacctcg accccaaaaa acttgatttg ggtgatggtt cacgtagtgg gccatcgccc 3720 tgatagacgg tttttcgccc tttgacgttg gagtccacgt tctttaatag tggactcttg 3780 ttccaaactg gaacaacact caaccctatc tcgggctatt cttttgattt ataagggatt 3840 ttgccgattt cggcctattg gttaaaaaat gagctgattt aacaaaaatt taacgcgaat 3900 tttaacaaaa tattaacgtt tacaatttta tggtgcagtc tcagtacaat ctgctctgat 3960 gccgcatagt taagccagcc ccgacacccg ccaacacccg ctgacgcgcc ctgacgggct 4020 tgtctgctcc cggcatccgc ttacagacaa gctgtgaccg tctccgggag ctgcatgtgt 4080 cagaggtttt caccgtcatc accgaaacgc gcga 4114 <210> 166 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 166 Lys Met Leu Glu Glu Leu Lys Thr Gln Leu Asp Ser Leu Ala Gln Glu 1 5 10 15 Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Cys Leu             20 25 30 <210> 167 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 167 Asp Leu Lys Thr Gln Val Glu Lys Leu Trp Arg Glu Val Asn Ala Leu 1 5 10 15 Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 168 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 168 Asp Leu Lys Thr Gln Val Glu Lys Leu Trp Arg Glu Val Asn Ala Leu 1 5 10 15 Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 169 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 169 Asp Leu Lys Thr Gln Val Glu Lys Leu Trp Arg Glu Val Asn Ala Leu 1 5 10 15 Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 170 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 170 Asp Leu Lys Thr Gln Ile Glu Lys Leu Trp Thr Glu Val Asn Ala Leu 1 5 10 15 Lys Glu Ile Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 171 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 171 Asp Asp Leu Lys Thr Gln Ile Asp Lys Leu Trp Arg Glu Val Asn Ala 1 5 10 15 Leu Lys Glu Ile Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 172 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 172 Asp Leu Lys Thr Gln Val Glu Lys Leu Trp Arg Glu Val Asn Ala Leu 1 5 10 15 Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 173 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 173 Asp Leu Lys Ser Gln Val Glu Lys Leu Trp Arg Glu Val Asn Ala Leu 1 5 10 15 Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 174 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 174 Asp Leu Lys Thr Gln Val Glu Lys Leu Trp Arg Glu Val Asn Ala Leu 1 5 10 15 Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <175> 175 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 175 Asp Asp Leu Arg Asn Glu Ile Asp Lys Leu Trp Arg Glu Val Asn Ser 1 5 10 15 Leu Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 176 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 176 Lys Met Ile Glu Asp Leu Lys Ala Met Ile Asp Asn Ile Ser Gln Glu 1 5 10 15 Val Ala Leu Leu Lys Glu Lys Gln Ala Leu Gln Thr Val Cys Leu             20 25 30 <210> 177 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 177 Lys Met Ile Glu Asp Leu Lys Ala Met Ile Asp Asn Ile Ser Gln Glu 1 5 10 15 Val Ala Leu Leu Lys Glu Lys Gln Ala Leu Gln Thr Val Cys Leu             20 25 30 <210> 178 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 178 Asp Asp Met Lys Thr Gln Ile Asp Lys Leu Trp Gln Glu Val Asn Ser 1 5 10 15 Leu Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 179 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 179 Asp Asp Leu Lys Thr Gln Ile Asp Lys Leu Trp Arg Glu Val Asn Ala 1 5 10 15 Leu Lys Glu Met Gln Ala Leu Gln Ser Val Cys Leu             20 25 <210> 180 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 180 Asp Asp Leu Lys Ser Gln Val Glu Lys Leu Trp Arg Glu Val Asn Ala 1 5 10 15 Leu Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 181 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 181 Asp Asp Leu Lys Thr Gln Ile Asp Lys Leu Trp Arg Glu Val Asn Ala 1 5 10 15 Leu Lys Glu Met Gln Ala Leu Gln Ser Val Cys Leu             20 25 <210> 182 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 182 Asp Asp Val Arg Ser Gln Ile Glu Lys Leu Trp Gln Glu Val Asn Ser 1 5 10 15 Leu Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 183 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 183 Asp Leu Lys Thr Gln Ile Asp Lys Leu Trp Arg Glu Ile Asn Ser Leu 1 5 10 15 Lys Glu Met Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 184 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 184 Glu Glu Leu Arg Arg Gln Val Ser Asp Leu Ala Gln Glu Leu Asn Ile 1 5 10 15 Leu Lys Glu Gln Gln Ala Leu His Thr Val Cys Leu             20 25 <210> 185 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 185 Lys Met Tyr Glu Glu Leu Lys Gln Lys Val Gln Asn Ile Glu Leu Glu 1 5 10 15 Val Ile His Leu Lys Glu Gln Gln Ala Leu Gln Thr Ile Cys Leu             20 25 30 <210> 186 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 186 Lys Met Tyr Glu Asp Leu Lys Lys Lys Val Gln Asn Ile Glu Glu Asp 1 5 10 15 Val Ile His Leu Lys Glu Gln Gln Ala Leu Gln Thr Ile Cys Leu             20 25 30 <210> 187 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 187 Glu Glu Leu Lys Lys Gln Ile Asp Asn Ile Val Leu Glu Leu Asn Leu 1 5 10 15 Leu Lys Glu Gln Gln Ala Leu Gln Ser Val Cys Leu             20 25 <210> 188 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 188 Glu Glu Leu Lys Lys Gln Ile Asp Gln Ile Ile Gln Asp Leu Asn Leu 1 5 10 15 Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Cys Leu             20 25 <210> 189 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 189 Glu Gln Met Gln Lys Gln Ile Asn Asp Ile Val Gln Glu Leu Asn Leu 1 5 10 15 Leu Lys Glu Gln Gln Ala Leu Gln Ala Val Cys Leu             20 25 <210> 190 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 190 Glu Gln Met Gln Lys Gln Ile Asn Asp Ile Val Gln Glu Leu Asn Leu 1 5 10 15 Leu Lys Glu Gln Gln Ala Leu Gln Ala Val Cys Leu             20 25 <210> 191 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 191 Asn Thr Gly Leu Leu Glu Ser Gln Leu Ser Arg His Asp Gln Met Leu 1 5 10 15 Ser Val His Asp Ile Arg Leu Ala Asp Met Asp Leu Arg Phe Gln Val             20 25 30 Leu Glu Thr Ala Ser Tyr Asn Gly Val Leu Ile Trp Lys Ile Arg Asp         35 40 45 Tyr Lys Arg Arg Lys Gln Glu Ala Val Met     50 55 <210> 192 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 192 Ala Ala Ser Glu Arg Lys Ala Leu Gln Thr Glu Met Ala Arg Ile Lys 1 5 10 15 Lys Trp Leu Thr Phe             20 <210> 193 <211> 37 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 193 Phe Asp Met Ser Cys Arg Ser Arg Leu Ala Thr Leu Asn Glu Lys Leu 1 5 10 15 Thr Ala Leu Glu Arg Arg Ile Glu Tyr Ile Glu Ala Arg Val Thr Lys             20 25 30 Gly Glu Thr Leu Thr         35 <210> 194 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 194 Ala Asp Ile Tyr Lys Ala Asp Phe Gln Ala Glu Arg Gln Ala Arg Glu 1 5 10 15 Lys Leu Ala Glu Lys Lys Glu Leu Leu Gln Glu Gln Leu Glu Gln Leu             20 25 30 Gln Arg Glu Tyr Ser Lys Leu Lys Ala Ser Cys Gln Glu Ser Ala Arg         35 40 45 Ile      <210> 195 <211> 71 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 195 Leu Thr Gly Ser Ala Gln Asn Ile Glu Phe Arg Thr Gly Ser Leu Gly 1 5 10 15 Lys Ile Lys Leu Asn Asp Glu Asp Leu Ser Glu Cys Leu His Gln Ile             20 25 30 Gln Lys Asn Lys Glu Asp Ile Ile Glu Leu Lys Gly Ser Ala Ile Gly         35 40 45 Leu Pro Ile Tyr Gln Leu Asn Ser Lys Leu Val Asp Leu Glu Arg Lys     50 55 60 Phe Gln Gly Leu Gln Gln Thr 65 70 <210> 196 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 196 Leu Arg Gly Leu Arg Thr Ile Val Thr Thr Leu Gln Asp Ser Ile Arg 1 5 10 15 Lys Val Thr Glu Glu Asn Lys Glu Leu Ala Asn Glu             20 25 <210> 197 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 197 Val Ala Ser Leu Arg Gln Gln Val Glu Ala Leu Gln Gly Gln Val Gln 1 5 10 15 His Leu Gln Ala Ala Phe Ser Gln Tyr Lys Lys             20 25 <210> 198 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 198 Val Asn Ala Leu Arg Gln Arg Val Gly Ile Leu Glu Gly Gln Leu Gln 1 5 10 15 Arg Leu Gln Asn Ala Phe Ser Gln Tyr Lys Lys             20 25 <210> 199 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 199 Ser Ala Ala Leu Arg Gln Gln Met Glu Ala Leu Asn Gly Lys Leu Gln 1 5 10 15 Arg Leu Glu Ala Ala Phe Ser Arg Tyr Lys Lys             20 25 <210> 200 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 200 Val Asn Ala Leu Lys Gln Arg Val Thr Ile Leu Asp Gly His Leu Arg 1 5 10 15 Arg Phe Gln Asn Ala Phe Ser Gln Tyr Lys Lys             20 25 <210> 201 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 201 Val Asp Thr Leu Arg Gln Arg Met Arg Asn Leu Glu Gly Glu Val Gln 1 5 10 15 Arg Leu Gln Asn Ile Val Thr Gln Tyr Arg Lys             20 25 <210> 202 <211> 64 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 202 Gly Ser Pro Gly Leu Lys Gly Asp Lys Gly Ile Pro Gly Asp Lys Gly 1 5 10 15 Ala Lys Gly Glu Ser Gly Leu Pro Asp Val Ala Ser Leu Arg Gln Gln             20 25 30 Val Glu Ala Leu Gln Gly Gln Val Gln His Leu Gln Ala Ala Phe Ser         35 40 45 Gln Tyr Lys Lys Val Glu Leu Phe Pro Gly Gly Ile Pro His Arg Asp     50 55 60 <210> 203 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 203 Asp Met Ala Ala Glu Gly Thr Trp 1 5 <210> 204 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 204 Asp Met Thr Gly Ala Arg 1 5 <210> 205 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 205 Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro 1 5 10 <210> 206 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 206 Asp Gly Gly Lys Thr Glu Asn 1 5 <210> 207 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (3) .. (9) <223> Xaa can be any naturally occurring amino acid <400> 207 