RU2774895C2 - T-cells modified with chimeric antigen receptor targeted to cs1 for treatment of amyloidosis al - Google Patents

Abstract

FIELD: genetic engineering; molecular biology; medicine.

SUBSTANCE: group of inventions relates to the field of genetic engineering, molecular biology and medicine, in particular to methods for the treatment of amyloidosis of a light chain, using chimeric antigen receptors (hereinafter – CAR) targeted to CS1. The method for the treatment of amyloidosis of a light chain includes the administration to a patient of a population of human T-cells transduced by a vector containing an expression cassette encoding CAR, or T-cells expressing CAR. The chimeric antigen receptor contains an amino acid sequence selected from SEQ ID NO: 30, 31, 33, 34, 36, 37, 39, 40, 42, 43, 44 and 45.

EFFECT: inventions allow for an increase in the efficiency of therapy of amyloidosis of a light chain by CAR T-cells.

10 cl, 9 dwg, 5 tbl, 7 ex

Description

PRIOR ART

Light chain amyloidosis (AL amyloidosis) is characterized by a clonal population of plasma cells in the bone marrow that produce monoclonal kappa or lambda restriction light chains. Amyloidogenic light chains misfold, thereby forming beta-pleated conformations that combine to form fibers. These amyloid fibers are deposited in tissues and organs, including the heart, kidneys, and peripheral nerves, where they progressively interfere with structure and function (Falk et al. 1997 N Engl J Med 337: 898-909). Without treatment, the prognosis is poor, with a median survival of only 8 months (Kyle et al. 1997 N Engl J Med 336:1202-120). The treatment of AL amyloidosis is mainly focused on targeting the underlying plasma cell clone to stop the production of amyloid fibers and allow organ repair. Treatment options include chemotherapeutic regimens derived from regimens used to treat multiple myeloma, as well as high dose melphalan followed by autologous stem cell transplantation. Although patients with AL amyloidosis have benefited from many of the advances made generally in the treatment of plasma cell diseases, treatment is complicated by the unstable nature of the population due to amyloid-related organ dysfunction and the need to obtain a rapid, profound response to prevent further fiber deposition by residual clone. While long-term remissions are possible using both stem cell transplantation and novel agents, including proteasome inhibitors and immunomodulatory drugs, novel, well-tolerated and effective treatments are required.

SUMMARY OF THE INVENTION

This document describes methods for the treatment of AL amyloidosis using chimeric antigen receptors (CARs) targeting the cell surface CS1 glycoprotein, which is a member of the signaling lymphocyte-activating molecule (SLAM) receptor family. The results of studies evaluating bone marrow samples from patients with plasma cell diseases are described below. These patients had complete clinical assessments for a diagnosis of either multiple myeloma (MM) or AL amyloidosis, including characterization of the hematologic clone as well as organ involvement. Multicolor flow cytometry analysis was used to distinguish between malignant and normal plasma cells by analyzing abnormal ratios of intracellular kappa/lambda circuits. A highly deviant kappa to lambda ratio is a reliable indicator of a malignant AL amyloidosis clone. Clonal plasma cell populations were then assessed for B cell maturation antigen (BCMA) and CS1 expression. These studies demonstrated that CS1 is expressed on clonal plasma cells of AL amyloidosis patients and that BCMA is not significantly expressed on plasma cells of AL amyloidosis patients. This is different from MM where the BCMA is believed to be ubiquitously expressed. Additional studies described below indicate that CS1-targeted CAR can effectively eliminate CS1-expressing cells in a mouse model.

This document describes a method for the treatment of light chain amyloidosis comprising administering to a patient in need thereof a population of human T cells transduced with a vector containing an expression cassette encoding a chimeric antigen receptor, wherein the chimeric antigen receptor contains: scFv (single chain variable fragment) against CS1 ; spacer area; transmembrane domain; cosignaling domain and CD3 signaling domain

In various embodiments: the chimeric antigen receptor comprises: anti-CS1 scFv; spacer area; transmembrane domain of CD28; CD28 cosignaling domain and CD3 signaling domain chimeric antigen receptor contains: anti-CS1 scFv; spacer area; transmembrane domain of CD4; 4-1 BB cosignaling domain and CD3 signaling domain chimeric antigen receptor contains: anti-CS1 scFv; a spacer region containing an amino acid sequence selected from SEQ ID NOs: 2-5 and 9-12; transmembrane domain of CD4; 4-1 BB cosignaling domain and CD3 signaling domain chimeric antigen receptor contains: anti-CS1 scFv; a spacer region containing an amino acid sequence selected from SEQ ID NOs: 2-5 and 9-12; transmembrane domain of CD28; CD28 cosignaling domain and CD3 signaling domain ζ; the chimeric antigen receptor contains: anti-CS1 scFv; a spacer containing an amino acid sequence selected from SEQ ID NOs: 2-5 and 9-12; transmembrane domain of CD4; a 4-1 BB cosignaling domain and a CD3 ζ signaling domain; the chimeric antigen receptor contains: a spacer containing an amino acid sequence selected from SEQ ID NOs: 2-5 and 9-12; transmembrane domain of CD28; CD28 cosignaling domain and CD3 signaling domain ζ; the chimeric antigen receptor contains an amino acid sequence at least 95% identical to the amino acid sequence selected from: SEQ ID NOs: 30, 31, 33, 34, 36, 37, 39, 40, 42, 43, 44 and 45; the chimeric antigen receptor contains an amino acid sequence identical to the amino acid sequence selected from: SEQ ID NOs: 30, 31, 33, 34, 36, 37, 39, 40, 42, 43, 44 and 45; the chimeric antigen receptor contains an amino acid sequence identical to the amino acid sequence selected from: SEQ ID NOs: 30, 31, 33, 34, 36, 37, 39, 40, 42, 43, 44 and 45, each having no more than 5 single amino acid substitutions; at least 20%, 30%, or 40% of transduced human T cells are central memory T cells; at least 30% of transduced human T cells are CD4+ and CD62L+ or CD8+ and CD62L+; the human T cell population is autologous to the patient; and the human T cell population is allogeneic to the patient.

DESCRIPTION OF THE DRAWINGS

FIG. 1A-C show the results of studies demonstrating that the neoplastic plasma cell in AL amyloidosis preferentially expresses CS1. (A) Mononuclear bone marrow cells were isolated from patients diagnosed with AL amyloidosis and multiple myeloma and labeled with antibodies against CS1 and BCMA followed by intracellular κ/λ staining. CS1 and BCMA expression was analyzed on the sorted dominant κ light chain. (B) Shown are the percentages of CS1 and BCMA positive cells in dominant AL amyloidosis clones (N=14). (C) The percentages of CS1- and BCMA-positive cells in dominant clones of multiple myeloma are shown (N is 10).

FIG. 2A-D show the results of studies using CS1-targeted CAR T cells showing that they are cytotoxic against CS1 positive cells and induce reliable tumor regression in mice. (A) Diagrams of CAR CS1 constructs, each including an antigen-specific scFv, an IgG4 hinge region, a CD28 co-stimulatory domain, and a CD3ζ signaling domain. The IgG4 hinge region was shortened by the deletion of the CH2 portion. The CAR sequence is followed by the T2A ribosome jump sequence and then the EGFRt/suicide gene tracking coding sequence. (B) Purified central memory T cells (TM T _cells ) were activated and transduced with a lentiviral vector encoding CAR CS1. CAR expression was detected by staining cells with anti-EGFR (epidermal growth factor receptor) antibody cetuximab. (C) Cytotoxicity of expanded T cells with CAR CS1 was assessed using 4-hour ⁵¹ Cr release assays after co-culture with ⁵¹ Cr labeled CSI-positive -MM.1S target cells. LCL (lymphoblastic cell lines) expressing OKT3 was used as a positive control, and KG1A myeloid leukemia cells were used as a negative control. Non-transduced mimic T cells were negative effector cells. (D) 2×10 ⁶ fflucGFP MM.1S cells that were genetically modified to express luciferase (ffluc) and green fluorescent protein (GFP) were injected into the tibia of (it) NOD/Scid IL2RγCnull (NSG) mice. Five days after the inoculation of the tumor, the mice i.v. 1×10 ⁶ CAR CS1 T cells were injected and non-transduced mimic cells were infused into control mice. Tumor signals were monitored using Xenogen imaging once a week.

