An antibody targeting human ceacam5 / 6, preparation method and application

Abstract

The present application provides a monoclonal antibody targeting human carcinoembryonic antigen CEACAM5 / 6, and a bispecific antibody capable of simultaneously targeting human carcinoembryonic antigen CEACAM5 / 6 and human CD47, a preparation method and applications. Specifically, it relates to an anti-human CD47 antibody and antigen-binding fragments thereof capable of simultaneously (1) specifically binding to human CD47 protein and blocking its binding to SIRPalpha, thereby thus blocking the inhibitory effect of CD47 on SIRPalpha-expressing macrophages; (2) specifically binding to human carcinoembryonic protein CEACAM5 / 6. The present application also relates to a preparation method and uses of the bispecific antibody.

Description

Technical Field

[0001] This invention belongs to the field of bioimmunotechnology. Specifically, this invention provides an antibody targeting human CEACAM5 / 6, its preparation method, and its application. Background Technology

[0002] The human carcinoembryonic antigen (CEACAM) cell adhesion molecule gene family was discovered as early as the 1960s, comprising 35 genes / pseudogenes located on chromosome 19 (q13.1-13.3), 21 of which encode proteins. CEACAMs belong to the immunoglobulin superfamily of adhesion molecules, and their domains are highly glycosylated, typically including 1-2 immunoglobulin variable region-like domains (N domains) and 0-6 immunoglobulin constant region-like domains. CEACAM proteins are located extracellularly, with CEACAM1, CEACAM3, and CEACAM4 attached to the cell membrane via hydrophobic transmembrane domains; CEACAM5-8 are attached to the cell membrane via glycosylphosphatidylinositol. These extracellular domains typically function as adhesion molecules between cells (e.g., epithelial, endothelial, dendritic, and leukocytes).

[0003] CEACAM is involved in a variety of cellular functions, based on cell-cell adhesion, regulating cell growth and differentiation through signal transduction, and playing important roles in insulin homeostasis, angiogenesis, and immune regulation. Members of the CEACAM gene family participate in a wide range of pathophysiological roles, including acting as receptors for microbial pathogens. They play a crucial role in carcinogenesis, particularly in cancer detection, progression, and metastasis. Carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5, abbreviated as CEA, also known as CD66e) is a glycoprotein with a molecular weight of approximately 180 kDa. CEACAM5 contains seven domains that are anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor. These seven domains include a single N-terminal Ig variable domain and six domains homologous to the Ig constant domain (A1-B1-A2-B2-A3-B3). Initially classified as a protein expressed only in fetal tissues, CEACAM5 has now been identified in several normal adult tissues. Overexpression of CEACAM5 has been observed in many types of cancer. For example, CEACAM5 can be detected in the blood of patients with colon cancer, and further studies have identified its overexpression as associated with many malignancies, often with poor prognosis. In prostate and colorectal cancer, overexpression of CEACAM5 has been shown to serve as a tumor biomarker.

[0004] Furthermore, CEACAM5 / CEACAM6 has been found to be overexpressed in various malignant tumors, such as breast, pancreatic, ovarian, colon, lung, and gastric gland tumors, and is associated with tumor invasiveness and metastasis. During the initiation of liver metastasis, CEACAM5 binds to its receptor CEAr, and their interaction leads to the activation and production of pro-inflammatory cytokines, primarily IL-1, IL-6, IL-10, and TNF-α. In summary, these cytokines alter the microenvironment of hepatocytes and Kupffer cells, as well as their interactions with hepatic sinusoidal cells. These interactions not only affect tumor cells or other hepatocytes but also appear to promote the activity of CSCs and other circulating tumor cells in the cerebrospinal fluid.

[0005] In summary, CEACAM5 has emerged as a potentially useful tumor-associated antigen for targeted therapy, but existing drugs targeting CEACAM5 still have many shortcomings. Therefore, there is an urgent need in this field to develop a specific antibody molecule targeting CEACAM5. Summary of the Invention

[0006] The purpose of this invention is to provide an antibody targeting human CEACAM5 / 6, its preparation method, and its application.

[0007] In a first aspect of the invention, a heavy chain variable region of an anti-human CEACAM5 / 6 antibody is provided, said heavy chain variable region comprising the following three complementarity-determining regions:

[0008] VH-CDR1 shown in SEQ ID NO.1,

[0009] VH-CDR2 shown in SEQ ID NO.2, and

[0010] VH-CDR3 as shown in SEQ ID NO.3; wherein any of the above amino acid sequences further includes a derivative sequence which has been optionally added, deleted, modified and / or substituted with at least one amino acid and is capable of retaining the binding affinity for CEACAM5 / 6.

[0011] In another preferred embodiment, the amino acid sequence of the heavy chain variable region is selected from the group consisting of SEQ ID NO.7, 11 or 13.

[0012] In a second aspect of the invention, a heavy chain for an anti-human CEACAM5 / 6 antibody is provided, said heavy chain having a heavy chain variable region as described in the first aspect of the invention.

[0013] In another preferred embodiment, the heavy chain of the antibody further includes a heavy chain constant region.

[0014] In another preferred embodiment, the heavy chain constant region is of human, mouse, camel, or rabbit origin, preferably of human origin.

[0015] In another preferred embodiment, the heavy chain constant region is selected from the heavy chain constant regions of human IgG1, IgG2, IgG3 or IgG4, preferably the heavy chain constant region of human IgG1.

[0016] In another preferred embodiment, the heavy chain sequence of the antibody is as shown in SEQ ID NO. 9, 14 or 15.

[0017] In a third aspect of the invention, a light chain variable region of an anti-human CEACAM5 / 6 antibody is provided, said light chain variable region comprising the following three complementarity-determining regions (CDRs):

[0018] VL-CDR1 shown in SEQ ID NO.4,

[0019] VL-CDR2 shown in SEQ ID NO.5, and

[0020] VL-CDR3 as shown in SEQ ID NO.6; wherein any of the above amino acid sequences further includes a derivative sequence which has been optionally added, deleted, modified and / or substituted with at least one amino acid and is capable of retaining the binding affinity for CEACAM5 / 6.

[0021] In another preferred embodiment, the sequence of the light chain variable region is as shown in SEQ ID NO. 8 or 12.

[0022] In a fourth aspect of the invention, a light chain for an anti-human CEACAM5 / 6 antibody is provided, said light chain having a light chain variable region as described in the third aspect of the invention.

[0023] In another preferred embodiment, the light chain of the antibody further includes a light chain constant region.

[0024] In another preferred embodiment, the light chain constant region is of human, mouse, camel, or rabbit origin, preferably of human origin.

[0025] In another preferred embodiment, the light chain constant region is selected from the light chain constant region of the human κ or λ subtype.

[0026] In another preferred embodiment, the light chain of the antibody is as shown in SEQ ID NO. 10 or 16.

[0027] In a fifth aspect of the invention, an anti-human CEACAM5 / 6 antibody is provided, the antibody having:

[0028] (1) the heavy chain variable region as described in the first aspect of the invention; and / or

[0029] (2) The light chain variable region as described in the third aspect of the present invention;

[0030] Alternatively, the antibody may have: a heavy chain as described in the second aspect of the invention; and / or a light chain as described in the fourth aspect of the invention.

[0031] In another preferred embodiment, the antibody is a humanized antibody.

[0032] In another preferred embodiment, the antibody specifically binds to human CEACAM5 and / or human CEACAM6.

[0033] In another preferred embodiment, the antibody is a double-chain antibody or a single-chain antibody.

[0034] In another preferred embodiment, the antibody is a monoclonal antibody.

[0035] In another preferred embodiment, the antibody includes monospecific, bispecific, trispecific, or multispecific antibodies.

[0036] In another preferred embodiment, the light chain of the antibody includes the three light chain CDRs and a light chain framework region for connecting the light chain CDRs; and the heavy chain of the antibody includes the three heavy chain CDRs and a heavy chain framework region for connecting the heavy chain CDRs.

[0037] In another preferred embodiment, the heavy chain variable region of the antibody is as shown in SEQ ID NO. 7, 11, 13; and / or the light chain variable region of the antibody is as shown in SEQ ID NO. 8, 12.

[0038] In another preferred embodiment, the heavy chain variable region of the antibody is shown in SEQ ID NO.7, and the light chain variable region of the antibody is shown in SEQ ID NO.8.

[0039] In another preferred embodiment, the heavy chain variable region of the antibody is shown in SEQ ID NO.11, and the light chain variable region of the antibody is shown in SEQ ID NO.12.

[0040] In another preferred embodiment, the heavy chain variable region of the antibody is shown in SEQ ID NO.13, and the light chain variable region of the antibody is shown in SEQ ID NO.12.

[0041] In another preferred embodiment, the multispecific antibody includes:

[0042] (1) The CEACAM5 / 6 antibody or its antigen-binding fragment as described in the fifth aspect of the present invention;

[0043] (2) Antibodies or antigen-binding fragments that bind to other targets.

[0044] In another preferred embodiment, the other targets are selected from the group consisting of: CD47, CD73, CD47, CD3, CTLA4, PD-1, PD-L1, CD28, CD40, OX40, LAG3, DR5, TIM-3, TIGIT, VEGF, VEGFR, Ang2, CD39, CD73, and GITR.

[0045] In a sixth aspect of the invention, a multispecific antigen-binding molecule is provided, comprising:

[0046] First antigen-binding domain D1; and

[0047] Second antigen-binding domain D2;

[0048] Among them, D1 specifically binds to the target molecule CEACAM5 / 6 protein;

[0049] D2 specifically binds to the target molecule CD47 protein;

[0050] D1 is an antibody or its antigen-binding fragment that specifically binds to CEACAM5 / 6 protein;

[0051] D2 is an antibody or its antigen-binding fragment that specifically binds to the CD47 protein;

[0052] Wherein, D1 has a heavy chain variable region comprising the following three complementary determinant regions (CDRs):

[0053] VH-CDR1 shown in SEQ ID NO.1,

[0054] VH-CDR2 shown in SEQ ID NO.2, and

[0055] VH-CDR3 as shown in SEQ ID NO.3; and

[0056] Light chain variable regions containing the following three complementary determinant regions (CDRs):

[0057] VL-CDR1 shown in SEQ ID NO.4,

[0058] VL-CDR2 shown in SEQ ID NO.5, and

[0059] VL-CDR3 as shown in SEQ ID NO. 6;

[0060] The structure of the antigen-binding fragment is selected from the following group: (i) Fab fragment; (ii) F(ab')2 fragment; (iii) Fd fragment; (iv) Fv fragment; (v) single-chain Fv (scFv) molecule; or (vi) dAb fragment.

[0061] In another preferred embodiment, the heavy chain of the antibody that specifically binds to the CD47 protein includes a heavy chain variable region as shown in SEQ ID NO. 17; and the light chain of the antibody that specifically binds to the CD47 protein includes a light chain variable region as shown in SEQ ID NO. 18.

[0062] In another preferred embodiment, the heavy chain variable region or the light chain variable region of the anti-human CD47 antibody each contains 1-6 mutations, more preferably 1-4 mutations.

[0063] In another preferred embodiment, the mutation in the heavy chain variable region of the anti-human CD47 antibody is selected from the group consisting of:

[0064] H-I37V, H-P45L, H-I48V, H-T52S, H-T52L, H-T52I, H-T52H, H-T52A, H-T52G, H-T52N, H-T52Q, H-T64K, H-R94K, H-P101D, or combinations thereof.

[0065] In another preferred embodiment, the mutation in the light chain variable region of the anti-human CD47 antibody is selected from the group consisting of:

[0066] L-L4M, L-I46L, L-V58I, L-T93N, or combinations thereof.

[0067] In another preferred embodiment, the heavy chain of the antibody that specifically binds to the CD47 protein includes a heavy chain variable region as shown in SEQ ID NO. 19; and the light chain of the antibody that specifically binds to the CD47 protein includes a light chain variable region as shown in SEQ ID NO. 20.

[0068] In another preferred embodiment, any of the above-mentioned amino acid sequences further includes a derived sequence that has optionally been added, deleted, modified and / or substituted at least one amino acid and is capable of retaining the binding affinity for CD47.

[0069] In another preferred embodiment, the bispecific antigen-binding molecule is a bispecific antibody.

[0070] In another preferred embodiment, D1 and / or D2 are single-chain antibodies (scFv).

[0071] In another preferred embodiment, in the bispecific antigen-binding molecule, only D2 is a single-chain antibody (scFv).

[0072] In another preferred embodiment, D1 and D2 are connected by a connector that includes an antibody constant region.

[0073] In another preferred embodiment, D1 is an anti-human CEACAM5 / 6 antibody.

[0074] In another preferred embodiment, D2 is an anti-CD47 single-chain antibody (scFv).

[0075] In another preferred embodiment, the anti-CEACAM5 / 6 humanized antibody includes: single-chain antibody, double-chain antibody, monoclonal antibody, chimeric antibody, murine antibody, humanized antibody, and bispecific antibody.

[0076] In another preferred embodiment, the anti-human CEACAM5 / 6 antibody comprises the heavy chain variable region of the following three complementarity-determining regions (CDRs):

[0077] VH-CDR1 shown in SEQ ID NO.1,

[0078] VH-CDR2 shown in SEQ ID NO.2, and

[0079] VH-CDR3 as shown in SEQ ID NO.3; and

[0080] Light chain variable regions containing the following three complementary determinant regions (CDRs):

[0081] VL-CDR1 shown in SEQ ID NO.4,

[0082] VL-CDR2 shown in SEQ ID NO.5, and

[0083] VL-CDR3 as shown in SEQ ID NO.6.

[0084] In another preferred embodiment, the bispecific antibody comprises a selection from the heavy chains and / or light chains shown in Table 4:

[0085] Table 4.

[0086]

[0087]

[0088] In a seventh aspect of the invention, a recombinant protein is provided, said recombinant protein having:

[0089] (i) the heavy chain variable region as described in the first aspect of the invention, the heavy chain as described in the second aspect of the invention, the light chain variable region as described in the third aspect of the invention, the light chain as described in the fourth aspect of the invention, the antibody as described in the fifth aspect of the invention, or the multispecific antigen-binding molecule as described in the sixth aspect of the invention; and

[0090] (ii) Optional tag sequences to assist in expression and / or purification.

[0091] In another preferred embodiment, the tag sequence includes a 6His tag.

[0092] In another preferred embodiment, the recombinant protein (or polypeptide) includes a fusion protein.

[0093] In another preferred embodiment, the recombinant protein is a monomer, dimer, or polymer.

[0094] In another preferred embodiment, the recombinant protein also includes protein or peptide drugs that target other tumor targets.

[0095] In another preferred embodiment, the protein or polypeptide drug contains cytokines that regulate the function of the immune system.

[0096] In another preferred embodiment, the cytokines include wild-type or mutant types.

[0097] In another preferred embodiment, the cytokines are selected from the group consisting of IL-1, IL-2, IL-7, IL-8, IL-10, IL-12, IL-15, IL-18, IL-21, GM-CSF, IFNα / β / γ, OX40-L, 4-1BB-L, CTLA-4, or combinations thereof.

[0098] In an eighth aspect of the invention, a CAR construct is provided, wherein the scFv region of the antigen-binding domain of the CAR construct specifically binds to human CEACAM5 / 6, and the scFv region comprises a heavy chain variable region as described in the first aspect of the invention and a light chain variable region as described in the third aspect of the invention.

[0099] In a ninth aspect of the invention, a recombinant immune cell is provided, said immune cell expressing an exogenous CAR construct as described in the eighth aspect of the invention.

[0100] In another preferred embodiment, the immune cells are selected from the group consisting of NK cells and T cells.

[0101] In another preferred embodiment, the immune cells are derived from humans or non-human mammals (such as mice).

