CN114106174A

CN114106174A - Low toxicity anti-OX 40 antibodies, pharmaceutical compositions and uses thereof

Info

Publication number: CN114106174A
Application number: CN202010881362.1A
Authority: CN
Inventors: 李福彬; 严晓华; 毕艳侠; 王彩虹
Original assignee: Suzhou Jinglian Medical Technology Co ltd
Current assignee: Zhongshan Hengdong Biopharmaceutical Co.,Ltd.
Priority date: 2020-08-27
Filing date: 2020-08-27
Publication date: 2022-03-01
Also published as: CN116419970A; CN116419970B; WO2022042692A1

Abstract

The invention relates to a low-toxicity high-activity anti-OX 40 antibody, a pharmaceutical composition and application thereof. The sequences of the anti-OX 40 antibodies of the invention are described herein. The anti-OX 40 antibodies or antigen binding fragments thereof and pharmaceutical compositions thereof of the invention are useful for treating T cell related diseases.

Description

Low toxicity anti-OX 40 antibodies, pharmaceutical compositions and uses thereof

Technical Field

The present invention relates to anti-OX 40 antibodies, particularly low toxicity anti-OX 40 antibodies, pharmaceutical compositions and uses thereof.

Background

The breakthrough and development of tumor immunotherapy are great advances in the field of tumor therapy, and are selected as annual breakthrough in 2013 by the journal of science. There are currently mainly four approaches that can exploit the power of the immune system to combat tumors: 1) inputting antibodies against tumor antigens into a tumor patient to kill tumor cells, wherein the partial mechanism is that the tumor cells are killed by immune cells expressing Fc receptors after the antibodies are combined; 2) the anti-tumor immune cells separated from the tumor patient are expanded in vitro and then are infused back to the patient body to play the anti-tumor role; 3) the T cell is modified by genetic engineering to express a Chimeric Antigen Receptor (CAR) for recognizing tumor Antigen and is delivered into a patient with tumor; 4) monoclonal antibodies (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) directed against immunosuppressive signaling pathway targets that limit immune cell activity (referred to as "immune checkpoints") enhance the killing of tumors by blocking immunosuppressive signals by the killer T cell response generated by the immune system against tumor cells.

Although the above methods have been used clinically, there is still an urgent need in the field of tumor immunotherapy for new immunotherapies that act by different mechanisms. This is because 1) not all tumor species respond to current tumor immunotherapies; 2) even tumor species that respond to current immunotherapy, not all patients of these tumor species respond to these immunotherapies; 3) combination therapy is predicted to have greater therapeutic efficacy; 4) tumors are likely to develop mutations that escape these therapeutic approaches.

The agonistic antibody aiming at immune co-stimulatory molecules can enhance anti-tumor immune response to kill tumor cells by combining target molecules of immune cell surfaces to transmit immune activation signals and activating immune activation signal channels controlled by the target molecules, and belongs to a treatment method with wide prospects. Of the numerous immune co-stimulatory molecules, OX40 was one of the earliest molecules discovered and validated as having an intervening anti-tumor response.

OX40 is a member of the TNF receptor superfamily, expressed predominantly on the surface of activated T cells, including individual activated CD4 and CD 8T cell functional subsets, such as Th1, Th2, T_FHTh17, and regulatory T cells (Tregs). OX40 has also been reported to be expressed in small amounts on neutrophils, NK and NKT cells. The feature of OX40 not being expressed on naive T cells, specifically on activated T cells, allows for a certain selectivity of targeted OX40 without indiscriminate activation of all T cells (e.g., targeted expression of the more broadly expressed CD 28). OX40L/CD252 is a natural ligand of OX40, and is expressed mainly in antigen presenting cells such as B cells, Dendritic Cells (DCs) and macrophages. Both OX40L and OX40 were antigen-induced and OX40L expression was induced by CD40-CD40L signals, Toll-like receptors (TLRs) and inflammatory cytokines. The expression of OX40 is activated by a downstream signal of a T cell receptor activated by an antigen presented by an antigen presenting cell to present the antigen to the T cell, and is positively regulated by a CD28-B7.1/2 signal, and the peak expression level appears between 12 hours and 6 days after the T cell is activated. Structural analysis of OX40/OX40L supported that OX40 trimerized with OX40L interaction, and that OX40/OX40L binding was likely directly involved in cell interactions. Trimerization of OX40 enables intracellular segments to recruit TRAF2/3/5 and activate NF-kB signals, and up-regulates the expression of anti-apoptotic molecules such as Bcl-2 and Bcl-xL, thereby inhibiting apoptosis and enhancing cell survival. OX40 was also found to be able to influence T cell survival and proliferation through PI3K/Akt in concert with TCR signaling, as well as to regulate the expression of cytokines such as IL-2, IL-4, IL-5, and IFN-g through NFAT. Thus, activation of OX40 can inhibit apoptosis of activated T cells, promote their proliferation and produce cytokines. These are all agonistic anti-OX 40 functions that are capable of activating OX40 signaling.

anti-OX 40 (and OX40L-Fc fusion proteins) have been reported to inhibit tumor growth in a variety of tumor models, including melanoma, rectal cancer, fibrosarcoma, B-cell and T-cell lymphomas, and leukemia, including establishment of resistance to tumors in some mice. On this basis, a number of anti-human OX40 monoclonal antibodies have been introduced into clinical studies, including PF04518600 by feverfew, BMS-986178 by schuriuba, and a number of anti-OX 40 antibodies by MedImmune. However, the research and development of the anti-OX 40 as an anti-tumor drug is not smooth, the drugs of multiple companies are still in the way after the first clinical research is reported in 2013, no antibodies enter the clinical three-stage research, and one important reason is that the antibodies have high toxicity to organisms, so that the low-toxicity and high-efficiency anti-OX 40 antibody is urgently needed in the field. .

Disclosure of Invention

The present invention provides anti-OX 40 antibodies that are low in toxicity and highly potent.

In a first aspect, the invention provides anti-OX 40 antibodies or antigen-binding fragments thereof, comprising an anti-OX 40 antibody

(1) At least one CDR selected from the following sequences: 1, 2, 3,4, 5 and 6, and

(2) a heavy chain constant region comprising a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain connected in sequence from N-terminus to C-terminus, wherein the sequence of the CH1 domain and hinge region is a sequence of a CH1 domain and hinge region derived from human IgG2, the sequence of the CH2 domain and CH3 domain is a sequence of a CH2 domain and a CH3 domain derived from human IgG, and the affinity of the antibody heavy chain constant region to human Fc γ IIB is equal to or higher than that of human IgG1 to human Fc γ IIB, and the I/a ratio of the antibody heavy chain constant region is equal to or higher than that of human IgG 1.

In one or more embodiments, the heavy chain constant region comprises a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain, and the sequence of the CH1 domain and hinge region is derived from the sequence of the CH1 domain and hinge region of human IgG2, and the sequence of the CH2 domain and CH3 domain is selected from the group consisting of:

a) sequences derived from the CH2 and CH3 domains of human IgG1, and the CH2 and CH3 domains contain G237D, P238D, P271G, and a330R mutations; or

b) Sequences derived from the CH2 and CH3 domains of human IgG1, and the CH2 and CH3 domains contain G237D, P238D, H268D, P271G, and a330R mutations within the domains; or

c) Sequences derived from the CH2 and CH3 domains of human IgG2, and comprising the S267E and L328F mutations within the CH2 and CH3 domains; or

d) Sequences derived from the CH2 and CH3 domains of human IgG2, and the CH2 and CH3 domains contain H268D and P271G mutations.

In one or more embodiments, the anti-OX 40 antibody comprises HCDR1 as shown in SEQ ID NO. 1, HCDR2 as shown in SEQ ID NO. 2, and HCDR3 as shown in SEQ ID NO. 3, and/or comprises LCDR1 as shown in SEQ ID NO. 4, LCDR2 as shown in SEQ ID NO. 5, and LCDR3 as shown in SEQ ID NO. 6.

In one or more embodiments, the anti-OX 40 antibody comprises HCDR1 as shown in any one of SEQ ID NOS 7-38, HCDR2 as shown in any one of SEQ ID NOS 39-65, and HCDR3 as shown in any one of SEQ ID NOS 66-114, and/or LCDR1 as shown in any one of SEQ ID NOS 115-145, LCDR2 as shown in any one of SEQ ID NOS 146-159 and LCDR3 as shown in any one of SEQ ID NOS 160-199.

In one or more embodiments, the anti-OX 40 antibody contains HCDR1, HCDR2 and HCDR3 as set forth in any one of groups a1 through a 71:

and/or LCDR1, LCDR2 and LCDR3 as shown in any one of the following groups b1 through b 71:

more preferably, the anti-OX 40 antibody contains the HCDR and LCDR of any one of group c1 to group c71 of table 1.

In one or more embodiments, FR1 of the anti-OX 40 antibody VH may be selected from FR1 of the VH in each antibody number in table 2, FR2 of the VH may be selected from FR2 of the VH in each antibody number in table 2, FR3 of the VH may be selected from FR3 of the VH in each antibody number in table 2, FR4 of the VH may be selected from FR4 of the VH in each antibody number in table 2; and/or FR1 for VL may be selected from FR1 for VL, FR2 for VL, FR2 for VL, FR3 for VL, FR3 for VL, and FR4 for VL may be selected from FR4 for VL, in table 2, for each antibody number.

In one or more embodiments, the FR region of the VH of the anti-OX 40 antibody is the FR region of any one of the VH selected from the antibodies SEQ ID NO:200-270, and the FR region of the VL is the FR region of any one of the VL selected from the antibodies SEQ ID NO: 271-341.

In one or more embodiments, the amino acid sequence of the VH of the anti-OX 40 antibody is as set forth in any one of SEQ ID NO:200-270 and/or the amino acid sequence of the VL is as set forth in any one of SEQ ID NO: 271-341. Preferably, the amino acid sequence of the VH and the amino acid sequence of the VL of the anti-OX 40 antibody are as shown in any one row of table 2.

In some embodiments, the amino acid sequence of the heavy chain constant region of an antibody of the invention has the sequence shown in any one of SEQ ID NO:342-345, 348-351 and/or the amino acid sequence of the light chain constant region has the sequence shown in SEQ ID NO:346 or 347. In one or more embodiments, the heavy chain constant region of the anti-OX 40 antibody has the sequence shown in any one of SEQ ID NO 348-351, and/or the amino acid sequence of the light chain constant region has the sequence shown in SEQ ID NO 347. Preferably, the heavy chain constant region of the anti-OX 40 antibody has the sequence shown in SEQ ID NO: 350.

In one or more embodiments, an anti-OX 40 antibody according to any of the embodiments of the invention is a chimeric antibody or a fully human antibody; preferably fully human antibodies.

The invention also provides a pharmaceutical composition comprising an anti-OX 40 antibody, or antigen-binding fragment thereof, according to any one of the embodiments of the invention, and a pharmaceutically acceptable excipient or carrier.

The invention also provides the use of an anti-OX 40 antibody or antigen-binding fragment thereof according to any one of the embodiments of the invention in the preparation of a medicament for the prevention or treatment of a T-cell related disease; preferably, the T cell-associated disease is a T cell-associated tumor or an OX 40-mediated disorder.

In one or more embodiments, the OX 40-mediated disorder includes OX 40-mediated allergy, asthma, COPD, rheumatoid arthritis, psoriasis, autoimmune diseases, and inflammation-related diseases.

The invention also provides a method of treating or preventing a T cell related disorder, enhancing an endogenous immune response in an animal, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-OX 40 antibody or antigen-binding fragment thereof according to any one of the embodiments of the invention, or a pharmaceutical composition comprising an anti-OX 40 antibody or antigen-binding fragment thereof according to any one of the embodiments of the invention. Preferably, the T cell-associated disease is a T cell-associated tumor or an autoimmune disease.

Drawings

FIG. 1 shows an enzyme-linked immunosorbent assay (ELISA) method for determining the binding ability of anti-human OX40JAC3 antibody from single cell sequencing to human OX40 extracellular segment antigen. The results show that the antibody derived from anti-human OX40JAC3 after single cell sequencing has certain binding capacity to human OX40 extracellular segment antigen in certain concentration except a few antibodies, wherein the concentration of the purified single cell sequencing antibody (A) is 3.16 mu g/ml, the concentration of the purified single cell sequencing antibody (B) is 0.316 mu g/ml, and the concentration of the purified single cell sequencing antibody (C) is in a gradient dilution range (3.16 mu g/ml-1 ng/ml).

FIG. 2 shows hFCGR^TghOX40^TgAgonistic activity of anti-human OX40JAC3 antibody in mouse spleen cells activating T cells and promoting their proliferation. Purified anti-human OX40JAC3 antibody and control antibody were diluted to 3 concentration gradients, and cells were cultured with a primary cell culture medium containing 0.1. mu.g/ml anti-mouse CD3 for 72 hours, followed by analysis of mouse CD4 by flow technique⁺Mean Fluorescence Intensity (MFI) of CFSE of T cells stimulated with antibodies at 1. mu.g/ml (A), 0.1. mu.g/ml (B) and 0.01. mu.g/ml (C). CFSE is diluted in fluorescence intensity and the like according to cell division and proliferation, so that MFI of CFSE is inversely correlated with cell proliferation activation, that is, activity of anti-OX 40 antibody.