FIG. 3 is a schematic representation of a lentiviral vector expressing CAR CS1 (CS1scFv-IgG4(HL-CH3)-CD28gg-Zeta(CO)-T2A-EGFRt_epHIV7). The CS1 CAR construct includes the following: GMCSF (granulocyte macrophage colony stimulating factor) signal sequence, anti-CS1 scFv, IgG4 hinge region, linker, CH3 domain, CD28 costimulatory domain, and CD3ζ signaling domain. The CAR construct is followed by the T2A ribosome skipping sequence and then the EGFRt suicide gene coding sequence. CAR and EGFRt molecules are expressed from the same transcript.

FIG. 4 shows the amino acid sequence of CAR CS1, which includes the signal peptide, ribosome skipping sequence and EGFRt (SEQ ID NO: 29).

FIG. 5 shows the amino acid sequence of CS1scFv-IgG4(HL-CH3)-CD4tm-41BB-Zeta-T2A-EGFRt (SEQ ID NO: 32).

FIG. 6 shows the amino acid sequence of CSIscFv-IgG4(L235E, N297Q)-CD4tm-41BB-Zeta-T2A-EGFRt (SEQ ID NO: 35).

FIG. 7 shows the amino acid sequence of CSIscFv-IgG4(L235E, N297Q)-CD28tm-CD28gg-Zeta-T2A-EGFRt (SEQ ID NO: 38).

FIG. 8 shows the amino acid sequence of CSIscFv-Linker-CD4tm-41BB-Zeta-T2A-EGFRt (SEQ ID NO: 41).

FIG. 9 shows the amino acid sequence of CSIscFv-Linker-CD28tm-CD28gg-Zeta-T2A-EGFRt (SEQ ID NO: 44).

DETAILED DESCRIPTION OF THE INVENTION

Example 1: CS1 and BCMA expression in AL amyloidosis and multiple myeloma

Fourteen patients with AL amyloidosis were studied. Analysis of CS1 and BCMA expression on neoplastic plasma cells from these patients reveals that these cells preferentially express CS1 but not BCMA. Briefly, bone marrow mononuclear cells were isolated from patients diagnosed with AL amyloidosis and labeled with antibodies against CS and BCMA followed by kappa/lambda staining. An example of sorting a clonal population of plasma cells in a patient with kappa-limited disease followed by analysis of CS1 expression is shown in FIG. 1A. All AL amyloidosis samples expressed high levels of CS1 (76.5 plus/minus 4.7%) but were negative for BCMA or showed very low expression of BCMA (4.9 plus/minus 0.8%) (FIG. 1B) .

For comparison, bone marrow samples from 10 MM patients were analyzed over the same time period using the same methodology (FIG. 1C). Clonal plasma cells from MM patients express CS1 in a manner similar to that seen in AL; however, BCMA is comparatively much more frequently expressed. Interestingly, the lack of BCMA expression on plasma cells in AL patients suggests that the clonal plasma cell in AL is unique compared to myeloma cells.

Example 2: Cell Killing by CAR Targeting CS1

To investigate the usefulness of CS1 as a target for amyloidosis therapy with CAR ALT cells, the inventors analyzed the second generation of CAR CS1 (FIG. 2A) containing the CD28gg co-stimulatory domain, the T2A ribosome skipping sequence, and the truncated EGF receptor (EGFRt) sequence as a selection molecule, tracking and cutting, and included in the SIN lentiviral vector, described in more detail below. Purified central memory T cells ( _TM cells) were activated and transduced with a lentiviral vector encoding CAR CS1 and expanded in the presence of 50 U/ml IL-2 (interleukin-2) and 0.5 ng/ml IL-15 for 3 weeks . CAR expression was monitored by cell staining with cetuximab-biotin and streptavidin (SA) (FIG. 2B). Cytotoxicity of expanded anti-CS1 CAR T cells was assessed using ⁵¹ Cr release 4-hour assays after co-culture with ⁵¹ Cr-labeled CS1+ (MM.1S) target cells (FIG. 2C).

Six to ten week old NOD/Scid IL2RγC-Hynb mice were injected into the tibia with (it) 2×10 ⁶ fflucGFP MM.1S that had been genetically modified to express luciferase (ffluc) and green fluorescent protein (GFP). Five days after tumor inoculation, mice were intravenously injected (iv) with 1×10 ⁶ T cells with CAR CS1, and non-transduced mimic cells were infused into control mice. Anesthetized mice were imaged weekly using a Xenogen MS Series 100 system (Xenogen, Alameda, CA). Photons from ffLuc+ tumor xenografts were quantified using the Living Image software (Xenogen) and the bioluminescence signal was measured as total photon flux normalized by exposure time and surface area and expressed in units of photons per second per cm2 per steradian.

To assay antitumor activity, MM.1S was inoculated into NSG mice via tibia injection. Once tumor engraftment was confirmed, tumor-bearing mice were intravenously infused with 1 x 106 T cells with CAR CS1. T cells with CAR CS1 show specific and efficient killing of CS1 positive cells (MM.1S) (FIG. 2C). Antitumor studies in an animal model demonstrated that T cells with CAR CS1 induced significant tumor remission compared to mice treated with mimic T cells (FIG. 2D).

These data support the use of T-cell therapy with CS1-targeted CAR for patients with AL amyloidosis. AL is an ideal situation to explore CAR-mediated therapy. The relatively small number of malignant cells that should serve as a target allows the successful eradication of this small, destructive clone, as well as a minimal risk in terms of complications associated with cytokine release syndrome. In addition, the relatively safe profile of the CS1-targeted antibody elotuzumab indicates that T cells with CAR CS1, likewise, may be beneficial in this regard. The work of the present inventors presents a new application of T cells with CAR directed to CS1, in the discovery that, in contrast to preclinical experience with MM, BCMA would not be a suitable target. With the inventors' preclinical data showing the efficacy of CS1 directed CAR T cells, the present inventors plan to move forward with the clinical trial of CS1 CAR T cells against AL.

Example 3: CAR targeting CS1

A CS1-targeting CAR suitable for use in the treatment of AL amyloidosis includes a CAR that contains an extracellular domain, a transmembrane domain, and an intracellular signaling domain. The extracellular domain includes a CS1-specific scFv region or a variant thereof and a spacer containing, for example, a portion of the human Fc domain. The extracellular domain allows CAR, when expressed on the surface of a T cell, to direct T cell activity to cells expressing CS1. The transmembrane domain includes, for example, a CD4 transmembrane domain, a CD8 transmembrane domain, a CD28 transmembrane domain, or a CD3 transmembrane domain. The intracellular signaling domain includes a signaling domain from the human CD3 complex zeta chain (CD3ζ) and one or more costimulatory domains, for example, the BB 4-1 costimulatory domain. Incorporation of a co-stimulatory domain, such as the BB 4-1 co-stimulatory domain (CD137), in series with CD3ζ in the intracellular region allows the T cell to receive co-stimulatory signals. T cells, for example, patient-specific, autologous T cells, can be genetically modified to express the CARs described herein, and the genetically modified cells can be expanded and used therapeutically. You can use different subsets of T cells, including alpha beta T cells and gamma delta T cells. In addition, CAR can be expressed in other immune cells such as NK (natural killer) cells. When a patient is treated with an immune cell expressing the CAR described herein, the cell may be an autologous T cell or an allogeneic T cell. In some instances, the cells used are a cell population that includes both CD4+ and CD8+ central memory T cells ( _CM T cells), which are CD62L+, CCR7+, CD45RO+ and CD45RA-. This cell population may also include other types of T cells. Several CARs targeting CS1 are detailed in WO 2016/090369.

scFv targeting CS1

The CS1-targeted CAR described herein includes a CS1-targeted scFv (e.g., a scFv including the sequence:

EVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEIN PDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWG QGTLVTVSSGSTSGGGSGGGSGGGGSSDIQMTQSPSSLSASVGDRVTITCKASQDVGI AVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQ QYSSYPYTFGQGTKVEIK; SEQ ID NO: 1) or a variant thereof having 1-5 (eg 1 or 2) amino acid modifications (eg substitutions).