[0102] In a tenth aspect of the present invention, an antibody-drug conjugate is provided, the antibody-drug conjugate comprising:

[0103] (a) An antibody portion, said antibody portion being selected from the group consisting of: a heavy chain variable region as described in the first aspect of the invention, a heavy chain as described in the second aspect of the invention, a light chain variable region as described in the third aspect of the invention, a light chain as described in the fourth aspect of the invention, an antibody as described in the fifth aspect of the invention, or a multispecific antigen-binding molecule as described in the sixth aspect of the invention, or a combination thereof; and

[0104] (b) A conjugation portion conjugated to the antibody portion, the conjugation portion being selected from the group consisting of: detectable markers, drugs, toxins, cytokines, enzymes, or combinations thereof.

[0105] In another preferred embodiment, the antibody portion is coupled to the coupling portion via a chemical bond or a linker.

[0106] In an eleventh aspect of the present invention, there is provided a use of an active ingredient selected from the group consisting of: heavy chain variable regions as described in the first aspect of the present invention, heavy chains as described in the second aspect of the present invention, light chain variable regions as described in the third aspect of the present invention, light chains as described in the fourth aspect of the present invention, antibodies as described in the fifth aspect of the present invention, multispecific antigen-binding molecules as described in the sixth aspect of the present invention, recombinant proteins as described in the seventh aspect of the present invention, CAR constructs as described in the eighth aspect of the present invention, recombinant immune cells as described in the ninth aspect of the present invention, antibody-drug conjugates as described in the tenth aspect of the present invention, or combinations thereof, wherein the active ingredient is used for

[0107] (a) Preparation of detection reagents or kits;

[0108] (b) To prepare medicines or formulations for the prevention and / or treatment of human CEACAM5 / 6-related diseases; and / or

[0109] (c) To prepare a medicine or formulation for the prevention and / or treatment of human CEACAM5 / 6-related cancers or tumors.

[0110] In another preferred embodiment, the cancer or tumor is selected from the group consisting of: colon cancer, rectal cancer, lymphoma, pancreatic cancer, lung cancer, stomach cancer, hepatocellular carcinoma, breast cancer, or thyroid cancer, or combinations thereof.

[0111] In a twelfth aspect of the present invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising:

[0112] (i) an active ingredient selected from the group consisting of: a heavy chain variable region as described in the first aspect of the present invention, a heavy chain as described in the second aspect of the present invention, a light chain variable region as described in the third aspect of the present invention, a light chain as described in the fourth aspect of the present invention, an antibody as described in the fifth aspect of the present invention, a multispecific antigen-binding molecule as described in the sixth aspect of the present invention, a recombinant protein as described in the seventh aspect of the present invention, a CAR construct as described in the eighth aspect of the present invention, a recombinant immune cell as described in the ninth aspect of the present invention, an antibody-drug conjugate as described in the tenth aspect of the present invention, or a combination thereof; and

[0113] (ii) Pharmaceutically acceptable carriers.

[0114] In another preferred embodiment, the pharmaceutical composition is a liquid formulation.

[0115] In another preferred embodiment, the pharmaceutical composition is an injection.

[0116] In another preferred embodiment, the pharmaceutical composition is used to treat tumors.

[0117] In another preferred embodiment, the tumor is a tumor that highly expresses human CEACAM5 / 6.

[0118] In a thirteenth aspect of the invention, a polynucleotide is provided, said polynucleotide encoding a polypeptide selected from the group consisting of:

[0119] (1) The heavy chain variable region as described in the first aspect of the present invention, the heavy chain as described in the second aspect of the present invention, the light chain variable region as described in the third aspect of the present invention, the light chain as described in the fourth aspect of the present invention, and the antibody as described in the fifth aspect of the present invention; or

[0120] (2) The multispecific antigen-binding molecule as described in the sixth aspect of the present invention;

[0121] (3) The recombinant protein as described in the seventh aspect of the present invention; or

[0122] (4) The CAR construct as described in the eighth aspect of the present invention.

[0123] In a fourteenth aspect of the invention, a carrier is provided, said carrier containing the polynucleotide as described in a thirteenth aspect of the invention.

[0124] In another preferred embodiment, the vector includes: bacterial plasmids, bacteriophages, yeast plasmids, plant cell viruses, mammalian cell viruses such as adenoviruses, retroviruses, or other vectors.

[0125] In a fifteenth aspect of the invention, a genetically engineered host cell is provided, said host cell containing a vector as described in a fourteenth aspect of the invention or a genome in which polynucleotides as described in a thirteenth aspect of the invention are integrated.

[0126] In another preferred embodiment, the host cell is a mammalian cell, preferably a cell of a human, mouse, sheep, horse, dog, or cat, and more preferably a Chinese hamster ovary cell.

[0127] In a sixteenth aspect of the invention, a method is provided for the in vitro non-diagnostic detection of human CEACAM5 / 6 protein in a sample (including diagnostic or non-diagnostic samples), the method comprising the steps of:

[0128] (1) In vitro, the sample is contacted with an antibody as described in the fifth aspect of the present invention;

[0129] (2) Detect whether an antigen-antibody complex is formed, where the formation of a complex indicates the presence of CEACAM5 / 6 protein in the sample.

[0130] In a seventeenth aspect of the present invention, a method for treating human CEACAM5 / 6-related diseases is provided, the method comprising:

[0131] The antibody, a multispecific antibody, a drug conjugate of the antibody, or CAR-T cells expressing the antibody, or a combination thereof, is administered to the desired recipient.

[0132] In another preferred embodiment, the human CEACAM5 / 6-related disease is a tumor with high CEACAM5 / 6 expression, preferably colorectal cancer, pancreatic cancer, lung cancer, gastric cancer, hepatocellular carcinoma, breast cancer, and thyroid cancer.

[0133] In another preferred embodiment, the human CEACAM5 / 6-related disease is a tumor with high expression of CEACAM5 / 6 and CD47, preferably colorectal cancer.

[0134] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0135] Figure 1 The ELISA results for UM05-C9 and human CEACAM5 protein were shown.

[0136] Figure 2 The binding of UM05-C9 to CHO-CEACAM5 cells was demonstrated.

[0137] Figure 3 The ELISA results show the interaction between UM05-L9 and bispecific antibody L34 with (A) CEACAM5 and (B) CEACAM6 proteins in cynomolgus monkeys.

[0138] Figure 4 The results of UM05-C9 internalization are shown.

[0139] Figure 5 Different structural combinations of CD47-CEACAM5 / 6 bispecific antibodies are shown. Green or orange indicates the antigen-binding fragments of different antibodies (VH / VL of CD47 antibody or CEACAM5 / 6 antibody).

[0140] Figure 6The affinity tests of UM11-L34 molecules for (A) CEACAM5 and (B) CD47 molecules are shown.

[0141] Figure 7 The affinity tests of the UM11-L34 molecule for CEACAM5 and CD47 molecules are shown in sequence. Detailed Implementation

[0142] Through extensive and in-depth research and screening, the inventors have developed, for the first time, an antibody with excellent anti-CEACAM5 activity. Unexpectedly, they also discovered that this antibody exhibits excellent binding activity against CEACAM6. Furthermore, this invention also provides, for the first time, a highly efficient and safe bispecific antibody against human CD47-CEACAM5 / 6, its preparation method, and its uses. The bispecific antibody of this invention exhibits better targeting and specific killing effects on tumor cells highly expressing CEACAM5 / 6 and CD47, while simultaneously reducing binding to erythrocytes and / or platelets. Specifically, the anti-CEACAM5 / 6 and CD47 bispecific antibody of this invention binds to CD47... + -CEACAM5 / 6 + It exhibits stronger binding selectivity to tumor cells and weaker binding to CD47 protein on the surface of erythrocytes and platelets, thereby treating various cancers by modulating human immune function. This invention was developed based on these principles.

[0143] the term

[0144] As used herein, the term "antibody" refers to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The amino acid composition and sequence of the constant region of the heavy chain of immunoglobulins differ, thus their antigenicity also differs. Based on this, immunoglobulins can be divided into five classes, or different types of immunoglobulins: IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chain constant regions designated as α, δ, ε, γ, and μ, respectively. IgG represents the most important class of immunoglobulins, and due to differences in chemical structure and biological function, it can be further divided into four subclasses: IgG1, IgG2, IgG3, and IgG4. The light chains are classified as κ or λ chains based on differences in their constant regions. The subunit structures and three-dimensional configurations of different types of immunoglobulins are well known to those skilled in the art.

[0145] The complementation-determining region (CDR) is a key sequence structure that determines the specific binding of an antibody to an antigen. The heavy chain and light chain each contain three CDRs, named HCDR1, HCDR2, and HCDR3, and LCDR1, LCDR2, and LCDR3, respectively. In a given antibody's light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any of a number of known antibody CDR assignment systems or combinations thereof, including, for example: Chothia (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)) based on antibody three-dimensional structure and CDR loop topology; Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, USDapartment of Health and Human Services, National Institutes of Health (1987)) based on antibody sequence variability; AbM (University of Bath); Contact (University College London); and the International Immuno GeneTics. The database (IMGT) and the Chothia definition based on the location of the loop structure.

[0146] For example, depending on the different CDR determination schemes, the residues of each CDR are as follows.

[0147] Table 1 CDR Definition Scheme

[0148]

[0149] Note 1: The annotations vary slightly in different documents, especially the Chothia annotation scheme.

[0150] Note 2: Except for the contact labeling scheme which uses the Chothia or Martin numbering scheme, other labeling schemes are compatible with various numbering schemes.

[0151] Note 3: When using the Kabat numbering convention, the end of the Chothia CDR-H1 ring varies between H32 and H34 depending on the ring length. (This is because the Kabat numbering scheme places the insertion at H35A and H35B.) If neither H35A nor H35B exists, then CDR-H1 ends at bit 32; if only H35A exists, then CDR-H1 ends at bit 33; if both H35A and H35B exist, then CDR-H1 ends at bit 34.

[0152] Unless otherwise stated, in this invention, the term "CDR" or "CDR sequence" covers a CDR sequence determined in any of the foregoing manner.

[0153] Unless otherwise stated, in this invention, when referring to the position of a residue in the antibody variable region (including heavy chain variable region residues and light chain variable region residues), it means the position numbered according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0154] In one embodiment, the CDR of the antibody of the present invention is determined by the Kabat rule, or by the IMGT rule, or by a combination thereof.

[0155] Antibodies with different specificities (i.e., different binding sites against different antigens) have different core binding receptors (CDRs). However, although CDRs differ between antibodies, only a limited number of amino acid sites within a CDR are directly involved in antigen binding. Minimal overlapping regions can be determined using at least two of the Kabat, Chothia, AbM, Contact, and IMGT methods, thus providing a “minimum binding unit” for antigen binding. The minimum binding unit can be a sub-part of a CDR. As is well known to those skilled in the art, the residues of the remaining CDR sequence can be determined through the antibody’s structure and protein folding. Therefore, this invention also contemplates any variants of the CDRs given herein. For example, in a variant of a CDR, the amino acid residues of the minimum binding unit may remain unchanged, while the remaining CDR residues as defined by Kabat or IMGT may be substituted with conserved amino acid residues.

[0156] As used herein, the term "frame region" (FR) refers to the amino acid sequence inserted between CDRs, specifically those portions of the variable regions of the light and heavy chains of immunoglobulins that are relatively conserved among different immunoglobulins within a single species. Each immunoglobulin light and heavy chain has four FRs, designated FR1-L, FR2-L, FR3-L, FR4-L and FR1-H, FR2-H, FR3-H, FR4-H, respectively. Accordingly, the light chain variable domain can be represented as (FR1-L)-(CDR1-L)-(FR2-L)-(CDR2-L)-(FR3-L)-(CDR3-L)-(FR4-L) and the heavy chain variable domain as (FR1-H)-(CDR1-H)-(FR2-H)-(CDR2-H)-(FR3-H)-(CDR3-H)-(FR4-H). Preferably, the FR of the present invention is a human antibody FR or a derivative thereof, wherein the derivative of the human antibody FR is substantially identical to the naturally occurring human antibody FR, that is, the sequence identity reaches 85%, 90%, 95%, 96%, 97%, 98% or 99%.

[0157] Knowing the amino acid sequence of the CDR, those skilled in the art can easily determine the frame regions FR1-L, FR2-L, FR3-L, FR4-L and / or FR1-H, FR2-H, FR3-H, FR4-H.

[0158] As used herein, the term "human frame region" is a frame region that is substantially identical (approximately 85% or more, specifically 90%, 95%, 97%, 99%, or 100%) to the frame region of a naturally occurring human antibody.

[0159] As used herein, the terms “monoclonal antibody” or “mAb” refer to an antibody molecule that has a single amino acid composition against a specific antigen and should not be construed as requiring the antibody to be produced by any particular method. Monoclonal antibodies can be produced by a single clone of B cells or hybridomas, but can also be recombinant, i.e., produced through protein engineering.

[0160] As used herein, the term "antigen" or "target antigen" refers to a molecule or part of a molecule that can be bound by an antibody or antibody-like binding protein. The term further refers to a molecule or part of a molecule that can be used in animals to produce an antibody capable of binding to an epitope of that antigen. A target antigen may have one or more epitopes. For each target antigen recognized by an antibody or by an antibody-like binding protein, the antibody-like binding protein can compete with the intact antibody that recognizes the target antigen.

[0161] As used herein, the term "affinity" is theoretically defined by the balanced association between the intact antibody and the antigen. The affinity of the bispecific antibody of this invention can be assessed or measured by the KD value (dissociation constant) (or other assays), such as bio-layer interferometry (BLI), using Biacore8K measurement.

[0162] Anti-CEACAM5 / 6 antibody

[0163] CEACAM belongs to the immunoglobulin superfamily of adhesion molecules. Its domains are highly glycosylated, typically including 1-2 immunoglobulin variable region-like domains (N domains) and 0-6 immunoglobulin constant region-like domains. CEACAM proteins are located extracellularly, with CEACAM1, CEACAM3, and CEACAM4 attached to the cell membrane via hydrophobic transmembrane domains; CEACAM5-8 are attached to the cell membrane via glycosylphosphatidylinositol. These extracellular domains typically function as adhesion molecules between cells (e.g., epithelial, endothelial, dendritic, and leukocytes). CEACAM5 / CEACAM6 has been found to be overexpressed in various malignant tumors, such as breast, pancreatic, ovarian, colon, lung, and gastric gland tumors, and is associated with tumor invasiveness and metastasis.

[0164] As used herein, “anti-CEACAM5 / 6 antibody” and “anti-CEACAM5 / CEACAM6 antibody” refer to antibodies in this invention that can bind specifically to CEACAM5 and CEACAM6 molecules, that is, the antibodies have cross-reactivity against CEACAM5 and CEACAM6 molecules.

[0165] This invention provides an anti-CEACAM5 / 6 antibody (e.g., UM05-L9), which not only binds strongly to CEACAM5 molecules but also binds relatively strongly to CEACAM6 molecules.

[0166] Preferably, the antibody comprises a heavy chain and a light chain, wherein the heavy chain contains a heavy chain variable region (VH) amino acid sequence and the light chain contains a light chain variable region (VL) amino acid sequence.

[0167] The heavy chain variable region (VH) has a complementarity-determining region (VH-CDR) selected from the group consisting of:

[0168] VH-CDR1 shown in SEQ ID NO.1,

[0169] VH-CDR2 shown in SEQ ID NO.2, and

[0170] VH-CDR3 as shown in SEQ ID NO.3;

[0171] The light chain variable region (VL) has a complementary determinant region (VL-CDR) selected from the group consisting of:

[0172] VL-CDR1 shown in SEQ ID NO.4,

[0173] VL-CDR2 shown in SEQ ID NO.5, and

[0174] VL-CDR3 as shown in SEQ ID NO. 6;

[0175] Among them, any of the above amino acid sequences may also include a derivative sequence which has been optionally added, deleted, modified and / or substituted with at least one amino acid and is capable of retaining the binding affinity of CEACAM5 and / or CEACAM6.