Asp Met Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp 1 5 10 <210> 208 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature <222> (6) <223> Xaa can be any naturally occurring amino acid <400> 208 Asp Met Thr Gly Ala Xaa 1 5 <210> 209 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 209 Asp Gly Gly Ala Thr Glu Asn 1 5 <210> 210 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (3) .. (7) <223> Xaa can be any naturally occurring amino acid <400> 210 Asp Met Xaa Xaa Xaa Xaa Xaa Trp 1 5 <210> 211 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature &Lt; 222 > (3) <223> Xaa can be any naturally occurring amino acid <400> 211 Asp Met Xaa Xaa Xaa Xaa 1 5 <210> 212 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (1) .. (7) <223> Xaa can be any naturally occurring amino acid <400> 212 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp 1 5 <210> 213 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (4) .. (8) <223> Xaa can be any naturally occurring amino acid <400> 213 Asp Gly Gly Xaa Xaa Xaa Xaa Xaa Glu Asn 1 5 10 <210> 214 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (3) .. (8) <223> Xaa can be any naturally occurring amino acid <400> 214 Asn Trp Xaa Xaa Xaa Xaa Xaa Xaa Gln Pro 1 5 10 <210> 215 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (3) .. (9) <223> Xaa can be any naturally occurring amino acid <400> 215 Asn Trp Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gln Pro 1 5 10 <210> 216 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (3) .. (10) <223> Xaa can be any naturally occurring amino acid <400> 216 Asn Trp Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gln Pro 1 5 10 <210> 217 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (6) .. (12) <223> Xaa can be any naturally occurring amino acid <400> 217 Asn Trp Glu Thr Glu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Thr Ala Gln Pro 1 5 10 15 <210> 218 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (5) .. (10) <223> Xaa can be any naturally occurring amino acid <400> 218 Asn Trp Glu Thr Xaa Xaa Xaa Xaa Xaa Xaa Ala Gln Pro 1 5 10 <210> 219 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (4) .. (9) <223> Xaa can be any naturally occurring amino acid <400> 219 Asp Gly Gly Xaa Xaa Xaa Xaa Xaa Xaa Asn 1 5 10 <210> 220 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (4) .. (10) <223> Xaa can be any naturally occurring amino acid <400> 220 Asn Trp Glu Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 <210> 221 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (1) .. (1) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature (222) (4) .. (6) <223> Xaa can be any naturally occurring amino acid <400> 221 Xaa Gly Gly Xaa Xaa Xaa Asn 1 5 <210> 222 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (4) .. (8) <223> Xaa can be any naturally occurring amino acid <400> 222 Asn Trp Glu Xaa Xaa Xaa Xaa Xaa Gln Pro 1 5 10 <210> 223 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (4) .. (10) <223> Xaa can be any naturally occurring amino acid <400> 223 Asp Gly Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn 1 5 10 <210> 224 <211> 62 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (21) .. (22) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (23) <223> k is g or t <220> <221> misc_feature (222) (24) .. (25) <223> n is a, c, g, or t <220> <221> misc_feature (222) (26) .. (26) <223> k is g or t <220> <221> misc_feature (222) (27) .. (28) <223> n is a, c, g, or t <220> <221> misc_feature (222) (29) .. (29) <223> k is g or t <220> <221> misc_feature (222) (30) .. (31) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (32) <223> k is g or t <220> <221> misc_feature (222) (33) .. (34) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (35) <223> k is g or t <220> <221> misc_feature (222) (36) .. (37) <223> n is a, c, g, or t <220> <221> misc_feature (222) (38) .. (38) <223> k is g or t <220> <221> misc_feature (222) (39) .. (40) <223> n is a, c, g, or t <220> <221> misc_feature (222) (41) .. (41) <223> k is g or t <400> 224 ggctgggcct gaacgacatg nnknnknnkn nknnknnknn ktgggtggat atgactggcg 60 cc 62 <210> 225 <211> 60 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (37) .. (37) <223> m is a or c <220> <221> misc_feature (222) (38) .. (39) <223> n is a, c, g, or t <400> 225 ggcggtgatc tcagtttccc agttcttgta ggcgatmnng gcgccagtca tatccaccca 60 <210> 226 <211> 60 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 226 ggcggtgatc tcagtttccc agttcttgta ggcgatgcgg gcgccagtca tatccaccca 60 <210> 227 <211> 62 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 227 actgggaaac tgagatcacc gcccaacctg atggcggcgc aaccgagaac tgcgcggtcc 60 tg 62 <210> 228 <211> 60 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 228 ccctgcagcg cttgtcgaac cacttgccgt tggcggcgcc agacaggacc gcgcagttct 60 <210> 229 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 229 gccgagatct ggctgggcct gaacgacatg 30 <210> 230 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 230 atccctgcag cgcttgtcga acc 23 <210> 231 <211> 79 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (21) .. (22) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (23) <223> k is g or t <220> <221> misc_feature (222) (24) .. (25) <223> n is a, c, g, or t <220> <221> misc_feature (222) (26) .. (26) <223> k is g or t <220> <221> misc_feature (222) (27) .. (28) <223> n is a, c, g, or t <220> <221> misc_feature (222) (29) .. (29) <223> k is g or t <220> <221> misc_feature (222) (30) .. (31) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (32) <223> k is g or t <220> <221> misc_feature (222) (33) .. (34) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (35) <223> k is g or t <220> <221> misc_feature (222) (48) .. (49) <223> n is a, c, g, or t <220> <221> misc_feature (222) (50) .. (50) <223> k is g or t <220> <221> misc_feature (222) (51) .. (52) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (53) <223> k is g or t <220> <221> misc_feature <222> (54) .. (55) <223> n is a, c, g, or t <220> <221> misc_feature <222> (56) .. (56) <223> k is g or t <220> <221> misc_feature (222) (57) .. (58) <223> n is a, c, g, or t <220> <221> misc_feature (222) (59) .. (59) <223> k is g or t <400> 231 ggctgggcct gaacgacatg nnknnknnkn nknnktgggt ggatatgnnk nnknnknnka 60 tcgcctacaa gaactggga 79 <210> 232 <211> 77 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 232 gacaggacgg cgcagttctc ggttgcgccg ccatcaggtt gggcggtgat ctcagtttcc 60 cagttcttgt aggcgat 77 <210> 233 <211> 63 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 233 atccctgcag cgcttgtcga accacttgcc gttggcggcg ccagacagga cggcgcagtt 60 ctc 63 <210> 234 <211> 60 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature &Lt; 222 > (22) <223> n is a, c, g, or t <220> <221> misc_feature (222) (24) .. (24) <223> s is g or c <220> <221> misc_feature (222) (25) .. (26) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (27) <223> s is g or c <220> <221> misc_feature <222> (28) .. (29) <223> n is a, c, g, or t <220> <221> misc_feature (222) (30) .. (30) <223> s is g or c <220> <221> misc_feature (222) (31) .. (32) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (33) <223> s is g or c <220> <221> misc_feature &Lt; 222 > (34) <223> n is a, c, g, or t <220> <221> misc_feature <222> (36) .. (36) <223> s is g or c <220> <221> misc_feature (222) (37) .. (38) <223> n is a, c, g, or t <220> <221> misc_feature (222) (39) .. (39) <223> s is g or c <220> <221> misc_feature (222) (40) .. (41) <223> n is a, c, g, or t <220> <221> misc_feature (222) (42) .. (42) <223> s is g or c <400> 234 gagatctggc tgggcctcaa cnnsnnsnns nnsnnsnnsn nstgggtgga catgactggc 60 <210> 235 <211> 63 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 235 ttgcgcggtg atctcagtct cccagttctt gtaggcgata cgcgcgccag tcatgtccac 60 cca 63 <210> 236 <211> 64 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (32) .. (33) <223> n is a, c, g, or t <220> <221> misc_feature (222) (34) .. (34) <223> s is g or c <220> <221> misc_feature (222) (35) .. (36) <223> n is a, c, g, or t <220> <221> misc_feature (222) (37) .. (37) <223> s is g or c <220> <221> misc_feature (222) (38) .. (39) <223> n is a, c, g, or t <220> <221> misc_feature (222) (40) .. (40) <223> s is g or c <220> <221> misc_feature (222) (41) .. (42) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (43) <223> s is g or c <220> <221> misc_feature (222) (44) .. (45) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (46) .. (46) <223> s is g or c <400> 236 gactgagatc accgcgcaac ccgatggcgg cnnsnnsnns nnsnnsgaga actgcgcggt 60 cctg 64 <210> 237 <211> 60 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 237 ccctgcagcg cttgtcgaac cacttgccgt tggccgcgcc tgacaggacc gcgcagttct 60 <210> 238 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 238 gccgagatct ggctgggcct ca 22 <210> 239 <211> 78 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 239 atctggctgg gcctgaacga catggccgcc gagggcacct gggtggatat gaccggcgcg 60 cgtatcgcct acaagaac 78 <210> 240 <211> 62 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (18) .. (18) <223> m is a or c <220> <221> misc_feature (222) (19) .. (20) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (21) <223> m is a or c <220> <221> misc_feature &Lt; 222 > (22) <223> n is a, c, g, or t <220> <221> misc_feature (222) (24) .. (24) <223> m is a or c <220> <221> misc_feature (222) (25) .. (26) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (27) <223> m is a or c <220> <221> misc_feature <222> (28) .. (29) <223> n is a, c, g, or t <220> <221> misc_feature (222) (30) .. (30) <223> m is a or c <220> <221> misc_feature (222) (31) .. (32) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (33) <223> m is a or c <220> <221> misc_feature &Lt; 222 > (34) <223> n is a, c, g, or t <400> 240 ccgccatcgg gttgggcmnn mnnmnnmnnm nnmnnagttt cccagttctt gtaggcgata 60 cg 62 <210> 241 <211> 57 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (19) .. (20) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (21) <223> k is g or t <220> <221> misc_feature &Lt; 222 > (22) <223> n is a, c, g, or t <220> <221> misc_feature (222) (24) .. (24) <223> k is g or t <220> <221> misc_feature (222) (25) .. (26) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (27) <223> k is g or t <220> <221> misc_feature <222> (28) .. (29) <223> n is a, c, g, or t <220> <221> misc_feature (222) (30) .. (30) <223> k is g or t <220> <221> misc_feature (222) (31) .. (32) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (33) <223> k is g or t <220> <221> misc_feature &Lt; 222 > (34) <223> n is a, c, g, or t <220> <221> misc_feature <222> (36) .. (36) <223> k is g or t <400> 241 gcccaacccg atggcggcnn knnknnknnk nnknnkaact gcgccgtcct gtctggc 57 <210> 242 <211> 54 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 242 cctgcagcgc ttgtcgaacc acttgccgtt ggcggcgcca gacaggacgg cgca 54 <210> 243 <211> 84 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (22) .. (22) <223> m is a or c <220> <221> misc_feature (222) (23) .. (24) <223> n is a, c, g, or t <220> <221> misc_feature (222) (25) .. (25) <223> m is a or c <220> <221> misc_feature (222) (26) .. (27) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (28) <223> m is a or c <220> <221> misc_feature (222) (29) .. (30) <223> n is a, c, g, or t <220> <221> misc_feature (222) (37) .. (37) <223> m is a or c <220> <221> misc_feature (222) (38) .. (39) <223> n is a, c, g, or t <220> <221> misc_feature (222) (40) .. (40) <223> m is a or c <220> <221> misc_feature (222) (41) .. (42) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (43) <223> m is a or c <220> <221> misc_feature (222) (44) .. (45) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (46) .. (46) <223> m is a or c <220> <221> misc_feature (222) (47) .. (48) <223> n is a, c, g, or t <220> <221> misc_feature (222) (49) .. (49) <223> m is a or c <220> <221> misc_feature (222) (50) .. (51) <223> n is a, c, g, or t <220> <221> misc_feature (52). (52) <223> m is a or c <220> <221> misc_feature (222) (53) .. (54) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (55) <223> m is a or c <220> <221> misc_feature (222) (56) .. (57) <223> n is a, c, g, or t <220> <221> misc_feature <222> (58) .. (58) <223> m is a or c <220> <221> misc_feature (222) (59) .. (60) <223> n is a, c, g, or t <400> 243 gccagacagg acggcgcagt tmnnmnnmnn gccgccmnnm nnmnnmnnmn nmnnmnnmnn 60 ttcccagttc ttgtaggcga tacg 84 <210> 244 <211> 53 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 244 ccgccatcgg gttgggcggt gatctcagtt tcccagttct tgtaggcgat acg 53 <210> 245 <211> 60 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (19) .. (20) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (21) <223> k is g or t <220> <221> misc_feature &Lt; 222 > (22) <223> n is a, c, g, or t <220> <221> misc_feature (222) (24) .. (24) <223> k is g or t <220> <221> misc_feature (222) (25) .. (26) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (27) <223> k is g or t <220> <221> misc_feature <222> (28) .. (29) <223> n is a, c, g, or t <220> <221> misc_feature (222) (30) .. (30) <223> k is g or t <220> <221> misc_feature (222) (31) .. (32) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (33) <223> k is g or t <220> <221> misc_feature &Lt; 222 > (34) <223> n is a, c, g, or t <220> <221> misc_feature <222> (36) .. (36) <223> k is g or t <220> <221> misc_feature (222) (37) .. (38) <223> n is a, c, g, or t <220> <221> misc_feature (222) (39) .. (39) <223> k is g or t <400> 245 gcccaacccg atggcggcnn knnknnknnk nnknnknnka actgcgccgt cctgtctggc 60 <210> 246 <211> 74 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (30) .. (31) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (32) <223> k is g or t <220> <221> misc_feature (222) (33) .. (34) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (35) <223> k is g or t <220> <221> misc_feature (222) (36) .. (37) <223> n is a, c, g, or t <220> <221> misc_feature (222) (38) .. (38) <223> k is g or t <220> <221> misc_feature (222) (39) .. (40) <223> n is a, c, g, or t <220> <221> misc_feature (222) (41) .. (41) <223> k is g or t <220> <221> misc_feature (222) (42) .. (43) <223> n is a, c, g, or t <220> <221> misc_feature (222) (44) .. (44) <223> k is g or t <220> <221> misc_feature (222) (45) .. (46) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (47) .. (47) <223> k is g or t <400> 246 ctggcgcgcg tatcgcctac aagaactggn nknnknnknn knnknnkcaa cccgatggcg 60 gcgccaccga gaac 74 <210> 247 <211> 77 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (30) .. (31) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (32) <223> k is g or t <220> <221> misc_feature (222) (33) .. (34) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (35) <223> k is g or t <220> <221> misc_feature (222) (36) .. (37) <223> n is a, c, g, or t <220> <221> misc_feature (222) (38) .. (38) <223> k is g or t <220> <221> misc_feature (222) (39) .. (40) <223> n is a, c, g, or t <220> <221> misc_feature (222) (41) .. (41) <223> k is g or t <220> <221> misc_feature (222) (42) .. (43) <223> n is a, c, g, or t <220> <221> misc_feature (222) (44) .. (44) <223> k is g or t <220> <221> misc_feature (222) (45) .. (46) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (47) .. (47) <223> k is g or t <220> <221> misc_feature (222) (48) .. (49) <223> n is a, c, g, or t <220> <221> misc_feature (222) (50) .. (50) <223> k is g or t <400> 247 ctggcgcgcg tatcgcctac aagaactggn nknnknnknn knnknnknnk caacccgatg 60 gcggcgccac cgagaac 77 <210> 248 <211> 77 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (30) .. (31) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (32) <223> k is g or t <220> <221> misc_feature (222) (33) .. (34) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (35) <223> k is g or t <220> <221> misc_feature (222) (36) .. (37) <223> n is a, c, g, or t <220> <221> misc_feature (222) (38) .. (38) <223> k is g or t <220> <221> misc_feature (222) (39) .. (40) <223> n is a, c, g, or t <220> <221> misc_feature (222) (41) .. (41) <223> k is g or t <220> <221> misc_feature (222) (42) .. (43) <223> n is a, c, g, or t <220> <221> misc_feature (222) (44) .. (44) <223> k is g or t <220> <221> misc_feature (222) (45) .. (46) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (47) .. (47) <223> k is g or t <220> <221> misc_feature (222) (48) .. (49) <223> n is a, c, g, or t <220> <221> misc_feature (222) (50) .. (50) <223> k is g or t <400> 248 ctggcgcgcg tatcgcctac aagaactggn nknnknnknn knnknnknnk caacccgatg 60 gcggcgccac cgagaac 77 <210> 249 <211> 81 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 249 cctgcagcgc ttgtcgaacc acttgccgtt ggcggcgcca gacaggacgg cgcagttctc 60 ggtggcgccg ccatcgggtt g 81 <210> 250 <211> 89 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (24) .. (24) <223> s is g or c <220> <221> misc_feature (222) (25) .. (25) <223> m is a or c <220> <221> misc_feature &Lt; 222 > (28) <223> w is a or t <220> <221> misc_feature (222) (29) .. (29) <223> m is a or c <220> <221> misc_feature &Lt; 222 > (33) <223> s is g or c <220> <221> misc_feature (222) (42) .. (42) <223> m is a or c <220> <221> misc_feature (222) (43) .. (44) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (51) <223> m is a or c <220> <221> misc_feature <222> (52) .. (53) <223> n is a, c, g, or t <220> <221> misc_feature <222> (54) .. (54) <223> m is a or c <220> <221> misc_feature (222) (55) .. (56) <223> n is a, c, g, or t <220> <221> misc_feature (222) (57) .. (57) <223> m is a or c <220> <221> misc_feature (222) (58) .. (59) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (60) <223> m is a or c <220> <221> misc_feature (222) (61) .. (62) <223> n is a, c, g, or t <220> <221> misc_feature (222) (63) .. (63) <223> m is a or c <220> <221> misc_feature (222) (64) .. (65) <223> n is a, c, g, or t <400> 250 gacaggaccg cgcagttctc gccsmagwmc ccsaagccgc cmnngggttg mnnmnnmnnm 60 nnmnnctccc agttcttgta ggcgatacg 89 <210> 251 <211> 66 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 251 atccctgcag cgcttgtcga accacttgcc gttggccgcg cctgacagga ccgcgcagtt 60 ctcgcc 66 <210> 252 <211> 54 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 252 gagcgtgggc aacgaggccg agatctggct gggcctcaac gacatggccg ccga 54 <210> 253 <211> 70 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 253 ccagttcttg taggcgatac gcgcgccagt catatccacc caggtgccct cggcggccat 60 gtcgttgagg 70 <210> 254 <211> 74 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature <222> (28) .. (29) <223> n is a, c, g, or t <220> <221> misc_feature (222) (30) .. (30) <223> k is g or t <220> <221> misc_feature (222) (31) .. (32) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (33) <223> k is g or t <220> <221> misc_feature &Lt; 222 > (34) <223> n is a, c, g, or t <220> <221> misc_feature <222> (36) .. (36) <223> k is g or t <220> <221> misc_feature (222) (37) .. (38) <223> n is a, c, g, or t <220> <221> misc_feature (222) (39) .. (39) <223> k is g or t <220> <221> misc_feature (222) (40) .. (41) <223> n is a, c, g, or t <220> <221> misc_feature (222) (42) .. (42) <223> k is g or t <220> <221> misc_feature (222) (43) .. (44) <223> n is a, c, g, or t <220> <221> misc_feature (45). (45) <223> k is g or t <220> <221> misc_feature (222) (46) .. (47) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (48) <223> k is g or t <400> 254 atcgcctaca agaactggga gactgrgnnk nnknnknnkn nknnknnkac cgcgcaaccc 60 gatggcggtg caac 74 <210> 255 <211> 74 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 255 cgcttgtcga accacttgcc gttggcggcg ccagacagga cggcgcagtt ctcggttgca 60 ccgccatcgg gttg 74 <210> 256 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 256 gacatggccg cggaaggc 18 <210> 257 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 257 gcagatgtag ggcaactgat ctct 24 <210> 258 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 258 gccgagatct ggctgggcct ga 22 <210> 259 <211> 63 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (31) .. (32) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (33) <223> k is g or t <220> <221> misc_feature &Lt; 222 > (34) <223> n is a, c, g, or t <220> <221> misc_feature <222> (36) .. (36) <223> k is g or t <220> <221> misc_feature (222) (37) .. (38) <223> n is a, c, g, or t <220> <221> misc_feature (222) (39) .. (39) <223> k is g or t <220> <221> misc_feature (222) (40) .. (41) <223> n is a, c, g, or t <220> <221> misc_feature (222) (42) .. (42) <223> k is g or t <220> <221> misc_feature &Lt; 222 > (43) <223> w is a or t <400> 259 gccgagatct ggctgggcct caacggcagc nnknnknnkn nkwcctgggt ggacatgact 60 ggc 63 <210> 260 <211> 63 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 260 ttgcgcggtg atctcagtct cccagttctt gtaggcgata cgcgcgccag tcatgtccac 60 cca 63 <210> 261 <211> 64 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 261 gactgagatc accgcgcaac ccgatggcgg cttcggcgtg ttcggcgaga actgcgcggt 60 cctg 64 <210> 262 <211> 64 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 262 gactgagatc accgcgcaac ccgatggcgg ctggggcgtg ttcggcgaga actgcgcggt 60 cctg 64 <210> 263 <211> 64 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 263 gactgagatc accgcgcaac ccgatggcgg cttcgggtac ttcggcgaga actgcgcggt 60 cctg 64 <210> 264 <211> 64 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 264 gactgagatc accgcgcaac ccgatggcgg ctgggggtac ttcggcgaga actgcgcggt 60 cctg 64 <210> 265 <211> 64 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 265 gactgagatc accgcgcaac ccgatggcgg ctggggcgtg tggggcgaga actgcgcggt 60 cctg 64 <210> 266 <211> 77 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 266 tgggcctgaa cgacatggcc gccgagggca cctgggtgga tatgactggc gcgcgtatcg 60 cctacaagaa ctgggag 77 <210> 267 <211> 59 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature &Lt; 222 > (21) <223> m is a or c <220> <221> misc_feature &Lt; 222 > (22) <223> n is a, c, g, or t <220> <221> misc_feature (222) (24) .. (24) <223> m is a or c <220> <221> misc_feature (222) (25) .. (26) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (27) <223> m is a or c <220> <221> misc_feature <222> (28) .. (29) <223> n is a, c, g, or t <220> <221> misc_feature (222) (30) .. (30) <223> m is a or c <220> <221> misc_feature (222) (31) .. (32) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (33) <223> m is a or c <220> <221> misc_feature &Lt; 222 > (34) <223> n is a, c, g, or t <400> 267 gttgcgccgc catcgggttg mnnmnnmnnm nnmnnctccc agttcttgta ggcgatacg 59 <210> 268 <211> 44 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 268 caacccgatg gcggcgcaac cgagaactgc gccgtcctgt ctgg 44 <210> 269 <211> 73 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (44) .. (44) <223> m is a or c <220> <221> misc_feature (222) (45) .. (46) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (47) .. (47) <223> m is a or c <220> <221> misc_feature (222) (48) .. (49) <223> n is a, c, g, or t <220> <221> misc_feature (222) (50) .. (50) <223> m is a or c <220> <221> misc_feature (222) (51) .. (52) <223> n is a, c, g, or t <400> 269 tgtagggcaa ttgatccctg cagcgcttgt cgaaccactt gccmnnmnnm nngccagaca 60 ggacggcgca gtt 73 <210> 270 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 270 gccgagatct ggctgggcct gaacgacatg g 31 <210> 271 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 271 Gly Ser Asn Val Thr Gln Thr 1 5 <210> 272 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 272 Phe Gly Ala Phe Gly 1 5 <210> 273 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 273 Gly Ser Ser Val Ser Asp Val 1 5 <210> 274 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 274 Phe Gly Met Trp Gly 1 5 <210> 275 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 275 Ala Gly Arg Tyr Ser Leu Ile 1 5 <210> 276 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 276 Phe Gly Val Phe Gly 1 5 <210> 277 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 277 Gly Ser Arg Arg Ser Gly Val 1 5 <210> 278 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 278 Arg Gly Ala Thr Val Lys Val 1 5 <210> 279 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 279 Ala Asn Pro Ala Gln Asp Leu 1 5 <210> 280 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 280 Phe Gly Val Trp Gly 1 5 <210> 281 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 281 Ala Pro Gly Ala Met Glu Phe 1 5 <210> 282 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 282 Gly Ser Pro Asp Leu Gly Val 1 5 <210> 283 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 283 Gly Ser Val Arg Ser Ala Thr 1 5 <210> 284 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 284 Phe Gly Tyr Phe Gly 1 5 <210> 285 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 285 Gly Ser Pro Val Gly Asp Met 1 5 <210> 286 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 286 Ile Gly Val Trp Gly 1 5 <210> 287 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 287 Gly Ser Ser Lys Leu Gly Leu 1 5 <210> 288 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 288 Gly Ser Val Arg Gly Arg Thr 1 5 <210> 289 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 289 Thr Asn Val Thr Arg Thr Leu 1 5 <210> 290 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 290 Leu Gly Val Trp Gly 1 5 <210> 291 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 291 Gly Ser Ala Leu Thr Asn Thr 1 5 <210> 292 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 292 Ala Asn Arg Arg Arg Thr Met 1 5 <210> 293 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 293 Met Gly Val Trp Gly 1 5 <210> 294 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 294 Gly Ser Ser Val Ser Gly Leu 1 5 <210> 295 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 295 Val Gly Val Phe Gly 1 5 <210> 296 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 296 Gly Ser Trp Leu Gly Asp Val 1 5 <210> 297 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 297 Ser Gly Lys Ala Arg Asp Val 1 5 <210> 298 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 298 Gly Ser Arg Phe Gly His Leu 1 5 <210> 299 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 299 Trp Gly Val Phe Gly 1 5 <210> 300 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 300 Gly Ser Arg Ile Ser Gly Val 1 5 <210> 301 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 301 Ser Gly Lys Arg Arg Thr Val 1 5 <210> 302 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 302 Ser Gly Ser Trp Ala Arg Thr 1 5 <210> 303 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 303 Ala Gly Ala Arg Ala Glu Tyr 1 5 <210> 304 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 304 Trp Gly Val Trp Gly 1 5 <210> 305 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 305 Gly Pro Gly Gln Ala Gly Leu 1 5 <210> 306 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 306 Gly Ser Thr Tyr Thr Asp Leu 1 5 <210> 307 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 307 Gly Thr Arg Met Thr Asn Thr 1 5 <210> 308 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 308 Trp Gly Tyr Phe Gly 1 5 <210> 309 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 309 Gly Ser Leu Leu Thr Gly Leu 1 5 <210> 310 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 310 Tyr Gly Ala Trp Gly 1 5 <210> 311 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 311 Gly Ser Lys Ala Gly Lys Leu 1 5 <210> 312 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 312 Tyr Gly Val Phe Gly 1 5 <210> 313 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 313 Ala Ser Leu Arg Ser Arg Val 1 5 <210> 314 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 314 Tyr Gly Val Trp Gly 1 5 <210> 315 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 315 Gly Asn Pro Ser Gly Ser Val 1 5 <210> 316 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 316 Thr Gly Ala Leu His Gln Val 1 5 <210> 317 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 317 Trp Thr Lys Arg Thr Ala Leu 1 5 <210> 318 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 318 Met Phe Gly Met Gly 1 5 <210> 319 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 319 Trp Thr Leu Ala Lys Asn Leu 1 5 <210> 320 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 320 Leu Phe Gly Arg Gly 1 5 <210> 321 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 321 Val Leu Gly Trp Arg Arg Glu 1 5 <210> 322 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 322 Leu Val