Useful CAR CS1 consists of or contains the amino acid sequence of any of SEQ ID NOs: 31, 34, 37, 40, 43 and 46 (mature CAR lacking a signal sequence), or CAR CS1 consists of or contains the amino acid sequence of any of SEQ ID NOs: 30, 33, 36, 39, 42 and 45 (immature CAR having the GMCSFRa signal sequence). This CAR can be expressed in a form that includes a signal sequence, for example, the human GM-CSF (granulocyte-macrophage colony-stimulating factor) alpha (MLLLVTSLLLCELPHPAFLLIP; SEQ ID NO: 26) human GM-CSF receptor signal sequence. This CAR can be expressed with additional sequences that are useful for tracking expression, such as the T2A ribosome skipping sequence and truncated EGFRt. Thus, a CAR may contain or consist of an amino acid sequence of any of SEQ ID NOs: 29-46, or may contain or consist of an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 29-46. The CAR may contain or consist of the amino acid sequence of any of SEQ ID NOs: 29-46 with up to 1, 2, 3, 4 or 5 amino acid substitutions (preferably conservative amino acid substitutions).

spacer region

The CAR described herein may include a spacer located between the CS1 targeting domain (ie, anti-CS1 scFv or a variant thereof) and the transmembrane domain. A number of different spacers can be used. Some of these include at least a portion of a human Fc region, such as a hinge portion of a human Fc region or a CH3 domain, or variants thereof. Table 1 below lists the different spacers that can be used in the CARs described in this document.

Some spacer regions include all or part of the hinge region of an immunoglobulin (eg, IgG1, IgG2, IgG3, IgG4), ie. a sequence that falls between the CH1 and CH2 domains of an immunoglobulin, such as an IgG4 Fc hinge or a CD8 hinge. Some spacer regions include an immunoglobulin CH3 domain or both a CH3 domain and a CH2 domain. Immunoglobulin-derived sequences may include one or more amino acid modifications, such as 1, 2, 3, 4, or 5 substitutions, such as substitutions that reduce off-target binding.

The hinge/linker region may also comprise an IgG4 hinge region having the sequence ESKYGPPCPSCP (SEQ ID NO: 4) or ESKYGPPCPPCP (SEQ ID NO: 3).

Шарнирная/линкерная область также может содержать последовательность ESKYGPPCPPCP (SEQ ID NO: 3), с последующей линкерной последовательностью GGGSSGGGSG (SEQ ID NO: 2), с последующей последовательностью СНЗ IgG4: GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 12). Thus, the entire linker/spacer area can contain the sequence:

ESKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEA LHNHYTQKSLSLSLGK (SEQ ID NO: 11). In some instances, the spacer has 1, 2, 3, 4, or 5 single amino acid substitutions (e.g., conservative substitutions) compared to SEQ ID NO: 11. In some instances, the IgG4 Fc hinge/linker region is mutated at two positions (L235E; N297Q ) in a manner that reduces Fc receptor (FcR) binding.

transmembrane domain

A variety of transmembrane domains can be used in CAR. Table 2 includes examples of suitable transmembrane domains. When a spacer region is present, the transmembrane domain is located closer to the carboxy terminus relative to the spacer region.

Costimulatory domain

The co-stimulatory domain may be any domain that is suitable for use with the CD3ζ signaling domain. In some cases, the costimulatory domain is a CD28 costimulatory domain that includes a sequence that is at least 90%, at least 95%, at least 98% identical, or identical to: RSKRSR GG HSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO: 23 ; the amino acid substitution from LL to GG is underlined with a double line). In some instances, the CD28 cosignaling domain has 1, 2, 3, 4, or 5 amino acid substitutions (preferably conservative and preferably not in the underlined GG sequence) compared to SEQ ID NO: 23. In some instances, the cosignaling domain is a 4-1 cosignaling domain BB, which includes a sequence that is at least 90%, at least 95%, at least 98% identical or identical to KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO: 24). In some cases, the 4-1 BB cosignaling domain has 1, 2, 3, 4, or 5 amino acid substitutions (preferably conservative) compared to SEQ ID NO: 24.

The co-stimulatory domain(s) is(are) located between the transmembrane domain and the signaling domain of CD3ζ. Table 3 includes examples of suitable co-stimulatory domains along with the sequence of the CD3ζ signaling domain.

In various embodiments, the co-stimulatory domain is selected from the group consisting of the following: a co-stimulatory domain shown in Table 3 or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications, a CD28 co-stimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications, a BB 4-1 costimulatory domain or variant having 1-5 (e.g., 1 or 2) amino acid modifications, and a costimulatory domain or variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications. In some embodiments, a 4-1 BB co-stimulatory domain or a variant thereof is present having 1-5 (eg, 1 or 2) amino acid modifications. In some embodiments, there are two co-stimulatory domains, e.g., a CD28 co-stimulatory domain or variant having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions), and a 4-1 BB co-stimulatory domain or variant having 1- 5 (eg 1 or 2) amino acid modifications (eg substitutions). In various embodiments, 1-5 (eg, 1 or 2) amino acid modifications are substitutions. The costimulatory domain is amino-terminal to the CD3ζ signaling domain, and in some cases a short linker of 2-10, eg 3 amino acids (eg, GGG) is located between the costimulatory domain and the CD3ζ signaling domain.

CD3ζ signaling domain

The CD3ζ signaling domain may be any domain that is suitable for use with the CD3ζ signaling domain. In some cases, the CD3ζ signaling domain includes a sequence that is at least 90%, at least 95%, at least 98% identical or identical to RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQE GLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID: 21). In some cases, the CD3C signaling domain has 1, 2, 3, 4, or 5 amino acid substitutions (preferably conservative) compared to SEQ ID NO: 21.

Truncated EGFR

The CD3ζ signaling domain may be followed by a ribosome skipping sequence (e.g., LEGGGEGRGSLLTCGDVEENPGPR; SEQ ID NO: 27) and a truncated EGFR having a sequence that is at least 90%, at least 95%, at least 98% identical или идентичной LVTSLLLCELPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFR GDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSL AVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSC KATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECI QCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADA GHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM (SEQ ID NO: 28). In some instances, the truncated EGFR has 1, 2, 3, 4, or 5 amino acid substitutions (preferably conservative) compared to SEQ ID NO: 28.

A patient suffering from AL amyloidosis can be administered with a population of human T cells transduced with a vector containing an expression cassette encoding the chimeric CS1 antigen receptor described herein (e.g., CAR that contains or consists of the amino acid sequence of any of SEQ ID NO : 29-46, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 29-46, or an amino acid sequence of any of SEQ ID NOs: 29 -46 with up to 1, 2, 3, 4, or 5 amino acid substitutions (preferably conservative amino acid substitutions) In various embodiments, the human T cell population is central memory T cells (T _CM ), e.g., T _CM CD8+/CD4+ .

The term "amino acid modification" refers to the substitution, insertion and/or deletion of an amino acid in the sequence of a protein or peptide. The term "amino acid substitution" or "substitution" refers to the replacement of an amino acid at a specific position in the sequence of the parent peptide or protein with a different amino acid. A substitution can be made to change an amino acid in the resulting protein in a non-conservative way (i.e., changing the codon from an amino acid belonging to a group of amino acids having a particular size or characteristic to an amino acid belonging to a different group) or in a conservative way (i.e., changing a codon from an amino acid belonging to a group of amino acids having a particular size or characteristic to an amino acid belonging to the same group). This conservative substitution usually results in less change in the structure and function of the resulting protein. The following are examples of different groups of amino acids: 1) amino acids with non-polar R groups: alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine; 2) amino acids with uncharged polar groups R: glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine; 3) amino acids with charged polar groups R (negatively charged at pH 6.0): aspartic acid, glutamic acid; 4) basic amino acids (positively charged at pH 6.0): lysine, arginine, histidine (at pH 6.0). Another group may be those amino acids that have phenyl groups: phenylalanine, tryptophan and tyrosine.

CAR CS1 may include a sequence that is at least 90%, at least 95%, at least 98% identical or identical to the amino acid sequence shown in FIG. 4-9 (SEQ ID NOs: 29-46 either including or excluding the GMCSFRa signal sequence and either including or excluding the T2A ribosome skipping and truncated EGFRt sequence).

A variety of CS1-targeting CARs are described in WO 2016/090369 and these CARs may be useful in the treatment of AL amyloidosis.