[0176] In another preferred embodiment, the sequence formed by adding, deleting, modifying and / or substituting at least one amino acid sequence preferably has at least 80% homology or sequence identity, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the amino acid sequence.

[0177] In the above-described content of the present invention, the number of added, deleted, modified and / or substituted amino acids is preferably no more than 40% of the total number of amino acids in the initial amino acid sequence, more preferably no more than 35%, more preferably 1-33%, more preferably 5-30%, more preferably 10-25%, and more preferably 15-20%.

[0178] In the above-described content of the present invention, more preferably, the number of added, deleted, modified and / or substituted amino acids can be 1-7, more preferably 1-5, more preferably 1-3, and more preferably 1-2.

[0179] Preferably, the antibody described herein is one or more of the following: full-length antibody protein, antigen-antibody binding domain protein fragment, bispecific antibody, multispecific antibody, single-chain antibody fragment (scFv), single-domain antibody (sdAb), and single-domain antibody, as well as monoclonal or polyclonal antibodies prepared from the above antibodies. The monoclonal antibody can be developed using various methods and techniques, including hybridoma technology, phage display technology, and single-lymphocyte gene cloning technology. The mainstream method is to prepare monoclonal antibodies from wild-type or transgenic mice using hybridoma technology.

[0180] The full-length antibody protein is a conventional full-length antibody protein in the art, comprising a heavy chain variable region, a light chain variable region, a heavy chain constant region, and a light chain constant region. The heavy chain variable region and light chain variable region of the protein, together with the human heavy chain constant region and the human light chain constant region, constitute a fully human full-length antibody protein. Preferably, the full-length antibody protein is IgG1, IgG2, IgG3, or IgG4. The human light chain constant region is selected from the light chain constant region of the human κ or λ subtype; more preferably, the human heavy chain constant region is the heavy chain constant region of human IgG1, and the human light chain constant region is the κ chain.

[0181] The antibody (anti-CEACAM5 / 6 antibody) in this invention can be a full-length protein (such as IgG1, IgG2a, IgG2b or IgG2c) or a protein fragment containing an antigen-antibody binding domain or an antigen-binding fragment (e.g. Fab, F(ab'), sdAb, scFv fragment).

[0182] As used herein, non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable region of an antibody (e.g., independent complementarity-determining regions (CDRs) such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. In another preferred embodiment, the antibody of CEACAM5 / 6 of the present invention or its antigen-binding fragment is selected from the group consisting of camel-derived single-domain antibodies, scFv, scFv dimers, BsFv, dsFv2, dsFv-dsFv', Fv fragments, Fab, Fab', F(ab')2, ds bifunctional antibodies, nanobodies, domain antibodies, or bivalent domain antibodies.

[0183] The antibody (anti-CEACAM5 / 6 antibody) in this invention can be a wild-type protein or a mutant protein that has undergone specific mutations to achieve a specific effect, such as using mutations to eliminate the effector function of the antibody.

[0184] The antibody of the present invention can be a double-chain or single-chain antibody, and can be selected from animal-derived antibodies, chimeric antibodies, humanized antibodies, more preferably humanized antibodies, human-animal chimeric antibodies, and even more preferably fully humanized antibodies.

[0185] The antibody derivatives described in this invention can be single-chain antibodies and / or antibody fragments, such as Fab, Fab', (Fab')2, or other known antibody derivatives in the art, as well as any one or more of IgA, IgD, IgE, IgG, and IgM antibodies or other subtypes of antibodies. The single-chain antibody is a conventional single-chain antibody in the art, comprising a heavy chain variable region, a light chain variable region, and a short peptide of 15-20 amino acids.

[0186] The animal is preferably a mammal, such as a mouse.

[0187] The antibodies of this invention may be chimeric antibodies, humanized antibodies, CDR-grafted and / or modified antibodies that target CEACAM5 / 6 (e.g., human CEACAM5 / 6).

[0188] In another preferred embodiment, the heavy chain variable region of the antibody contains the amino acid sequence shown in SEQ ID NO. 7, 11 or 13.

[0189] In another preferred embodiment, the light chain variable region of the antibody contains the amino acid sequence shown in SEQ ID NO. 8 or 12.

[0190] In another preferred embodiment, the heavy chain variable region (VH) amino acid sequence and / or light chain variable region (VL) amino acid sequence of the antibody targeting CEACAM5 / 6 are shown in Table 2 below:

[0191] Table 2. Antibody IDs and sequence numbers of VH and VL (SEQ ID NO.)

[0192] Antibody number VH sequence number VL sequence number UM05-L9 7 8 UM05-C9 11 12 UM05-C9' 13 12

[0193] Among them, UM05-L9 is a human-mouse chimeric antibody, UM05-C9 is a humanized antibody, and UM05-C9' is another version of the humanized antibody. All three have the same VH-CDR and VL-CDR.

[0194] CD47 and its antibodies

[0195] CD47 is a 45-50 kDa transmembrane glycoprotein belonging to the immunoglobulin (Ig) superfamily. Studies have found that CD47, highly expressed on tumor cells, binds to its ligand SIRPα on macrophages, leading to SIRPα tyrosine phosphorylation and the emission of an inhibitory regulatory signal that suppresses macrophage phagocytosis. Correspondingly, blocking this pathway can relieve the inhibitory effect of macrophages on tumor cell phagocytosis, enhance the body's immune response to tumor cells, and provide a new avenue for tumor immunotherapy.

[0196] In tumor therapy targeting the CD47-SIRPα axis, the most important mechanism is the activation of macrophages, thereby enhancing their phagocytosis of tumor cells. Secondly, blocking CD47 may further recruit macrophages to tumor tissue and recruit additional immune cell cytokines and chemokines, such as monocyte chemoattractant protein 3 (MCP-3), to the tumor tissue. The secretion of these cytokines contributes to the efficacy of CD47 blockade therapy. Thirdly, CD47-SIRPα-targeting therapy may also alter the polarization state of macrophages in tumors. Macrophages can be classified into two types based on their phenotype and functional activity: M1 (type I) and M2 (type II). M1 macrophages produce a large number of pro-inflammatory cytokines and mediate resistance to intracellular parasites and inhibition of tumor growth; M2 macrophages produce fewer pro-inflammatory molecules and participate in tissue damage repair, angiogenesis, and tumor growth promotion. Studies have found that blocking CD47-SIRPα significantly increases the number of M1 macrophages in the mouse microenvironment, while there is no significant increase in M2 macrophages. Finally, other immune cells can also respond to CD47 blockade therapy. SIRPα is highly expressed on bone marrow immune cells, thus it may be a key regulator of the bone marrow lineage. In mice, CD47 regulates antigen uptake through SIRPα+ dendritic cells, and using a homologous immune-active tumor model, the therapeutic efficacy of CD47 blockade depends on dendritic cells. Therapies targeting the CD47-SIRPα axis can promote adaptive immune responses in tumors by stimulating antigen presentation by macrophages or dendritic cells.

[0197] CD47 is widely expressed in various cell types, especially in newly formed erythrocytes. Therefore, therapeutic antibodies targeting CD47 may cause anemia. On the other hand, the concentration of free anti-human CD47 antibodies in the body can be greatly reduced due to the adsorption of anti-human CD47 antibodies by erythrocytes.

[0198] Therefore, developing new therapeutic anti-human CD47 antibodies that bind more selectively to CD47 protein on the surface of tumor cells and less selectively to CD47 protein on the surface of erythrocytes has become one of the goals of novel therapeutic anti-human CD47 antibodies.

[0199] The preferred anti-human CD47 antibody of this invention includes the anti-human CD47 antibody or its antigen-binding fragment described in Chinese Patent 202010240238.7, which is incorporated herein by reference (as used herein, denoted by the designation UM03-C4, whose heavy chain variable region is shown in SEQ ID NO. 17; and whose light chain variable region is shown in SEQ ID NO. 18). The IgG4 subtype of this CD47 antibody is denoted by the designation UM03-C4 in this patent. Furthermore, based on this anti-human CD47 antibody, it also includes a derived human CD47 antibody obtained by mutating its VH and VL regions (as used herein, denoted by the designation UM03-C4'). The mutant anti-human CD47 antibody involved includes the following mutations or combinations of the following mutations:

[0200] Heavy chain: H-I37V, H-P45L, H-I48V, H-R94K, H-T52R, H-T52S, H-T52L, H-T52I, H-T52H, H-T52A, H-T52N, H-T52Q;

[0201] Light chains: L-L4M, L-I46L, L-V58I, L-T93N.

[0202] Preferably, the bispecific antibody described in this invention is obtained by combining anti-human CD47 antibody or its antigen-binding domain with anti-human CEACAM5 / 6 antibody or its antigen-binding domain in different ways.

[0203] Bispecific antibodies

[0204] Bispecific antibodies (bsAbs) are non-natural antibodies that simultaneously target two different antigens or proteins, blocking two different signaling pathways and stimulating a specific immune response. Their specificity and dual functionality are playing an increasingly important role in tumor immunotherapy, making them a research hotspot in antibody engineering for cancer treatment worldwide. Studies have shown that bispecific antibodies in tumor immunotherapy primarily mediate the killing of tumors by immune cells; bind to two targets, block two signaling pathways, and exert unique or overlapping functions, effectively preventing drug resistance; possess strong specificity and targeting capabilities, and reduce off-target toxicity; and effectively reduce treatment costs (excerpt from Antibody Circle). Therefore, using bispecific antibody drugs can reduce the chance of tumor cell escape, eliminate tumor cells, and improve efficacy.

[0205] Bispecific antibodies can be prepared using methods such as hybridoma cells, chemical conjugation, and recombinant genes. Among these, recombinant gene technology offers greater flexibility in terms of binding sites and yield. According to incomplete statistics, there are currently more than 60 types of bispecific antibodies. Based on their characteristics and structural differences, bispecific antibody structures mainly fall into two categories: those containing an Fc fragment (IgG-like bispecific antibodies, which have Fc-mediated effector functions) and those without an Fc fragment (non-IgG-like bispecific antibodies, which function through antigen-binding affinity and have advantages such as small molecular weight and low immunogenicity).

[0206] The present invention also includes antibodies that simultaneously bind to anti-human CEACAM5 / 6 antibodies and other targets. Preferably, the other targets are selected from the group consisting of: CD47, CD73, CD47, CD3, CTLA4, PD-1, PD-L1, CD28, CD40, OX40, LAG3, DR5, TIM-3, TIGIT, VEGF, VEGFR, Ang2, CD39, CD73, GITR, or combinations thereof.

[0207] In another preferred embodiment, the antibody that binds to other targets in the bispecific antibody of the present invention is an anti-human CD47 antibody.

[0208] As used herein, the terms “bispecific antibody,” “bifunctional antibody,” “antibody of the present invention,” “bispecific antibody of the present invention,” “bispecific antibody,” “bifunctional fusion antibody,” “anti-human CEACAM5 / 6 and CD47 bispecific antibody,” and “anti-CEACAM5 / 6 and CD47 antibody” are used interchangeably and refer to bispecific antibodies that bind to both CEACAM5 / 6 and CD47 simultaneously.

[0209] As used herein, the term "linker" refers to one or more amino acid residues inserted into the immunoglobulin domain that provide sufficient mobility for both the light and heavy chain domains to fold into an exchangeable dual variable region immunoglobulin.

[0210] As used herein, the linker is a flexible linker, preferably a peptide linker. Suitable examples of peptide linkers include monoglycine (Gly) or serine (Ser) residues, and the identification and sequence of amino acid residues in the peptide linker may vary depending on the type of secondary structural element that needs to be achieved in the peptide linker.

[0211] This invention provides a bispecific antibody constructed based on the aforementioned anti-human CEACAM5 / 6 antibody and anti-human CD47 antibody or their antigen-binding fragments. These bispecific antibodies link the anti-human CEACAM5 / 6 antibody and the anti-human CD47 antibody or their antigen-binding fragments via a linker, forming a symmetrical or asymmetrical multivalent antibody structure, achieving the effect of simultaneously binding to CEACAM5 / 6 and CD47 proteins. The linker sequences that can be selected include:

[0212] (G)n, (GGGGS)n, (GGGSG)n, (GGSGG)n,

[0213] GGGGSGSAGSAAGSGEFGGGGSGGG (SEQ ID NO.65),

[0214] SSSSKAPPPSLPSPSRLPGPSDTPILPQ(SEQ ID NO.66),

[0215] KESGSSVSSEQLAQFRSLD(SEQ ID NO.67)、

[0216] EGKSSGSGSESKST(SEQ ID NO.68),

[0217] GSAGSAAGSGEF (SEQ ID NO. 69), etc. Preferably, the connector is (GGGGS)n, where n is an integer between 0 and 5; or SSSSKAPPPSLPSPSRLPGPSDTPILPQ, or GGGSSSSKAPPPSLPSPSRLPGPSDTPILPQGGG; more preferably, the connector is GGGSSSSKAPPPSLPSPSRLPGPSDTPILPQGGG.

[0218] In one specific embodiment of the present invention, the preferred connector sequence is as shown in positions 119-152 of SEQ ID NO.64 or SEQ ID NO.66.

[0219] The bispecific antibody constructed from the anti-human CEACAM5 / 6 antibody and the anti-human CD47 antibody or their antigen-binding fragments as described in this invention may further include a human heavy chain constant region and / or a human light chain constant region; more preferably, the human heavy chain constant region is selected from the heavy chain constant region of human IgG1, IgG2 or IgG4, and the human light chain constant region is selected from the light chain constant region of human κ or λ chain; even more preferably, the human heavy chain constant region is the heavy chain constant region of human IgG1, and the human light chain constant region is the κ chain; even more preferably, the human heavy chain constant region of human IgG1 may carry mutations known to those skilled in the art to enhance or weaken the biological functions mediated by the IgG1 antibody constant region, including ADCC, ADCP (Antibody-dependent cellular phagocytosis), CDC and FcRn binding activity, etc. These mutations include, but are not limited to, those listed in the literature (Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life. Front. Immunol., 2019, 10: 1296):

[0220] Table 3. Mutations in the IgG1 heavy chain constant region and their functions

[0221]

[0222]

[0223] Based on the above technology, the inventors designed bispecific antibodies against human CEACAM5 / 6-CD47 with different structural forms. Preferably, the sequences of the composed bispecific antibodies against human CEACAM5 / 6-CD47 are shown in Table 4.

[0224] Table 4. Sequences of anti-human CEACAM5 / 6-CD47 bispecific antibodies

[0225]

[0226] Compared with the prior art, the anti-human CEACAM5 / 6-CD47 antibody of the present invention and CEACAM5 / 6 + -CD47 + Double-positive tumor cells exhibit stronger binding selectivity and killing effect with CD47 protein on their surface, but weaker binding with CD47 protein on the surface of erythrocytes and platelets, and have no agglutination effect on erythrocytes.

[0227] In this invention, the bispecific antibody also includes its conserved variants, which are polypeptides formed by replacing up to 10, preferably up to 8, more preferably up to 5, and most preferably up to 3 amino acids with amino acids of similar or analogous properties compared to the amino acid sequence of the bispecific antibody of this invention. These conserved variant polypeptides are preferably generated by amino acid substitutions according to Table A.