FIG. 3 shows the hFCGR^TghOX40^TgAgonistic activity of anti-human OX40JAC3 antibody having a certain immune-activating ability in fig. 2 activating T cells and promoting their proliferation was detected in mouse spleen cells. Purified anti-human OX40JAC 33 #, 13#, 24#, 37# antibodies and control antibodies were diluted in a gradient (1. mu.g/ml-1 ng/ml) and cells were cultured with a primary cell culture medium containing 0.1. mu.g/ml anti-mouse CD3 for 72 hours, and then mouse CD4 was analyzed by flow technique⁺Mean Fluorescence Intensity (MFI) (A) of T cell CFSE and CD4 of each group of antibodies stimulated with 0.01. mu.g/ml antibody⁺Mean Fluorescence Intensity (MFI) of T cell CFSE (B). CFSE is diluted in fluorescence intensity and the like according to cell division and proliferation, so that MFI of CFSE is inversely correlated with cell proliferation activation, that is, activity of anti-OX 40 antibody.

FIG. 4 shows that anti-human OX40JAC3 antibody has better in vitro activity (vs Pogalizumab and IBI 101). By detecting OVA-specific CD8⁺T cell proliferation, it can be seen that anti-human OX40 JAC324# antibody screened by single cell sequencing technique has stronger stimulatory OVA-specific CD8 than Pogalizumab and IBI101⁺The ability of T cells to secrete IFN-g, A is IFNg⁺CD8⁺T accounts for the proportion of CD8+ T cells, and B is the absolute number of cells.

Fig. 5 shows that the anti-human OX40JAC3 antibody has good anti-tumor activity (MC38 system). After different antibodies of mice inoculated with MC38 tumors are used for treatment, the anti-human OX40 JAC324# antibody can achieve the effect (A and B) of curing the tumors equivalent to the effect of Pogalizumab, and the hepatotoxicity (serum AST level) of the anti-human OX40 JAC324# antibody is obviously weaker than that of Pogalizumab (C), which shows that compared with Pogalizumab, the anti-human OX40 JAC324# antibody can achieve better curative effect and toxic and side effects.

Fig. 6 shows that the anti-human OX40JAC3 antibody has good anti-tumor activity (MO4 system). After different antibody treatments are given to mice inoculated with MO4 tumor, the anti-human OX40 JAC324# antibody can achieve better tumor curing effect (A and B) than high-dose Pogalizumab and IBI101, and the hepatotoxicity (serum AST level) of the anti-human OX40 JAC324# antibody is obviously weaker than that of Pogalizumab (C) after the high-dose (5mg/Kg) and low-dose (1.5mg/Kg) anti-human OX40 JAC324# antibody is given, which shows that the anti-human OX40 JAC324# antibody has better anti-tumor activity compared with the Pogalizumab.

Fig. 7 shows that anti-human OX40JAC3 antibody is less toxic (MO4 system). After different antibodies of mice inoculated with MO4 tumors are used for treatment, the anti-human OX40 JAC324# antibody with high dose (5mg/Kg) and low dose (1.5mg/Kg) can achieve better tumor curing effect than high dose Pogalizumab and IBI101 (figure 6), and blood collection on the 7 th day detects that the hepatotoxicity (serum AST level) of the anti-human OX40 JAC324# antibody is obviously weaker than that of the Pogalizumab (A and B), which shows that compared with the Pogalizumab and IBI101, the anti-human OX40 JAC324# antibody can better take both curative effect and toxic and side effect into consideration.

FIGS. 8A-C show the results of detecting binding of anti-human OX40 antibody to OX40 over-expressing cell surface OX40 using flow cytometry.

FIG. 9 is a graph showing the results of antigen binding activity assays, showing that anti-human OX40 antibody in hybridoma supernatants was able to specifically bind to human OX40 extracellular segment antigen. Binding of anti-human OX40 antibody in hybridoma supernatants to human OX40 extracellular antigen was analyzed by ELISA, which shows ELISA signals detected by HRP-labeled anti-mouse IgG Fc after binding of various antibodies diluted 1:100 in supernatants to coated human OX40 (a 650).

Detailed Description

The practice of the present invention will employ, unless otherwise defined, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. These techniques are explained fully in the literature, such as Molecular Cloning: a Laboratory Manual, second edition (Sambrook et al, 1989); oligonucleotide Synthesis (m.j. gait editors, 1984); animal Cell Culture (r.i. freshney, editors, 1987); methods in Enzymology (Academic Press, Inc.); current Protocols in Molecular Biology (edited by F.M. Ausubel et al, 1987 edition and periodically updated versions thereof); and (3) PCR: the Polymerase Chain Reaction (edited by Mullis et al, 1994); a Practical Guide to Molecular Cloning (Perbal Bernard V., 1988); phage Display: a Laboratory Manual (Barbas et al, 2001).

OX40 is a cell surface receptor that binds to OX40L (CD252, TNFSF4) or a receptor complex comprising OX 40. The NCBI accession number of the amino acid sequence of human OX40(hOX40) is (NP-003318). OX40 protein may also include variants and fragments. The fragments include extracellular domains that do not have all or part of the transmembrane, and/or fragments of both the intracellular domain and the extracellular domain. The soluble form of hOX40 includes an extracellular domain or fragment of an extracellular domain that retains the ability to bind BAFF and/or APRIL. "OX 40" also includes post-translational modifications of the OX40 amino acid sequence. Post-translational modifications include, but are not limited to, N-and O-linked glycosylation.

OX40 is expressed primarily on activated effector T cells (Teffs) and regulatory T cells (Tregs), as well as on NKT cells, NK cells and neutrophils. In cancer, activated T cells expressing OX40 are found in tumor infiltrating lymphocytes. OX40 and its ligand OX40L play a key role in the induction and maintenance of T cell responses. Enhancing anti-tumor T cell function can be useful against cancer as well as other OX 40-mediated disorders, including, for example, OX 40-mediated allergies, asthma, COPD, rheumatoid arthritis, psoriasis, autoimmune diseases, and inflammation-related diseases.

anti-OX 40 antibodies

The invention provides antibodies that specifically bind to OX 40.

Herein, the term "antibody" includes monoclonal antibodies (including full length antibodies having an immunoglobulin Fc region), antibody compositions having polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies), diabodies and single chain molecules, and antibody fragments, particularly antigen-binding fragments, e.g., Fab, F (ab') 2, and Fv. Herein, the terms "immunoglobulin" (Ig) and "antibody" are used interchangeably.

The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light chains (L) and two identical heavy chains (H). IgM antibodies consist of 5 basic heterotetrameric units and an additional polypeptide called the J chain, containing 10 antigen binding sites; while IgA antibodies comprise 2-5 basic 4 chain units, which can polymerize in combination with the J chain to form multivalent assemblies. In the case of IgG, the 4-chain unit is typically about 150,000 daltons. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the two heavy chains are linked to each other by one or more disulfide bonds, the number of disulfide bonds depending on the isotype of the heavy chain. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at the N-terminus, followed by three (CH1, CH2 and CH3 for each of the alpha and gamma chains) and four (CH1, CH2, CH3 and CH4 for the mu and epsilon isotypes) constant domains (CH) and a Hinge region (Hinge) located between the CH1 and CH2 domains. Each light chain has a variable domain at the N-terminus (VL) followed by a constant domain at its other end (CL). VL is aligned with VH, while CL is aligned with the first constant domain of the heavy chain (CH 1). Specific amino acid residues are believed to form an interface between the light and heavy chain variable domains. The paired VH and VL together form an antigen binding site. For the structure and properties of different classes of antibodies see e.g. Basic and Clinical Immunology, eighth edition, Daniel p.sties, Abba i.terr and Tristram g.parsolw editions, Appleton & Lange, Norwalk, CT, 1994, page 71 and chapter 6. Light chains from any vertebrate species can be classified into one of two distinct types called kappa and lambda, depending on their constant domain amino acid sequences. Depending on its heavy chain constant domain (CH) amino acid sequence, immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, have heavy chains called α, δ, ε, γ and μ, respectively. The γ and α classes can be further divided into subclasses based on the relatively small differences in CH sequence and function, for example humans express the following subclasses: IgG1, IgG2A, IgG2B, IgG3, IgG4, IgA1, and IgA 2.

The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains may be referred to as "VH" and "VL", respectively. These domains are usually the most variable parts of an antibody (relative to other antibodies of the same type) and contain an antigen binding site.

The term "variable" refers to the situation where certain segments in the variable domains differ widely in antibody sequence. The variable domains mediate antigen binding and define the specificity of a particular antibody for its particular antigen. However, variability is not evenly distributed across all amino acids spanned by the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs), both in the light and heavy chain variable domains, namely HCDR1, HCDR2, HCDR3 for the heavy chain variable region and LCDR1, LCDR2 and LCDR3 for the light chain variable region, respectively. The more highly conserved portions of the variable domains are called Framework Regions (FR). The variable domains of native heavy and light chains each comprise four FR regions (FR1, FR2, FR3 and FR4) which mostly adopt a β -sheet conformation, connected by three HVRs that form loops and, in some cases, form part of the β -sheet structure. The HVRs in each chain are held together in close proximity by the FR region and, together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of the antibody (see Kabat et al, Sequences of Immunological Interest, fifth edition, national institute of health, Bethesda, Md., 1991). Generally, the light chain variable region has the structure FR1-LCDR1-FR2-LCDR2-FR3-LCDR3-FR4, and the heavy chain variable region has the structure FR1-HCDR1-FR2-HCDR2-FR3-HCDR3-FR 4. The constant domains are not directly involved in binding of the antibody to the antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cell-mediated cytotoxicity.

"Fc region" (crystallizable fragment region) or "Fc domain" or "Fc" refers to the C-terminal region of an antibody heavy chain that mediates binding of an immunoglobulin to host tissues or factors, including binding to Fc receptors located on various cells of the immune system (e.g., effector cells), or to the first component of the classical complement system (C1 q). In IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments from the CH2 and CH3 domains of the two heavy chains of an antibody; the Fc region of IgM and IgE comprises three heavy chain constant domains (CH domains 2-4) in each polypeptide chain. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, the human IgG heavy chain Fc region is generally defined as the stretch of sequence from the amino acid residue at heavy chain position C226 or P230 to the carboxy-terminus, where the numbering is according to the EU index, as in Kabat. As used herein, an Fc region can be a native sequence Fc or a variant Fc.

An "Fc receptor" or "FcR" is a receptor that binds the Fc region of an immunoglobulin. FcR binding to IgG antibodies include receptors of the Fc γ R family, including allelic variants and alternatively spliced forms of these receptors. The human Fc γ receptor family includes several members: fc γ RI (CD64), Fc γ RIIA (CD32a), Fc γ RIIB (CD32b), Fc γ RIIIA (CD16a), Fc γ RIIIB (CD16 b). Among them, Fc γ RIIB is the only inhibitory Fc γ receptor, and others are all activated Fc γ receptors. Most natural effector cell types co-express one or more activating Fc γ R and inhibitory Fc γ RIIB, while Natural Killer (NK) cells selectively express one activating Fc γ receptor (Fc γ RIII in mice, Fc γ RIIIA in humans), but do not express inhibitory Fc γ RIIB in mice and humans. These Fc γ receptors differ in their molecular structure and therefore have different affinities for the respective IgG antibody subclasses. Among these Fc γ receptors, Fc γ RI is a high affinity receptor, while Fc γ RIIA, Fc γ RIIB, and Fc γ RIIIA are low affinity receptors. Genetic polymorphisms are also present in these different Fc γ receptors and affect their binding affinity. The most common gene polymorphisms are polymorphic forms of R131/H131 of Fc gamma RIIA and V158/F158 of Fc gamma RIIIA. Some of these polymorphic forms have been found to be associated with a variety of diseases, and the efficacy of certain therapeutic antibodies also depends on whether the patient carries a particular polymorphic form of the Fc γ receptor gene.

The "affinity ratio to inhibitory Fc γ receptor and activating Fc γ receptor" or "I/a ratio" described herein refers to the ratio of the affinity of a protein molecule to inhibitory Fc receptor and the affinity to activating Fc receptor, and in the present invention the I/a ratio is calculated as follows: i/a ratio ═ KD (hFc γ RIIA) or lower KD value in KD (hFc γ RIIIA)/KD (hFc γ RIIB); wherein KD (hFc gamma RIIA) is the equilibrium dissociation constant of the molecule for hFc gamma RIIA receptor (represented by variant hFc gamma RIIA-R131), KD (hFc gamma RIIIA) is the equilibrium dissociation constant of the molecule for hFc gamma RIIIA receptor (represented by variant hFc gamma RIIIA-F158), and KD (hFc gamma RIIB) is the equilibrium dissociation constant of the molecule for hFc gamma RIIB receptor; hfcyriia refers to the human Fc γ RIIA receptor, hfcyriiia refers to the human Fc γ RIIIA receptor, and hfcyriib refers to the human Fc γ RIIB receptor. By "affinity" is meant the amount of binding capacity between two molecules, usually measured by KD.

"KD" refers to the equilibrium dissociation constant for the interaction of two molecules (e.g., a particular antibody and antigen or a ligand and receptor). "antigen binding module" refers to a protein that specifically binds to an antigen with high affinity, including, but not limited to, antigen binding fragments of antibodies, adnectins, nanobodies, minibodies, affibodies, affilins, target binding regions of receptors, cell adhesion molecules, ligands, enzymes, cytokines, chemokines, and the like. Antigens targeted by the antigen binding module include, but are not limited to, TNF receptor superfamily members, immunosuppressive receptor molecules, and the like.