Among the CS1-targeting CARs described herein are the CARs summarized in Table 4, which lists the spacer region, transmembrane domain, and co-stimulatory domain(s) for each CAR.

In some cases, CAR CS1 can be generated using a vector in which the CAR open reading frame is followed by a T2A ribosome skipping sequence and a truncated EGFR (EGFRt) that lacks a cytoplasmic signaling tail. With this arrangement, EGFRt co-expression provides an inert, non-immunogenic surface marker that provides accurate measurement of GM cells and allows positive selection of GM cells as well as efficient in vivo cellular tracking of therapeutic T cells after adoptive transfer. Effective control of proliferation in order to avoid cytokine storm and off-target toxicity is an important barrier to the success of T-cell immunotherapy. EGFRt included in the lentiviral vector for CAR CS1 can act as a suicide gene to eliminate CAR+ T cells in cases of treatment-related toxicity.

The CAR described herein can be obtained by any means known in the art, although it is preferably obtained using genetic engineering techniques. Nucleic acids encoding multiple regions of the chimeric receptor can be obtained and assembled into a complete coding sequence by standard molecular cloning techniques known in the art (genomic library screening, overlapping PCR (polymerase chain reaction), primer ligation, site-directed mutagenesis, and etc.), whichever is convenient. The resulting coding region is preferably inserted into an expression vector and used to transform an appropriate expression host cell line, preferably a T-lymphocyte cell line, and most preferably an autologous T-lymphocyte cell line.

Different subsets of T cells isolated from a patient can be transduced with a vector to express CAR. Central memory T cells are one useful subset of T cells. The central memory T cell can be isolated from peripheral blood mononuclear cells (PBMCs) by selection for CD45RO+/CD62L+ cells using, for example, the CliniMACS® immunomagnetic selection instrument for cells expressing the desired receptors. Cells enriched in central memory T cells can be activated with anti-CD3/CD28 antibodies, transduced with, for example, a lentiviral vector that directs CAR CS1 expression, as well as a non-immunogenic surface marker for in vivo detection, elimination and potential ex vivo selection. Activated/genetically modified central memory T cells targeting CS1 can be expanded in vitro using IL-2/IL-15 (interleukin-2/interleukin-15) and then cryopreserved.

Example 4: construction and structure of epHIV7 used to express a CS1-specific CAR

Plasmid pHIV7 is a parent plasmid from which clinical vectors expressing CAR CS1 can be derived. The epHIV7 vector used to express CAR was derived from the pHIV7 vector (Wang et al. 2011 Blood 118:1255). Importantly, this vector uses the human EF1 promoter to drive CAR expression. Both the 5' and 3' sequences of this vector were derived from pv653RSN, which was previously derived from the HXBc2 provirus. Polyurine tract DNA displaced sequences (cPPTs) were obtained from HIV-1 strain pNL4-3 (human immunodeficiency virus-1) from the NIH AIDS reagent repository.

Construction of pHIV7 was performed as follows. Briefly, pv653RSN containing 653 bp. from gag-pol plus 5'- and 3'-long terminal repeats (LTR) with the SL3-neomycin phosphotransferase (Neo) gene located between them, were subcloned into pBluescript as follows: in step 1, from sequences from 5'LTR to the element responding to rev (RRE), p5'HIV-1 51 was made, and then the 5'LTR was modified by removing sequences upstream of the TATA box and ligated first to the CMV enhancer (cytomegalovirus) and then to the SV40 replicator (p5'HIV-2). In step 2, after cloning the 3'LTR into pBluescript to give p3'HIV-1, a 400 bp deletion was made. in a 3'LTR enhancer/promoter to remove cis-regulatory elements in HIV U3 and generate p3'HIV-2. In step 3, fragments isolated from p5'HIV-3 and p3'HIV-2 were ligated to give pHIV-3. In step 4, p3'HIV-2 was further modified by removing additional upstream HIV sequences to obtain p3'HIV-3, and a 600 bp fragment. BamHI-Sall containing WPRE was added to p3'HIV-3 to give p3'HIV-4. In step 5, the pHIV-3 RRE was reduced in size by PCR and ligated to the 5' fragment from pHIV-3 (not shown) and to p3'HIV-4 to give pHIV-b. In Step 6, a 190 bp BgIII-BamHI fragment containing the cPPT DNA displacement sequence from HIV-1 pNL4-3 (55) was amplified from pNL4-3 and placed between the RRE and WPRE sequences in pHIV6 to give pHIV-7. This parental plasmid, pHIV7-GFP (GFP - Green Fluorescent Protein), was used to package the parental vector using a four plasmid system.

The packaging signal - psi (ψ) - is required for efficient packaging of the viral genome into the vector. RRE and WPRE enhance RNA transcript transport and transgene expression. The displaced sequence, in combination with WPRE, has been shown to enhance the transduction efficiency of the lentiviral vector in mammalian cells.

The helper functions required for the production of a viral vector are split into three separate plasmids to reduce the likelihood of generating a replication-competent lentivirus by recombination: 1) pCgp encodes the gag/pol protein required for assembly of the viral vector; 2) pCMV-Rev2 encodes a Rev protein that acts on the RRE sequence to help transport the viral genome for efficient packaging; and 3) pCMV-G encodes a vesiculostomatitis virus (VSV) glycoprotein that is required for the infectivity of the viral vector.

There is minimal DNA sequence homology between the pHIV7 encoded vector genome and the helper plasmids. Regions of homology include a packaging signal region of approximately 600 nucleotides located at the gag/pol sequence of the pCgp helper plasmid; the CMV promoter sequence in all three helper plasmids; and the RRE sequence in the pCgp helper plasmid. It is highly unlikely that, due to the homology in these regions, a replication-competent recombinant virus could be generated, as this would require numerous recombination events. In addition, any resulting recombinants would lack the functional LTR and tat sequences required for lentiviral replication.

The CMV promoter was replaced by the EF1α-HTLV (EF1p) promoter and the new plasmid was named epHIV7. EF1p had 563 bp. and was introduced into epHIV7 using NruI and NheI, then the CMV promoter was excised.

The lentiviral genome was removed from this system, excluding gag/pol and rev, which are essential for the pathogenicity of the wild-type virus and are required for productive infection of target cells. In addition, the epHIV7 vector construct does not contain an intact 3'LTR promoter, thus the resulting expressed and reverse transcribed proviral genome DNA in target cells will have inactive LTRs. As a result of this design, sequences derived from HIV-1 will not be transcribed from the provirus, and only therapeutic sequences will be expressed from their respective promoters. It is expected that the removal of the LTR promoter activity in the SIN vector significantly reduces the possibility of inadvertent activation of host genes. Table 5 summarizes the various regulatory elements present in epHIV7.

Fig. 1 is a schematic representation of a CAR CS1 (CS1scFv-IgG4(HL-CH3)-CD28gg-Zeta(CO)-T2A-EGFRt_epHIV7), a lentiviral vector containing this CAR construct, consisting of an anti-CS1 scFv, an IgG4 hinge, a linker, a costimulatory the CD28 domain; and the CD3ζ signaling domain. The CAR construct is followed by the T2A ribosome skipping sequence and then the sequence encoding the suicide gene EGFRt. CAR and EGFRt molecules are expressed from the same transcript. TABLE 5 shows the position of the different elements of the vector.

Example 5 Preparation of Vectors for Transducing Patient T Cells For each plasmid (CS1 CAR_epHIV7; pCgp; pCMV-G and pCMV-Rev2), a seed bank was prepared and used to inoculate the fermenter to obtain sufficient amounts of plasmid DNA. This plasmid DNA is tested for identity, sterility and the presence of endotoxin before it is used in the production of a lentiviral vector.

Briefly, cells were propagated from a 293T working cell (WCB) which was tested to be sterile and free from viral contamination. The vessel with 293T cells from WCB 293T was thawed. Cells were grown and expanded until there were enough cells to seed in an appropriate number of 10 layer cell factories (CF) for vector production and cell line maintenance. A single cell line can be used for production.