Met Pro Met 1 5 <210> 323 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 323 Leu Ala Thr Trp Leu Arg Trp 1 5 <210> 324 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 324 Gln Arg Met Ser Tyr 1 5 <210> 325 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 325 Gln His Leu Gly Ser Phe Trp 1 5 <210> 326 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 326 Val Glu Phe Gln Gly 1 5 <210> 327 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 327 Gly Ser Ala Thr Thr Ala Thr 1 5 <210> 328 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 328 Gly Ser Ala Thr Thr Asp Thr 1 5 <210> 329 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 329 Ser Gly His Trp Arg Ala Val 1 5 <210> 330 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 330 Ala Pro Pro Asp Leu Gly Leu 1 5 <210> 331 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 331 Ala Pro Lys Ser Arg Gln Tyr 1 5 <210> 332 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 332 Val Met Gln Leu Pro Arg Lys 1 5 <210> 333 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 333 Ala Gly Arg Met Gly Leu Val 1 5 <210> 334 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 334 Ala Gly Tyr Thr Lys Gln Pro Ser 1 5 <210> 335 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 335 Leu Leu Leu Arg Asn Gln Pro Pro 1 5 <210> 336 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 336 Gln Glu Pro Ala Lys Gln Pro Thr 1 5 <210> 337 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 337 His Pro Leu Pro Pro Gln Pro Ser 1 5 <210> 338 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 338 His Gln Pro Val Tyr Gln Pro Gly 1 5 <210> 339 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 339 Leu Pro Pro Pro Gly His Pro Gln 1 5 <210> 340 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 340 Asn Gly His Glu Pro Gln Pro Arg 1 5 <210> 341 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 341 Asn Asn Leu Ser Ala Gln Pro Arg 1 5 <210> 342 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 342 Pro Pro Glu Pro Leu His Pro Met 1 5 <210> 343 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 343 Pro Pro Gly Pro His His Pro Met 1 5 <210> 344 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 344 Pro Pro Pro Pro His His Pro Met 1 5 <210> 345 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 345 Arg Pro Ala Leu Val Gln Pro Arg 1 5 <210> 346 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 346 Arg Pro Pro Leu Tyr Gln Pro Gly 1 5 <210> 347 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 347 Arg Thr Pro Pro Trp Gln Pro Glu 1 5 <210> 348 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 348 Pro Pro Pro Pro His His Pro Gln 1 5 <210> 349 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 349 Pro Pro Gly Pro Ala His Pro Gln 1 5 <210> 350 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 350 Leu Ala Gly Trp Gly Met Ser 1 5 <210> 351 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 351 Thr Pro Pro Arg Thr Gln Pro Pro 1 5 <210> 352 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <352> 352 Pro Pro Ala Pro Tyr His Pro Met 1 5 <210> 353 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 353 Gly Val Phe Gly One <210> 354 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 354 Gly Ser Thr Leu Thr Arg Ile 1 5 <210> 355 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 355 Leu Gly Ala Phe Gly 1 5 <210> 356 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 356 Gly Ser Ala Gly Thr Asn Thr 1 5 <210> 357 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 357 Gly Ser Ala His Thr Asp Thr 1 5 <210> 358 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 358 Gly Ser Ala Ile Thr Asp Thr 1 5 <210> 359 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 359 Gly Ser Ala Ile Thr Asn Thr 1 5 <210> 360 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 360 Gly Ser Ala Lys Thr Asp Thr 1 5 <210> 361 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 361 Gly Ser Ala Lys Thr Gly Thr 1 5 <210> 362 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 362 Gly Ser Ala Lys Thr Asn Thr 1 5 <210> 363 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 363 Gly Ser Ala Leu Thr Asp Thr 1 5 <210> 364 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 364 Gly Ser Ala Leu Thr Arg Thr 1 5 <210> 365 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 365 Gly Ser Ala Leu Thr Ser Leu 1 5 <210> 366 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 366 Gly Ser Ala Arg Gly Arg Val 1 5 <210> 367 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 367 Gly Ser Ala Arg Thr Asp Thr 1 5 <210> 368 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 368 Gly Ser Ala Arg Thr Gly Thr 1 5 <210> 369 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 369 Gly Ser Ala Val Thr Asn Thr 1 5 <210> 370 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 370 Gly Ser Ala Tyr Thr Asn Thr 1 5 <210> 371 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 371 Gly Ser Gly Leu Thr Asp Thr 1 5 <210> 372 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 372 Gly Ser Gly Trp Thr Gly Leu 1 5 <210> 373 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 373 Gly Ser Lys Leu Thr Asp Thr 1 5 <210> 374 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 374 Gly Ser Lys Val Ser Gly Leu 1 5 <210> 375 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 375 Gly Ser Lys Val Thr Glu Thr 1 5 <210> 376 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 376 Gly Ser Leu Lys Thr Asp Thr 1 5 <210> 377 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 377 Gly Ser Leu Lys Thr Gln Thr 1 5 <210> 378 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 378 Gly Ser Leu Leu Thr Asp Thr 1 5 <210> 379 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 379 Gly Ser Leu Leu Thr Asn Thr 1 5 <210> 380 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 380 Gly Ser Leu Arg Ser Asp Leu 1 5 <210> 381 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 381 Gly Ser Leu Arg Thr Asp Thr 1 5 <210> 382 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 382 Gly Ser Leu Arg Thr Gly Thr 1 5 <210> 383 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 383 Gly Ser Leu Arg Thr His Thr 1 5 <210> 384 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 384 Gly Ser Leu Arg Thr Asn Thr 1 5 <210> 385 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 385 Gly Ser Met Leu Thr Asp Thr 1 5 <210> 386 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 386 Gly Ser Met Arg Thr Asp Thr 1 5 <210> 387 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 387 Gly Ser Asn His Thr Asp Thr 1 5 <210> 388 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 388 Gly Ser Pro Ile Thr Asp Thr 1 5 <210> 389 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 389 Gly Ser Pro Ile Thr Asn Thr 1 5 <210> 390 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 390 Gly Ser Pro Lys Thr Asp Thr 1 5 <210> 391 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 391 Gly Ser Pro Lys Thr Gly Thr 1 5 <210> 392 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 392 Gly Ser Pro Lys Thr His Thr 1 5 <210> 393 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 393 Gly Ser Pro Leu Thr Asp Thr 1 5 <210> 394 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 394 Gly Ser Pro Leu Thr Asn Thr 1 5 <210> 395 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 395 Gly Ser Pro Arg Thr Asp Thr 1 5 <210> 396 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 396 Gly Ser Pro Arg Thr Glu Thr 1 5 <210> 397 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 397 Gly Ser Pro Arg Thr Gly Thr 1 5 <210> 398 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 398 Gly Ser Pro Arg Thr His Thr 1 5 <210> 399 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 399 Gly Ser Pro Arg Thr Asn Thr 1 5 <210> 400 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 400 Gly Ser Pro Arg Thr Gln Thr 1 5 <210> 401 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 401 Gly Ser Pro Arg Thr Ser Val 1 5 <210> 402 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 402 Gly Ser Pro Thr Thr Asp Thr 1 5 <210> 403 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 403 Gly Ser Pro Val Asn Asp Val 1 5 <210> 404 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 404 Gly Ser Pro Val Thr Asp Thr 1 5 <210> 405 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 405 Gly Ser Pro Val Thr Gly Thr 1 5 <210> 406 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 406 Gly Ser Pro Val Thr Asn Thr 1 5 <210> 407 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 407 Gly Ser Gln Leu Thr Asp Thr 1 5 <210> 408 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 408 Gly Ser Gln Leu Thr Asn Thr 1 5 <210> 409 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 409 Gly Ser Gln Arg Thr Asp Thr 1 5 <210> 410 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 410 Gly Ser Arg Ala Thr Asp Thr 1 5 <210> 411 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 411 Gly Ser Arg His Thr Asp Thr 1 5 <210> 412 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 412 Gly Ser Arg Leu Thr Asp Thr 1 5 <210> 413 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 413 Gly Ser Arg Leu Thr Asn Thr 1 5 <210> 414 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 414 Gly Ser Arg Arg Thr Asp Thr 1 5 <210> 415 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 415 Gly Ser Ser Ile Thr Asp Thr 1 5 <210> 416 