In the present invention, a partial antibody is an agonistic antibody, and a partial antibody is a non-agonistic antibody. An "agonistic antibody" is an antibody that binds to and activates a receptor. Preferably, the CDRs of the agonist antibody can be combined arbitrarily, so as to form an agonist antibody CDR set or be used for forming an agonist antibody variable region; the CDRs of the non-excitant antibody can be combined at will to form an effective CDR set, so that the CDR set of the non-excitant antibody is formed or is used for forming a variable region of the non-excitant antibody. Herein, "agonistic antibody variable region" refers to a variable region having agonistic activity against an antigen in the form of an intact antibody, such as an OX40 agonistic antibody variable region or an agonistic OX40 antibody variable region; by "non-agonistic antibody variable region" is meant an antibody variable region that does not have any agonistic activity in the form of an intact antibody, for example the OX40 non-agonistic antibody variable region or the non-agonistic OX40 antibody variable region.

Herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post-translational modifications (e.g., isomerization, amidation) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are synthesized by hybridoma culture and are uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, Monoclonal Antibodies to be used according to the invention may be generated by a variety of techniques, including, for example, the Hybridoma method (e.g., Kohler and Milstein, Nature, 256: 495-97 (1975); Hongo et al, Hybridoma, 14 (3): 253-260(1995), Harlow et al, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, second edition 1988; Hammerling et al, Monoclonal Antibodies and T-Cell hybrids, 563-, And techniques for generating human or human-like antibodies from animals having part or all of a human immunoglobulin locus or a gene encoding a human immunoglobulin sequence (e.g., WO 1998/24893; WO 1996/34096; WO 1996/33735; WO 1991/10741; Jakobovits et al, Proc. Natl. Acad. Sci. USA, 90: 2551 (1993); Jakobovits et al, Nature, 362: 255-152 (1993); Bruggemann et al, Yeast in Immunol, 7: 33 (1993); US 5,545,807; US 5,545,806; US 5,569,825; US 5,625,126; US 5,633,425; and US 5,661,016; Marks et al, Biotech: 812, 10: 779-783 (1992); Lonberg et al, Nature, 368: 859 (1994); Morrison, Nature, Humul technologies: 812; Nature 3: 78, Nature technologies: 78, Nature 31: 14: Nature, Nature technologies; Biotech. 14: Nature 31: 14: Nature Biotech. (Biosche et al.): 166-9.).

The terms "full-length antibody," "intact antibody," or "complete antibody" are used interchangeably to refer to an antibody (as opposed to an antibody fragment) that is substantially its intact form. In particular, full antibodies include those having heavy and light chains comprising an Fc region. The constant domain can be a native sequence constant domain (e.g., a human native sequence constant domain) or an amino acid sequence variant thereof. In some cases, an intact antibody may have one or more effector functions.

An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen binding and/or variable regions of an intact antibody. The antibody fragment is preferably an antigen-binding fragment of an antibody. Examples of antibody fragments include Fab, Fab ', F (ab') 2 and Fv fragments; a diabody; linear antibodies (see U.S. Pat. No. 5,641,870, example 2; Zapata et al, Protein Eng., 8 (10): 1057-1062, 1995); a single chain antibody molecule; a scFv-Fc fragment; multispecific antibodies formed from antibody fragments; and any fragment that should be able to increase half-life by chemical modification or by incorporation into liposomes. Digestion of an antibody with papain produces two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, the name of which reflects its ability to crystallize readily. Fab fragments consist of the entire light and heavy chain variable domain (VH) and one heavy chain first constant domain (CH 1). Each Fab fragment is monovalent in terms of antigen binding, i.e., it has a single antigen binding site. Pepsin treatment of an antibody produces a larger F (ab') 2 fragment, roughly equivalent to two Fab fragments linked by disulfide bonds, with different antigen binding activity and still capable of crosslinking the antigen. Fab' fragments differ from Fab fragments by the addition of some additional residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. F (ab ') 2 antibody fragments were originally generated as pairs of Fab ' fragments with hinge cysteines between the Fab ' fragments. Other chemical couplings of antibody fragments are also known. The Fc fragment comprises the carboxy-terminal portions of two heavy chains held together by disulfide bonds. The effector functions of antibodies are determined by sequences in the Fc region, which is also the region recognized by Fc receptors (fcrs) found on certain types of cells.

"Fv" is the smallest antibody fragment that contains the entire antigen recognition and binding site. The fragment consists of a dimer of one heavy chain variable domain and one light chain variable domain in tight, non-covalent association. Six hypervariable loops (3 loops each for the heavy and light chains) are highlighted from the folding of these two domains, contributing the amino acid residues for antigen binding and conferring antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, albeit with less avidity than the entire binding site.

"Single-chain Fv" which may also be abbreviated as "sFv" or "scFv" is an antibody fragment comprising the VH and VL domains of an antibody, joined as a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains such that the sFv forms the desired antigen binding structure. For an overview of sFv see The Pharmacology of Monoclonal Antibodies, Vol.113, edited by Rosenburg and Moore, Springer-Verlag, New York, pp.269-315 (1994).

"chemical modifications" of the fragment include addition of polyalkylene glycols such as polyethylene glycol ("PEGylation, PEGylation"), PEGylated fragments including Fv, scFv, Fab, F (ab ') 2 and Fab', i.e., Fv-PEG, scFv-PEG, Fab-PEG, F (ab ') 2-PEG and Fab' -PEG. Such fragments have EGFR binding activity.

Preferably, the antibody fragment, in particular the antigen-binding fragment, consists of or comprises a partial sequence of the heavy chain variable region or the light chain variable region of the antibody from which it is derived, said partial sequence being sufficient to retain the same binding specificity and sufficient affinity as the antibody from which it is derived, preferably at least equal to 1/100, in a more preferred manner at least equal to 1/10, for OX 40. Such antibody fragments will comprise a minimum of 5 amino acids, preferably 10, 15, 25, 50 and 100 consecutive amino acids of the antibody sequence from which they are derived.

Monoclonal antibodies also include "chimeric" antibodies (immunoglobulins) wherein a portion of the heavy and/or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, and the remainder of the chain is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al, Proc. Nat. Acad. Sci. USA, 81: 6851, 6855, 1984).

"humanized" forms of non-human (e.g., murine) antibodies refer to chimeric antibodies that contain minimal sequences derived from non-human immunoglobulins. Thus, a "humanized antibody" generally refers to a non-human antibody in which the variable domain framework regions are exchanged with sequences found in a human antibody. Typically in humanized antibodies, the entire antibody (except for the CDRs) is encoded by a polynucleotide of human origin or is identical to such an antibody (except for the CDRs). CDRs, some or all of which are encoded by nucleic acids derived from non-human organisms, are grafted into the β -sheet framework of human antibody variable regions to produce antibodies, the specificity of which is determined by the grafted CDRs. The production of such antibodies is described, for example, in WO 92/11018; jones, 1986, Nature, 321: 522-525; verhoeyen et al, 1988, Science, 239: 1534 and 1536. Humanized antibodies can also be generated using mice with genetically engineered immune systems (see Roque et al, 2004, Biotechnol. prog., 20: 639-654).

"human antibody" refers to an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human and/or produced using any of the techniques disclosed herein for producing human antibodies. This definition of human antibodies specifically excludes humanized antibodies comprising non-human antigen binding residues. Human antibodies can be generated using a variety of techniques known in the art, including phage display libraries. Such techniques can be found in Hoogenboom and Winter, journal of molecular biology, 227: 381 (1991); marks et al, journal of molecular biology, 222: 581(1991). Available methods for preparing human monoclonal antibodies are described in Cole et al, monoclonal antibodies and cancer therapy, Alan r.loss, p.77 (1985); boerner et al, J Immunol, 147 (1): 86-95 (1991). See also van Dijk and van de Winkel, modern pharmaceutical reviews, 5: 368-74(2001). Human antibodies can be prepared by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to antigen challenge, but whose endogenous locus has been disabled, for example, immunized xenografted mice (xenomice) (see, e.g., US 6,075,181 and 6,150,584 for xenoousetm technology). See also, e.g., Li et al, proceedings of the national academy of sciences of the united states, 103: 3557-3562(2006), on human antibodies produced by the human B cell hybridoma technique.

The anti-OX 40 antibodies of the invention can also be minibodies. Minibodies are minibody-like proteins comprising an scFv linked to a CH3 domain (Hu et al, 1996, Cancer Res., 56: 3055-3061). The anti-OX 40 antibodies of the invention may also be domain antibodies, see, e.g., US 6,248,516. Domain antibodies (dabs) are functional binding domains of antibodies, corresponding to the variable region of the heavy (VH) or light (VL) chain of the human antibody dAb, having a molecular weight of about 13kDa or less than one tenth the size of the complete antibody. dabs are well expressed in a variety of hosts including bacterial, yeast and mammalian cell systems. In addition, dabs are highly stable and retain activity even after being subjected to harsh conditions such as freeze-drying or heat denaturation. See, e.g., US 6,291,158; US 6,582,915; US 6,593,081; US 6,172,197; US 2004/0110941; EP 0368684; U.S. Pat. No. 6,696,245, WO04/058821, WO04/003019 and WO 03/002609.

The HCDR1 of the anti-OX 40 antibodies of the invention can contain X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀(SEQ ID NO:1) wherein X₁Is G or S, X₂A, D, F is,G. V or Y, X₃Is S, T or I, X₄Is I, L or F, X₅Is I, S, D, N, T or A, X₆Is N, S, T, D, R or G, X₇Is N, S, T, Y, A, G or F, X₈Is N, Y, A, G, W, S, I, K, F, T or D, X₉Is W, V or none, X₁₀N, G or none. In one or more embodiments, X₁Is G or S, X₂Is D, F, G or Y, X₃Is S or T, X₄Is I, L or F, X₅Is S, D or T, X₆Is N, S, T or D, X₇Is S, T or Y, X₈Is N, Y, A, G or I, X₉Is W, V or none, X₁₀Is N or none. In one or more embodiments, X₁Is G or S, X₂Is F, G or Y, X₃Is S, T or I, X₄Is I, L or F, X₅Is S, D or T, X₆Is N, S, T, D, R or G, X₇Is S, Y or A, X₈Is N, G, T, A, Y, W or I, X₉Is W, V or none, X₁₀G or none. An exemplary HCDR1 amino acid sequence is shown in any of SEQ ID NOs 7-38. Preferably, the amino acid sequence of HCDR1 is as shown in any one of SEQ ID NOs 9, 10, 12, 13, 19, 21, 23, 33, 34, 38. Also preferably, the amino acid sequence of HCDR1 is as set forth in any one of SEQ ID NOs 11, 12, 14, 21, 23, 27, 28, 32, 33, 34, 35, 38.

The HCDR2 of the anti-OX 40 antibodies of the invention can contain X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀(SEQ ID NO:2) wherein X₁Is M or I; x₂N, Y, S, K, H or F; x₃P, W, Q, H, S, G, A or R; x₄N, S, G, Y, K or D; x₅S, D, G, N, A or T; x₆T, N, S, D or G; x₇N, K, T, S, D, Y, H, G, A or E; x₈T, I, K, G or none; x₉T or none; x₁₀T, I or none. In one or more embodiments, X₁Is I; x₂N, Y, S, H or F; x₃W, H, S or A; x₄N, S is,G or Y; x₅S, D, G or N; x₆T, N, S, D or G; x₇N, K, T, S or D; x₈T, I, K or none; x₉And X₁₀Is absent. In one or more embodiments, X₁Is I; x₂N, Y, S, K or H; x₃P, W, H, S or A; x₄N, S, G, Y or K; x₅S, D, G, N or A; x₆N, S, D or G; x₇T, D, N, S, G or K; x₈T, I, K, G or none; x₉T or none; x₁₀Is I or none. An exemplary HCDR2 amino acid sequence is shown in any of SEQ ID NOs 39-65. Preferably, the amino acid sequence of HCDR2 is as shown in any one of SEQ ID NOs 42, 43, 46, 47, 50,58, 59, 63, 64. Also preferably, the amino acid sequence of HCDR2 is as set forth in any one of SEQ ID NOs 40, 43, 46, 48, 50, 52, 54, 56, 57, 59, 60, 63.

The HCDR3 of the anti-OX 40 antibodies of the invention may contain CX₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇X₁₈(SEQ ID NO:3) wherein X₁Is V, T, S or A, X₂Is R, K, I, G, A, T, S, H, Q, N or E, X₃Is S, D, W, G, Y, A, E, R, L, V, T, M or K, X₄Is G, Y, F, V, L, A, P, D, S, W, R, Q, E, N or K, X₅Is D, Y, G, S, R, F, T, V, A, P, L, I, E, W or N, X₆Is W, G, E, D, S, R, P, Y, N, L, A, T, I or V, X₇Is H, S, L, A, T, Y, G, F, W, V, E, D or M, X₈Is C, G, L, F, Y, S, W, D, M, T, N, R, H, V or P, X₉Is F, S, D, Y, W, G, T, E, P, L, R, N or none, X₁₀Is D, Y, F, I, N, W, V, P, E, L, G, S, Q or none, X₁₁Is Y, G, D, W, F, A, I, Q, S, N or none, X₁₂Is W, D, Y, F, N, G, R, P or none, X₁₃Is I, W, Y, D, S, F, G, L or none, X₁₄Is Q, W, I, Y, F, D, V, H or none, X₁₅Is H, W, M, D, Y, F or none, X₁₆Is W, D, S, Y or none, X₁₇Is V, W, Y or none, X₁₈W or none. In one or more embodiments, X₁Is V or A, X₂Is R, K, S or Q, X₃Is S, D, G, Y, A or E, X₄Is G, Y, D, S, W or N, X₅Is Y, S, F, T, A, L, I or W, X₆Is G, D, P, Y, N, L or T, X₇Is S, L, T, Y, F, W, E or D, X₈Is G, F, Y, S, W, M, T or H, X₉Is F, S, D, Y, E, L or none, X₁₀Is D, Y, V, L, G or none, X₁₁Is Y, G, W, F, Q, N or none, X₁₂-X₁₈Is absent. In one or more embodiments, X₁Is V, T or A, X₂Is S, R, K, G, T or H, X₃Is E, D, S, G, R or A, X₄Is D, W, G, P, Y or L, X₅Is F, A, T, Y, P, G or L, X₆Is D, G, Y or S, X₇Is Y, D, G, A, S, T, E or L, X₈Is W, H, Y, F, G, S, R or T, X₉Is Y, F, D, W, S, G, L, E or none, X₁₀Is Y, D, I, L, S or none, X₁₁Is F, Y, W, G, A, Q, S or none, X₁₂Is W, D, Y, F or none, X₁₃Is I, W, Y, D, F or none, X₁₄Is Q, W, I, Y, F or none, X₁₅Is H, W, M, D or none, X₁₆Is W, D, S or none, X₁₇W, V or none, and X₁₈W or none. An exemplary HCDR3 amino acid sequence is shown in any of SEQ ID NOs 66-114. Preferably, the amino acid sequence of HCDR3 is as shown in any one of

SEQ ID NOs

67, 78, 79, 80, 86, 93, 96, 99, 100, 107, 108. Also preferably, the amino acid sequence of HCDR3 is as set forth in any one of

SEQ ID NOs

67, 69, 71, 75, 79, 86, 90, 98, 99, 105, 107, 110.