The lentiviral vector was produced in sub-batches of up to 10 CF. Two sub-batches can be produced in the same week, resulting in the production of approximately 20 L of lentiviral supernatant/week. The material produced from all sub-lots was pooled during the subsequent processing phase in order to produce one batch of product. 293T cells were seeded in CF in 293T medium (DMEM (Dulbecco's Modified Eagle's Medium) with 10% FBS (fetal calf serum)). Factories were placed in an incubator at 37°C and horizontally leveled to obtain a uniform distribution of cells on all layers of CF. Two days later, cells were transfected with the four lentiviral plasmids described above using the CaPO ₄ method, which includes a mixture of Tris:EDTA (ethylenediaminetetraacetic acid), 2 M CaCl ₂ , 2x HBS (human serum albumin) and four DNA plasmids. On day 3 post-transfection, the supernatant containing the secreted lentiviral vectors was collected, purified and concentrated. After removing the supernatant from the CF, end-of-production cells were selected from each CF. Cells were selected from each CF. Cells from each factory were trypsinized and collected by centrifugation. Cells were resuspended in freezing medium and cryopreserved. These cells were later used to test for replication competent lentivirus (RCL).

To purify and prepare the vectors as a preparation, the crude supernatant was clarified by membrane filtration to remove cellular debris. The host cell DNA and residual plasmid DNA were degraded by cleavage with an endonuclease (Benzonase®). The viral supernatant was cleared of cell debris using a 0.45 μm filter. The clarified supernatant was taken into a pre-weighed container, to which Benzonase® was added (final concentration 50 U/ml). Endonuclease digestion of residual plasmid DNA and host genomic DNA is carried out at 37°C for 6 hours. To remove residual small molecular weight components from the crude supernatant, the initial concentration of the endonuclease-treated supernatant by tangential flow ultrafiltration (TFF) was used, concentrating the virus by -20 times . The clarified, endonuclease-treated viral supernatant was circulated through a 500 kDa NMWCO hollow fiber cartridge at a flow rate adjusted to maintain a shear rate of -4000 s ^-1 or less while maximizing the flow rate. During the concentration process, diafiltration of the nuclease-treated supernatant is started to maintain cartridge efficiency. Using 4% lactose in PBS (phosphate buffered saline) as diafiltration buffer, a permeate replacement rate of 80% was set. The viral supernatant was adjusted to the target volume, representing 20-fold concentration of the crude supernatant, and diafiltration continued for 4 additional volume changes at a permeate replacement rate of 100%.

Further concentration of the viral product was carried out using a high speed centrifugation technique. Each sublot of lentivirus was pelleted using a Sorvall RC-26 plus centrifuge at 6000 rpm (6088 RCF (relative centrifugation force) at 6°C for 16-20 hours. The virus pellet from each sublot was then dissolved in a 50 ml volume of 4% of lactose in PBS The pellet dissolved in this buffer represents the final composition of the viral preparation The entire vector concentration process resulted in an approximately 200-fold reduction in volume Once all sublots were completed, the material was then placed at -80°C, with samples from each sublots for sterility Once sample sterility was confirmed, sublots were rapidly thawed at 37°C with frequent shaking Material was then pooled and manually aliquoted in a Class II Type A/B3 biosafety cabinet A fill configuration of 1 ml concentrated lentivirus in USP class 6 sterile cryovessels was used ( USP) with male thread and O-ring Quality Control Systems (QS) C Application Technology Development Center (CATD) in the City of Nore released all materials in accordance with the policy and standard operating procedures for CBG and in accordance with modern good manufacturing practices (cGMP).

To ensure purity, the lentiviral vector preparation was tested for residual host DNA contamination and transfer of residual host DNA and plasmids. Among other tests, vector identity was assessed by PCR-RT (Reverse Transcription-Coupled Polymerase Chain Reaction) to ensure that the correct vector was present. The vector for use in this study meets all release criteria.

Example 6 Generation of Suitable Tem Cells for CAR CS1 Expression

T lymphocytes are obtained from the patient via leukapheresis and a suitable subset of allogeneic or autologous T cells, e.g., central memory T cells (T _Cm ), is genetically altered to express CAR, then administered to the patient via any clinically acceptable means to achieve anti-cancer therapy.

Those that are CD8+ are isolated essentially as described in Wang et al. (J Immunology 35:689, 2012). Briefly, on the day of leukapheresis, PBMCs were isolated by Ficoll-Paque density gradient centrifugation, followed by two washes in PBS/EDTA. The PBMCs were then washed once in PBS, resuspended in X Vivo15 medium containing 10% calf bovine serum (FCS), transferred to a 300 ^cc transfer bag and stored on a 3D rotator at room temperature (RT). The next day up to 5×10 ⁹ PBMCs were incubated in a 300 cm ³ transfer bag with clinical grade microbeads against CD4 (2.5 ml), against CD14 (1.25 ml) and against CD45RA (2.5 ml) ( Miltenyi Biotec) for 30 minutes at RT in X Vivo15 containing 10% FCS. Depletion of CD4+, CD14+ and CD45RA+ cells was then immediately performed using the CliniMACS™ depletion mode according to the manufacturer's instructions (Miltenyi Biotec). After centrifugation, the unlabeled negative cell fraction was resuspended in PBS/EDTA CliniMACS™ buffer (Miltenyi Biotec) containing 0.5% human serum albumin (HSA) and then labeled with clinical grade biotinylated-DREG56 mAb (monoclonal antibody) (COHNMC CBG) in amount of 0.1 mg/10 ⁶ cells for 30 minutes at RT. The cells were then washed and resuspended in a final volume of 100 ml PBS/EDTA CliniMACS™ containing 0.5% HSA and transferred to a new 300 ^cc transfer bag. After 30 minutes incubation with 1.25 ml anti-biotin microbeads ( _Miltenyi Biotec), the CD62L+ fraction of PBMC (TCM CD8+) was purified using positive selection on CliniMACS™ according to the manufacturer's instructions and resuspended in X Vivo15 containing 10% FCS.

Those that are CD8+/CD4+ are obtained using a modification of the above method by modifying selection for CD4+, CD14+ and CD45RA+ with selection for CD14+ and CD45RA+. This method uses a two-step process on the CliniMACS™ instrument to first deplete CD14+ and CD45RA+ cells, then positively select for CD62L+ cells. This modified platform generates a volume of 50×10 ⁶ T cm from a single _{leukapheresis} .

After enrichment, TCM cells are prepared in full X- _Vivo15 plus 50 IU/mL IL-2 and 0.5 ng/mL IL-15 and transferred to a Teflon cell culture bag where they are stimulated with Dynal ClinEx™ beads Vivo CD3/CD28. Up to five days post-stimulation, cells are transduced with a lentiviral vector encoding CAR CS1 at a multiplicity of infection (MOI) of about 3. Cultures are maintained for up to 42 days with complete X-Vivo15 supplementation and cytokines IL-2 and IL-15 as required. for cell expansion (maintaining a cell density of 3x10 ⁵ to 2x10 ⁶ viable cells/ml and supplementing with cytokines every Monday, Wednesday and Friday of culture). Under these conditions, cells typically proliferate to about 109 cells within 21 days. At the end of the culture period, cells are harvested, washed twice and prepared as a preparation in a clinical grade cryopreservation medium.

On the day of T-cell infusion, the cryopreserved and discharged product will be thawed, washed and re-infused. Cryopreserved vials containing the released cell product will be removed from liquid nitrogen storage, thawed, cooled and washed with PBS/2% human serum albumin (HSA) wash buffer. After centrifugation, the supernatant will be removed and the cells will be resuspended in preservative-free normal saline (PFNS)/2% HSA infusion diluent. Samples will be removed for quality control.

Example 7: CAR CS1 Amino Acid Sequence (CS1scFv-IqG4(HL-CH3)-CD28tm-CD28qq-Zeta-T2A-EGFRt)

The complete amino acid sequence of CS1scFv-IgG4(HL-CH3)-CD28tm-CD28gg-Zeta-T2A-EGFRt is shown in FIG. 4. The complete sequence (SEQ ID NO: 29) includes: GMCSF 22-amino acid signal peptide (SEQ ID NO: 26), anti-CS1 scFv sequence (SEQ ID NO: 1), IgG4 hinge sequence (SEQ ID NO: 3; c amino acid substitutions from S to P, highlighted in shading); 10 amino acid linker (SEQ ID NO: 2), IgG4 CH3 sequence (SEQ ID NO: 12), 28 amino acid CD28 transmembrane domain sequence (SEQ ID NO: 14); CD28gg co-stimulatory domain sequence (SEQ ID NO: 23; amino acid substitutions LL to GG highlighted); 3-amino acid Gly linker; 112 amino acid sequence of CD3ζ (SEQ ID NO: 21); The 24 amino acid T2A ribosome jump sequence (SEQ ID NO: 27) and the EGFRt sequence (SEQ ID NO: 28).