[0228] Table A

[0229] The initial residues Representative substitution Preferred replacement Ala(A) Val; Leu; Ile Val Arg(R) Lys;Gln;Asn Lys Asn(N) Gln; His; Lys; Arg Gln Asp(D) Glu Glu Cys(C) Ser Ser Gln(Q) Asn Asn Glu(E) Asp Asp Gly(G) Pro; Ala Ala His(H) Asn; Gln; Lys; Arg Arg Ile(I) Leu; Val; Met; Ala; Phe Leu Leu(L) Ile; Val; Met; Ala; Phe Ile Lys(K) Arg;Gln;Asn Arg Met(M) Leu; Phe; Ile Leu Phe(F) Leu; Val; Ile; Ala; Tyr Leu Pro(P) Ala Ala Ser(S) Thr Thr Thr(T) Ser Ser Trp(W) Tyr; Phe Tyr Tyr(Y) Trp; Phe; Thr; Ser Phe Val(V) Ile; Leu; Met; Phe; Ala Leu

[0230] Nucleic acid encoding and expression vector

[0231] The present invention also provides polynucleotide molecules encoding the aforementioned antibodies or fragments thereof or fusion proteins thereof. The polynucleotides of the present invention may be in DNA or RNA form. DNA form includes cDNA, genomic DNA, or artificially synthesized DNA. DNA may be single-stranded or double-stranded. DNA may be a coding strand or a non-coding strand. Polynucleotides encoding the mature polypeptides of the present invention include: a coding sequence encoding only the mature polypeptide; a coding sequence of the mature polypeptide and various additional coding sequences; a coding sequence of the mature polypeptide (and optional additional coding sequences) and a non-coding sequence.

[0232] The term "polynucleotide encoding a polypeptide" can refer to a polynucleotide that includes the polypeptide, or it can also include additional coding and / or non-coding sequences.

[0233] The nucleic acids (and combinations of nucleic acids) of the present invention can be used to generate the recombinant antibodies of the present invention in a suitable expression system.

[0234] The present invention also relates to polynucleotides that hybridize with the above-described sequences and have at least 50%, preferably at least 70%, and more preferably at least 80% identity between the two sequences. The present invention particularly relates to polynucleotides that hybridize with the polynucleotides described herein under stringent conditions. In the present invention, “stringent conditions” means: (1) hybridization and elution at lower ionic strength and higher temperatures, such as 0.2×SSC, 0.1% SDS, 60°C; or (2) hybridization with a denaturing agent, such as 50% (v / v) formamide, 0.1% fetal bovine serum / 0.1% Ficoll, 42°C, etc.; or (3) hybridization only occurs when the identity between the two sequences is at least 90%, more preferably at least 95%. Furthermore, the polypeptide encoded by the hybridizable polynucleotide has the same biological function and activity as the mature polypeptide.

[0235] The full-length nucleotide sequence or fragments of the antibody of the present invention can generally be obtained by PCR amplification, recombinant methods, or artificial synthesis. One feasible method is to synthesize the relevant sequence artificially, especially when the fragment length is short. Typically, long fragments can be obtained by first synthesizing multiple small fragments and then ligating them. Furthermore, the coding sequence of the heavy chain and an expression tag (such as 6His) can be fused together to form a fusion protein.

[0236] Once the relevant sequence is obtained, it can be obtained in large quantities using recombination methods. This typically involves cloning it into a vector, transforming it into cells, and then isolating the sequence from the proliferated host cells using conventional methods. The biomolecules (nucleic acids, proteins, etc.) involved in this invention include biomolecules existing in isolated forms.

[0237] Currently, the DNA sequence encoding the protein of this invention (or a fragment thereof, or a derivative thereof) can be obtained entirely through chemical synthesis. This DNA sequence can then be introduced into various existing DNA molecules (or vectors) and cells known in the art. Furthermore, mutations can be introduced into the protein sequence of this invention through chemical synthesis.

[0238] The present invention also relates to vectors comprising the aforementioned suitable DNA sequences and suitable promoters or control sequences. These vectors can be used to transform suitable host cells to enable them to express proteins.

[0239] The host cell can be a prokaryotic cell, such as a bacterial cell; a lower eukaryotic cell, such as a yeast cell; or a higher eukaryotic cell, such as a mammalian cell. Representative examples include: Escherichia coli, Streptomyces; bacterial cells of Salmonella typhimurium; fungal cells such as yeast; insect cells of Drosophila S2 or Sf9; and animal cells of CHO, COS7, and 293 cells.

[0240] Preferably, the present invention also provides a host cell comprising the vector of the present invention, wherein the host cell is a mammalian cell, more preferably a cell of a human, mouse, sheep, horse, dog or cat, and even more preferably a Chinese hamster ovary cell.

[0241] Transformation of host cells with recombinant DNA can be performed using conventional techniques well known to those skilled in the art. When the host is a prokaryote such as *E. coli*, competent cells capable of uptake DNA can be harvested after the exponential growth phase and treated with CaCl2, the steps of which are well known in the art. Another method is to use MgCl2. If desired, transformation can also be performed using electroporation. When the host is a eukaryote, the following DNA transfection methods can be used: calcium phosphate coprecipitation, conventional mechanical methods such as microinjection, electroporation, liposome packaging, etc.

[0242] The obtained transformants can be cultured using conventional methods to express the polypeptide encoded by the gene of this invention. Depending on the host cells used, the culture medium can be selected from various conventional media. Culture is carried out under conditions suitable for host cell growth. Once the host cells have grown to an appropriate cell density, the selected promoter is induced using a suitable method (such as temperature adjustment or chemical induction), and the cells are cultured for a further period.

[0243] In the early culture conditions, the expression level of bispecific antibodies can reach 3.9 g / L, with a purity of over 97%, and they can effectively metabolize lactic acid during the culture process.

[0244] The recombinant peptides used in the methods described above can be expressed intracellularly, on the cell membrane, or secreted extracellularly. If desired, the recombinant proteins can be separated and purified using various separation methods based on their physical, chemical, and other properties. These methods are well known to those skilled in the art. Examples of these methods include, but are not limited to: conventional refolding treatment, treatment with protein precipitants (salting out), centrifugation, permeation, ultrafiltration, ultracentrifugation, molecular sieve chromatography (gel filtration), adsorption chromatography, ion exchange chromatography, high-performance liquid chromatography (HPLC), and various other liquid chromatography techniques, as well as combinations of these methods.

[0245] The bispecific antibody of the present invention can be used alone or in combination or conjugated with a detectable marker (for diagnostic purposes), a therapeutic agent, or any combination of the above substances.

[0246] Detectable markers for diagnostic purposes include, but are not limited to: fluorescent or luminescent markers, radioactive markers, MRI (magnetic resonance imaging) or CT (computed tomography) contrast agents, or enzymes capable of producing detectable products.

[0247] Therapeutic agents that can bind to or conjugate with the antibodies of the present invention include, but are not limited to: 1. radionuclides; 2. biotoxicants; 3. cytokines such as IL-2; 4. gold nanoparticles / nanorobars; 5. viral particles; 6. liposomes; 7. magnetic nanoparticles; 8. tumor therapeutic agents (e.g., cisplatin) or any form of antitumor drug, etc.

[0248] Pharmaceutical Composition

[0249] The present invention also provides a composition. Preferably, the composition is a pharmaceutical composition containing the anti-human CEACAM5 / 6 antibody or its active fragment or fusion protein described above, and a pharmaceutically acceptable carrier. Typically, these substances are formulated in a non-toxic, inert, and pharmaceutically acceptable aqueous carrier medium, wherein the pH is typically about 5-8, preferably about 6-8, although the pH may vary depending on the nature of the formulated substance and the condition to be treated. The formulated pharmaceutical composition can be administered via conventional routes, including (but not limited to): intravenous injection, intravenous infusion, subcutaneous injection, local injection, intramuscular injection, intratumoral injection, intraperitoneal injection (e.g., intraperitoneal), intracranial injection, or intracavitary injection.

[0250] The pharmaceutical compositions of the present invention can be directly used to bind CEACAM5 / 6, and therefore can be used to treat tumors. Furthermore, other therapeutic agents can be used simultaneously.

[0251] The pharmaceutical compositions of the present invention contain a safe and effective amount (e.g., 0.001-99 wt%, preferably 0.01-90 wt%, more preferably 0.1-80 wt%) of the anti-human CEACAM5 / 6 antibody of the present invention and a pharmaceutically acceptable carrier or excipient. Such carriers include (but are not limited to): saline, buffer, glucose, water, glycerol, ethanol, and combinations thereof. The pharmaceutical formulation should be matched to the route of administration. The pharmaceutical compositions of the present invention can be formulated into injectable forms, for example, prepared by conventional methods using physiological saline or an aqueous solution containing glucose and other excipients. Pharmaceutical compositions such as injections and solutions are preferably manufactured under sterile conditions. The dosage of the active ingredient is a therapeutically effective amount, for example, about 10 micrograms / kg body weight to about 50 mg / kg body weight per day. Furthermore, the anti-human CEACAM5 / 6 antibody of the present invention can also be used with other therapeutic agents.

[0252] In this invention, the anti-human CEACAM5 / 6 antibody of this invention can be used alone, and the optimal target response can be obtained by adjusting the dosing regimen. For example, a single dose, multiple doses over a period of time, or the dose can be reduced or increased proportionally according to the urgency of the treatment situation.

[0253] When using the pharmaceutical composition, a safe and effective amount of the anti-human CEACAM5 / 6 antibody of the present invention is administered to mammals, wherein the safe and effective amount is generally at least about 10 micrograms per kilogram of body weight, and in most cases does not exceed about 50 milligrams per kilogram of body weight, preferably about 10 micrograms per kilogram of body weight to about 10 milligrams per kilogram of body weight. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0254] application

[0255] The present invention also provides the use of the antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), recombinant proteins, and / or immune cells of the present invention, for example, for the preparation of diagnostic agents or pharmaceuticals. Furthermore, the present invention also provides the use of antibodies comprising the antibodies of the present invention or antigen-binding fragments thereof in cells for the preparation of pharmaceuticals or for cell therapy, said pharmaceuticals or cells for the prevention and / or treatment of conditions in which enhanced immune responses are benefited.

[0256] Preferably, the drug is a drug for the prevention and / or treatment of diseases associated with abnormal expression or function of CEACAM5 / 6 (CEACAM5 protein or CEACAM6 protein).

[0257] In one embodiment of the invention, the disease is cancer, preferably a tumor with high expression of CEACAM5 or CEACAM6, and more preferably colorectal cancer.

[0258] In another preferred embodiment, the human CEACAM5 / 6-related disease is a tumor that simultaneously highly expresses CEACAM5 / 6 and CD47, preferably colorectal cancer.

[0259] The main advantages of this invention include

[0260] (1) The anti-human CEACAM5 / 6 antibody of the present invention has cross-reactivity with simultaneous binding to CEACAM5 and CEACAM6;

[0261] (2) The anti-human CEACAM5 / 6 and CD47 bispecific antibody of the present invention has better targeting and specific killing effect on tumor cells with high expression of CEACAM5 / 6 and CD47, while reducing the binding effect with red blood cells and / or platelets.

[0262] The present invention will be further described below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0263] The antibody sequences of this invention are shown in Table 5:

[0264] Table 5. Antibody sequences of the present invention

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] Example 1: Mutation of humanized CD47 monoclonal antibody

[0278] The parent sequence of the humanized CD47 monoclonal antibody is derived from Chinese Patent 202010240238.7, and its heavy chain variable region sequence is shown in SEQ ID NO:17; its light chain variable region sequence is shown in SEQ ID NO:18. The IgG4 subtype of this humanized CD47 monoclonal antibody is designated UM03-C4 in this patent.

[0279] UM03-C4 heavy chain VH:

[0280] QVQLVESGGGVVQPGGSLRLSCAASGFTFS DYGMA WIRQAPGKGPEWIA FITNLASSIYYADTVTG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR AGDYRSFPY WGQGTLVTVSA (SEQ ID NO.17)

[0281] UM03-C4 Light Chain VL:

[0282] EIVLTQSPATLSLSPGERATLSC SASSSVNYVN WYQQKPGQAPRILIY GISNLAS GVPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQRSTFPP YTFGQGTKLEIK(SEQ ID NO.18)

[0283] In the CD47 antibody, the CDR sequences defined by Kabat in the heavy and light chains are underlined.

[0284] In addition, based on this anti-human CD47 antibody, there is also a derived human CD47 antibody obtained by mutating its VH and VL regions (represented by the code UM03-C4' as used herein, the heavy chain variable region sequence of which is shown in SEQ ID NO:19; the light chain variable region sequence of which is shown in SEQ ID NO:20). The mutant anti-human CD47 antibody involved includes the following mutations or combinations of the following mutations:

[0285] Heavy chain: H-I37V, H-P45L, H-I48V, H-R94K, H-P101D, H-T64K, H-T52R, H-T52S, H-T52L, H-T52I, H-T52H, H-T52A, H-T52G, H-T52N, H-T52Q;

[0286] Light chains: L-L4M, L-I46L, L-V58I, L-T93N.

[0287] Among them, the mutations in M18 are all in the FR region, while M19, M20 and M21 are based on M18 with the addition of one or two CDR mutations.

[0288] The effects of some mutations on the activity of CD47 monoclonal antibodies are listed in Table 6 below:

[0289] Table 6. CD47 monoclonal antibody mutations and their functional effects

[0290]

[0291] Note: The location numbers are all based on the Kabat rules.

[0292] Example 2: Obtaining humanized CEACAM5 / 6 monoclonal antibodies

[0293] 2.1 Obtaining mouse anti-human CEACAM5 / 6 monoclonal antibody

[0294] The inventors constructed a CHO cell line overexpressing human CEACAM5 protein and used it to immunize mice. Spleen cells from immunized mice were fused with SP2 / 0-AG14 cells to form hybridoma cells, and an appropriate amount of the fused cells were seeded into 96-well plates. On day 10 post-fusion, the supernatant from each well was collected, and the binding activity of mouse antibodies secreted by the hybridoma cells to human CEACAM5 was detected by ELISA (see Example 3 for the method), yielding a series of hybridoma cells with high activity.

[0295] Among the hybridoma cells selected, one antibody surprisingly showed excellent binding activity against CEACAM6.

[0296] Sequencing revealed the cDNA sequences of the heavy chain variable region and light chain variable region corresponding to the secreted antibody. The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO.7, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO.8. The heavy chain variable region and light chain variable region of the mouse antibody were ligated to the constant region of the human IgG1 heavy chain and constant region of the κ chain, respectively, to obtain the human-mouse chimeric antibody UM05-L9, whose heavy chain sequence is shown in SEQ ID NO.9 and light chain sequence is shown in SEQ ID NO.10.

[0297] 2.2 Humanization of mouse anti-human CEACAM5 / 6 antibody

[0298] The heavy chain variable region and light chain variable region sequences of the mouse antibody UM05-L9 obtained in Example 2 were analyzed, and its heavy chain complementarity-determining region (CDR) was obtained as shown in the table below:

[0299] Table 7. CDR region delineation of mouse CEACAM5 / 6 monoclonal antibody UM05-L9

[0300] Kabat definition IMGT definition H-CDR1 DYAMH GYTFTDYA H-CDR2 VISTYSGHTNYNQKFKG ISTYSGHT H-CDR3 GSTTAHYYTMDF VRGSTTAHYYTMDF L-CDR1 GASENIYGTLN ENIYGT L-CDR2 GATNLAD GAT L-CDR3 QNVLSIPYT QNVLSIPYT

[0301] Simultaneously, referring to the definitions of CDR in Kabat and IMGT, human germline antibody sequence databases (IGMT and IgBlast) were searched to obtain human germline antibody sequences with high homology to the heavy / light chain variable regions of mouse antibodies. These sequences were then combined with the CDRs of the aforementioned mouse antibodies, a process known as CDR grafting. Reversion mutations were performed on some amino acids in the frame regions, ultimately yielding humanized antibodies UM05-C9 and UM05-C9'. Their heavy chain variable region sequences are shown in SEQ ID NO.11 and SEQ ID NO.13, respectively; the light chain variable region sequences are identical in both, as shown in SEQ ID NO.12.