LCDR1 of anti-OX 40 antibodies of the invention can contain X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂(SEQ ID NO:4) wherein X₁Is H or Q, X₂Is G, D, S or T, X₃Is S, I, L, T or V, X₄Is S, N, R, W, L, V or F, X₅Is T, D, N, S, H, Y or G, X₆Is Y, D, W, S, R, N, G or T, X₇Is N, D, S, Y or none, X₈Is G, N or none, X₉Is Y, N, D, H, S or none, X₁₀Is N, T, R, K or none, X₁₁Is Y, F, S, N or none, X₁₂Is Y or none. In one or more embodiments, X₁Is H or Q, X₂Is G, D or S, X₃Is S, I, L or V, X₄Is S, N, W, L or F, X₅Is T, N, S, H, Y or G, X₆Is Y, D, S, R or N, X₇Is N, D, Y or none, X₈G or none, X₉Is Y, N, D or none, X₁₀Is N, T or none, X₁₁Is Y or none, X₁₂Is absent. In one or more embodiments, X₁Is Q, X₂Is D or S, X₃Is I, L or V, X₄Is S, V or L, X₅Is D, N, S, H, Y or G, X₆Is Y, D, W, S, R or N, X₇Is N, D, S, Y or none, X₈Is G, N or none, X₉Is Y, N, D or none, X₁₀Is N, T, K or none, X₁₁Is Y, F, N or none, X₁₂Is Y or none. Exemplary LCDR1 amino acid sequences are shown in any of SEQ ID NO: 115-145. Preferably, the amino acid sequence of LCDR1 is as shown in any one of SEQ ID NO 115, 116, 120, 122, 124, 126, 130, 134, 135, 140, 141. Also preferably, the amino acid sequence of LCDR1 is as set forth in any one of SEQ ID NOs 117, 118, 121, 124, 125, 126, 128, 130, 133, 134, 135, 139, 141.

LCDR2 of anti-OX 40 antibodies of the invention can contain X₁X₂X₃(SEQ ID NO:5) wherein X₁T, K, G, W, E, M, L, D, A or Q; x₂V, A, T or G; x₃Is S or A. In one or more embodiments, X₁K, G, L, D or A; x₂V, A or G; x₃Is S. In one or more embodimentsIn the table, X₁T, K, G, W, E, M, L or D; x₂V, A or G; x₃Is S. An exemplary LCDR2 amino acid sequence is shown in any of SEQ ID NO 146-159. Preferably, the amino acid sequence of LCDR2 is as shown in any one of SEQ ID NOs 147, 148, 153, 154, 155. Also preferably, the amino acid sequence of LCDR2 is as shown in any one of SEQ ID NOs 146, 147, 148, 149, 150, 151, 153, 154.

LCDR3 of anti-OX 40 antibodies of the invention may contain CX₁QX₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁(SEQ ID NO:6) wherein X₁Is M, Q, L or H, X₂Is G, Y, A, V, H, T, F or S, X₃Is T, G, Y, N, L, D or S, X₄Is H, S, T, Q, D, N, G, I or R, X₅Is W, S, T, Y, L, I or N, X₆Is P, S, M, I, W or T, X₇Is W, F, L, P, I, Y, R or T, X₈Is T, L, A, F or W, X₉Is F, L, T or none, X₁₀Is T, F or none, X₁₁F or none. In one or more embodiments, X₁Is M, Q or L, X₂Is G, Y, A or S, X₃Is T, G, Y, N, L or D, X₄Is H, S, Q or N, X₅Is W, S, T, Y, L, I or N, X₆Is P or I, X₇Is W, F, L, I, Y, R or T, X₈Is T or F, X₉Is F or none, X₁₀And X₁₁Is absent. In one or more embodiments, X₁Is M or Q, X₂Is G, Y or A, X₃Is T, G, Y, N, L or D, X₄Is H, S, Q, D, N or G, X₅Is W, S, T, Y or L, X₆Is P or S, X₇Is W, F, L, P, I or Y, X₈Is T or L, X₉Is F or L, X₁₀Is T or absent, X₁₁F or none. Exemplary LCDR3 amino acid sequences are shown in any of SEQ ID NO 160-199. Preferably, the amino acid sequence of LCDR3 is as shown in any one of SEQ ID NOs 160, 161, 166, 168, 172, 182, 192, 193, 195, 198. Also preferably, the amino acid sequence of LCDR3As shown in any one of SEQ ID NO 160, 161, 162, 163, 164, 166, 167, 168, 169, 170.

In some embodiments, the anti-OX 40 antibodies of the invention contain HCDR1 as shown in SEQ ID NO. 1, HCDR2 as shown in SEQ ID NO. 2, and HCDR3 as shown in SEQ ID NO. 3, and/or LCDR1 as shown in SEQ ID NO. 4, LCDR2 as shown in SEQ ID NO. 5, and LCDR3 as shown in SEQ ID NO. 6. Preferably, the anti-OX 40 antibody of the invention comprises HCDR1 as shown in any one of SEQ ID NOs 7-38, HCDR2 as shown in any one of SEQ ID NOs 39-65, and HCDR3 as shown in any one of SEQ ID NOs 66-114, and/or LCDR1 as shown in any one of SEQ ID NOs 115-145, LCDR2 as shown in any one of SEQ ID NOs 146-159 and LCDR3 as shown in any one of SEQ ID NOs 160-199.

More preferably, the anti-OX 40 antibody of the invention comprises HCDR1 as shown in any one of SEQ ID NOs 9, 10, 12, 13, 19, 21, 23, 33, 34, 38, HCDR2 as shown in any one of SEQ ID NOs 42, 43, 46, 47, 50,58, 59, 63, 64, and HCDR3 as shown in any one of

SEQ ID NOs

67, 78, 79, 80, 86, 93, 96, 99, 100, 107, 108, and/or LCDR1 as shown in any one of SEQ ID NOs 115, 116, 120, 122, 124, 126, 130, 134, 135, 140, 141, LCDR2 as shown in any one of SEQ ID NOs 147, 148, 153, 154, 155, and LCDR3 as shown in any one of SEQ ID NOs 160, 161, 166, 168, 172, 182, 192, 193, 195, 198.

Alternatively, preferably, the anti-OX 40 antibody of the invention comprises HCDR1 as shown in any of SEQ ID NOs 11, 12, 14, 21, 23, 27, 28, 32, 33, 34, 35, 38, HCDR2 as shown in any of SEQ ID NOs 40, 43, 46, 48, 50, 52, 54, 56, 57, 59, 60, 63 and HCDR3 as shown in any of

SEQ ID NOs

67, 69, 71, 75, 79, 86, 90, 98, 99, 105, 107, 110, and/or LCDR1 as shown in any of SEQ ID NOs 117, 118, 121, 124, 125, 126, 128, 130, 133, 134, 135, 139, 141, LCDR2 as shown in any of SEQ ID NOs 146, 147, 148, 149, 150, 151, 153, 154 and LCDR2 as shown in any of SEQ ID NOs 161, 162, 163, 164, 166, 167, 168, 169, 3, 169.

Further preferably, the anti-OX 40 antibody of the invention contains HCDR1, HCDR2 and HCDR3 as shown in any one of the following groups a1 to a 71:

preferably contains HCDR1, HCDR2 and HCDR3 selected from any one of the group consisting of: a3, a5, a11, a16, a19, a20, a21, a41, a59, a63, a65, a68, a 69;

preferably selected from any one of LCDR1, LCDR2 and LCDR3 shown in the group consisting of: b3, b5, b11, b16, b19, b20, b21, b41, b59, b63, b65, b68 and b 69.

More preferably, the anti-OX 40 antibodies of the invention contain HCDR and LCDR of any one of group c1 to group c71 of table 1:

TABLE 1

In one or more embodiments, the anti-OX 40 antibodies of the invention contain HCDR and LCDR in any one of the groups selected from table 1 below: c3, c5, c11, c16, c19, c20, c21, c41, c59, c63, c65, c68 and c 69.

FR1 of the VH of the anti-OX 40 antibody of the present invention may be selected from FR1, FR2 from FR2, FR3 from FR3, and FR4 from FR4 of the VH of each antibody number in table 2; and/or FR1 for VL may be selected from FR1 for VL of each antibody number in table 2, FR2 may be selected from FR2 for VL of each antibody number in table 2, FR3 may be selected from FR3 for VL of each antibody number in table 2, and FR4 may be selected from FR4 for VL of each antibody number in table 2.

TABLE 2

In a preferred embodiment, the FR region of the VH of the anti-OX 40 antibody of the invention is the FR region of any one of the VH selected from the antibodies SEQ ID NO:200-270, and the FR region of the VL is the FR region of any one of the VL selected from the antibodies SEQ ID NO: 271-341. Further preferably, the HCDR of such antibodies is selected from any one of the aforementioned groups a1 to a71, and the LCDR is selected from any one of the aforementioned groups b1 to b 71; more preferably, the CDRs of such antibodies are selected from any of the aforementioned groups c1 to c 71.

The amino acid sequence of the VH of the anti-OX 40 antibody of the invention can be as shown in any one of SEQ ID NO:200-270 and/or the amino acid sequence of the VL can be as shown in any one of SEQ ID NO: 271-341. Preferably, the amino acid sequence of the VH and the amino acid sequence of the VL of the anti-OX 40 antibodies of the invention are shown in any one of the rows of table 1.

The amino acid sequence of the heavy chain constant region of the antibody of the present invention may have a sequence as shown in any one of SEQ ID NOS: 342-345, 348-351, and/or the amino acid sequence of the light chain constant region may have a sequence as shown in SEQ ID NO:346 or 347. In one or more embodiments, the heavy chain constant region of the anti-OX 40 antibody has the sequence shown as SEQ ID NO 348-351 and/or the amino acid sequence of the light chain constant region has the sequence shown as SEQ ID NO 347. Preferably, the heavy chain constant region of the anti-OX 40 antibody has the sequence shown in SEQ ID NO: 350. The affinity of the antibody heavy chain constant region of the antibody of the invention to human Fc gamma IIB is equal to or higher than that of human IgG1 to human Fc gamma IIB, and the I/A ratio of the antibody heavy chain constant region is equal to or higher than that of human IgG 1. Preferably, the affinity of the antibody heavy chain constant region to human Fc γ IIB is improved by 3.2-fold or more as compared with the affinity of human IgG1 to human Fc γ IIB, the I/a ratio of the antibody heavy chain constant region is equal to or higher than 0.32; also preferably, the affinity of said antibody heavy chain constant region to human Fc γ IIB is equal to or higher than the affinity of human IgG1 to human Fc γ IIB, the I/a ratio of said antibody heavy chain constant region is equal to or higher than 1; more preferably, the affinity of the antibody heavy chain constant region to human Fc γ IIB is improved by 30-fold or more as compared to the affinity of human IgG1 to human Fc γ IIB, the I/a ratio of the antibody heavy chain constant region is equal to or higher than 1; more preferably, the affinity of the antibody heavy chain constant region to human Fc γ IIB is improved by 60-fold or more as compared to the affinity of human IgG1 to human Fc γ IIB, the I/a ratio of the antibody heavy chain constant region is equal to or higher than 40; particularly preferably, the affinity of the antibody heavy chain constant region to human Fc γ IIB is improved by 90-fold or more as compared with the affinity of human IgG1 to human Fc γ IIB, and the I/a ratio of the antibody heavy chain constant region is equal to or higher than 100. The heavy chain constant region has higher affinity of an inhibitory Fc receptor, can remarkably enhance the crosslinking of an agonistic antibody or an agonistic molecule (such as an agonistic fusion protein) and the inhibitory Fc receptor, thereby improving the agonistic activity of the agonistic antibody or the agonistic molecule; meanwhile, the Fc has lower affinity of an activated Fc receptor, and can reduce cytotoxicity such as ADCC mediated by the binding of the activated receptor. Based on the heavy chain constant region of the present embodiments, agonistic antibodies or agonistic molecules with superior activity can be developed.