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 416 Gly Ser Ser Lys Thr Asn Thr 1 5 <210> 417 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 417 Gly Ser Ser Leu Thr Asp Thr 1 5 <210> 418 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 418 Gly Ser Ser Leu Thr Asn Thr 1 5 <210> 419 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 419 Gly Ser Ser Arg Thr Asp Thr 1 5 <210> 420 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 420 Gly Ser Ser Arg Thr Asn Thr 1 5 <210> 421 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 421 Gly Ser Ser Val Thr Asn Thr 1 5 <210> 422 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 422 Gly Ser Ser Val Thr Ser Thr 1 5 <210> 423 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 423 Gly Ser Thr Leu Thr Asp Thr 1 5 <210> 424 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 424 Gly Ser Thr Leu Thr Asn Thr 1 5 <210> 425 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 425 Gly Ser Thr Met Thr Gln Thr 1 5 <210> 426 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 426 Gly Ser Thr Arg Thr Asp Thr 1 5 <210> 427 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 427 Gly Ser Thr Arg Thr Asn Thr 1 5 <210> 428 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 428 Gly Ser Val Ile Thr Gly Thr 1 5 <210> 429 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 429 Gly Ser Val Ile Thr Asn Thr 1 5 <210> 430 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 430 Gly Ser Val Lys Thr Asp Thr 1 5 <210> 431 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 431 Gly Ser Val Leu Thr Asp Thr 1 5 <210> 432 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 432 Gly Ser Val Leu Thr Gly Thr 1 5 <210> 433 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 433 Gly Ser Val Leu Thr Asn Thr 1 5 <210> 434 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 434 Gly Ser Val Arg Thr Asp Thr 1 5 <210> 435 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 435 Gly Ser Val Arg Thr Glu Ser 1 5 <210> 436 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 436 Gly Ser Val Arg Thr Gly Thr 1 5 <210> 437 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 437 Gly Ser Val Arg Thr Asn Thr 1 5 <210> 438 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 438 Gly Ser Val Thr Thr Asp Thr 1 5 <210> 439 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 439 Gly Ser Trp Gly Ser Gly Ile 1 5 <210> 440 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 440 Gly Ser Trp Leu Thr Asp Thr 1 5 <210> 441 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 441 Gly Ser Tyr Leu Thr Asn Thr 1 5 <210> 442 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 442 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 443 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 443 Ala Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 444 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 444 Asn Ala Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 445 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 445 Asn Gly Ala Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 446 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 446 Asn Gly Ser Ala Ala Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 447 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 447 Asn Gly Ser Ala Leu Ala Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 448 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 448 Asn Gly Ser Ala Leu Thr Ala Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 449 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 449 Asn Gly Ser Ala Leu Thr Asn Ala Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 450 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 450 Asn Gly Ser Ala Leu Thr Asn Thr Ala Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 451 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 451 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Ala 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 452 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 452 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Ala Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 453 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 453 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Ala Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 454 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 454 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Ala Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 455 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 455 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Ala Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 456 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 456 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Ala Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 457 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 457 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Ala Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 458 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 458 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ala Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 459 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 459 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Ala Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 460 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 460 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Ala Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 461 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 461 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Ala Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 462 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 462 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Ala             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 463 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 463 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Ala Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 464 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 464 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Ala Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 465 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 465 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Ala Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg     50 55 <210> 466 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 466 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Ala Cys Arg     50 55 <210> 467 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 467 Asn Gly Ser Ala Leu Thr Asn Thr Trp Val Asp Met Thr Gly Ala Arg 1 5 10 15 Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly             20 25 30 Gly Phe Gly Val Phe Gly Glu Asn Cys Ala Val Leu Ser Gly Ala Ala         35 40 45 Asn Gly Lys Trp Phe Asp Lys Arg Cys Ala     50 55 <210> 468 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (4) .. (11) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (14) .. (16) <223> Xaa can be any naturally occurring amino acid <400> 468 Asn Trp Glu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Gly Xaa Xaa Xaa 1 5 10 15 Asn      <210> 469 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 469 Ala Ala Glu Gly Thr 1 5 <210> 470 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature <222> (1) (2) <223> n is a, c, g, or t <220> <221> misc_feature (222) (3) .. (3) <223> k is g or t <220> <221> misc_feature <222> (4) <223> n is a, c, g, or t <220> <221> misc_feature <222> (6) <223> k is g or t <220> <221> misc_feature (222) (7) .. (8) <223> n is a, c, g, or t <220> <221> misc_feature (222) (9) .. (9) <223> k is g or t <220> <221> misc_feature (222) (10) .. (11) <223> n is a, c, g, or t <220> <221> misc_feature (222) (12) .. (12) <223> k is g or t <220> <221> misc_feature (222) (13) .. (14) <223> n is a, c, g, or t <220> <221> misc_feature (222) (15) .. (15) <223> k is g or t <220> <221> misc_feature <222> (16) .. (17) <223> n is a, c, g, or t <220> <221> misc_feature (222) (18) .. (18) <223> k is g or t <220> <221> misc_feature (222) (19) .. (20) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (21) <223> k is g or t <400> 470 nnknnknnkn nknnknnknn k 21 <210> 471 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature <222> (1) (2) <223> n is a, c, g, or t <220> <221> misc_feature (222) (3) .. (3) <223> k is g or t <220> <221> misc_feature <222> (4) <223> n is a, c, g, or t <220> <221> misc_feature <222> (6) <223> k is g or t <220> <221> misc_feature (222) (7) .. (8) <223> n is a, c, g, or t <220> <221> misc_feature (222) (9) .. (9) <223> k is g or t <220> <221> misc_feature (222) (10) .. (11) <223> n is a, c, g, or t <220> <221> misc_feature (222) (12) .. (12) <223> k is g or t <220> <221> misc_feature (222) (13) .. (14) <223> n is a, c, g, or t <220> <221> misc_feature (222) (15) .. (15) <223> k is g or t <400> 471 nnknnknnkn nknnk 15 <210> 472 <211> 12 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature <222> (1) (2) <223> n is a, c, g, or t <220> <221> misc_feature (222) (3) .. (3) <223> k is g or t <220> <221> misc_feature <222> (4) <223> n is a, c, g, or t <220> <221> misc_feature <222> (6) <223> k is g or t <220> <221> misc_feature (222) (7) .. (8) <223> n is a, c, g, or t <220> <221> misc_feature (222) (9) .. (9) <223> k is g or t <220> <221> misc_feature (222) (10) .. (11) <223> n is a, c, g, or t <220> <221> misc_feature (222) (12) .. (12) <223> k is g or t <400> 472 nnknnknnkn nk 12 <210> 473 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 473 Asp Met Ala Ala Glu Gly Thr 1 5 <210> 474 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature <222> (1) (2) <223> n is a, c, g, or t <220> <221> misc_feature (222) (3) .. (3) <223> s is g or c <220> <221> misc_feature <222> (4) <223> n is a, c, g, or t <220> <221> misc_feature <222> (6) <223> s is g or c <220> <221> misc_feature (222) (7) .. (8) <223> n is a, c, g, or t <220> <221> misc_feature (222) (9) .. (9) <223> s is g or c <220> <221> misc_feature (222) (10) .. (11) <223> n is a, c, g, or t <220> <221> misc_feature (222) (12) .. (12) <223> s is g or c <220> <221> misc_feature (222) (13) .. (14) <223> n is a, c, g, or t <220> <221> misc_feature (222) (15) .. (15) <223> s is g or c <220> <221> misc_feature <222> (16) .. (17) <223> n is a, c, g, or t <220> <221> misc_feature (222) (18) .. (18) <223> s is g or c <220> <221> misc_feature (222) (19) .. (20) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (21) <223> s is g or c <400> 474 nnsnnsnnsn nsnnsnnsnn s 21 <210> 475 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature <222> (1) (2) <223> n is a, c, g, or t <220> <221> misc_feature (222) (3) .. (3) <223> s is g or c <220> <221> misc_feature <222> (4) <223> n is a, c, g, or t <220> <221> misc_feature <222> (6) <223> s is g or c <220> <221> misc_feature (222) (7) .. (8) <223> n is a, c, g, or t <220> <221> misc_feature (222) (9) .. (9) <223> s is g or c <220> <221> misc_feature (222) (10) .. (11) <223> n is a, c, g, or t <220> <221> misc_feature (222) (12) .. (12) <223> s is g or c <220> <221> misc_feature (222) (13) .. (14) <223> n is a, c, g, or t <220> <221> misc_feature (222) (15) .. (15) <223> s is g or c <400> 475 nnsnnsnnsn nsnns 15 <210> 476 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature <222> (1) (2) <223> n is a, c, g, or t <220> <221> misc_feature (222) (3) .. (3) <223> k is g or t <220> <221> misc_feature <222> (4) <223> n is a, c, g, or t <220> <221> misc_feature <222> (6) <223> k is g or t <220> <221> misc_feature (222) (7) .. (8) <223> n is a, c, g, or t <220> <221> misc_feature (222) (9) .. (9) <223> k is g or t <220> <221> misc_feature (222) (10) .. (11) <223> n is a, c, g, or t <220> <221> misc_feature (222) (12) .. (12) <223> k is g or t <220> <221> misc_feature (222) (13) .. (14) <223> n is a, c, g, or t <220> <221> misc_feature (222) (15) .. (15) <223> k is g or t <220> <221> misc_feature <222> (16) .. (17) <223> n is a, c, g, or t <220> <221> misc_feature (222) (18) .. (18) <223> k is g or t <400> 476 nnknnknnkn nknnknnk 18 <210> 477 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 477 Thr Glu Ile Thr Ala Gln Pro Asp Gly Gly Lys Thr Glu 1 5 10 <210> 478 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> MISC_FEATURE (222) (1) .. (8) <223> Xaa represents a random amino acid encoded by the nucleotide        sequence nnk (n is a, c, g, or t; k is g or t) <220> <221> MISC_FEATURE (222) (11) .. (13) <223> Xaa represents a random amino acid encoded by the nucleotide        sequence nnk (n is a, c, g, or t; k is g or t) <400> 478 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Gly Xaa Xaa Xaa 1 5 10 <210> 479 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 479 Glu Thr Glu Ile Thr Ala 1 5 <210> 480 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature <222> (1) (2) <223> n is a, c, g, or t <220> <221> misc_feature (222) (3) .. (3) <223> k is g or t <220> <221> misc_feature <222> (4) <223> n is a, c, g, or t <220> <221> misc_feature <222> (6) <223> k is g or t <220> <221> misc_feature (222) (7) .. (8) <223> n is a, c, g, or t <220> <221> misc_feature (222) (9) .. (9) <223> k is g or t <220> <221> misc_feature (222) (10) .. (11) <223> n is a, c, g, or t <220> <221> misc_feature (222) (12) .. (12) <223> k is g or t <220> <221> misc_feature (222) (13) .. (14) <223> n is a, c, g, or t <220> <221> misc_feature (222) (15) .. (15) <223> k is g or t <220> <221> misc_feature <222> (16) .. (17) <223> n is a, c, g, or t <220> <221> misc_feature (222) (18) .. (18) <223> k is g or t <220> <221> misc_feature (222) (19) .. (20) <223> n is a, c, g, or t <220> <221> misc_feature &Lt; 222 > (21) <223> k is g or t <220> <221> misc_feature &Lt; 222 > (22) <223> n is a, c, g, or t <220> <221> misc_feature (222) (24) .. (24) <223> k is g or t <400> 480 nnknnknnkn nknnknnknn knnk 24 <210> 481 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 481 Thr Glu Ile Thr Ala 1 5 <210> 482 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <220> <221> misc_feature (222) (9) .. (13) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (16) .. (16) <223> Xaa can be any naturally occurring amino acid <220> <221> MISC_FEATURE <222> (19). (19) &Lt; 223 > Xaa is Phe or Leu <220> <221> MISC_FEATURE &Lt; 222 > (21) <223> Xaa is Phe, Tyr, Val, or Asp <220> <221> MISC_FEATURE (222) (22) .. (22) <223> Xaa is Phe, Trp, Leu, or Cys <400> 482 Arg Ile Ala Tyr Lys Asn Trp Glu Xaa Xaa Xaa Xaa Xaa Gln Pro Xaa 1 5 10 15 Gly Gly Xaa Gly Xaa Xaa Gly Glu Asn Cys Ala Val Leu Ser             20 25 30 <210> 483 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 483 His Met Lys Cys Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu 1 5 10 15 Ala Ser Glu Asp Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln             20 25 30 Thr Gly Ser Glu Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val         35 40 45 Gly Asn Glu Ala Glu Ile Trp Leu Gly Leu Asn Asp Met Ala Ala Glu     50 55 60 Gly Thr Trp Val Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp 65 70 75 80 Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly Gly Lys Thr Glu Asn Cys                 85 90 95 Ala Val Leu Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys             100 105 110 Arg Asp Gln Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val         115 120 125 <210> 484 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 484 Gly Asn Lys Phe Phe Leu Thr Asn Gly Glu Ile Met Thr Phe Glu Lys 1 5 10 15 Val Lys Ala Leu Cys Val Lys Phe Gln Ala Ser Val Ala Thr Pro Arg             20 25 30 Asn Ala Ala Glu Asn Gly Ala Ile Gln Asn Leu Ile Lys Glu Glu Ala         35 40 45 Phe Leu Gly Ile Thr Asp Glu Lys Thr Glu Gly Gln Phe Val Asp Leu     50 55 60 Thr Gly Asn Arg Leu Thr Tyr Thr Asn Trp Asn Glu Gly Glu Pro Asn 65 70 75 80 Asn Ala Gly Ser Asp Glu Asp Cys Val Leu Leu Leu Lys Asn Gly Gln                 85 90 95 Trp Asn Asp Val Pro Cys Ser Thr Ser His Leu Ala Val Cys Glu Phe             100 105 110 Pro yle          <210> 485 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 485 Lys Tyr Phe Met Ser Ser Val Arg Arg Met Pro Leu Asn Arg Ala Lys 1 5 10 15 Ala Leu Cys Ser Glu Leu Gln Gly Thr Val Ala Thr Pro Arg Asn Ala             20 25 30 Glu Glu Asn Arg Ala Ile Gln Asn Val Ala Lys Asp Val Ala Phe Leu         35 40 45 Gly Ile Thr Asp Gln Arg Thr Glu Asn Val Phe Glu Asp Leu Thr Gly     50 55 60 Asn Arg Val Arg Tyr Thr Asn Trp Asn Glu Gly Glu Pro Asn Asn Val 65 70 75 80 Gly Ser Gly Glu Asn Cys Val Val Leu Leu Thr Asn Gly Lys Trp Asn                 85 90 95 Asp Val Pro Cys Ser Asp Ser Phe Leu Val Val Cys Glu Phe Ser Asp             100 105 110 <210> 486 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 486 Gly Glu Lys Ile Phe Lys Thr Ala Gly Phe Val Lys Pro Phe Thr Glu 1 5 10 15 Ala Gln Leu Leu Cys Thr Gln Ala Gly Gly Gln Leu Ala Ser Pro Arg             20 25 30 Ser Ala Ala Glu Asn Ala Ala Leu Gln Gln Leu Val Val Ala Lys Asn         35 40 45 Glu Ala Ala Phe Leu Ser Met Thr Asp Ser Lys Thr Glu Gly Lys Phe     50 55 60 Thr Tyr Pro Thr Gly Glu Ser Leu Val Tyr Ser Asn Trp Ala Pro Gly 65 70 75 80 Glu Pro Asn Asp Asp Gly Gly Ser Glu Asp Cys Val Glu Ile Phe Thr                 85 90 95 Asn Gly Lys Trp Asn Asp Arg Ala Cys Gly Glu Lys Arg Leu Val Val             100 105 110 Cys glu phe         115 <210> 487 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 487 Gly Lys Lys Phe Phe Val Thr Asn His Glu Arg Met Pro Phe Ser Lys 1 5 10 15 Val Lys Ala Leu Cys Ser Glu Leu Arg Gly Thr Val Ala Ile Pro Arg             20 25 30 Asn Ala Glu Glu Asn Lys Ala Ile Gln Glu Val Ala Lys Thr Ser Ala         35 40 45 Phe Leu Gly Ile Thr Asp Glu Val Thr Glu Gly Gln Phe Met Tyr Val     50 55 60 Thr Gly Gly Arg Leu Thr Tyr Ser Asn Trp Lys Lys Asp Glu Pro Asn 65 70 75 80 Asp Val Gly Ser Gly Glu Asp Cys Val Thr Ile Val Asp Asn Gly Leu                 85 90 95 Trp Asn Asp Val Ser Cys Gln Ala Ser His Thr Ala Val Cys Glu Phe             100 105 110 Pro ala          <210> 488 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 488 Gly Asp Lys Val Phe Ser Thr Asn Gly Gln Ser Val Asn Phe Asp Thr 1 5 10 15 Ile Lys Glu Met Cys Thr Arg Ala Gly Gly Asn Ile Ala Val Pro Arg             20 25 30 Thr Pro Glu Glu Asn Glu Ala Ile Ala Ser Ile Ala Lys Lys Tyr Asn         35 40 45 Asn Tyr Val Tyr Leu Gly Met Ile Glu Asp Gln Thr Pro Gly Asp Phe     50 55 60 His Tyr Leu Asp Gly Ala Ser Val Ser Tyr Thr Asn Trp Tyr Pro Gly 65 70 75 80 Glu Pro Arg Gly Gln Gly Lys Glu Lys Cys Val Glu Met Tyr Thr Asp                 85 90 95 Gly Thr Trp Asn Asp Arg Gly Cys Leu Gln Tyr Arg Leu Ala Val Cys             100 105 110 Glu phe          <210> 489 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 489 Thr Lys Phe Gln Gly His Cys Tyr Arg His Phe Pro Asp Arg Glu Thr 1 5 10 