[0302] Example 3: Binding of antibody UM05-C9 / UM05-L9 to CEACAM family proteins

[0303] 3.1 Binding of antibody to human CEACAM5 protein

[0304] A 1 μg / mL human CEACAM5 protein solution was coated onto a 96-well high-affinity plate at 100 μL / well and incubated overnight at 4°C with shaking. The next day, the plate was washed three times with 300 μL PBST (Tween 20: 0.5‰), then blocked with 100 μL / well of 5% BSA / PBS for 1 hour with shaking at room temperature. The plate was washed three times with 300 μL PBST. A serial dilution of the antibody samples was prepared using PBS. 100 μL / well of the solution was added to each well of the 96-well plate and incubated for 1 hour with shaking at room temperature. The plate was washed three times with 300 μL PBST. A secondary antibody, goat anti-human IgG HRP solution, was prepared and added to each well at 100 μL / well. The plate was incubated for 30 minutes with shaking at room temperature. The plate was washed four times with 300 μL PBST. 100 μL / well of TMB was added, and the plate was incubated for 20 minutes. 100 μL / well of 0.6N H2SO4 was added to stop the incubation, and the OD was measured. 450 nm.

[0305] The test results are as follows: Figure 1 As shown, the EC50 of the humanized antibody UM05-C9 binding to human CEACAM5 is 0.399 nM.

[0306] 3.2 Binding of antibodies to CHO-CEACAM5 cells

[0307] The binding of the antibody to CHO cells overexpressing human CEACAM5 was detected using FACS. In short, cells were first collected, washed once with PBS, counted, and diluted to 2 × 10⁻⁶ cells / cells. 6 / ml cell suspension; take 10μl of antibody working solution and add it to 100μl of cell suspension, incubate at 4℃ in the dark for 30min; wash twice with PBS, add the corresponding fluorescently labeled secondary antibody Goat-anti-Human IgG(H+L) (Invitrogen), incubate at 4℃ in the dark for 30min, wash twice with PBS, suspend in 400μl FACS buffer, and detect the binding of antibody to cells by flow cytometry.

[0308] Test results as follows Figure 2 As shown, the EC50 of UM05-C9 binding to CHO-CEACAM5 is 636.9 ng / mL.

[0309] 3.3 Affinity test of UM05-L9

[0310] The affinity of antigen-antibody binding was detected using SPR (Surface Plasmon Resonance) technology. In simple terms, a 4 μg / mL concentration of the chimeric antibody UM05-L9 was incubated with a protein A sensor chip (GE, Cat#29127556) for 30 seconds to capture the antibody. During the antigen binding phase, serially diluted human CEACAM5 protein was used as the mobile phase to bind with the UM05-L9 antibody captured on the sensor chip for 120 seconds. In the dissociation phase, elution was performed continuously with HBS-EP buffer for 360 seconds. The binding of CEACAM5 protein to the antibody on the sensor chip was quantitatively detected using a Biacore T20x0 (GE Healthcare). The results are shown in Table 8; the affinity of UM05-L9 was 0.68 nM.

[0311] Table 8. Affinity and kinetic data of UM05-L9 with human CEACAM5

[0312] receptor ligands ka(1 / Ms) kd(1 / s) KD(M) CEACAM5 UM05-L9 <![CDATA[6.54×10 4 ]]> <![CDATA[4.45×10 -4 ]]> <![CDATA[6.80×10 -9 ]]>

[0313] 3.4 Binding of UMO5-L9 antibody to other molecules in the human CEACAM family

[0314] The binding of CEACAM to other members of the CEACAM family was further investigated using UM05-L9. Stable cell lines including SW620-CEACAM1, SW620-CEACAM3, CHO-CEACAM6, CHO-CEACAM7, and CHO-CEACAM8 were used. The detection methods are as described in section 3.2. The results are shown in Table 9 below.

[0315] The results showed that the UM05-L9 molecule not only strongly bound to the CEACAM5 molecule, but also to the CEACAM6 molecule. However, it showed virtually no binding to other molecules tested, including CEACAM1, 3, 7, and 8. Since both CEACAM5 and CEACAM6 are molecules specifically highly expressed by tumor cells, this suggests that UM05-L9 (and presumably also UM05-C9) has good tumor targeting properties.

[0316] Table 9. Binding of UM05-L9 with other molecules in the human CEACAM family

[0317]

[0318]

[0319] 3.5UM05-L9 binding to CEACAM5 and CEACAM6 molecules in cynomolgus monkeys

[0320] The binding of UM05-L9 to CEACAM5 and CEACAM6 proteins in cynomolgus monkeys was further detected using an ELISA method. The detection method is as described in section 3.1. Results Figure 3 As shown.

[0321] The results showed that UM05-L9 had strong binding to CEACAM5 and CEACAM6 molecules from cynomolgus monkeys, with binding EC50 values ​​of 0.6784 nM and 0.4629 nM, respectively.

[0322] The ability of the CEACAM5 / 6 antibody of this invention to bind to the CEACAM5 / 6 protein of cynomolgus monkeys provides a convenient animal model for drug development of related antibodies.

[0323] Example 4: Tumor tissue specificity of UM05-C9

[0324] Tumor tissue specificity analysis of UM05-C9 was performed by Sichuan Xiapaison Pharmaceutical Technology Co., Ltd. using a multi-organ tumor tissue microarray from Shanghai Xinchao Biotechnology Co., Ltd. (Cat No: HORgC120PG04, Lot No: XT19-008).

[0325] Image scanning and semi-quantitative analysis of the immunohistochemical results showed that UM05-C9 was strongly stained in colorectal cancer tumor tissues, and also showed strong staining in some lung cancers and pancreatic cancers, while it was negative or low-expressed in the corresponding adjacent tissues (Table 10).

[0326] Table 10. Results of UM05-C9 staining of multi-organ tumor tissue microarrays (partial).

[0327]

[0328]

[0329] Example 5: Intracellular properties of CEACAM5 / 6 antibody UM05-C9

[0330] Experimental procedure: A549 cells were cultured in F12K medium with 10% FBS and 1% P / S. The culture volume was 50,000 cells / well, and 200 μl / well was inoculated into 96-well plates. SiteClick was used to... TM Antibody Azido Modification Kit (Invitrogen, Cat#S20026) and Click-iT TM pHrodo TMThe iFL Red sDIBO Alkyne for Antibody Labeling (Invitrogen, Cat#C20034) kit was used to label antibodies according to the manufacturer's instructions. The labeled antibodies were diluted with complete culture medium at ratios of 1:20, 1:40, 1:80, 1:160, 1:320, and 1:640 to concentrations of 45, 22.5, 11.25, 5.62, 2.8, and 1.4 μg / ml, respectively. The supernatant from cells inoculated the previous day was removed, and 100 μl of the prepared antibody was added to each well. Cells were incubated for 16 hours. Cells were then digested with trypsin, collected, and antibody endocytosis was detected by flow cytometry (Ex = 560 nM, Em = 585 nM). Antibodies endocytosed by cells showed fluorescence excitation, while unendocytosed antibodies did not.

[0331] The results are as follows Figure 4 As shown, this indicates that CEACAM5 / 6 antibodies undergo internalization after binding to A549 cells.

[0332] Example 6: Design of CD47-CEACAM5 / 6 Bispecific Antibody

[0333] Bispecific antibodies can be formed by combining anti-human CD47 antibodies or their antigen-binding domains with anti-human CEACAM5 / 6 antibodies or their antigen-binding domains in different ways. (The following text appears to be a separate, unrelated sentence: "As shown in the example...") Figure 5 Several attempts at dual-antibody structures are shown.

[0334] The resulting dual-antibody combinations are shown in Table 11.

[0335] Table 11. Sequences and types of CEACAM5 / 6-CD47 bispecific antibodies

[0336]

[0337]

[0338] Example 7: Preparation of Bispecific Antibodies

[0339] The cDNA sequences encoding the antibody heavy or light chain were ligated to the sequences encoding the signal peptide and cloned into the mammalian cell expression vector pcDNA3.4, respectively. HEK293 cells were transfected with the heavy chain and light chain expression plasmids at a 2:1 molar ratio using Lipofectamine 2000 transfection reagent (Invitrogen) and cultured at 37°C and 5% CO2 for 7 days. The culture supernatant was collected, and the antibody was purified from the supernatant using Protein A affinity chromatography. The quality of the purified antibody was analyzed using classic protein analysis methods such as SDS-PAGE electrophoresis and molecular sieve chromatography. The purified antibody was dialyzed against PBS and lyophilized for concentration before being stored at -20°C.

[0340] Example 8: Binding of bispecific antibodies to CD47 protein or CEACAM family proteins

[0341] 8.1 Binding of bispecific antibodies to CD47 protein

[0342] Coat 96-well high-affinity plates with 100 μL / well of 1 μg / mL human CD47 protein solution and incubate overnight at 4°C with shaking. The next day, wash three times with 300 μL PBST (Tween 20: 0.5‰), then block with 100 μL / well of 5% BSA / PBS for 1 hour with shaking at room temperature. Wash three times with 300 μL PBST. Prepare serial dilutions of antibody samples using PBS. Add 100 μL / well to each 96-well plate and incubate for 1 hour with shaking at room temperature. Wash three times with 300 μL PBST. Prepare secondary antibody solutions of goat anti-mouse IgG HRP or goat anti-human IgG HRP, add 100 μL / well to each 96-well plate, and incubate for 1 hour with shaking at room temperature. Wash four times with 300 μL PBST. Add 100 μL / well of TMB and incubate for 20 minutes. Add 100 μL / well of 0.6 N H2SO4 to stop color development, then measure the OD. 450 nm.

[0343] Representative data on the binding of the antibody to CD47 protein involved in this invention are shown in Table 12.

[0344] 8.2 Binding of bispecific antibodies to CEACAM5 protein

[0345] The detection method for the binding of the bispecific antibody to human CEACAM5 protein was the same as described in Example 5.1, except that the coating protein was replaced with a 1 μg / mL human CEACAM5 protein solution. The data are shown in Table 12.

[0346] Table 12 Bispecific antibody binding activity to target

[0347]

[0348]

[0349] Example 9: Bispecific antibody and CD47 + -CEACAM5 + Binding of A549 to human tumor cells

[0350] Lung cancer cell line A549 (ATCC) is a human tumor cell line that simultaneously expresses CD47 and CEACAM5. The inventors of this application used flow cytometry to detect antibody binding on A549 cells. A concentration gradient solution of the antibody to be tested was prepared using PBS to a final concentration of 2× working solution. A549 cells were collected, washed once with PBS, counted, and diluted to 4×10⁻⁶. 6 / ml cell suspension; 50μL of antibody working solution was added to 50μL of cell suspension and incubated at 4℃ in the dark for 60min; after washing twice with PBS, the corresponding fluorescently labeled secondary antibody (anti-huIgG 633) was added and incubated at 4℃ in the dark for 30min. After washing twice with PBS, the cells were resuspended in 400μL FACS buffer and the binding of the antibody to the cells was detected by flow cytometry. The data are shown in Table 13.

[0351] Table 13 shows the EC50 (nM) of the binding of the dual antibodies to human tumor cells A549.

[0352]

[0353]

[0354] * indicates that these molecules were within the detection concentration range, but the detection signal did not reach the plateau, making it impossible to accurately calculate EC50. "NA" indicates that no detection was performed.

[0355] Example 10: Binding of bispecific antibodies to human erythrocytes and their agglutination effect on human erythrocytes

[0356] The inventors tested the binding of the partially bispecific antibody designed in this invention and the positive control antibody Hu5F9 (US Patent 9017675B2 and literature PLoS ONE 2015, 10(9):e0137345) to human erythrocytes and their agglutination effect on human erythrocytes. First, erythrocytes were isolated from peripheral blood of volunteers and suspended in physiological saline to a 1% concentration. Antibody concentration gradient solutions were prepared using PBS to prepare a final concentration of 2× working solution. 50 μL of antibody working solution was added to 50 μL of erythrocyte suspension and incubated at 4°C in the dark for 60 min. After washing twice with PBS, the corresponding fluorescently labeled secondary antibody was added and incubated at 4°C in the dark for 30 min. After washing twice with PBS, the solution was suspended in 400 μL of FACS buffer, and the binding of the antibody to erythrocytes was detected by flow cytometry. For the erythrocyte agglutination assay, erythrocytes were suspended in physiological saline to a 2% concentration. Similarly, 50 μL of antibody working solution was added to 50 μL of the erythrocyte suspension, and the mixture was placed in a 96-well round-bottom plate. After standing at room temperature for 2 hours, the plate was observed and photographed. The data are shown in Table 14.

[0357] Table 14 Binding and Agglutination of Bispecific Antibodies with Human Erythrocytes

[0358]

[0359]

[0360] Note 1: The number of "+" signs indicates the strength of binding to human erythrocytes. "-" indicates that no significant binding of the antibody to erythrocytes was detected within the detection range of the highest antibody concentration of 100 nM. "NA" indicates that no detection was performed.

[0361] Note 2: The number of "+" signs indicates the antibody's ability to induce agglutination of human erythrocytes. "-" indicates that the antibody did not induce significant erythrocyte agglutination within the detection range of a maximum antibody concentration of 200 μg / mL. "NA" indicates that no test was performed.

[0362] Example 11: Bispecific antibody inhibits the binding of CD47 to SIRPα protein on A549 cells

[0363] Lung cancer cell line A549 (ATCC) is a human tumor cell line that simultaneously expresses CD47 and CEACAM5. In this application, the inventors used flow cytometry to detect the inhibition of CD47 binding to SIRPα protein on A549 cells by an antibody. A concentration gradient solution of the antibody to be tested was prepared using PBS to a final concentration of 2× working solution. A549 cells were collected, washed once with PBS, counted, and diluted to 4×10⁻⁶. 6 / ml cell suspension; 50μL of antibody working solution was added to 50μL of cell suspension and incubated at 4℃ in the dark for 60min; after washing twice with PBS, human-SIRPa-mouse-Fc tag protein (SIA-H52A8) was added and incubated at 4℃ in the dark for 30min; after washing twice with PBS, goat anti-mouse IgG1-Fc specific detection secondary antibody (115-095-071) was added and incubated at 4℃ in the dark for 30min; after washing twice with PBS, the cells were resuspended in 400μL FACS buffer and the binding of the labeled secondary antibody was detected by flow cytometry to obtain the antibody's activity in inhibiting the binding of CD47 and SIRPα protein on A549 cells. The results are shown in Table 15.

[0364] Table 15 Activity of bispecific antibodies blocking CD47-SIRPα binding on A549 cells

[0365] Antibody code Suppression (referencing UM03-C4) UM03-C4 +++ L8 +++ L10 +++ L11 + L12 +++ L13 ++ L14 +++ L15 +++ L16 +++ L17 ++ L18 + L23 + L25 +++ L26 +++ L27 ++ L28 ++ L29 + L30 + L31 + L32 + L33 + L34 ++ L35 + L36 + L37 + L38 + L39 + L40 +++ L41 +++

[0366] Note: The number of "+" signs indicates the antibody's ability to block the binding of CD47 to SIRPα on A549 cells.

[0367] Example 12: ADCC of bispecific antibodies

[0368] The inventors of this application tested the ADCC cytotoxicity of a subset of antibodies on A549 cells and human erythrocytes. A549 cells were collected, resuspended in culture medium, counted, and diluted to 1.5 × 10⁻⁶. 5 A549 cells were seeded at 50 μL / well one day in advance using a cell suspension of / ml. The next day, the culture medium was discarded, and the prepared antibody serial dilution was added to the wells. The cells were incubated at 37°C for 1 hour. After washing twice with PBS, effector cells Jurkat-NFAT-luc / CD16A were added, and the cell count was diluted to 3×10⁶ cells / well. 6 Cell suspension of 1 / ml was added to each well of a plate at a rate of 30 μL / well, and the plates were incubated at 37°C for 4 hours. Then, 30 μL of One-Glo was added to each well, and the bioluminescence intensity was measured using a microplate reader after 3 minutes. For the detection of erythrocyte killing activity, erythrocytes were first isolated from peripheral blood of volunteers, washed twice with culture medium, counted, and prepared into 1×10⁶ cells / well plates. 7 / mL cell suspension, take 50ul / well of cell suspension and mix with 50ul of 2× antibody serial dilution buffer, and incubate at 37°C for 1 hour; wash twice with PBS, add effector cells Jurkat-NFAT-CD16A, and dilute to 3×10⁹ cells / well. 6Cell suspension of 1 / ml was added to each well at a rate of 30 μL / well, and the cells were incubated at 37°C for 4 hours. Then, 30 μL / well of One-Glo was added, and after 3 minutes, the bioluminescence intensity was measured using a microplate reader. The results are shown in Table 16 below.