In some embodiments, the amino acid sequence of the heavy chain constant region and/or the amino acid sequence of the light chain constant region of the antibodies of groups d1-d40 in Table 2 have the sequences as set forth in any one of SEQ ID NOS 345, 348-351 and/or SEQ ID NO 347. In one or more embodiments, the heavy chain constant region of the antibodies of groups d1-d40 in Table 2 has the sequence shown as SEQ ID NO:348-351 and/or the amino acid sequence of the light chain constant region has the sequence shown as SEQ ID NO: 347. Preferably, the heavy chain constant region has the sequence shown as SEQ ID NO:350, and/or the amino acid sequence of the light chain constant region has the sequence shown as SEQ ID NO: 347.

In other specific embodiments, the amino acid sequences of the heavy chain constant regions and/or the amino acid sequences of the light chain constant regions of the antibodies of groups d41-d71 in Table 2 are shown in any one of SEQ ID NO:342-344 and/or SEQ ID NO: 346; preferably, the amino acid sequences of the heavy chain constant regions of the antibodies of groups d41-d71 in Table 2 are as shown in the respective corresponding groups in the table below. Herein, the heavy and light chain constant regions of each antibody may use any other heavy and light chain constant regions known in the art without affecting the binding ability of the antibody to the antigen.

Group of	Antibody numbering	Name of antibody	CH
				e41	PN101	16E4-10-5	343
e42	PN102	24F8-7	342
				e43	PN103	21F9-12	342
e44	PN104	23C4-1-5	343
				e45	PN105	24E10-4	343
e46	PN106	20G6-7-1	343
				e47	PN107	21F3-11	344
e48	PN108	26G9-9	344
				e49	PN109	24A12-12	343
e50	PN110	29B8-3	343
				e51	PN111	17D5-11	344
e52	PN112	26C3-4	343
				e53	PN113	55H6-6	343
e54	PN114	18F5-2	343
				e55	PN115	24F10-1	343
e56	PN116	23D1-8	344
				e57	PN117	20D2-12	343
e58	PN118	24B9-10	343
				e59	PN119	35B8-6	344
e60	PN120	14D3-7-3	343
				e61	PN121	28E3-4	344
e62	PN122	20G2-3-7	344
				e63	PN123	38D9-12	344
e64	PN124	18F11-4	342
				e65	PN125	21D2-3	344
e66	PN126	15A7-6	344
				e67	PN127	30B1-3	343
e68	PN128	1F10-12-3	Is unknown
				e69	PN129	4D9-12	344
e70	PN130	48D10-5	343
				e71	PN131	29A9-5	344

The antibody of the invention may be a chimeric antibody, a humanized antibody or a fully human antibody; preferably fully human antibodies. It is understood that the antibodies provided in the examples of the invention are fully human antibodies.

One skilled in the art may substitute, add and/or delete one or more (e.g., 1, 2, 3,4, 5,6, 7, 8, 9 or 10 or more) amino acids to the sequences of the invention to obtain variants of the sequences of the antibodies or functional fragments thereof, without substantially affecting the activity of the antibodies. All of which are considered to be included within the scope of the present invention. Such as substituting amino acids having similar properties in the FR and/or CDR regions of the variable region. The substitution is preferably a conservative substitution; amino acid residues that can be conservatively substituted are well known in the art. In some embodiments, the sequence of a variant of the invention may be at least 95%, 96%, 97%, 98% or 99% identical to the sequence from which it was derived. The sequence identity described in the present invention can be measured using sequence analysis software. For example the computer program BLAST, in particular BLASTP or TBLASTN, using default parameters.

The anti-OX 40 antibodies of the invention can be modified to affect function. The invention includes anti-OX 40 antibodies having modified glycosylation patterns. Modifications may be made to remove undesired glycosylation sites, or the absence of fucose moieties on the oligosaccharide chains to enhance antibody-dependent cellular cytotoxicity (ADCC) function, or galactosylation modifications may be made to alter complement-dependent cytotoxicity (CDC).

anti-OX 40 antibodies of the invention can generally possess an affinity constant of about 10-9 to about 10-13M.

anti-OX 40 antibodies of the invention can be prepared using methods conventional in the art, such as hybridoma technology, which is well known in the art. Alternatively, the anti-OX 40 antibodies of the invention can be expressed in cell lines other than hybridoma-free cell lines. Suitable mammalian host cells can be transformed with sequences encoding the antibodies of the invention. Transformation can be carried out by any known method, including, for example, packaging the polynucleotide in a virus (or viral vector) and transducing the host cell with the virus (or vector). The transformation procedure used depends on the host to be transformed. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, electroporation, encapsulation of polynucleotides in liposomes, and direct microinjection of DNA into the nucleus, among others. Mammalian cell lines useful as hosts for expression are well known in the art and include, but are not limited to, a variety of immortalized cell lines available from the American Type Culture Collection (ATCC), including, but not limited to, Chinese Hamster Ovary (CHO) cells, HeLa cells, Baby Hamster Kidney (BHK) cells, monkey kidney Cells (COS), human hepatocellular carcinoma cells (e.g., HepG2), and the like. Particularly preferred cell lines are selected by determining which cell lines have high expression levels and produce antibodies with substantial OX40 binding properties.

Polynucleotide sequences encoding anti-OX 40 antibodies

The invention provides nucleic acid molecules comprising polynucleotide sequences encoding anti-OX 40 antibodies of the invention. Provided herein are polynucleotide sequences encoding a heavy chain variable region, a light chain variable region, a heavy chain, a light chain, and each CDR.

The nucleic acid molecules of the invention include DNA and RNA in single-and double-stranded form, as well as the corresponding complementary sequences. DNA includes, for example, cDNA, genomic DNA, chemically synthesized DNA, PCR amplified DNA, and combinations thereof. The nucleic acid molecules of the invention include combinations of full-length gene or cDNA molecules and fragments thereof. The nucleic acids of the invention are preferably derived from human sources, but the invention also encompasses nucleic acids derived from non-human sources.

In the present invention, an isolated nucleic acid molecule refers to a nucleic acid molecule in the form of an independent fragment or as a component of a larger nucleic acid construct. In a preferred embodiment, the nucleic acid is substantially free of contaminating endogenous material. The nucleic acid molecule is preferably derived from DNA or RNA isolated at least once in a substantially pure form and in an amount or concentration such that its component nucleotide sequences can be identified, manipulated and recovered by standard biochemical methods. The sequences are preferably provided and/or constructed in the form of an open reading frame uninterrupted by internal untranslated sequences or introns, typically present in eukaryotic genes. The sequence of the untranslated DNA may be present 5 'or 3' to the open reading frame, which likewise does not affect the manipulation or expression of the coding region.

The invention also includes nucleic acids that hybridize under moderately stringent conditions, preferably under highly stringent conditions, to nucleic acids encoding anti-OX 40 antibodies as described herein. Basic parameters that influence the selection of hybridization conditions and guidance regarding designing appropriate conditions can be found in Sambrook, Fritsch and Maniatis (1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters 9 and 11; and Current Protocols in Molecular Biology, 1995, eds. Ausubel et al, John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4).

As outlined herein, variants according to the invention are typically prepared by site-specific mutagenesis of nucleotides in DNA encoding the anti-OX 40 antibody to produce DNA encoding the variant, using cassette mutagenesis or PCR mutagenesis, or other techniques well known in the art, and thereafter expressing the recombinant DNA in cell culture. However, antigen-binding fragments comprising residues having up to about 100-150 residues can be prepared by in vitro synthesis using established techniques.

As will be appreciated by those skilled in the art, due to the degeneracy of the genetic code, a very large number of nucleic acids can be made, all of which encode the anti-OX 40 antibodies or antigen-binding fragments thereof of the invention. Thus, where a particular amino acid sequence has been identified, one of skill in the art can make any number of different nucleic acids by simply modifying the sequence of one or more codons in a manner that does not alter the amino acid sequence encoding the protein.

The invention also provides expression systems and constructs in the form of plasmids, expression vectors, transcription cassettes or expression cassettes comprising at least one polynucleotide as described above. In addition, the invention provides host cells comprising the expression systems or constructs.

Expression vectors used in any host cell typically contain sequences for plasmid maintenance and for cloning and expression of exogenous nucleotide sequences. The sequences (collectively referred to as "flanking sequences" in certain embodiments) typically include one or more of the following nucleotide sequences: a promoter, one or more enhancer sequences, an origin of replication, a transcription termination sequence, a complete intron sequence containing donor and acceptor splice sites, a sequence encoding a leader sequence for polypeptide secretion, a ribosome binding site, a polyadenylation sequence, a polylinker region for insertion of a nucleic acid encoding an antibody to be expressed, and a selectable marker element. Each of these sequences is discussed below.

The vector may optionally contain a "tag" coding sequence, i.e., an oligonucleotide molecule located at the 5 'or 3' end of the anti-OX 40 antibody coding sequence; the oligonucleotide sequence encodes polyhistidine (such as 6His) or another "tag" such as FLAG, HA (hemagglutinin influenza virus) or myc, which are present in commercially available antibodies. This tag is typically fused to the polypeptide when the polypeptide is expressed, and can serve as a means for affinity purification or detection of anti-OX 40 antibodies from the host cell. Affinity purification can be accomplished, for example, by column chromatography using an antibody against this tag as an affinity matrix. The tag optionally can be subsequently removed from the purified OX40 anti-OX 40 antibody by various means, such as using certain peptidases for cleavage.

The flanking sequences may be homologous (i.e., from the same species and/or strain as the host cell), heterologous (i.e., from a species other than the host cell species or strain), hybrid (i.e., a combination of flanking sequences from more than one source), synthetic, or natural. Likewise, the source of the flanking sequences may be any prokaryotic or eukaryotic organism, any vertebrate or invertebrate organism or any plant, provided that the flanking sequences play a role in and are activatable by the host cell machinery.

The origin of replication is typically part of those prokaryotic expression vectors that are commercially available, and this origin facilitates the expansion of the vector in the host cell. If the vector of choice does not contain an origin of replication site, it can be chemically synthesized based on the known sequence and ligated into the vector. For example, origins of replication from plasmid pBR322(New England Biolabs, Beverly, MA) are suitable for most gram-negative bacteria, and various viral origins (e.g., SV40, polyoma virus, adenovirus, Vesicular Stomatitis Virus (VSV) or papilloma virus, such as HPV or BPV) are suitable for cloning vectors in mammalian cells. Mammalian expression vectors typically do not require an origin of replication component (e.g., often only the SV40 origin is used because it also contains a viral early promoter).

Transcription termination sequences are typically located at the 3' end of the polypeptide coding region to terminate transcription. Transcription termination sequences in prokaryotic cells are usually G-C rich fragments followed by poly-thymidine sequences.

The selectable marker gene encodes a protein necessary for the survival and growth of host cells grown in selective media. Typical selectable marker genes encode (a) confer resistance to antibiotics or other toxins (e.g., ampicillin, tetracycline or kanamycin for prokaryotic host cells); (b) complementing the auxotrophy of the cell; or (c) proteins that provide important nutrients not available from the complex or defined medium. Specific selectable markers are the kanamycin resistance gene, the ampicillin resistance gene, and the tetracycline resistance gene. Advantageously, the neomycin resistance gene may also be used for selection in prokaryotic and eukaryotic host cells.

Ribosome binding sites are usually necessary for the initiation of translation of mRNA and are characterized by Shine-Dalgarno sequences (prokaryotes) or Kozak sequences (eukaryotes). This element is typically located 3 'to the promoter and 5' to the coding sequence for the polypeptide to be expressed.

Expression and cloning vectors of the invention will typically contain a promoter that is recognized by the host organism and operably linked to a molecule encoding an anti-OX 40 antibody. A promoter is a non-transcribed sequence located upstream of the start codon of a structural gene (typically within about 100 to 1000 bp) that controls transcription of the structural gene.

Suitable promoters for use with yeast hosts are also well known in the art. Yeast enhancers are advantageously used with yeast promoters. Suitable promoters for use with mammalian host cells are well known and include, but are not limited to, those obtained from the viral genomes such as polyoma virus, fowlpox virus, adenovirus (such as adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis B virus and most preferably simian virus 40(SV 40). Other suitable mammalian promoters include heterologous mammalian promoters, such as heat shock promoters and actin promoters.

Enhancer sequences can be inserted into the vector to increase transcription of DNA encoding the light or heavy chain that constitutes the anti-OX 40 antibody of the invention by higher eukaryotes. Enhancers are cis-acting elements of DNA that act on a promoter to increase transcription, and are generally about 10-300bp in length. Enhancers have relative orientation and positional independence, and are found at the 5 'and 3' positions of the transcriptional unit. Several enhancer sequences are known that are available from mammalian genes, such as those for globulin, elastase, albumin, alpha-fetoprotein, and insulin. However, typically an enhancer from a virus is used. The SV40 enhancer, cytomegalovirus early promoter enhancer, polyoma enhancer, and adenovirus enhancers known in the art are exemplary enhancing elements for activating eukaryotic promoters.

The expression vector of the present invention may be constructed from a starting vector, such as a commercially available vector. Such vectors may or may not contain all of the desired flanking sequences. If one or more of the flanking sequences described herein are not already present in the vector, they may be obtained separately and ligated to the vector. The person skilled in the art is familiar with methods for obtaining the individual flanking sequences.

After constructing the vector and inserting the nucleic acid molecule encoding the light, heavy, or light and heavy chains comprising the anti-OX 40 antibody into the appropriate site of the vector, the completed vector can be inserted into a suitable host cell for amplification and/or polypeptide expression. Expression vectors for anti-OX 40 antibodies can be transformed into selected host cells by well-known methods including transfection, infection, calcium phosphate co-precipitation, electroporation, microinjection, lipofection, DEAE-dextran mediated transfection or other known techniques. The method selected may vary in part depending on the type of host cell to be used.