15 Trp Val Asp Ala Glu Arg Arg Cys Arg Glu Gln Gln Ser His Leu Ser             20 25 30 Ser Ile Val Thr Pro Glu Glu Gln Glu Phe Val Asn Lys Asn Ala Gln         35 40 45 Asp Tyr Gln Trp Ile Gly Leu Asn Asp Arg Thr Ile Glu Gly Asp Phe     50 55 60 Arg Trp Ser Asp Gly His Ser Leu Gln Phe Glu Lys Trp Arg Pro Asn 65 70 75 80 Gln Pro Asp Asn Phe Phe Ala Thr Gly Glu Asp Cys Val Val Met Ile                 85 90 95 Trp His Glu Arg Gly Glu Trp Asn Asp Val Pro Cys Asn Tyr Gln Leu             100 105 110 Pro Phe Thr Cys Lys Lys Gly         115 <210> 490 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 490 Ser His Cys Tyr Ala Leu Phe Leu Ser Pro Lys Ser Trp Thr Asp Ala 1 5 10 15 Asp Leu Ala Cys Gln Lys Arg Pro Ser Gly Asn Leu Val Ser Val Leu             20 25 30 Ser Gly Ala Glu Gly Ser Phe Val Ser Ser Leu Val Lys Ser Ile Gly         35 40 45 Asn Ser Tyr Ser Tyr Val Trp Ile Gly Leu His Asp Pro Thr Gln Gly     50 55 60 Thr Glu Pro Asn Gly Glu Gly Trp Glu Trp Ser Ser Ser Asp Val Met 65 70 75 80 Asn Tyr Phe Ala Trp Glu Arg Asn Pro Ser Thr Ile Ser Ser Pro Gly                 85 90 95 His Cys Ala Ser Leu Ser Arg Ser Thr Ala Phe Leu Arg Trp Lys Asp             100 105 110 Tyr Asn Cys Asn Val Arg Leu Pro Tyr Val Cys Lys Phe Thr Asp         115 120 125 <210> 491 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 491 Asp Lys Cys Tyr Tyr Phe Ser Val Glu Lys Glu Ile Phe Glu Asp Ala 1 5 10 15 Lys Leu Phe Cys Glu Asp Lys Ser Ser His Leu Val Phe Ile Asn Thr             20 25 30 Arg Glu Glu Gln Gln Trp Ile Lys Lys Gln Met Val Gly Arg Glu Ser         35 40 45 His Trp Ile Gly Leu Thr Asp Ser Glu Arg Glu Asn Glu Trp Lys Trp     50 55 60 Leu Asp Gly Thr Ser Pro Asp Tyr Lys Asn Trp Lys Ala Gly Gln Pro 65 70 75 80 Asp Asn Trp Gly His Gly His Gly Pro Gly Glu Asp Cys Ala Gly Leu                 85 90 95 Ile Tyr Ala Gly Gln Trp Asn Asp Phe Gln Cys Glu Asp Val Asn Asn             100 105 110 Phe Ile Cys Glu Lys Asp Arg         115 <210> 492 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 492 Asp Lys Cys Tyr Tyr Phe Ser Leu Glu Lys Glu Ile Phe Glu Asp Ala 1 5 10 15 Lys Leu Phe Cys Glu Asp Lys Ser Ser His Leu Val Phe Ile Asn Ser             20 25 30 Arg Glu Glu Gln Gln Trp Ile Lys Lys His Thr Val Gly Arg Glu Ser         35 40 45 His Trp Ile Gly Leu Thr Asp Ser Glu Gln Glu Ser Glu Trp Lys Trp     50 55 60 Leu Asp Gly Ser Pro Val Asp Tyr Lys Asn Trp Lys Ala Gly Gln Pro 65 70 75 80 Asp Asn Trp Gly Ser Gly His Gly Pro Gly Glu Asp Cys Ala Gly Leu                 85 90 95 Ile Tyr Ala Gly Gln Trp Asn Asp Phe Gln Cys Asp Glu Ile Asn Asn             100 105 110 Phe Ile Cys Glu Lys Glu Arg Glu         115 120 <210> 493 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 493 Gly Asn Cys Tyr Phe Met Ser Asn Ser Gln Arg Asn Trp His Asp Ser 1 5 10 15 Val Thr Ala Cys Gln Glu Val Arg Ala Gln Leu Val Val Ile Lys Thr             20 25 30 Ala Glu Glu Gln Asn Phe Leu Gln Leu Gln Thr Ser Arg Ser Asn Arg         35 40 45 Phe Ser Trp Met Gly Leu Ser Asp Leu Asn Gln Glu Gly Thr Trp Gln     50 55 60 Trp Val Asp Gly Ser Pro Leu Ser Pro Ser Phe Gln Arg Tyr Trp Asn 65 70 75 80 Ser Gly Glu Pro Asn Asn Ser Gly Asn Glu Asp Cys Ala Glu Phe Ser                 85 90 95 Gly Ser Gly Trp Asn Asp Asn Arg Cys Asp Val Asp Asn Tyr Trp Ile             100 105 110 Cys Lys Lys Pro Ala Ala Cys Phe Arg         115 120 <210> 494 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 494 Pro Ala Arg Gln Pro Gln Pro Gly 1 5

Claims (34)

A polypeptide comprising a trimerizing domain and at least one polypeptide sequence that binds human IL-23R without activating the IL-23 heterodimeric receptor. The polypeptide of claim 1, wherein said polypeptide does not bind at least one of human IL-12Rβ1 or human IL-12Rβ2. The polypeptide of claim 1, wherein said polypeptide competes with natural human IL-23 for binding to human IL-23R. The method of claim 1, wherein the trimerization domain has up to 5 amino acid substitutions at positions 26, 30, 33, 36, 37, 40, 31, 42, 45, 46, 47, 48, 49, 50, and 51. A polypeptide comprising a polypeptide of human tetranectin trimerization domain (SEQ ID NO: 108), wherein the three trimerization domains form a trimer complex. The method of claim 1, wherein the trimerization domain is hTRAF3 [SEQ ID NO: _], hMBP [SEQ ID NO: _], hSPC300 [SEQ ID NO: _], hNEMO [SEQ ID NO: _], hcubiline (hcubilin) [SEQ ID NO: _], hThrombospondin [SEQ ID NO: _], and the neck region [SEQ ID NO: _] of human SP-D, of bovine SP-D Neck area [SEQ ID NO: _], neck area of rat SP-D [SEQ ID NO: _], neck area of bovine conglutinin [SEQ ID NO: _]; Neck region of bovine collector [SEQ ID NO: _]; And a trimerized polypeptide selected from the group consisting of neck region [SEQ ID NO: _] of human SP-D. The polypeptide of claim 1, wherein human IL-23R comprises the sequence of SEQ ID NO: 5. The method of claim 1, wherein the at least one polypeptide that binds IL-23R is linked to one of the N-terminus and C-terminus of the trimerization domain and is located at the rest of the N-terminus and C-terminus. A polypeptide further comprising a modulator. The method of claim 1, wherein the at least one polypeptide that binds IL-23R comprises a C-type lectin-like domain (CTLD) and comprises one of loops 1, 2, 3, or 4 of loop segment A or loop segment B of CTLD. A polypeptide comprising a polypeptide sequence, one of which binds to IL-23. 8. The polypeptide of claim 7 wherein the polypeptide sequence of the CTLD is selected from the group consisting of SEQ ID NOs: 133, 134, 135, 167, 137, 138, 139, 140, and 141. The method of claim 1, wherein the polypeptide that binds IL-23 is linked to one of the N-terminus and C-terminus of the trimerization domain, and adds a modulator of inflammation located at the rest of the N-terminus and C-terminus. Polypeptides, including. The polypeptide of claim 1, having a polypeptide that binds to IL-23 linked to each of the N-terminus and C-terminus, wherein the N-terminal polypeptide is the same as or different from the C-terminal polypeptide. The polypeptide of claim 1, wherein said polypeptide is a fusion protein. The method of claim 1, wherein the polypeptide that binds IL-23R is located at one of the N-terminus and C-terminus of the trimerization domain and has a tumor associated antigen (TAA) or tumor at the rest of the N-terminus and C-terminus. A polypeptide further comprising a polypeptide sequence that binds to a specific antigen (TSA). The polypeptide of claim 1, further comprising a therapeutic agent covalently attached to the polypeptide. A trimer complex comprising the three polypeptides of claim 1. 16. The trimer complex of claim 15 wherein said trimerization domain is a tetranectin trimerization structural element. A method for preventing activation of IL-23R by IL-23 in a cell expressing IL-23R, comprising contacting the cell expressing IL-23R with the trimer complex of claim 15. A pharmaceutical composition comprising the trimer complex of claim 16 and at least one pharmaceutically acceptable excipient. A method of treating an immune disorder in a subject comprising administering the pharmaceutical composition of claim 18 to the animal. The method of claim 19, further comprising administering a modulator of inflammation to the subject simultaneously or sequentially. A method of treating cancer in an animal comprising administering the pharmaceutical composition of claim 18 to a subject in need thereof. The method of claim 21, further comprising administering at least one of the chemotherapeutic or cytotoxic agent to the animal simultaneously or sequentially. a) selecting a first polypeptide that binds IL-23R; And
b) fusing the first polypeptide with either the N-terminus or the C-terminus of the multimerization domain. 24. The method of claim 23,
a) selecting a second polypeptide sequence that is a modulator of inflammation; And
b) fusing said second polypeptide with the rest of the N-terminus or C-terminus of said multimerization domain. The method of claim 21, wherein in step a) the polypeptide is selected to not bind to at least one of IL-12Rβ1 or IL-12Rβ2. A method of preparing a polypeptide complex that prevents activation of IL-23R in a cell expressing IL-23R, comprising trimerizing three polypeptides prepared according to claim 23. a) generating a library of polypeptides comprising CTLDs comprising at least one randomized loop region; And
b) selecting from said library a first polypeptide that binds to IL-23R but not to at least one of IL-12Rβ1 or IL-12Rβ2. The method of claim 27, further comprising (c) attaching the selected polypeptide to the N-terminus or C-terminus of the multimerization domain. A polypeptide that competes with natural human IL-23 for binding to natural IL-23R, wherein the polypeptide does not activate human IL-23R and does not bind to at least one of IL-12β1 or IL-12β2. 31. The polypeptide of claim 30, wherein the polypeptide is CTLD modified in one of loops 1, 2, 3 or 4 of loop segment A or loop segment B for binding to IL-23R. 31. The polypeptide of claim 30 comprising a polypeptide selected from the group consisting of SEQ ID NOs: 133, 134, 135, 167, 137, 138, 139, 140 and 141. An isolated polynucleotide encoding a polypeptide comprising the polypeptide of claim 1. A vector comprising the polynucleotide of claim 32. A host cell comprising the vector of claim 34.

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