--->

<110> SEQUENCE LIST

<120> T-CELLS MODIFIED WITH A CHIMERIC ANTIGEN RECEPTOR TARGETED

ON CS1, FOR THE TREATMENT OF AMYLOIDOSIS AL

<130> 40056-0033WO1

<140> PCT/US2018/023381

<141> 2018-03-20

<150> 62/473.980

<151> 2017-03-20

<160> 46

<170>PatentIn version 3.5

<210> 1

<211> 244

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 1

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu

50 55 60

Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser

130 135 140

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

145 150 155 160

Lys Ala Ser Gln Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His

180 185 190

Thr Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys

225 230 235 240

Val Glu Ile Lys

<210> 2

<211> 10

<212> PRT

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<220>

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polypeptide"

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Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly

1 5 10

<210> 3

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

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polypeptide"

<400> 3

Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro

1 5 10

<210> 4

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 4

Glu Ser Lys Tyr Gly Pro Cys Pro Ser Cys Pro

1 5 10

<210> 5

<211> 22

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 5

Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gly Gly Ser

1 5 10 15

Ser Gly Gly Gly Ser Gly

twenty

<210> 6

<211> 39

<212> PRT

<213> Homo sapiens

<400> 6

Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn

1 5 10 15

Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu

20 25 30

Phe Pro Gly Pro Ser Lys Pro

35

<210> 7

<211> 48

<212> PRT

<213> Homo sapiens

<400> 7

Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

1 5 10 15

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

20 25 30

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

35 40 45

<210> 8

<211> 45

<212> PRT

<213> Homo sapiens

<400> 8

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

1 5 10 15

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

20 25 30

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

35 40 45

<210> 9

<211> 129

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 9

Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gly Gly Ser

1 5 10 15

Ser Gly Gly Gly Ser Gly Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

20 25 30

Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

35 40 45

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

50 55 60

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

65 70 75 80

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys

85 90 95

Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu

100 105 110

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

115 120 125

Lys

<210> 10

<211> 229

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 10

Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe

1 5 10 15

Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

20 25 30

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

35 40 45

Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val

50 55 60

Glu Val His Gln Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser

65 70 75 80

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

85 90 95

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser

100 105 110

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

115 120 125

Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln

130 135 140

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

145 150 155 160

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

165 170 175

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu

180 185 190

Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser

195 200 205

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

210 215 220

Leu Ser Leu Gly Lys

225

<210> 11

<211> 229

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 11

Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe

1 5 10 15

Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

20 25 30

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

35 40 45

Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val

50 55 60

Glu Val His Gln Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser

65 70 75 80

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

85 90 95

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser

100 105 110

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

115 120 125

Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln

130 135 140

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

145 150 155 160

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

165 170 175

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu

180 185 190

Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser

195 200 205

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

210 215 220

Leu Ser Leu Gly Lys

225

<210> 12

<211> 107

<212> PRT

<213> Homo sapiens

<400> 12

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

1 5 10 15

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

20 25 30

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

35 40 45

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

50 55 60

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

65 70 75 80

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

85 90 95

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

100 105

<210> 13

<211> 21

<212> PRT

<213> Homo sapiens

<400> 13

Leu Cys Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu

1 5 10 15

Thr Ala Leu Phe Leu

twenty

<210> 14

<211> 27

<212> PRT

<213> Homo sapiens

<400> 14

Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu

1 5 10 15

Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val

20 25

<210> 15

<211> 28

<212> PRT

<213> Homo sapiens

<400> 15

Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser

1 5 10 15

Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val

20 25

<210> 16

<211> 22

<212> PRT

<213> Homo sapiens

<400> 16

Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile

1 5 10 15

Gly Leu Gly Ile Phe Phe

twenty

<210> 17

<211> 21

<212> PRT

<213> Homo sapiens

<400> 17

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

1 5 10 15

Ser Leu Val Ile Thr

twenty

<210> 18

<211> 23

<212> PRT

<213> Homo sapiens

<400> 18

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

1 5 10 15

Ser Leu Val Ile Thr Leu Tyr

twenty

<210> 19

<211> 24

<212> PRT

<213> Homo sapiens

<400> 19

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

1 5 10 15

Ser Leu Val Ile Thr Leu Tyr Cys

twenty

<210> 20

<211> 27

<212> PRT

<213> Homo sapiens

<400> 20

Ile Ile Ser Phe Phe Leu Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu

1 5 10 15

Leu Phe Phe Leu Thr Leu Arg Phe Ser Val Val

20 25

<210> 21

<211> 112

<212> PRT

<213> Homo sapiens

<400> 21

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

1 5 10 15

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

20 25 30

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

35 40 45

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

50 55 60

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

65 70 75 80

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

85 90 95

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

100 105 110

<210> 22

<211> 41

<212> PRT

<213> Homo sapiens

<400> 22

Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr

1 5 10 15

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

20 25 30

Pro Arg Asp Phe Ala Ala Tyr Arg Ser

35 40

<210> 23

<211> 41

<212> PRT

<213> Homo sapiens

<400> 23

Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr

1 5 10 15

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

20 25 30

Pro Arg Asp Phe Ala Ala Tyr Arg Ser

35 40

<210> 24

<211> 42

<212> PRT

<213> Homo sapiens

<400> 24

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

1 5 10 15

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

20 25 30

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

35 40

<210> 25

<211> 42

<212> PRT

<213> Homo sapiens

<400> 25

Ala Leu Tyr Leu Leu Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His

1 5 10 15

Lys Pro Pro Gly Gly Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln

20 25 30

Ala Asp Ala His Ser Thr Leu Ala Lys Ile

35 40

<210> 26

<211> 22

<212> PRT

<213> Homo sapiens

<400> 26

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro

twenty

<210> 27

<211> 24

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 27

Leu Glu Gly Gly Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp

1 5 10 15

Val Glu Glu Asn Pro Gly Pro Arg

twenty

<210> 28

<211> 354

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 28

Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Ala Phe Leu

1 5 10 15

Leu Ile Pro Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys

20 25 30

Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys

35 40 45

Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly

50 55 60

Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile

65 70 75 80

Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp

85 90 95

Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile

100 105 110

Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser

115 120 125

Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp

130 135 140

Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr

145 150 155 160

Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile

165 170 175

Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys

180 185 190

His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp

195 200 205

Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys

210 215 220

Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu

225 230 235 240

Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr

245 250 255

Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile

260 265 270

Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu

275 280 285

Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His

290 295 300

Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu

305 310 315 320

Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met

325 330 335

Val Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu

340 345 350

Phe Met

<210> 29

<211> 960

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 29

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro

260 265 270

Pro Cys Pro Pro Cys Pro Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly

275 280 285

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

290 295 300

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

305 310 315 320

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

325 330 335

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

340 345 350

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

355 360 365

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

370 375 380

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Phe Trp Val Leu

385 390 395 400

Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val

405 410 415

Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His

420 425 430

Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys

435 440 445

His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser

450 455 460

Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

465 470 475 480

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

485 490 495

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

500 505 510

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

515 520 525

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

530 535 540

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

545 550 555 560

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

565 570 575

Pro Pro Arg Leu Glu Gly Gly Gly Glu Gly Arg Gly Ser Leu Leu Thr

580 585 590

Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Arg Met Leu Leu Leu Val

595 600 605

Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Ala Phe Leu Leu Ile

610 615 620

Pro Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser

625 630 635 640

Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser

645 650 655

Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser

660 665 670

Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys

675 680 685

Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu

690 695 700

Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly

705 710 715 720

Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn

725 730 735

Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp

740 745 750

Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn

755 760 765

Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser

770 775 780

Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala

785 790 795 800

Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val

805 810 815

Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn

820 825 830

Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile

835 840 845

Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr

850 855 860

Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly

865 870 875 880

Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn

885 890 895

Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys

900 905 910

His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys

915 920 925

Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly

930 935 940

Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met

945 950 955 960

<210> 30

<211> 579

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 30

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro

260 265 270

Pro Cys Pro Pro Cys Pro Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly

275 280 285

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

290 295 300

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

305 310 315 320

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

325 330 335

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

340 345 350

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

355 360 365

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

370 375 380

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Phe Trp Val Leu

385 390 395 400

Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val

405 410 415

Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His

420 425 430

Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys

435 440 445

His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser

450 455 460

Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

465 470 475 480

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

485 490 495

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

500 505 510

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

515 520 525

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

530 535 540

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

545 550 555 560

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

565 570 575

Pro Pro Arg

<210> 31

<211> 557

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 31

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu

50 55 60

Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser

130 135 140

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

145 150 155 160

Lys Ala Ser Gln Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His

180 185 190

Thr Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys

225 230 235 240

Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro

245 250 255

Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly Gly Gln Pro Arg Glu Pro

260 265 270

Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln

275 280 285

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

290 295 300

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

305 310 315 320

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu

325 330 335

Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser

340 345 350

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

355 360 365

Leu Ser Leu Gly Lys Met Phe Trp Val Leu Val Val Val Gly Gly Val

370 375 380

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

385 390 395 400

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

405 410 415

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

420 425 430

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Gly Gly Gly Arg Val Lys

435 440 445

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln

450 455 460

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

465 470 475 480

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

485 490 495

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

500 505 510

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

515 520 525

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

530 535 540

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

545 550 555

<210> 32

<211> 955