When the host cell is cultured under appropriate conditions such that it synthesizes anti-OX 40 antibody, the anti-OX 40 antibody can then be collected from the culture medium (if the host cell secretes it into the culture medium) or directly from the host cell from which it is produced (if not secreted). Suitable host cells are as described above.

Use of anti-OX 40 antibodies for therapeutic purposes

All aspects of the anti-OX 40 antibodies described herein are useful in the preparation of medicaments for the prevention or treatment of various conditions and diseases described herein, particularly diseases or conditions in which the conditions are associated with OX 40-expressing immune cells (particularly T cells, NK cells, and neutrophils). In some embodiments, the conditions and diseases are T cell-associated cancers, including but not limited to: bladder cancer, breast cancer, uterine/cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasms of the central nervous system, lymphoma, leukemia, myeloma, cancer of the urogenital system, urothelial cancer, renal cell cancer, gastric adenocarcinoma, non-small cell lung cancer, diffuse large B-cell lymphoma, head and neck squamous cell cancer, hodgkin's lymphoma, gastroesophageal junction adenocarcinoma, melanoma, sarcoma, and virus-related cancers. In certain embodiments, the cancer is a metastatic cancer, a refractory cancer, or a recurrent cancer. The conditions and diseases may also be other OX40 mediated disorders including, for example, OX40 mediated allergies, asthma, COPD, rheumatoid arthritis, psoriasis, ulcerative colitis, atopic dermatitis, autoimmune diseases and inflammation related diseases.

The anti-OX 40 antibodies described herein can also be used as vaccine adjuvants. The vaccine adjuvant can be used in combination with a vaccine (e.g., OVA) to form a vaccine composition, which can be used for preventing and/or treating tumors, and can also be used for preventing and/or treating infections.

In addition, the anti-OX 40 antibodies described herein can also be used to prepare medicaments for enhancing endogenous immune responses. As used herein, "enhancing an endogenous immune response" refers to enhancing the effectiveness or intensity of an existing immune response in a subject. Such enhancement of efficiency and potential can be achieved, for example, by overcoming mechanisms that suppress the endogenous host immune response, or by stimulating mechanisms that enhance the endogenous host immune response.

Diagnostic use, assay and kit

The anti-OX 40 antibodies of the invention can be used in diagnostic assays, e.g., binding assays, to detect and/or quantify OX40 expressed in tissues (such as bone marrow) or cells (such as plasma cells). anti-OX 40 antibodies can be used in studies to further investigate the role of OX40 in disease. anti-OX 40 antibodies can be used to further study the role of OX40 in the formation of homo-and/or heteromeric receptor complexes and the role of the OX40 receptor complex in disease.

The serum level of OX40 may be prognostic. Embodiments of the invention include diagnostic assays and kits to measure that soluble OX40 is a potential replacement for membrane-bound OX40 on tumor cells.

The anti-OX 40 antibodies of the invention can be used for diagnostic purposes to detect, diagnose, or monitor diseases and/or conditions associated with OX 40. The present invention provides for detecting the presence of OX40 in a sample using classical immunohistological methods known to those skilled in the art. Detection of OX40 can be performed in vivo or in vitro. Examples of methods suitable for detecting the presence of OX40 include ELISA, FACS, RIA, and the like.

For diagnostic applications, anti-OX 40 antibodies are typically labeled with a detectable label group. Suitable labeling groups include (but are not limited to) the following: radioisotopes or radionuclides (e.g., 3H, 14C, 15N, 35S, 90Y, 99Tc, 111In, 125I, 131I), fluorescent groups (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic groups (e.g., horseradish peroxidase, beta galactosidase, luciferase, alkaline phosphatase), chemiluminescent groups, biotin groups, or predetermined polypeptide epitopes recognized by secondary reporters (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags). In some embodiments, the labeling group is coupled to the anti-OX 40 antibody through spacer arms of various lengths to reduce potential steric hindrance. Various methods for labeling proteins are known in the art and can be used to carry out the present invention.

One aspect of the invention provides identifying a cell that expresses OX 40. In a specific embodiment, the antibody is labeled with a labeling group and binding of the labeled antibody to OX40 is detected. In another specific embodiment, binding of the antibody to OX40 is detected in vivo. In another specific embodiment, the antibody-OX 40 is isolated and measured using techniques known in the art.

Another aspect of the invention provides detecting the presence of a test molecule that competes with an antibody of the invention for binding to OX 40. One example of such an assay would involve detecting the amount of free antibody in a solution containing an amount of OX40 in the presence or absence of a test molecule. An increase in the amount of free antibody (i.e., antibody that does not bind OX40) would indicate that the test molecule is able to compete with the antibody for binding to OX 40. In one embodiment, the antibody is labeled with a labeling group. Alternatively, the test molecule is labeled and the amount of free test molecule is monitored in the presence or absence of antibody.

Pharmaceutical composition, route of administration

The invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more anti-OX 40 antibodies of the invention and a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and/or adjuvant.

In certain embodiments, acceptable diluents, carriers, solubilizing agents, emulsifiers, preservatives, adjuvants and/or the like in the pharmaceutical composition are preferably non-toxic to the recipient at the dosages and concentrations employed. In certain embodiments, the pharmaceutical compositions may contain such agents for improving, maintaining or retaining, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, absorption or permeation of the composition. These substances are known in the art and can be found, for example, in REMINGTON' S PHARMACEUTICAL SCIENCES, 18 th edition, ed.A.R.Genrmo, 1990, Mack Publishing Company. The optimal pharmaceutical composition can be determined depending on the intended route of administration, mode of delivery and the desired dosage.

The pharmaceutical compositions of the present invention may be selected for parenteral delivery. Alternatively, the composition may be selected for inhalation or delivery through the digestive tract (such as orally). The preparation of such pharmaceutically acceptable compositions is within the skill of the art.

Other pharmaceutical compositions will be apparent to those skilled in the art, including formulations comprising anti-OX 40 antibody in sustained or controlled release delivery formulations. Techniques for formulating a variety of other sustained or controlled delivery means, such as liposome carriers, bioerodible microparticles or porous beads, and depot injections, are also known to those skilled in the art.

Pharmaceutical compositions for in vivo administration are generally provided in the form of sterile preparations. Sterilization is achieved by filtration through sterile filtration membranes. In the case of lyophilization of the composition, sterilization can be performed using this method before or after lyophilization and reconstitution. Compositions for parenteral administration may be stored in lyophilized form or in solution. Parenteral compositions are typically placed in a container having a sterile access port, such as an intravenous solution strip or vial having a stopper pierceable by a hypodermic injection needle.

Once formulated, the pharmaceutical compositions are stored in sterile vials as solutions, suspensions, gels, emulsions, solids, crystals, or as dehydrated or lyophilized powders. The formulation may be stored in a ready-to-use form or reconstituted prior to administration (e.g., lyophilized). The invention also provides kits for producing a single dose administration unit. The kits of the invention may each contain a first container having a dried protein and a second container having an aqueous formulation. In certain embodiments of the invention, kits are provided that contain single and multi-chamber pre-filled syringes (e.g., liquid syringes and lyophilized syringes).

The invention also provides methods of treating a patient, particularly a T cell-related disease in a patient, such as a T cell-related cancer and an autoimmune disease, by administering an anti-OX 40 antibody, or antigen-binding fragment thereof, or a pharmaceutical composition thereof, according to any of the embodiments of the invention.

Herein, the terms "patient," "subject," "individual," "subject" are used interchangeably herein and include any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit, etc.), and most preferably a human. "treatment" refers to the subject taking a treatment regimen described herein to achieve at least one positive therapeutic effect (e.g., a decrease in the number of cancer cells, a decrease in tumor volume, a decrease in the rate of cancer cell infiltration into peripheral organs, or a decrease in the rate of tumor metastasis or tumor growth). The treatment regimen effective to treat a patient may vary depending on a variety of factors, such as the disease state, age, weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject.

The therapeutically effective amount of a pharmaceutical composition containing an anti-OX 40 antibody or antigen-binding fragment thereof of the invention that will be employed will depend, for example, on the degree of treatment and the goal. One skilled in the art will appreciate that the appropriate dosage level for treatment will vary depending, in part, on the molecule delivered, the indication, the route of administration, and the size (body weight, body surface or organ size) and/or condition (age and general health) of the patient. In certain embodiments, the clinician may titrate the dosage and alter the route of administration to achieve optimal therapeutic effect.

The frequency of dosing will depend on the pharmacokinetic parameters of the particular anti-OX 40 antibody in the formulation used. The clinician typically administers the composition until a dosage is reached that achieves the desired effect. The compositions may thus be administered as a single dose, or over time as two or more doses (which may or may not contain the same amount of the desired molecule), or by continuous infusion through an implanted device or catheter.

The route of administration of the pharmaceutical composition is according to known methods, e.g., oral, by intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, portal vein or intralesional injection; by a sustained release system or by an implanted device.

The present invention will be illustrated below by way of specific examples. It should be understood that these examples are illustrative only and are not intended to limit the scope of the present invention. The methods and materials used in the examples are, unless otherwise indicated, all those materials and methods conventional in the art.

Examples

Materials and methods

1) Immunoglobulin variable region genes humanized mouse AceMuoseGBTM was derived from Henan Hua kang constant health Biotechnology, Inc. The mice are all raised in the Henan Hua kang constant health biotechnology Limited company, the development of related animal experiments conforms to the laws and regulations of all levels in China, and the permission of the animal care and use committee of the Henan Hua kang constant health biotechnology Limited company is obtained.

2) OX40 humanized mouse (hOX40)^TgMouse): human murine chimeric Tnfrsf4(OX40) cDNA-wpre-polyA (in which the extracellular region (about 2.3kb) and the first half of the transmembrane region of the OX40 gene are of human origin, including the first half of Exon1-5 and Exon6, and the latter half of the transmembrane region and the intracellular region are of murine origin, including the latter half of Exon7 and Exon 6.) this strain of mice was obtained by CRISPR/Cas9 technology from shanghai south modular biotechnology limited. Mice of this genotype are suitable for the study of murine anti-human OX40 antibodies.

3) Fc gamma R humanized OX40 humanized mouse (hFCGR)^TghOX40^TgMouse): i.e., mice humanized with Fc receptor (murine Fc γ Rs knock-out (Fc γ R α)^-/-) Transfer of human Fc γ Rs (hFc γ RI) into mice⁺/hFcγRIIA^R131+/hFcγRIIB⁺/hFcγRIIIA^F158+/hFcγRIIIB⁺) (the mouse has been in Nat Commun.2019Sep 27; 10(1) 4206.doi 10.1038/s41467-019-12097-6. described in OX40 humanized mouse (hOX40)^TgMouse), mice of this genotype express both human Fc receptor and human OX40 molecules, suitable for use in the study of human anti-human OX40 antibodies.

4) Bone marrow chimeric mice: hFCGR with respect to reproduction^TghOX40^TgThe number of mice is limited, and the number of mice is hFCGR for obtaining a large number of genotypes^TghOX40^TgMice, a large number of mice of interest are obtained in a short period of time by means of bone marrow reconstitution. The specific method for bone marrow reconstitution is as follows: ordering a given number of 8-week-sized C57BL/6 female mice (Ling Chang or Slek, China), feeding with water containing a certain concentration of streptomycin for 1-2 weeks, and then administering a dose of 8Gy (4Gy +4Gy) of X-ray (RS 2000pro X-ray bi)Irradiating mice with a logical Irradator (Rad Source Technologies, Inc., U.S. A.)) to cause the death of the original bone marrow cells, and 3 hours later injecting 2 x 10^6 hFCGR-derived mice into the tail vein^TghOX40^TgBone marrow cells of mice. After 2 months of bone marrow reconstitution, a portion of the mice was sampled for orbital blood, anticoagulated with heparin, and assayed for B cells by flow analysis (CD 19)⁺) And myeloid cell line (CD11 b)⁺) Expression of surface Fc γ RIIB (human Fc γ RIIB vs. mouse Fc γ RIIB), the extent of reconstitution was assessed by the expression level of human Fc γ RIIB.

All mice are raised in the animal science experiment center of Shanghai traffic university medical college, all animal experiments are developed according with the laws and regulations of all levels in China, and the approval of the animal care and use committee of the Shanghai traffic university medical college is obtained.

Example 1 immunization of mice to produce monoclonal antibodies against human OX40

The first immunization was performed using commercial recombinant human OX40 antigen protein (6His tag, cat No. CK60, supplier Novoprotein) and standard freund's complete adjuvant at a dose of 40 micrograms human recombinant OX40 protein antigen per 20 grams body weight of mice. The second to fourth immunizations were performed on 6-week-old mice using a proprietary expression vector expressing the full-length human OX40 protein (sequence reference NCBI database, accession No. NM — 003327.2). The fifth immunization was performed using commercial recombinant human OX40 antigen protein (6His tag, cat No. CK60, supplier Novoprotein) and PBS at a dose of 25 micrograms human recombinant OX40 protein antigen per mouse.