[0369] Table 16. Effects of bispecific antibodies on ADCC in A549 and RBC cells.

[0370]

[0371]

[0372] Note: The number of "+" signs qualitatively represents the antibody-mediated ADCC activity on target cells.

[0373] “NA” means not detected.

[0374] Example 13 ADCP effect of bispecific antibodies

[0375] In this application, the inventors detected the partial antibody-mediated ADCP activity on A549 cells and human erythrocytes. A549 cells were collected, resuspended in culture medium, counted, and diluted to 1×10⁻⁶. 5 A549 cells were seeded at 50 μL / well one day in advance using a cell suspension of / ml. The next day, the culture medium was discarded, and the prepared antibody serial dilution was added to the wells. The cells were incubated at 37°C for 1 hour. After washing twice with PBS, effector cells Jurkat-NFAT-luc / CD32A were added, and the cell count was diluted to 3 × 10⁶ cells / well. 6 Cell suspension of 1 / ml was added to each well at a rate of 30 μL / well, and the cells were incubated at 37°C for 4 hours. Then, 30 μL of One-Glo was added to each well, and the bioluminescence intensity was measured using a microplate reader after 3 minutes. The results are shown in Table 17.

[0376] Table 17. Effects of bispecific antibodies on ADCP in A549 and RBC cells.

[0377]

[0378] Note: The number of "+" signs qualitatively represents the antibody-mediated ADCP activity on target cells.

[0379] “NA” means not detected.

[0380] Example 14: Antigen-antibody affinity detection

[0381] The affinity of L34 molecules for human CEACAM5 and human CD47 was detected using SPR (Surface Plasmon Resonance) technology. In simple terms, antibody capture was achieved by incubating a 4 μg / mL antibody solution with a protein A sensor chip (GE, Cat#29127556) for 30 s. During the antigen-binding phase, human CEACAM5 and human CD47 proteins were used as mobile phases for 120 s of binding with the captured antibodies on the sensor chip. In the dissociation phase, elution was performed continuously with HBS-EP buffer for 360 s. The binding of antigens to antibodies on the sensor chip was quantitatively detected using a Biacore 8K. Results are as follows: Figure 6 As shown in Table 18.

[0382] Table 18 shows the affinity of L34 molecules for human CEACAM5 and human CD47 proteins.

[0383] receptor ka(1 / Ms) kd(1 / s) KD(M) CD47 <![CDATA[6.86×10 5 ]]> <![CDATA[4.51×10 -2 ]]> <![CDATA[6.57×10 -8 ]]> CEACAM5 <![CDATA[2.33×10 4 ]]> <![CDATA[1.73×10 -4 ]]> <![CDATA[7.43×10 -9 ]]>

[0384] The above affinity test results show that the affinity of bispecific antibody molecules, represented by L34 molecules, for the human CD47 target is significantly weakened, while the affinity for CEACAM5 is maintained.

[0385] Based on the affinity assay described above, the epitope competition between the two antigens and the bispecific antibodies was also detected using SPR technology, following the same method as described previously. In this experiment, the antibody solution was first incubated with a protein A sensor chip for 30 seconds to capture the antibody. During the antigen binding phase, CEACAM5 and CD47 proteins were used sequentially as mobile phases to bind to the antibodies captured on the sensor chip for 120 seconds each. The binding of the antigen and antibody on the sensor chip was quantitatively detected using a Biacore 8K. The results are as follows: Figure 7 As shown.

[0386] Example 15: Mouse Tumor Drug Efficacy Model

[0387] A549 cells (ATCC, human non-small cell lung cancer cells) are CD47 + -CEACAM + Tumor cells, at 6×10 6 A549 cells were subcutaneously inoculated into female NOD-Scid mice. Tumors were allowed to grow to approximately 70 mm. 3 Subsequently, the antibody solution prepared in physiological saline was administered intravenously. Six mice in each group were given the drug once every three days for a total of three weeks.

[0388] Example 16: Drug metabolism and toxicology in cynomolgus monkeys

[0389] The antibody solution was administered intravenously to cynomolgus monkeys (n=2) at a dose of 20 mg / kg. Blood samples were collected at 0, 0.25, 4, 8, 24, 48, 72, 96, 144, 192, 240, and 336 hours before and after administration. Blood drug concentrations were measured by ELISA, and pharmacokinetic curves were plotted. Pharmacokinetic parameters were also calculated.

[0390] discuss

[0391] Besides its known use as a tumor marker, and the clinical application of immunological assays measuring elevated CEACAM5 levels in the blood of cancer patients for cancer prognosis and control, CEACAM5 has become a potentially useful tumor-associated antigen for targeted therapy. Two main approaches to CEACAM5-targeted immunotherapy for cancer have been reported. One approach uses anti-CEACAM5 antibodies to induce lysogenic activity in immune cells, particularly through antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC), to eliminate CEACAM5-expressing tumor cells. The other approach involves conjugating anti-CEACAM5 antibodies or antibody fragments to effector molecules such as drugs, toxins, radioactive nucleotides, immunomodulators, or cytokines to specifically target CEACAM5-expressing tumor cells, thereby exerting the therapeutic effect of the effector molecules. Given that CEACAM5 is more frequently overexpressed in solid tumors such as colorectal cancer, pancreatic cancer, lung cancer, gastric cancer, hepatocellular carcinoma, breast cancer, and thyroid cancer, current research focuses on the antigen recognition capabilities of anti-CEACAM5 antibodies.

[0392] In summary, current research indicates that treatments targeting CEACAM5 will help inhibit tumor metastasis. Therefore, the anti-CEACAM5 / 6 antibody with affinity for both CEACAM5 and CEACAM6 provided in this invention has significant application value. Furthermore, the anti-human CEACAM5 / 6 and CD47 bispecific antibody of this invention not only exhibits better targeting and specific killing effects on tumor cells highly expressing CEACAM5 / 6 and CD47, but also reduces binding to erythrocytes and / or platelets.