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 32

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro

260 265 270

Pro Cys Pro Pro Cys Pro Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly

275 280 285

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

290 295 300

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

305 310 315 320

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

325 330 335

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

340 345 350

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

355 360 365

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

370 375 380

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val

385 390 395 400

Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe

405 410 415

Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

420 425 430

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

435 440 445

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly Gly Arg Val

450 455 460

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

465 470 475 480

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

485 490 495

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

500 505 510

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

515 520 525

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

530 535 540

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

545 550 555 560

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Leu Glu

565 570 575

Gly Gly Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu

580 585 590

Glu Asn Pro Gly Pro Arg Met Leu Leu Leu Val Thr Ser Leu Leu Leu

595 600 605

Cys Glu Leu Pro His Pro Ala Phe Leu Leu Ile Pro Arg Lys Val Cys

610 615 620

Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn Ala

625 630 635 640

Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp Leu

645 650 655

His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr Pro

660 665 670

Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu Ile

675 680 685

Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp Leu

690 695 700

His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln His

705 710 715 720

Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu Gly

725 730 735

Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser Gly

740 745 750

Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu Phe

755 760 765

Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu Asn

770 775 780

Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro Glu

785 790 795 800

Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn Val

805 810 815

Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly Glu

820 825 830

Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro Glu

835 840 845

Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro Asp

850 855 860

Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val Lys

865 870 875 880

Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp Lys

885 890 895

Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys Thr

900 905 910

Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly Pro

915 920 925

Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu Leu

930 935 940

Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met

945 950 955

<210> 33

<211> 574

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 33

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro

260 265 270

Pro Cys Pro Pro Cys Pro Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly

275 280 285

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

290 295 300

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

305 310 315 320

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

325 330 335

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

340 345 350

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

355 360 365

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

370 375 380

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val

385 390 395 400

Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe

405 410 415

Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

420 425 430

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

435 440 445

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly Gly Arg Val

450 455 460

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

465 470 475 480

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

485 490 495

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

500 505 510

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

515 520 525

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

530 535 540

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

545 550 555 560

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

565 570

<210> 34

<211> 552

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 34

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu

50 55 60

Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser

130 135 140

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

145 150 155 160

Lys Ala Ser Gln Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His

180 185 190

Thr Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys

225 230 235 240

Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro

245 250 255

Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly Gly Gln Pro Arg Glu Pro

260 265 270

Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln

275 280 285

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

290 295 300

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

305 310 315 320

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu

325 330 335

Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser

340 345 350

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

355 360 365

Leu Ser Leu Gly Lys Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly

370 375 380

Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys

385 390 395 400

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

405 410 415

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

420 425 430

Gly Gly Cys Glu Leu Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala

435 440 445

Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

450 455 460

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

465 470 475 480

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

485 490 495

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

500 505 510

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

515 520 525

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

530 535 540

His Met Gln Ala Leu Pro Pro Arg

545 550

<210> 35

<211> 1055

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 35

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro

260 265 270

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val

275 280 285

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

290 295 300

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

305 310 315 320

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

325 330 335

Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser

340 345 350

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

355 360 365

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

370 375 380

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

385 390 395 400

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

405 410 415

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

420 425 430

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

435 440 445

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

450 455 460

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

465 470 475 480

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met

485 490 495

Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly

500 505 510

Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

515 520 525

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

530 535 540

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly

545 550 555 560

Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln

565 570 575

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

580 585 590

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

595 600 605

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

610 615 620

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

625 630 635 640

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

645 650 655

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

660 665 670

Pro Arg Leu Glu Gly Gly Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys

675 680 685

Gly Asp Val Glu Glu Asn Pro Gly Pro Arg Met Leu Leu Leu Val Thr

690 695 700

Ser Leu Leu Leu Cys Glu Leu Pro His Pro Ala Phe Leu Leu Ile Pro

705 710 715 720

Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu

725 730 735

Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile

740 745 750

Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe

755 760 765

Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr

770 775 780

Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn

785 790 795 800

Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg

805 810 815

Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile

820 825 830

Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val

835 840 845

Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp

850 855 860

Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn

865 870 875 880

Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu

885 890 895

Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser

900 905 910

Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu

915 920 925

Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln

930 935 940

Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly

945 950 955 960

Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro

965 970 975

His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr

980 985 990

Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His

995 1000 1005

Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys

1010 1015 1020

Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val

1025 1030 1035

Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu

1040 1045 1050

Phe Met

1055

<210> 36

<211> 674

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 36

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro

260 265 270

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val

275 280 285

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

290 295 300

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

305 310 315 320

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

325 330 335

Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser

340 345 350

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

355 360 365

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

370 375 380

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

385 390 395 400

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

405 410 415

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

420 425 430

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

435 440 445

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

450 455 460

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

465 470 475 480

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met

485 490 495

Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly

500 505 510

Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

515 520 525

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

530 535 540

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly

545 550 555 560

Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln

565 570 575

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

580 585 590

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

595 600 605

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

610 615 620

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

625 630 635 640

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

645 650 655

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

660 665 670

Pro Arg

<210> 37

<211> 652

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 37

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu

50 55 60

Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser

130 135 140

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

145 150 155 160

Lys Ala Ser Gln Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His

180 185 190

Thr Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys

225 230 235 240

Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro

245 250 255

Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

260 265 270

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

275 280 285

Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr

290 295 300

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu

305 310 315 320

Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His

325 330 335

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

340 345 350

Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

355 360 365

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met

370 375 380

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

385 390 395 400

Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

405 410 415

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu

420 425 430

Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val

435 440 445

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln

450 455 460

Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val Leu Gly

465 470 475 480

Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe Lys

485 490 495

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

500 505 510

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

515 520 525

Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly Gly Arg Val Lys Phe

530 535 540

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

545 550 555 560

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

565 570 575

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

580 585 590

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

595 600 605

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

610 615 620

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

625 630 635 640

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

645 650

<210> 38

<211> 1060

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 38

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro

260 265 270

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val

275 280 285

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

290 295 300

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

305 310 315 320

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

325 330 335

Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser

340 345 350

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

355 360 365

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

370 375 380

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

385 390 395 400

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

405 410 415

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

420 425 430

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

435 440 445

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

450 455 460

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

465 470 475 480

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met

485 490 495

Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu

500 505 510

Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser

515 520 525

Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly

530 535 540

Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala

545 550 555 560

Ala Tyr Arg Ser Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp

565 570 575

Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

580 585 590

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

595 600 605

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

610 615 620

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

625 630 635 640

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

645 650 655

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

660 665 670

Met Gln Ala Leu Pro Pro Arg Leu Glu Gly Gly Gly Glu Gly Arg Gly

675 680 685

Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Arg Met

690 695 700

Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Ala

705 710 715 720

Phe Leu Leu Ile Pro Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu

725 730 735

Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys

740 745 750

Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe

755 760 765

Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu

770 775 780

Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln

785 790 795 800

Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu

805 810 815

Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val

820 825 830

Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile

835 840 845

Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala

850 855 860

Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr

865 870 875 880

Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln

885 890 895

Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro

900 905 910

Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val

915 920 925

Asp Lys Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn

930 935 940

Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn

945 950 955 960

Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His

965 970 975

Tyr Ile Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met

980 985 990

Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val

995 1000 1005

Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro

1010 1015 1020

Gly Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile

1025 1030 1035

Ala Thr Gly Met Val Gly Ala Leu Leu Leu Leu Leu Val Val Ala

1040 1045 1050

Leu Gly Ile Gly Leu Phe Met

1055 1060

<210> 39

<211> 679

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 39

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro

260 265 270

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val

275 280 285

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

290 295 300

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

305 310 315 320

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

325 330 335

Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser

340 345 350

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

355 360 365

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

370 375 380

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

385 390 395 400

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

405 410 415

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

420 425 430

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

435 440 445

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

450 455 460

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

465 470 475 480

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met

485 490 495

Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu

500 505 510

Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser

515 520 525

Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly

530 535 540

Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala

545 550 555 560

Ala Tyr Arg Ser Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp

565 570 575

Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

580 585 590

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

595 600 605

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

610 615 620

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

625 630 635 640

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

645 650 655

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

660 665 670

Met Gln Ala Leu Pro Pro Arg

675

<210> 40

<211> 657

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 40

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu

50 55 60

Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser

130 135 140

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

145 150 155 160

Lys Ala Ser Gln Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His

180 185 190

Thr Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys

225 230 235 240

Val Glu Ile Lys Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro

245 250 255

Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

260 265 270

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

275 280 285

Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr

290 295 300

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu

305 310 315 320

Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His

325 330 335

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

340 345 350

Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

355 360 365

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met

370 375 380

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

385 390 395 400

Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

405 410 415

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu

420 425 430

Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val

435 440 445

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln

450 455 460

Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Phe Trp Val Leu Val Val

465 470 475 480

Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe

485 490 495

Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp

500 505 510

Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr

515 520 525

Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Gly Gly

530 535 540

Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

545 550 555 560

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

565 570 575

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

580 585 590

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

595 600 605

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

610 615 620

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

625 630 635 640

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

645 650 655

Arg

<210> 41

<211> 836

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 41

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Ser Gly

260 265 270

Gly Gly Ser Gly Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu

275 280 285

Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys

290 295 300

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

305 310 315 320

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

325 330 335

Gly Cys Glu Leu Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp

340 345 350

Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

355 360 365

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

370 375 380

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

385 390 395 400

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

405 410 415

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

420 425 430

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

435 440 445

Met Gln Ala Leu Pro Pro Arg Leu Glu Gly Gly Gly Glu Gly Arg Gly

450 455 460

Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Arg Met

465 470 475 480

Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Ala

485 490 495

Phe Leu Leu Ile Pro Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu

500 505 510

Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys

515 520 525

Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe

530 535 540

Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu

545 550 555 560

Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln

565 570 575

Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu

580 585 590

Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val

595 600 605

Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile

610 615 620

Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala

625 630 635 640

Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr

645 650 655

Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln

660 665 670

Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro

675 680 685

Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val

690 695 700

Asp Lys Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn

705 710 715 720

Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn

725 730 735

Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His

740 745 750

Tyr Ile Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met

755 760 765

Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val

770 775 780

Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly

785 790 795 800

Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr

805 810 815

Gly Met Val Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile

820 825 830

Gly Leu Phe Met

835

<210> 42

<211> 455

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 42

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Ser Gly

260 265 270

Gly Gly Ser Gly Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu

275 280 285

Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys

290 295 300

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

305 310 315 320

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

325 330 335

Gly Cys Glu Leu Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp

340 345 350

Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

355 360 365

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

370 375 380

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

385 390 395 400

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

405 410 415

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

420 425 430

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

435 440 445

Met Gln Ala Leu Pro Pro Arg

450 455

<210> 43

<211> 433

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 43

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu

50 55 60

Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser

130 135 140

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

145 150 155 160

Lys Ala Ser Gln Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His

180 185 190

Thr Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys

225 230 235 240

Val Glu Ile Lys Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly Met Ala

245 250 255

Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu

260 265 270

Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

275 280 285

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

290 295 300

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly

305 310 315 320

Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

325 330 335

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

340 345 350

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

355 360 365

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

370 375 380

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

385 390 395 400

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

405 410 415

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

420 425 430

Arg

<210> 44

<211> 841

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 44

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Ser Gly

260 265 270

Gly Gly Ser Gly Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu

275 280 285

Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val

290 295 300

Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr

305 310 315 320

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

325 330 335

Pro Arg Asp Phe Ala Ala Tyr Arg Ser Gly Gly Gly Arg Val Lys Phe

340 345 350

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

355 360 365

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

370 375 380

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

385 390 395 400

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

405 410 415

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

420 425 430

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

435 440 445

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Leu Glu Gly Gly

450 455 460

Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn

465 470 475 480

Pro Gly Pro Arg Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu

485 490 495

Leu Pro His Pro Ala Phe Leu Leu Ile Pro Arg Lys Val Cys Asn Gly

500 505 510

Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn

515 520 525

Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile

530 535 540

Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu

545 550 555 560

Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly

565 570 575

Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala

580 585 590

Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln

595 600 605

Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg

610 615 620

Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys

625 630 635 640

Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr

645 650 655

Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys

660 665 670

Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys

675 680 685

Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg

690 695 700

Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly Glu Pro Arg

705 710 715 720

Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu

725 730 735

Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys

740 745 750

Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val Lys Thr Cys

755 760 765

Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala

770 775 780

Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly

785 790 795 800

Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile

805 810 815

Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu Leu Leu Val

820 825 830

Val Ala Leu Gly Ile Gly Leu Phe Met

835 840

<210> 45

<211> 460

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 45

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile

65 70 75 80

Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn

85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe

115 120 125

Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr

130 135 140

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Ser Gly

260 265 270

Gly Gly Ser Gly Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu

275 280 285

Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val

290 295 300

Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr

305 310 315 320

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

325 330 335

Pro Arg Asp Phe Ala Ala Tyr Arg Ser Gly Gly Gly Arg Val Lys Phe

340 345 350

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

355 360 365

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

370 375 380

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

385 390 395 400

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

405 410 415

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

420 425 430

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

435 440 445

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

450 455 460

<210> 46

<211> 438

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: synthetic

polypeptide"

<400> 46

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu

50 55 60

Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser

130 135 140

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

145 150 155 160

Lys Ala Ser Gln Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His

180 185 190

Thr Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys

225 230 235 240

Val Glu Ile Lys Gly Gly Gly Ser Ser Gly Gly Gly Ser Gly Met Phe

245 250 255

Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu

260 265 270

Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg

275 280 285

Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro

290 295 300

Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala

305 310 315 320

Tyr Arg Ser Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

325 330 335

Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

340 345 350

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

355 360 365

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

370 375 380

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

385 390 395 400

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

405 410 415

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

420 425 430

Gln Ala Leu Pro Pro Arg

435

<---

Claims (10)

1. A method for treating light chain amyloidosis, comprising administering to a patient in need thereof a population of human T cells transduced with a vector containing an expression cassette encoding a chimeric antigen receptor, wherein the chimeric antigen receptor contains an amino acid sequence selected from SEQ ID NO: 30, 31, 33, 34, 36, 37, 39, 40, 42, 43, 44 and 45. 2. The method of claim 1 wherein at least 20%, 30%, or 40% of the transduced human T cells are central memory T cells. 3. The method of claim 1 wherein at least 30% of the transduced human T cells are CD4+ and CD62L+ or CD8+ and CD62L+. 4. The method of claim 1, wherein the human T cell population is autologous to the patient. 5. The method of claim 1, wherein the human T cell population is allogeneic to the patient. 6. A method for treating light chain amyloidosis comprising administering to a patient in need thereof a population of human T cells expressing a chimeric antigen receptor, wherein the chimeric antigen receptor comprises an amino acid sequence selected from SEQ ID NOs: 30, 31, 33, 34, 36 , 37, 39, 40, 42, 43, 44 and 45. 7. The method of claim 6, wherein at least 20%, 30%, or 40% of the transduced human T cells are central memory T cells. 8. The method of claim 6 wherein at least 30% of the transduced human T cells are CD4+ and CD62L+ or CD8+ and CD62L+. 9. The method of claim 6, wherein the human T cell population is autologous to the patient. 10. The method of claim 6 wherein the human T cell population is allogeneic to the patient.

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