Example 2 ELISA assay of sera from immunized mice

Human recombinant OX40 antigen protein (Novoprotein, cat # CK60) was diluted to 0.5 ng/L in PBS, 100. mu.L/L antigen was added to a 96-well flat bottom ELISA plate of Maxisorp, sealed with preservative film and left overnight at 4 ℃. After decanting the antigen every other day, it was washed once with PBS (200. mu.l/well), after pouring off the PBS, it was patted dry on absorbent paper and 200. mu.l of blocking solution (PBS containing 10% fetal bovine serum) was added to each well and blocked for 2 hours at room temperature. After the sealing is finished, the sealing liquid is poured out and then the water absorption paper is patted dry. Adding 50 microliter of diluentSerum was diluted with concentration gradient (PBS containing 5% fetal bovine serum) and added to a 96-well plate, left at room temperature for 1 hour, after which the sample was decanted, washed 3 times with washing solution (PBS containing 0.05% Tween-20), finally decanted and blotted dry on absorbent paper. HRP goat anti-mouse IgG secondary antibody (final concentration 0.4. mu.g/ml; manufacturer Biolegend, cat. No. 405306) was diluted by adding 50. mu.l of diluent (PBS containing 5% fetal bovine serum) at room temperature for 1 hour, after which the liquid was decanted, washed 5 times (200. mu.l/well) with wash solution (PBS containing 0.05% Tween-20), and finally decanted and blotted dry on absorbent paper. 50 microliter/well TMB-urea hydrogen peroxide solution (manufacturer Thermo Scientific) was added^TM34029) at room temperature for 3-5 minutes in dark, adding 0.25M sulfuric acid of 50 microliter/hole to terminate the reaction, and detecting the light absorption of 450nm wavelength on a multifunctional microplate reader.

Example 3 Single cell sequencing to generate monoclonal antibodies

AceCoueGBTM mice were immunized with His-tagged human OX40 extracellular domain protein (hOX40-EC-His, Novoprotein, Cat. No. CK60, Lot. No.0331348), spleen, inguinal and popliteal lymph node cells were taken for flow sorting, and single cell sequencing was performed on the sorted IgD negative B linkage cells (10X Genomics). According to the characteristics of clone expansion of antigen-specific B cells after immunization, target sequences (light chain variable region and heavy chain variable region) are selected from a plurality of sequences and are constructed into a complete antibody structure with a constant region (the light chain is Ck, and the heavy chain constant region is a human IgG2 constant region (JAC3) with mutation for enhancing the combination with Fc gamma RIIB). The antibody sequences were inserted into expression vectors, co-transfected into suspension 293 cells, the supernatant collected and affinity purified using protein G beads. Removing polymer from the purified antibody by using a molecular Sieve (SEC), and storing the obtained monomer antibody in a refrigerator at 4 ℃ or-20 ℃ for later use.

Example 4 ELISA to determine the ability of Single cell sequencing antibodies to bind to hOX40-EC

1) Coating 100 μ l of hOX40-EC-His (novoprotein) in 96-well high-adsorptivity enzyme-labeled detection plate (nunc) with the concentration of 2 μ g/ml, and incubating overnight in a four-degree refrigerator;

2) the plate was discarded, washed 2 times with PBST (PBS with 0.05% Tween 20), added 200. mu.l of 1% BSA (in PBS) and blocked for 2 hours at room temperature;

3) the purified single cell sequencing antibody, negative control antibody Ctrl hIgG, positive control antibody IBI101 (Nedada), and Pogalizumab (Roche) were diluted appropriately (3.16. mu.g/ml-1 ng/ml), 100. mu.l each was added to the above-mentioned closed wells (PBST was washed 3 times, and the solution was discarded), and incubated at room temperature for 1 hour;

4) PBST washing the plate for 4 times, patting the liquid dry, adding 100 μ l of goat anti-human IgG Fc HRP (1:100000, Bethyyl) detection antibody into each well, and incubating for 1 hour at room temperature;

5) the PBST plate is washed for 5 times, liquid is photographed, 100 mu l of HRP substrate TMB (liquid A and liquid B are mixed in equal volume, KPL) is added into each hole, and after 10-30 minutes of color development, an enzyme-linked immunosorbent assay is used for reading the signal value of OD 650.

As shown in fig. 1, anti-human OX40JAC3 antibody has OX40 binding ability.

Example 5 in vitro immune activation Activity assay of anti-human OX40JAC3 antibody

1) Preparation of hFCGR^TghOX40^TgMouse spleen leukocyte single cell suspension: taking hFCGR under aseptic conditions^TghOX40^TgGrinding spleens of mice, then using 5ml of erythrocyte lysate ACK to perform lysis on ice for 5 minutes, adding 9ml of PBS to stop the lysis, washing the splenocytes, centrifuging for 5 minutes at 400g, and using 2ml of PBS to re-suspend the splenocytes, thus obtaining a splenic single cell suspension. Taking a small amount of single cell suspension, diluting the single cell suspension at a ratio of 1:100, and counting the cells by using an improved Nebull counting plate;

2) CFSE labeled splenocytes: according to the experiment required to remove a portion of the cells, with PBS dilution, cell density in (2-4) ^ 10^7/ml, volume less than 5ml, adding CFSE, so that its final concentration is 5 u M. Mixing, and incubating in 37 deg.C incubator for 15 min. The cells were then washed 2 times with a wash solution containing 9ml of 5% FBS, centrifuged at 400g for 5min, and the supernatant was discarded. Resuspend the cells by adding 2ml of primary cell culture medium (RPMI + 10% FBS + 1% Pen/Strep + 1% HEPES + 1% sodium pyruvate + 0.1% 2ME (final concentration 50uM) + 1% L-glutamine + 1% non-essential amino acids) and counting;

3) in addition to controls (untreated, CFSE only, CD3 only, CD3+ CD28), anti-mouse CD3e (clone: 145-2C11, BD Pharmingen) at 0.2. mu.g/ml was used^TM) The primary cell culture medium re-suspended the CFSE-labeled cells to a cell density of 2 x 10^ 6/ml. Add 100. mu.l of the above cells to a 96 well cell culture flat bottom plate according to the experimental design, resulting in a cell count per well of 2 x 10^ 5. Untreated groups were added cells not labeled with CFSE and were not added anti-murine CD3 and other antibodies. Only CFSE groups were added with CFSE labeled cells, but not with anti-mouse CD3 and other antibodies. Only the CD3 group was supplemented with CFSE labeled cells and anti-murine CD3, but no other antibodies. The CD3+ CD28 group was supplemented with CFSE-labeled cells and anti-murine CD3, and anti-murine CD28 antibody (clone 37.51(RUO), BD Pharmingen) at a concentration of 2. mu.g/ml was added^TM) (after equal volume dilution in step 4, the final concentrations of anti-mouse CD3 and CD28 were 0.1. mu.g/ml and 1. mu.g/ml, respectively);

4) preparing antibodies with different concentrations: anti-hOX40 JAC3 antibody, Ctrl hIgG (Jackson ImmunoResearch) and positive control antibodies IBI101 (dada), Pogalizumab (roche) were diluted with primary medium gradient to 2-fold concentration of the final concentration and 100 μ l was added to the above well plate to which anti-mouse CD3 antibody and CFSE-labeled splenocytes were added, respectively. Adding 100 μ l of culture medium to each control group;

5) culturing the cells in an incubator at 37 ℃ for 3 days;

6) flow cytometry to detect proliferation of T cells: the cultured cells were transferred to a 96-well U-plate, washed 2 times with PBS, centrifuged at 500g for 5 minutes, the supernatant was discarded, the cells were resuspended in 50. mu.l of FACS buffer (PBS containing 0.5% FBS, 2mM EDTA) containing PE anti-mouse CD4 (clone: GK1.5, 1:500, BD) and APC anti-mouse CD8a (clone: 53-6.7, 1:500, BioLegend), incubated on ice away from light for 15 minutes, and then the cells were washed twice with PBS buffer, resuspended in DAPI (0.5. mu.g/ml, Invitrogen) and CountBright^TMAbsolute Counting Beads (Life Technologies, 2. mu.l/sample) in 200. mu.l FACS buffer and analyzed by flow cytometry.

As shown in fig. 2 and fig. 3, the anti-human OX40JAC3 antibody had in vitro activity, with the anti-human OX40 JAC324# and 37# antibodies having more superior in vitro activity.

Example 6 analysis of in vivo Immunoactivating Activity of anti-human OX40JAC3 antibody

The in vivo immune activation activity of anti-human OX40JAC3 antibody was tested using OVA-specific CD8+ T cell proliferation model. The specific process is as follows:

1) immunization of hFCGR with 5. mu.g/DEC-OVA protein and a dose of antibody by intraperitoneal injection at day0^TghOX40^TgA mouse. Grouping and antibody doses were as follows:

group 1 ctrl hIgG, 100. mu.g/n ═ 4

Group 2 IBI101,100 μ g/n ═ 5

Group 3:37#,100 mug/n ═ 3

Group 4 Pogalizumab, 100. mu.g/n ═ 5

Group 5 Pogalizumab, 30. mu.g/n ═ 4

Group 6:24#,100 mug/n ═ 4

Group 7:24#,30 μ g/n ═ 5

Group 8:24#,10 μ g/n ═ 4

2) Mice were sacrificed at day7, mouse spleens were aseptically removed, single cell suspensions were prepared, 1/10 spleen cells were resuspended in 150. mu.l of medium containing 1. mu.g/ml anti-mouse CD28 antibody and 1. mu.g/ml OVA peptide SIINFEKL (RPMI with 10% FBS, 1% Pen Strep,10mM HEPES, 50. mu.M 2-thiol ethanol), and after incubation in a 96-well flat-bottom plate at 37 ℃ for 1 hour, Brefeldin A (BFA) was diluted with the above-described medium containing 1. mu.g/ml anti-mouse CD28 antibody and 1. mu.g/ml OVA peptide SIINFEKL at 50. mu.l per well to give a final concentration of 10. mu.g/ml. Placing the mixture in a cell culture box at 37 ℃ for further culture for 5 hours;

3) after centrifugation (400g for 5min), the culture cells were discarded and washed twice with 200. mu.l of PBS, 50. mu.l of Fixable visual Stain 510(BD) diluted with PBS was added to each well and stained at room temperature for 15 minutes.

4) Washed twice with PBS and ice stained with 50. mu.l of anti-murine CD4 containing PE-labeling (clone: GK1.5, 1:500, BD) and APC-labeled anti-murine CD8 α (clone: 53-6.7, 1:500, BioLegend) for 15 minutes;

5) washing twice with PBS, discarding supernatant, resuspending cells with 100. mu.l BD cell fixation/membrane disruption solution (BD), and placing on ice for 20 min;

6) using Perm/Wash^TMWashing with washing solution (BD) for 2 times, and staining with PECy 7-labeled anti-mouse IFN-. gamma. (clone: XMG1.2(RUO), 1:200, BD) for 30 minutes on ice in the dark;

7) using Perm/Wash^TMWashing with a washing solution (BD) for 2 times, using a washing solution containing CountBright^TMAbsolute Counting Beads (Life Technologies, 2. mu.l/sample) in 200. mu.l PBS were resuspended and analyzed by flow cytometry.

As shown in FIG. 4, the anti-human OX40 JAC324# antibody had a stronger ability to stimulate IFN-g secretion from OVA-specific CD8+ T cells than Pogalizumab and IBI 101.

Example 7 anti-human OX40JAC3 antibody had good anti-tumor activity (MC38)

MC38 is a mouse colon cancer cell line, and is administered to hFCGR at day-8^TghOX40^TgMice were inoculated subcutaneously with 2 x 10^6 MC38 cells each, and one week later (day-1) long (L1) and short (L2) edges of the tumors were measured with a slide caliper and tumor size was calculated with (L1 x L2^ 2)/2. Mice were divided into groups according to tumor size ranking, and groups were given 63 μ g of Ctrl hIgG, Pogalizumab, anti-human OX40IAC 324# antibody and 3# antibody by intraperitoneal injection at day0 and day3, respectively, and serum AST levels were determined at day3 and day6 orbital bleeds to measure the hepatotoxicity of the antibodies, and tumor sizes were measured at day-1, 3, 6, 10, 13, 16, 20, 23 to evaluate the anti-tumor activity of the antibodies. As a result, as shown in fig. 5, the anti-human OX40 JAC324# antibody was able to achieve both better therapeutic effects and toxic side effects than Pogalizumab.

Example 8 anti-human OX40JAC3 antibody had good anti-tumor activity (MO4)

MO4 is OVA transfected mouse melanoma cell line, and hFCGR is given at day-10^TghOX40^TgMice were inoculated subcutaneously with 2 x 10^6 MO4 cells each, and 9 days later (day-1) with a vernier caliperThe long side (L1) and short side (L2) of the tumor were measured and (L1X L2^2)/2 was used to calculate the tumor size. Mice were divided into groups according to tumor size ranking, and each group was given 2 μ g of DEC-OVA antigen and varying concentrations of antibody in DEC-OVA solution comprising Ctrl hIgG (5mg/kg), Pogalizumab (5mg/kg), IBI101(5mg/kg), anti-human OX40IAC 324# antibody (5mg/kg and 1.5mg/kg) and anti-human OX40IAC 337 # antibody (5mg/kg) by intraperitoneal injection at day0, and serum AST levels were measured in day4 and day7 orbital bleeds to measure the hepatotoxicity of the antibodies, and tumor sizes were measured at day-1, 4, 7, 11, 14, 18, 21 to assess the anti-tumor activity of the antibodies. As shown in fig. 6, anti-human OX40 JAC324# antibody had better anti-tumor activity compared to Pogalizumab. As shown in fig. 7, the hepatotoxicity (serum AST levels) of anti-human OX40 JAC324# antibody was significantly weaker than Pogalizumab. Therefore, compared with Pogalizumab and IBI101, the anti-human OX40 JAC324# antibody can better take both curative effect and toxic and side effect into consideration.