[0393] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims. sequence list <110> Umai Biotechnology (Lianyungang) Co., Ltd. <120> An antibody targeting human CEACAM5 / 6, its preparation method and application <130> P2021-1402 <160> 69 <170> SIPOSequenceListing 1.0 <210> 1 <211> 5 <212> PRT <213> Artificial Sequence <400> 1 Asp Tyr Ala Met His 1 5 <210> 2 <211> 17 <212> PRT <213> Artificial Sequence <400> 2 Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 3 <211> 12 <212> PRT <213> Artificial Sequence <400> 3 Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe 1 5 10 <210> 4 <211> 11 <212> PRT <213> Artificial Sequence <400> 4 Gly Ala Ser Glu Asn Ile Tyr Gly Thr Leu Asn 1 5 10 <210> 5 <211> 7 <212> PRT <213> Artificial Sequence <400> 5 Gly Ala Thr Asn Leu Ala Asp 1 5 <210> 6 <211> 9 <212> PRT <213> Artificial Sequence <400> 6 Gln Asn Val Leu Ser Ile Pro Tyr Thr 1 5 <210> 7 <211> 121 <212> PRT <213> Artificial Sequence <400> 7 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 8 <211> 107 <212> PRT <213> Artificial Sequence <400> 8 Asp Ile Gln Met Thr Gln Ser Pro Val Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr 20 25 30 Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Asn Leu Ala Asp Gly Val Ser Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Arg Gln Tyr Ser Leu Lys Ile Ser Ser Leu His Pro 65 70 75 80 Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 9 <211> 451 <212> PRT <213> Artificial Sequence <400> 9 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 10 <211> 214 <212> PRT <213> Artificial Sequence <400> 10 Asp Ile Gln Met Thr Gln Ser Pro Val Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr 20 25 30 Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Asn Leu Ala Asp Gly Val Ser Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Arg Gln Tyr Ser Leu Lys Ile Ser Ser Leu His Pro 65 70 75 80 Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 11 <211> 121 <212> PRT <213> Artificial Sequence <400> 11 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 12 <211> 107 <212> PRT <213> Artificial Sequence <400> 12 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 13 <211> 121 <212> PRT <213> Artificial Sequence <400> 13 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 14 <211> 451 <212> PRT <213> Artificial Sequence <400> 14 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 15 <211> 451 <212> PRT <213> Artificial Sequence <400> 15 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 16 <211> 214 <212> PRT <213> Artificial Sequence <400> 16 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 17 <211> 118 <212> PRT <213> Artificial Sequence <400> 17 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile 35 40 45 Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala 115 <210> 18 <211> 107 <212> PRT <213> Artificial Sequence <400> 18 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr 35 40 45 Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 19 <211> 118 <212> PRT <213> Artificial Sequence <400> 19 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 20 <211> 107 <212> PRT <213> Artificial Sequence <400> 20 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 35 40 45 Gly Ile Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 21 <211> 584 <212> PRT <213> Artificial Sequence <400> 21 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly 130 135 140 Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 145 150 155 160 Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala Trp Ile Arg Gln Ala 165 170 175 Pro Gly Lys Gly Pro Glu Trp Ile Ala Phe Ile Thr Asn Leu Ala Ser 180 185 190 Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg Phe Thr Ile Ser Arg 195 200 205 Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala 210 215 220 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Gly Asp Tyr Arg Ser 225 230 235 240 Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser 245 250 255 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 260 265 270 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 275 280 285 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 290 295 300 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 305 310 315 320 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 325 330 335 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 340 345 350 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 355 360 365 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 370 375 380 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 385 390 395 400 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 405 410 415 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 420 425 430 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 435 440 445 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 450 455 460 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 465 470 475 480 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 485 490 495 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 500 505 510 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 515 520 525 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 530 535 540 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 545 550 555 560 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 565 570 575 Ser Leu Ser Leu Ser Pro Gly Lys 580 <210> 22 <211> 336 <212> PRT <213> Artificial Sequence <400> 22 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln 115 120 125 Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser 130 135 140 Cys Ser Ala Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys 145 150 155 160 Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala 165 170 175 Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190 Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr 195 200 205 Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr 210 215 220 Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 23 <211> 589 <212> PRT <213> Artificial Sequence <400> 23 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln 130 135 140 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg 145 150 155 160 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala 165 170 175 Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile Ala Phe Ile 180 185 190 Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg 195 200 205 Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met 210 215 220 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala 225 230 235 240 Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr 245 250 255 Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 260 265 270 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 275 280 285 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 290 295 300 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 305 310 315 320 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 325 330 335 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 340 345 350 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 355 360 365 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 370 375 380 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 385 390 395 400 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 405 410 415 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 420 425 430 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 435 440 445 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 450 455 460 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 465 470 475 480 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 485 490 495 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 500 505 510 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 515 520 525 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 530 535 540 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 545 550 555 560 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 565 570 575 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 580 585 <210> 24 <211> 341 <212> PRT <213> Artificial Sequence <400> 24 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 115 120 125 Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu 130 135 140 Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val Asn 145 150 155 160 Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr Gly 165 170 175 Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly 180 185 190 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp 195 200 205 Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr Thr 210 215 220 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 225 230 235 240 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 245 250 255 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 260 265 270 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 275 280 285 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 290 295 300 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 305 310 315 320 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 325 330 335 Asn Arg Gly Glu Cys 340 <210> 25 <211> 589 <212> PRT <213> Artificial Sequence <400> 25 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln 130 135 140 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg 145 150 155 160 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala 165 170 175 Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile Ala Phe Ile 180 185 190 Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg 195 200 205 Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met 210 215 220 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala 225 230 235 240 Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr 245 250 255 Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 260 265 270 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 275 280 285 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 290 295 300 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 305 310 315 320 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 325 330 335 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 340 345 350 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 355 360 365 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 370 375 380 Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu 385 390 395 400 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 405 410 415 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 420 425 430 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 435 440 445 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 450 455 460 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 465 470 475 480 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 485 490 495 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 500 505 510 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 515 520 525 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 530 535 540 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 545 550 555 560 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 565 570 575 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 580 585 <210> 26 <211> 589 <212> PRT <213> Artificial Sequence <400> 26 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln 130 135 140 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg 145 150 155 160 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala 165 170 175 Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile Ala Phe Ile 180 185 190 Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg 195 200 205 Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met 210 215 220 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala 225 230 235 240 Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr 245 250 255 Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 260 265 270 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 275 280 285 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 290 295 300 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 305 310 315 320 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 325 330 335 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 340 345 350 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 355 360 365 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 370 375 380 Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu 385 390 395 400 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 405 410 415 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 420 425 430 Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu 435 440 445 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 450 455 460 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 465 470 475 480 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 485 490 495 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 500 505 510 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 515 520 525 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 530 535 540 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 545 550 555 560 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 565 570 575 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 580 585 <210> 27 <211> 472 <212> PRT <213> Artificial Sequence <400> 27 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile 35 40 45 Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln 130 135 140 Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser 145 150 155 160 Cys Ser Ala Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala 180 185 190 Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr 210 215 220 Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr 225 230 235 240 Lys Leu Glu Ile Lys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 245 250 255 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 260 265 270 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 275 280 285 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 290 295 300 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 305 310 315 320 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 325 330 335 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 340 345 350 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 355 360 365 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 370 375 380 Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser 385 390 395 400 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 405 410 415 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val 420 425 430 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 435 440 445 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 450 455 460 Ser Leu Ser Leu Ser Pro Gly Lys 465 470 <210> 28 <211> 451 <212> PRT <213> Artificial Sequence <400> 28 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 29 <211> 589 <212> PRT <213> Artificial Sequence <400> 29 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln 130 135 140 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg 145 150 155 160 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala 165 170 175 Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile Ala Phe Ile 180 185 190 Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg 195 200 205 Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met 210 215 220 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala 225 230 235 240 Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr 245 250 255 Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 260 265 270 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 275 280 285 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 290 295 300 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 305 310 315 320 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 325 330 335 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 340 345 350 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 355 360 365 Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu 370 375 380 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 385 390 395 400 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 405 410 415 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 420 425 430 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 435 440 445 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 450 455 460 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 465 470 475 480 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 485 490 495 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 500 505 510 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 515 520 525 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 530 535 540 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 545 550 555 560 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 565 570 575 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 580 585 <210> 30 <211> 716 <212> PRT <213> Artificial Sequence <400> 30 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile Tyr Gly Ala 180 185 190 Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val 210 215 220 Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly 245 250 255 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu 260 265 270 Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu 275 280 285 Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala Trp 290 295 300 Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile Ala Phe Ile Thr 305 310 315 320 Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg Phe 325 330 335 Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn 340 345 350 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Gly 355 360 365 Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 370 375 380 Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 385 390 395 400 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 405 410 415 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 420 425 430 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 435 440 445 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 450 455 460 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 465 470 475 480 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 485 490 495 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 500 505 510 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 515 520 525 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 530 535 540 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 545 550 555 560 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 565 570 575 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 580 585 590 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 595 600 605 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 610 615 620 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly 625 630 635 640 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 645 650 655 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 660 665 670 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 675 680 685 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 690 695 700 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 705 710 715 <210> 31 <211> 475 <212> PRT <213> Artificial Sequence <400> 31 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile Tyr Gly Ala 180 185 190 Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val 210 215 220 Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys Asp Lys Thr His Thr Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 370 375 380 Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 32 <211> 214 <212> PRT <213> Artificial Sequence <400> 32 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr 35 40 45 Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 33 <211> 594 <212> PRT <213> Artificial Sequence <400> 33 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Ser 115 120 125 Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro 145 150 155 160 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 165 170 175 Asp Tyr Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu 180 185 190 Trp Ile Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp 195 200 205 Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 210 215 220 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 225 230 235 240 Tyr Cys Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln 245 250 255 Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val 260 265 270 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 275 280 285 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 290 295 300 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 305 310 315 320 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 325 330 335 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 340 345 350 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 355 360 365 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 370 375 380 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 385 390 395 400 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 405 410 415 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 420 425 430 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 435 440 445 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 450 455 460 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 465 470 475 480 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 485 490 495 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 500 505 510 Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 515 520 525 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 530 535 540 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 545 550 555 560 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 565 570 575 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 580 585 590 Gly Lys <210> 34 <211> 470 <212> PRT <213> Artificial Sequence <400> 34 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gly 145 150 155 160 Ala Ser Glu Asn Ile Tyr Gly Thr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ser Pro Lys Leu Leu Ile Tyr Gly Ala Thr Asn Leu Ala Asp 180 185 190 Ala Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys 210 215 220 Gln Asn Val Leu Ser Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 370 375 380 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys 465 470 <210> 35 <211> 346 <212> PRT <213> Artificial Sequence <400> 35 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser 130 135 140 Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser 145 150 155 160 Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 165 170 175 Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg 180 185 190 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser 195 200 205 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr 210 215 220 Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 225 230 235 240 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 245 250 255 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 260 265 270 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 275 280 285 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 290 295 300 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 305 310 315 320 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 325 330 335 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 340 345 <210> 36 <211> 584 <212> PRT <213> Artificial Sequence <400> 36 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile 35 40 45 Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 130 135 140 Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr 145 150 155 160 Thr Phe Thr Asp Tyr Ala Met His Trp Val Lys Gln Ala Pro Gly Gln 165 170 175 Gly Leu Glu Trp Ile Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn 180 185 190 Tyr Asn Gln Lys Phe Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser 195 200 205 Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr 210 215 220 Ala Val Tyr Tyr Cys Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr 225 230 235 240 Met Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser 245 250 255 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 260 265 270 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 275 280 285 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 290 295 300 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 305 310 315 320 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 325 330 335 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 340 345 350 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 355 360 365 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 370 375 380 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 385 390 395 400 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 405 410 415 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 420 425 430 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 435 440 445 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 450 455 460 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 465 470 475 480 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 485 490 495 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 500 505 510 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 515 520 525 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 530 535 540 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 545 550 555 560 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 565 570 575 Ser Leu Ser Leu Ser Pro Gly Lys 580 <210> 37 <211> 336 <212> PRT <213> Artificial Sequence <400> 37 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr 35 40 45 Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 115 120 125 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 130 135 140 Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr Leu Asn Trp Tyr Gln Gln 145 150 155 160 Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile Tyr Gly Ala Thr Asn Leu 165 170 175 Ala Asp Ala Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 180 185 190 Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr 195 200 205 Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr Thr Phe Gly Gly Gly Thr 210 215 220 Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 38 <211> 589 <212> PRT <213> Artificial Sequence <400> 38 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile 35 40 45 Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln 130 135 140 Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys 145 150 155 160 Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala Met His Trp Val Lys 165 170 175 Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Ser Thr Tyr 180 185 190 Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys Gly Lys Ala Ile Met 195 200 205 Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu 210 215 220 Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val Arg Gly Ser Thr Thr 225 230 235 240 Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln Gly Thr Thr Val Thr 245 250 255 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 260 265 270 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 275 280 285 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 290 295 300 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 305 310 315 320 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 325 330 335 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 340 345 350 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 355 360 365 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 370 375 380 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 385 390 395 400 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 405 410 415 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 420 425 430 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 435 440 445 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 450 455 460 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 465 470 475 480 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 485 490 495 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 500 505 510 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 515 520 525 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 530 535 540 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 545 550 555 560 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 565 570 575 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 580 585 <210> 39 <211> 341 <212> PRT <213> Artificial Sequence <400> 39 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr 35 40 45 Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 115 120 125 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 130 135 140 Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Thr Leu 145 150 155 160 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile Tyr 165 170 175 Gly Ala Thr Asn Leu Ala Asp Ala Val Pro Ser Arg Phe Ser Gly Ser 180 185 190 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 195 200 205 Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Ile Pro Tyr Thr 210 215 220 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 225 230 235 240 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 245 250 255 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 260 265 270 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 275 280 285 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 290 295 300 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 305 310 315 320 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 325 330 335 Asn Arg Gly Glu Cys 340 <210> 40 <211> 594 <212> PRT <213> Artificial Sequence <400> 40 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile 35 40 45 Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 130 135 140 Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser 145 150 155 160 Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala 165 170 175 Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 180 185 190 Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys 195 200 205 Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met 210 215 220 Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val 225 230 235 240 Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln 245 250 255 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 260 265 270 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 275 280 285 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 290 295 300 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 305 310 315 320 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 325 330 335 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 340 345 350 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 355 360 365 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 370 375 380 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 385 390 395 400 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 405 410 415 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 420 425 430 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 435 440 445 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 450 455 460 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 465 470 475 480 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 485 490 495 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 500 505 510 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 515 520 525 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 530 535 540 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 545 550 555 560 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 565 570 575 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 580 585 590 Gly Lys <210> 41 <211> 346 <212> PRT <213> Artificial Sequence <400> 41 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr 35 40 45 Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 130 135 140 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn 145 150 155 160 Ile Tyr Gly Thr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro 165 170 175 Lys Leu Leu Ile Tyr Gly Ala Thr Asn Leu Ala Asp Ala Val Pro Ser 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser 195 200 205 Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu 210 215 220 Ser Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 225 230 235 240 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 245 250 255 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 260 265 270 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 275 280 285 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 290 295 300 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 305 310 315 320 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 325 330 335 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 340 345 <210> 42 <211> 706 <212> PRT <213> Artificial Sequence <400> 42 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro 465 470 475 480 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 485 490 495 Asp Tyr Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu 500 505 510 Trp Ile Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp 515 520 525 Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 530 535 540 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 545 550 555 560 Tyr Cys Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln 565 570 575 Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala 595 600 605 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala 610 615 620 Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln 625 630 635 640 Ala Pro Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val 645 650 655 Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 660 665 670 Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 675 680 685 Arg Ser Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu 690 695 700 Ile Lys 705 <210> 43 <211> 589 <212> PRT <213> Artificial Sequence <400> 43 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln 130 135 140 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg 145 150 155 160 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala 165 170 175 Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile Ala Phe Ile 180 185 190 Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg 195 200 205 Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met 210 215 220 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala 225 230 235 240 Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr 245 250 255 Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 260 265 270 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 275 280 285 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 290 295 300 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 305 310 315 320 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 325 330 335 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 340 345 350 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 355 360 365 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 370 375 380 Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu 385 390 395 400 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 405 410 415 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 420 425 430 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 435 440 445 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 450 455 460 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 465 470 475 480 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 485 490 495 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 500 505 510 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 515 520 525 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 530 535 540 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 545 550 555 560 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 565 570 575 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 580 585 <210> 44 <211> 706 <212> PRT <213> Artificial Sequence <400> 44 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro 465 470 475 480 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 485 490 495 Asp Tyr Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 500 505 510 Trp Val Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp 515 520 525 Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 530 535 540 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 545 550 555 560 Tyr Cys Ala Lys Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln 565 570 575 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala 595 600 605 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala 610 615 620 Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln 625 630 635 640 Ala Pro Arg Leu Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Ile 645 650 655 Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 660 665 670 Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 675 680 685 Arg Ser Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu 690 695 700 Ile Lys 705 <210> 45 <211> 706 <212> PRT <213> Artificial Sequence <400> 45 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro 465 470 475 480 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 485 490 495 Asp Tyr Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 500 505 510 Trp Val Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp 515 520 525 Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 530 535 540 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 545 550 555 560 Tyr Cys Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln 565 570 575 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala 595 600 605 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala 610 615 620 Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln 625 630 635 640 Ala Pro Arg Leu Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Ile 645 650 655 Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 660 665 670 Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 675 680 685 Arg Ser Asn Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu 690 695 700 Ile Lys 705 <210> 46 <211> 706 <212> PRT <213> Artificial Sequence <400> 46 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro 465 470 475 480 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 485 490 495 Asp Tyr Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 500 505 510 Trp Val Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp 515 520 525 Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 530 535 540 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 545 550 555 560 Tyr Cys Ala Lys Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln 565 570 575 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala 595 600 605 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala 610 615 620 Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln 625 630 635 640 Ala Pro Arg Leu Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Ile 645 650 655 Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 660 665 670 Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 675 680 685 Arg Ser Asn Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu 690 695 700 Ile Lys 705 <210> 47 <211> 706 <212> PRT <213> Artificial Sequence <400> 47 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro 465 470 475 480 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 485 490 495 Asp Tyr Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 500 505 510 Trp Val Ala Phe Ile Arg Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp 515 520 525 Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 530 535 540 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 545 550 555 560 Tyr Cys Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln 565 570 575 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala 595 600 605 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala 610 615 620 Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln 625 630 635 640 Ala Pro Arg Leu Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Ile 645 650 655 Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 660 665 670 Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 675 680 685 Arg Ser Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu 690 695 700 Ile Lys 705 <210> 48 <211> 706 <212> PRT <213> Artificial Sequence <400> 48 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile 35 40 45 Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser 145 150 155 160 Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser 210 215 220 Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 245 250 255 Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser 260 265 270 Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala 275 280 285 Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 290 295 300 Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys 305 310 315 320 Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met 325 330 335 Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val 340 345 350 Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln 355 360 365 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 370 375 380 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 385 390 395 400 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 405 410 415 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 420 425 430 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 435 440 445 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 450 455 460 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 465 470 475 480 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 485 490 495 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 500 505 510 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 515 520 525 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 530 535 540 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 545 550 555 560 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 565 570 575 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 580 585 590 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 595 600 605 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 610 615 620 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 625 630 635 640 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 645 650 655 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 660 665 670 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 675 680 685 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 690 695 700 Gly Lys 705 <210> 49 <211> 706 <212> PRT <213> Artificial Sequence <400> 49 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr 35 40 45 Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu 115 120 125 Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140 Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala Trp Ile Arg 145 150 155 160 Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile Ala Phe Ile Thr Asn Leu 165 170 175 Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg Phe Thr Ile 180 185 190 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 195 200 205 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Gly Asp Tyr 210 215 220 Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 245 250 255 Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser 260 265 270 Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala 275 280 285 Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 290 295 300 Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys 305 310 315 320 Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met 325 330 335 Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val 340 345 350 Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln 355 360 365 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 370 375 380 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 385 390 395 400 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 405 410 415 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 420 425 430 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 435 440 445 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 450 455 460 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 465 470 475 480 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 485 490 495 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 500 505 510 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 515 520 525 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 530 535 540 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 545 550 555 560 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 565 570 575 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 580 585 590 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 595 600 605 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 610 615 620 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 625 630 635 640 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 645 650 655 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 660 665 670 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 675 680 685 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 690 695 700 Gly Lys 705 <210> 50 <211> 711 <212> PRT <213> Artificial Sequence <400> 50 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser 145 150 155 160 Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Leu Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Ile Pro Ala 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser 210 215 220 Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 245 250 255 Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val 260 265 270 Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr 275 280 285 Phe Thr Asp Tyr Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly 290 295 300 Leu Glu Trp Ile Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr 305 310 315 320 Asn Gln Lys Phe Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile 325 330 335 Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala 340 345 350 Val Tyr Tyr Cys Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met 355 360 365 Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 370 375 380 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 385 390 395 400 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 405 410 415 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 420 425 430 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 435 440 445 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 450 455 460 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 465 470 475 480 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 485 490 495 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 500 505 510 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 515 520 525 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 530 535 540 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 545 550 555 560 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 565 570 575 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 580 585 590 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 595 600 605 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 610 615 620 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 625 630 635 640 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 645 650 655 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 660 665 670 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 675 680 685 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 690 695 700 Leu Ser Leu Ser Pro Gly Lys 705 710 <210> 51 <211> 711 <212> PRT <213> Artificial Sequence <400> 51 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser 145 150 155 160 Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Leu Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Ile Pro Ala 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser 210 215 220 Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 245 250 255 Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val 260 265 270 Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr 275 280 285 Phe Thr Asp Tyr Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly 290 295 300 Leu Glu Trp Ile Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr 305 310 315 320 Asn Gln Lys Phe Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile 325 330 335 Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala 340 345 350 Val Tyr Tyr Cys Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met 355 360 365 Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 370 375 380 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 385 390 395 400 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 405 410 415 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 420 425 430 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 435 440 445 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 450 455 460 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 465 470 475 480 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 485 490 495 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 500 505 510 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 515 520 525 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 530 535 540 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 545 550 555 560 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 565 570 575 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 580 585 590 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 595 600 605 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 610 615 620 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 625 630 635 640 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 645 650 655 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 660 665 670 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 675 680 685 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 690 695 700 Leu Ser Leu Ser Pro Gly Lys 705 710 <210> 52 <211> 706 <212> PRT <213> Artificial Sequence <400> 52 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro 465 470 475 480 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 485 490 495 Asp Tyr Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu 500 505 510 Trp Ile Ala Phe Ile Arg Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp 515 520 525 Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 530 535 540 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 545 550 555 560 Tyr Cys Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln 565 570 575 Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala 595 600 605 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala 610 615 620 Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln 625 630 635 640 Ala Pro Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val 645 650 655 Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 660 665 670 Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 675 680 685 Arg Ser Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu 690 695 700 Ile Lys 705 <210> 53 <211> 706 <212> PRT <213> Artificial Sequence <400> 53 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile 35 40 45 Ala Phe Ile Arg Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser 145 150 155 160 Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser 210 215 220 Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 245 250 255 Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser 260 265 270 Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala 275 280 285 Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 290 295 300 Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys 305 310 315 320 Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met 325 330 335 Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val 340 345 350 Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln 355 360 365 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 370 375 380 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 385 390 395 400 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 405 410 415 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 420 425 430 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 435 440 445 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 450 455 460 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 465 470 475 480 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 485 490 495 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 500 505 510 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 515 520 525 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 530 535 540 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 545 550 555 560 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 565 570 575 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 580 585 590 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 595 600 605 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 610 615 620 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 625 630 635 640 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 645 650 655 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 660 665 670 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 675 680 685 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 690 695 700 Gly Lys 705 <210> 54 <211> 706 <212> PRT <213> Artificial Sequence <400> 54 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro 465 470 475 480 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 485 490 495 Asp Tyr Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu 500 505 510 Trp Ile Ala Phe Ile Asn Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp 515 520 525 Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 530 535 540 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 545 550 555 560 Tyr Cys Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln 565 570 575 Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala 595 600 605 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala 610 615 620 Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln 625 630 635 640 Ala Pro Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val 645 650 655 Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 660 665 670 Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 675 680 685 Arg Ser Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu 690 695 700 Ile Lys 705 <210> 55 <211> 706 <212> PRT <213> Artificial Sequence <400> 55 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile 35 40 45 Ala Phe Ile Asn Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser 145 150 155 160 Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser 210 215 220 Thr Phe Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 245 250 255 Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser 260 265 270 Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala 275 280 285 Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 290 295 300 Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys 305 310 315 320 Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met 325 330 335 Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val 340 345 350 Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln 355 360 365 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 370 375 380 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 385 390 395 400 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 405 410 415 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 420 425 430 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 435 440 445 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 450 455 460 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 465 470 475 480 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 485 490 495 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 500 505 510 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 515 520 525 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 530 535 540 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 545 550 555 560 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 565 570 575 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 580 585 590 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 595 600 605 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 610 615 620 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 625 630 635 640 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 645 650 655 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 660 665 670 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 675 680 685 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 690 695 700 Gly Lys 705 <210> 56 <211> 706 <212> PRT <213> Artificial Sequence <400> 56 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Cys Pro Glu Trp Ile 35 40 45 Ala Phe Ile Asn Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser 145 150 155 160 Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser 210 215 220 Thr Phe Pro Pro Tyr Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 245 250 255 Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser 260 265 270 Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala 275 280 285 Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 290 295 300 Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys 305 310 315 320 Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met 325 330 335 Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val 340 345 350 Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln 355 360 365 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 370 375 380 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 385 390 395 400 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 405 410 415 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 420 425 430 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 435 440 445 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 450 455 460 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 465 470 475 480 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 485 490 495 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 500 505 510 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 515 520 525 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 530 535 540 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 545 550 555 560 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 565 570 575 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 580 585 590 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 595 600 605 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 610 615 620 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 625 630 635 640 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 645 650 655 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 660 665 670 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 675 680 685 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 690 695 700 Gly Lys 705 <210> 57 <211> 719 <212> PRT <213> Artificial Sequence <400> 57 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Cys Pro Glu Trp Ile 35 40 45 Ala Phe Ile Asn Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser 145 150 155 160 Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser 210 215 220 Thr Phe Pro Pro Tyr Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 225 230 235 240 Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg 245 250 255 Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln Gln Val Gln Leu 260 265 270 Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser Val Lys Ile 275 280 285 Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala Met His Trp 290 295 300 Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Ser 305 310 315 320 Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys Gly Lys Ala 325 330 335 Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser 340 345 350 Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val Arg Gly Ser 355 360 365 Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln Gly Thr Thr 370 375 380 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 385 390 395 400 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 405 410 415 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 420 425 430 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 435 440 445 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 450 455 460 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 465 470 475 480 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 485 490 495 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 500 505 510 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 515 520 525 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 530 535 540 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 545 550 555 560 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 565 570 575 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 580 585 590 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 595 600 605 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 610 615 620 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 625 630 635 640 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 645 650 655 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 660 665 670 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 675 680 685 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 690 695 700 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 705 710 715 <210> 58 <211> 719 <212> PRT <213> Artificial Sequence <400> 58 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr 35 40 45 Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr 85 90 95 Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu 115 120 125 Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140 Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala Trp Ile Arg 145 150 155 160 Gln Ala Pro Gly Lys Cys Pro Glu Trp Ile Ala Phe Ile Asn Asn Leu 165 170 175 Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg Phe Thr Ile 180 185 190 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 195 200 205 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Gly Asp Tyr 210 215 220 Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 225 230 235 240 Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg 245 250 255 Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln Gln Val Gln Leu 260 265 270 Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser Val Lys Ile 275 280 285 Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala Met His Trp 290 295 300 Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Ser 305 310 315 320 Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys Gly Lys Ala 325 330 335 Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser 340 345 350 Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val Arg Gly Ser 355 360 365 Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln Gly Thr Thr 370 375 380 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 385 390 395 400 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 405 410 415 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 420 425 430 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 435 440 445 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 450 455 460 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 465 470 475 480 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 485 490 495 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 500 505 510 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 515 520 525 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 530 535 540 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 545 550 555 560 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 565 570 575 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 580 585 590 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 595 600 605 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 610 615 620 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 625 630 635 640 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 645 650 655 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 660 665 670 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 675 680 685 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 690 695 700 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 705 710 715 <210> 59 <211> 719 <212> PRT <213> Artificial Sequence <400> 59 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser 450 455 460 Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln Gln 465 470 475 480 Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser 485 490 495 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly 500 505 510 Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Cys Pro Glu Trp Ile Ala 515 520 525 Phe Ile Asn Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr 530 535 540 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 545 550 555 560 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 565 570 575 Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu 580 585 590 Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 595 600 605 Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser 610 615 620 Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser 625 630 635 640 Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 645 650 655 Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg 660 665 670 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser 675 680 685 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr 690 695 700 Phe Pro Pro Tyr Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 705 710 715 <210> 60 <211> 719 <212> PRT <213> Artificial Sequence <400> 60 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser 450 455 460 Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln Glu 465 470 475 480 Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu 485 490 495 Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr Val Asn 500 505 510 Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile Tyr Gly 515 520 525 Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly 530 535 540 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp 545 550 555 560 Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro Tyr Thr 565 570 575 Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly 580 585 590 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser 595 600 605 Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 610 615 620 Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala Trp Ile Arg Gln 625 630 635 640 Ala Pro Gly Lys Cys Pro Glu Trp Ile Ala Phe Ile Asn Asn Leu Ala 645 650 655 Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr Gly Arg Phe Thr Ile Ser 660 665 670 Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 675 680 685 Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Gly Asp Tyr Arg 690 695 700 Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 705 710 715 <210> 61 <211> 732 <212> PRT <213> Artificial Sequence <400> 61 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Cys Pro Glu Trp Ile 35 40 45 Ala Phe Ile Asn Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Ser Ser Ser Ser Light Ala Pro Pro Pro Ser 115 120 125 Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu 130 135 140 Pro Gln Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser 145 150 155 160 Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn 165 170 175 Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu 180 185 190 Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 195 200 205 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu 210 215 220 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro 225 230 235 240 Pro Tyr Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Ser Ser Ser 245 250 255 Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg Leu Pro Gly 260 265 270 Pro Ser Asp Thr Pro Ile Leu Pro Gln Gln Val Gln Leu Val Gln Ser 275 280 285 Gly Ala Glu Val Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys 290 295 300 Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala Met His Trp Val Lys Gln 305 310 315 320 Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Ser Thr Tyr Ser 325 330 335 Gly His Thr Asn Tyr Asn Gln Lys Phe Lys Gly Lys Ala Ile Met Thr 340 345 350 Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg 355 360 365 Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val Arg Gly Ser Thr Thr Ala 370 375 380 His Tyr Tyr Thr Met Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val 385 390 395 400 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 405 410 415 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 420 425 430 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 435 440 445 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 450 455 460 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 465 470 475 480 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 485 490 495 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 500 505 510 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 515 520 525 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 530 535 540 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 545 550 555 560 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 565 570 575 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 580 585 590 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 595 600 605 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 610 615 620 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 625 630 635 640 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 645 650 655 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 660 665 670 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 675 680 685 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 690 695 700 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 705 710 715 720 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 725 730 <210> 62 <211> 732 <212> PRT <213> Artificial Sequence <400> 62 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser 450 455 460 Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln Gln 465 470 475 480 Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser 485 490 495 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly 500 505 510 Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Cys Pro Glu Trp Ile Ala 515 520 525 Phe Ile Asn Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val Thr 530 535 540 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 545 550 555 560 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 565 570 575 Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu 580 585 590 Val Thr Val Ser Ala Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu 595 600 605 Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro 610 615 620 Gln Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro 625 630 635 640 Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn Tyr 645 650 655 Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu Ile 660 665 670 Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly 675 680 685 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 690 695 700 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro Pro 705 710 715 720 Tyr Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 725 730 <210> 63 <211> 816 <212> PRT <213> Artificial Sequence <400> 63 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Cys Pro Glu Trp Ile 35 40 45 Ala Phe Ile Thr Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser 115 120 125 Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu 130 135 140 Pro Gln Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser 145 150 155 160 Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Asn 165 170 175 Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Ile Leu 180 185 190 Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 195 200 205 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu 210 215 220 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Phe Pro 225 230 235 240 Pro Tyr Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Ser Ser Ser 245 250 255 Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg Leu Pro Gly 260 265 270 Pro Ser Asp Thr Pro Ile Leu Pro Gln Gln Val Gln Leu Val Gln Ser 275 280 285 Gly Ala Glu Val Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys 290 295 300 Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala Met His Trp Val Lys Gln 305 310 315 320 Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Ser Thr Tyr Ser 325 330 335 Gly His Thr Asn Tyr Asn Gln Lys Phe Lys Gly Lys Ala Ile Met Thr 340 345 350 Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg 355 360 365 Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val Arg Gly Ser Thr Thr Ala 370 375 380 His Tyr Tyr Thr Met Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val 385 390 395 400 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 405 410 415 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 420 425 430 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 435 440 445 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 450 455 460 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 465 470 475 480 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 485 490 495 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 500 505 510 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 515 520 525 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 530 535 540 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 545 550 555 560 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 565 570 575 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 580 585 590 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 595 600 605 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 610 615 620 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 625 630 635 640 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 645 650 655 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 660 665 670 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 675 680 685 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 690 695 700 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 705 710 715 720 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ser Leu Thr Cys 725 730 735 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 740 745 750 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 755 760 765 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 770 775 780 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 785 790 795 800 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 805 810 815 <210> 64 <211> 738 <212> PRT <213> Artificial Sequence <400> 64 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Cys Pro Glu Trp Ile 35 40 45 Ala Phe Ile Asn Asn Leu Ala Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asp Tyr Arg Ser Phe Pro Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Gly Gly Gly Ser Ser Ser Ser Lys Ala Pro 115 120 125 Pro Pro Ser Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr 130 135 140 Pro Ile Leu Pro Gln Gly Gly Gly Glu Ile Val Leu Thr Gln Ser Pro 145 150 155 160 Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser 165 170 175 Ala Ser Ser Ser Val Asn Tyr Val Asn Trp Tyr Gln Gln Lys Pro Gly 180 185 190 Gln Ala Pro Arg Ile Leu Ile Tyr Gly Ile Ser Asn Leu Ala Ser Gly 195 200 205 Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 210 215 220 Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln 225 230 235 240 Gln Arg Ser Thr Phe Pro Pro Tyr Thr Phe Gly Cys Gly Thr Lys Leu 245 250 255 Glu Ile Lys Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser 260 265 270 Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln Gln 275 280 285 Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala Ser 290 295 300 Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr Ala 305 310 315 320 Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 325 330 335 Val Ile Ser Thr Tyr Ser Gly His Thr Asn Tyr Asn Gln Lys Phe Lys 340 345 350 Gly Lys Ala Ile Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr Met 355 360 365 Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val 370 375 380 Arg Gly Ser Thr Thr Ala His Tyr Tyr Thr Met Asp Phe Trp Gly Gln 385 390 395 400 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 405 410 415 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 420 425 430 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 435 440 445 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 450 455 460 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 465 470 475 480 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 485 490 495 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 500 505 510 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 515 520 525 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 530 535 540 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 545 550 555 560 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 565 570 575 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 580 585 590 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 595 600 605 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 610 615 620 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 625 630 635 640 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 645 650 655 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 660 665 670 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 675 680 685 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 690 695 700 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 705 710 715 720 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 725 730 735 Gly Lys <210> 65 <211> 25 <212> PRT <213> Artificial Sequence <400> 65 Gly Gly Gly Gly Ser Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu 1 5 10 15 Phe Gly Gly Gly Gly Ser Gly Gly Gly 20 25 <210> 66 <211> 28 <212> PRT <213> Artificial Sequence <400> 66 Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg 1 5 10 15 Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln 20 25 <210> 67 <211> 18 <212> PRT <213> Artificial Sequence <400> 67 Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser 1 5 10 15 Leu Asp <210> 68 <211> 14 <212> PRT <213> Artificial Sequence <400> 68 Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr 1 5 10 <210> 69 <211> 12 <212> PRT <213> Artificial Sequence <400> 69 Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe 1 5 10

Claims

1. An anti-human CEACAM5 / 6 antibody, characterized in that, The antibody has a heavy chain and a light chain; The heavy chain has a heavy chain variable region, which includes the following three complementary determination regions: VH-CDR1 shown in SEQ ID NO.1, VH-CDR2 shown in SEQ ID NO.2, and VH-CDR3 as shown in SEQ ID NO.3; Furthermore, the light chain has a light chain variable region, which includes the following three complementary determining regions: VL-CDR1 shown in SEQ ID NO.4, VL-CDR2 shown in SEQ ID NO.5, and VL-CDR3 as shown in SEQ ID NO. 6; CDR is determined by the Kabat rule.

2. The anti-human CEACAM5 / 6 antibody as described in claim 1, characterized in that, The amino acid sequence of the heavy chain variable region is selected from the following group: SEQ ID NO.7, 11 or 13.

3. The anti-human CEACAM5 / 6 antibody as described in claim 1, characterized in that, The sequence of the variable region of the light chain is shown in SEQ ID NO. 8 or 12.

4. The anti-human CEACAM5 / 6 antibody as described in claim 1, characterized in that, The heavy chain variable region of the antibody is shown in SEQ ID NO. 7, and the light chain variable region of the antibody is shown in SEQ ID NO. 8; or The heavy chain variable region of the antibody is shown in SEQ ID NO. 11, and the light chain variable region of the antibody is shown in SEQ ID NO. 12; or The heavy chain variable region of the antibody is shown in SEQ ID NO. 13, and the light chain variable region of the antibody is shown in SEQ ID NO.

12.

5. The anti-human CEACAM5 / 6 antibody as described in claim 1, characterized in that, The heavy chain sequence of the antibody is shown in SEQ ID NO. 9, 14 or 15; and / or the light chain of the antibody is shown in SEQ ID NO. 10 or 16.

6. A bispecific antigen-binding molecule, characterized in that, Include: First antigen-binding domain D1; and Second antigen-binding domain D2; Among them, D1 specifically binds to the target molecule CEACAM5 / 6 protein; D2 specifically binds to the target molecule CD47 protein; D1 is an antibody or its antigen-binding fragment that specifically binds to CEACAM5 / 6 protein; D2 is an antibody or its antigen-binding fragment that specifically binds to the CD47 protein; Wherein, D1 has a heavy chain variable region comprising the following three complementary determinant regions (CDRs): VH-CDR1 shown in SEQ ID NO.1, VH-CDR2 shown in SEQ ID NO.2, and VH-CDR3 as shown in SEQ ID NO.3; and Light chain variable regions containing the following three complementary determinant regions (CDRs): VL-CDR1 shown in SEQ ID NO.4, VL-CDR2 shown in SEQ ID NO.5, and VL-CDR3 as shown in SEQ ID NO. 6; CDR is determined by the Kabat rules; The structure of the antigen-binding fragment is selected from the following group: (i) Fab fragment; (ii) F(ab')2 fragment; (iii) Fv fragment; or (iv) single-chain Fv (scFv) molecule.

7. The bispecific antigen-binding molecule as described in claim 6, characterized in that, The heavy chain of the antibody that specifically binds to the CD47 protein has the heavy chain variable region shown in SEQ ID NO. 17, and the light chain of the antibody that specifically binds to the CD47 protein has the light chain variable region shown in SEQ ID NO. 18; or The heavy chain of the antibody that specifically binds to the CD47 protein has the heavy chain variable region shown in SEQ ID NO.19, and the light chain of the antibody that specifically binds to the CD47 protein has the light chain variable region shown in SEQ ID NO.

20.

8. A recombinant protein, characterized in that, The recombinant protein consists of the following: (i) the antibody as claimed in claim 1 or the bispecific antigen-binding molecule as claimed in claim 6; and (ii) Optional tag sequences to assist in expression and / or purification.

9. An antibody conjugate, characterized in that, The antibody conjugate comprises the following: (a) An antibody portion, said antibody portion being selected from the group consisting of: the antibody of claim 1, or the bispecific antigen-binding molecule of claim 6, or combinations thereof; and (b) A conjugation portion coupled to the antibody portion, wherein the conjugation portion is a detectable marker.

10. The use of an active ingredient, characterized in that, The active ingredients are selected from the following group: The active ingredient is used in the antibody of claim 1, or the bispecific antigen-binding molecule of claim 6, the recombinant protein of claim 8, or a combination thereof. (a) Prepare a test reagent or kit for detecting human CEACAM5 / 6; and / or (b) To prepare a medicine or preparation for treating human CEACAM5 / 6-related cancers; said cancers being selected from the group consisting of rectal cancer, pancreatic cancer, lung cancer, or combinations thereof.

11. A pharmaceutical composition comprising: (i) an active ingredient selected from the group consisting of: the antibody of claim 1, the bispecific antigen-binding molecule of claim 6, or the recombinant protein of claim 8; and (ii) Pharmaceutically acceptable carriers.

12. A polynucleotide, characterized in that, The polynucleotides encode polypeptides selected from the following group: (1) The antibody as described in claim 1; or (2) The bispecific antigen-binding molecule as described in claim 6; or (3) The recombinant protein as described in claim 8.

13. A carrier, characterized in that, The carrier contains the polynucleotide as described in claim 12.

Images