Example 9 hybridoma cells were obtained from immunized mouse spleen cells using electrofusion technology

Resuscitating SP2/0 mouse myeloma cells in advance; taking SP2/0 mouse myeloma cells for counting on the day of fusion; OX40 mice after successful immunization were placed in spleen transport medium HB medium (with 1% P/S) and immediately extracted for cell counting in isolated spleen; take 1.5X 10⁸Spleen cells and 1.5X 10⁸The ratio of individual SP2/0 mouse myeloma; centrifuging for 5 minutes at 200G after mixing, removing supernatant, and washing twice with 20 ml of fusion liquid for later use; centrifuging at 200G room temperature for 5 minutes, removing the supernatant, and adding 6.4 ml of electrofusion buffer solution to resuspend the precipitate; preparing a 50 ml centrifuge tube, and adding 13 ml of preheated HB medium; the mixed cell suspension was added to CUY497X which had been sterilized with 75% alcohol and air dried₁₀Electrodes and cells were electrofused using the standard protocol of the ECFG21 electrofusion apparatus (manufacturer NEPAGENE, model ECFG 21); after the fusion was complete, the cells were aspirated and placed in 13 ml of HB medium previously preheated in an incubator; resuspend cells in HAT Medium at 5X 10⁵Cells/well in 96-well flat bottom plate; placing 96-well plate in 37 deg.C incubator, standing for culture, observing cells every day, and collecting supernatant on day 10Performing ELISA primary screening.

Example 10 screening of hybridoma anti-human OX40 monoclonal antibodies by enzyme-linked immunosorbent assay

OX40 antigen (Novoprotein cat: CK60) was diluted to 0.5 ng/l with PBS; adding 100 microliter/hole antigen into 96-hole flat-bottom ELISA plate of Maxisorp, sealing with preservative film, and standing at 4 deg.C overnight; after pouring off the antigen every other day, washing once with PBS (200. mu.l/well), pouring off PBS, patting dry on absorbent paper, adding 200. mu.l of blocking solution into each well, and sealing at room temperature for 2 hours; after the sealing is finished, pouring sealing liquid back, and then patting the paper on absorbent paper to be dry; adding 50 microliters of a sample (OX40 hybridoma cell culture supernatant obtained in example 9), standing at room temperature for 1 hour, then pouring off the sample, washing 3 times with a washing solution, finally pouring off the washing solution and then patting dry on absorbent paper; adding 50 microliters of secondary HRP goat anti-mouse IgG antibody diluted by diluent (PBS containing 5% fetal calf serum) and standing at room temperature for 1 hour, then pouring off the liquid, washing for 5 times (200 microliters/hole) by using washing liquid, finally pouring off the washing liquid and drying on absorbent paper; adding 50 microliter/hole TMB-hydrogen peroxide urea solution substrate liquid, placing at room temperature in the dark for 3-5 minutes, adding 50 microliter/hole 0.25M sulfuric acid to terminate the reaction, and then detecting the light absorption of 450nm wavelength on a multifunctional microplate reader. The results are shown in the following table:

example 11 detection of anti-human OX40 antibody binding to OX40 overexpressing cell surface OX40 assay by flow cytometry

OX 40-overexpressing cells were collected by centrifugation at 200G, washed once with 3% FCS-containing PBS, resuspended in 2.5 ml of 3% FCS-containing PBS, and the cells were added to a 96-well plate at 25. mu.l/well (2.5X 10 cells)⁵) 75 microliters of each sample (OX40 hybridoma cell culture supernatant obtained in example 9) was added, and a positive reference well was set to add 75 microliters of anti-OX 40 antibody (clone ACT35, manufacturer Biolegend final concentration 1. mu.g/ml); add 75. mu.l IgG2a isotype control to well 1 (clone MG2a-53, manufacturer Biolegend, final concentration 1. mu.g/ml); adding 75 μ l of P containing 3% FCS into the female ginseng well 2BS, incubated in a refrigerator at 4 ℃ for 1 hour, followed by washing twice with 3% FCS-containing PBS; after the supernatant was decanted, 50. mu.l of a 500 ng/ml secondary antibody (manufacturer Ebioscience, goat anti-mouse IgG-PE, cat # 12-4010-82) was added to the sample wells, the male ginseng wells, the female ginseng wells 1 and the female ginseng wells 2; the plates were then incubated at 4 ℃ in the dark for 30 minutes and washed twice with 3% FCS in PBS, and the cells were finally resuspended in 50. mu.l of 3% FCS in PBS and examined by flow cytometry. The results are shown in the following table and FIGS. 8A-C.

Clone name	28E3-4	21F3-11	29B8-3	24F10-1	55H6-6
						Y586 channel PE fluorescence value	195411	170723	388242	274205	479073
Clone name	24E10-4	30B1-3	15A7-6	22D6-3	23D1-8
						Y586 channel PE fluorescence value	343778	208478	180959	461976	166107
Clone name	24B9-10	24A12-12	29A9-5	26G9-9	35B8-6
						Y586 channel PE fluorescence value	313454	343068	220618	221755	243286
Clone name	38D9-12	4D9-12	48D10-5	18F11-4	18F5-2
						Y586 channel PE fluorescence value	243343	186812	358123	402043	431911
Clone name	26C3-4	25F4-10	25F4-7	16G2-10	22E6-11
						Y586 channel PE fluorescence value	416371	612396	616613	475068	549525
Clone name	17D5-11	27C8-12	21F9-12	23C4-1-5	16E4-10-5
						Y586 channel PE fluorescence value	475068	400528	423614	63905	376890
Clone name	1F10-3-1	14D3-7-3	1F10-12-3	20G6-7-1	19C12-9-6
						Y586 channel PE fluorescence value	172510	273719	169911	351786	315714
Clone name	20D2-12	24F8-7	21D2-3	anti-OX 40 Ab	IgG2a
						Y586 channel PE fluorescence value	540481	437030	201913	209583	1828
Clone name	PBS
						Y586 channel PE fluorescence value	1388

Example 12 ELISA testing of hybridoma supernatants anti-hOX40 murine antibody binding to hOX40-EC

1) Coating 100 μ l of hOX40-EC-His (novoprotein) in 96-well high-adsorptivity enzyme-labeled detection plate (nunc) with the concentration of 1 μ g/ml, and incubating overnight in a four-degree refrigerator;

2) the plate was discarded and washed 2 times with PBST (0.05% Tween 20 in PBS), 200. mu.l of 1% BSA (in PBS) was added and blocked for 2 hours at room temperature;

3) hybridoma supernatants were diluted in gradient (1:10/1:100/1:1000/1:10000) and 100. mu.l each was added to the above-mentioned closed wells (PBST washing 2 times, liquid was discarded), and incubated at room temperature for 1 hour;

4) PBST washing plate 4 times, clap the liquid, each hole add 100 u l detection antibody goat anti mouse IgG Fc HRP (1:5000, Jackson ImmunoResearch) room temperature 1 hours incubation;

5) washing the PBST for 5 times, patting the liquid, adding 100 mul of HRP substrate TMB (liquid A and liquid B are mixed in equal volume, KPL) into each hole, and reading the OD650 signal value by using a microplate reader after a period of time;

6) and selecting the signal value of the sample at the dilution of 1:100 for result statistics.

The results, shown in the table below and in FIG. 9, indicate that the hybridoma antibody clones have the ability to bind OX 40.

Example 13 construction of antibodies Using variable regions of hybridoma antibodies and determination of the ability of the antibodies to bind to hOX40-EC

The hybridoma antibodies obtained according to examples 10-12 were obtained for their light and heavy chain variable region sequences and constructed into complete antibody structures with constant regions (light chain ck, heavy chain constant region human IgG2 constant region with mutations that enhance binding to Fc γ RIIB (JAC 3)). The antibody sequences were inserted into expression vectors, co-transfected into suspension 293 cells, the supernatant collected and affinity purified using protein G beads. Removing polymer from the purified antibody by using a molecular Sieve (SEC), and storing the obtained monomer antibody in a refrigerator at 4 ℃ or-20 ℃ for later use. The ability of the antibody to bind to hOX40-EC was determined by ELISA as described in example 4, and the results showed that the reconstituted hybridoma anti-human OX40JAC3 antibody had OX40 binding ability.

Sequence listing

<110> Suzhou perpetual biopharmaceutical Co., Ltd

<120> Low-toxicity anti-OX 40 antibody, pharmaceutical composition and application thereof

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<221> MUTAGEN

<222> (4)..(4)

<223> Xaa S, N, R, W, L, V or F

<220>

<221> MUTAGEN

<222> (5)..(5)

<223> Xaa T, D, N, S, H, Y or G

<220>

<221> MUTAGEN

<222> (6)..(6)

<223> Xaa Y, D, W, S, R, N, G or T

<220>

<221> MUTAGEN

<222> (7)..(7)

<223> Xaa N, D, S, Y or none

<220>

<221> MUTAGEN

<222> (8)..(8)

<223> Xaa G, N or none

<220>

<221> MUTAGEN

<222> (9)..(9)

<223> Xaa Y, N, D, H, S or none

<220>

<221> MUTAGEN

<222> (10)..(10)

<223> Xaa N, T, R, K or none

<220>

<221> MUTAGEN

<222> (11)..(11)

<223> Xaa Y, F, S, N or none

<220>

<221> MUTAGEN

<222> (12)..(12)

<223> Xaa is Y or

<400> 4

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10

<210> 5

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<221> MUTAGEN

<222> (1)..(1)

<223> Xaa T, K, G, W, E, M, L, D, A or Q

<220>

<221> MUTAGEN

<222> (2)..(2)

<223> Xaa V, A, T or G

<220>

<221> MUTAGEN

<222> (3)..(3)

<223> Xaa is S or A

<400> 5

Xaa Xaa Xaa

1

<210> 6

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<221> MUTAGEN

<222> (1)..(1)

<223> Xaa M, Q, L or H

<220>

<221> MUTAGEN

<222> (2)..(2)

<223> Xaa G, Y, A, V, H, T, F or S

<220>

<221> MUTAGEN

<222> (3)..(3)

<223> Xaa T, G, Y, N, L, D or S

<220>

<221> MUTAGEN

<222> (4)..(4)

<223> Xaa H, S, T, Q, D, N, G, I or R

<220>

<221> MUTAGEN

<222> (5)..(5)

<223> Xaa W, S, T, Y, L, I or N

<220>

<221> MUTAGEN

<222> (6)..(6)

<223> Xaa P, S, M, I, W or

<220>

<221> MUTAGEN

<222> (7)..(7)

<223> Xaa W, F, L, P, I, Y, R or T

<220>

<221> MUTAGEN

<222> (8)..(8)

<223> Xaa T, L, A, F or W

<220>

<221> MUTAGEN

<222> (9)..(9)

<223> Xaa F, L, T or none

<220>

<221> MUTAGEN

<222> (10)..(10)

<223> Xaa T, F or none

<220>

<221> MUTAGEN

<222> (11)..(11)

<223> Xaa is F or

<400> 6

Cys Xaa Gln Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10

<210> 7

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 7

Gly Ala Ser Ile Ile Asn Asn Asn Trp

1 5

<210> 8

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 8

Gly Asp Ser Ile Ser Ser Ser Tyr Trp

1 5

<210> 9

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 9

Gly Asp Ser Ile Ser Ser Thr Asn Trp

1 5

<210> 10

<211> 10

<212> PRT

<213> Artificial Sequence

<400> 10

Gly Phe Ser Leu Ser Thr Ser Ala Val Asn

1 5 10

<210> 11

<211> 10

<212> PRT

<213> Artificial Sequence

<400> 11

Gly Phe Ser Leu Ser Thr Ser Gly Val Gly

1 5 10

<210> 12

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 12

Gly Phe Thr Phe Asp Asp Tyr Ala

1 5

<210> 13

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 13

Gly Phe Thr Phe Ser Asp Tyr Tyr

1 5

<210> 14

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 14

Gly Phe Thr Phe Ser Asn Ala Trp

1 5

<210> 15

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 15

Gly Phe Thr Phe Ser Asn Tyr Trp

1 5

<210> 16

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 16

Gly Gly Ser Ile Asn Ser Ser Ser Trp

1 5

<210> 17

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 17

Gly Gly Ser Ile Asn Ser Thr Asn Trp

1 5

<210> 18

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 18

Gly Gly Ser Ile Ser Asn Gly Asn Trp

1 5

<210> 19

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 19

Gly Gly Ser Ile Ser Asn Ser Asn Trp

1 5

<210> 20

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 20

Gly Gly Ser Ile Ser Arg Ser Asn Trp

1 5

<210> 21

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 21

Gly Gly Ser Ile Ser Ser Ser Ile Trp

1 5

<210> 22

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 22

Gly Gly Ser Ile Ser Ser Ser Lys Trp

1 5

<210> 23

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 23

Gly Gly Ser Ile Ser Ser Ser Asn Trp

1 5

<210> 24

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 24

Gly Gly Ser Ile Ser Ser Thr Asn Trp

1 5

<210> 25

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 25

Gly Gly Ser Ile Ser Ser Tyr Asn Trp

1 5

<210> 26

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 26

Gly Val Ser Ile Ser Ser Ser Asn Trp

1 5

<210> 27

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 27

Gly Tyr Ile Phe Thr Arg Tyr Ala

1 5

<210> 28

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 28

Gly Tyr Ile Phe Thr Ser Tyr Ala

1 5

<210> 29

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 29

Gly Tyr Thr Phe Ala Asn Phe Gly

1 5

<210> 30

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 30

Gly Tyr Thr Phe Ile Gly Tyr Tyr

1 5

<210> 31

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 31

Gly Tyr Thr Phe Thr Gly Tyr Phe

1 5

<210> 32

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 32

Gly Tyr Thr Phe Thr Gly Tyr Tyr

1 5

<210> 33

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 33

Gly Tyr Thr Phe Thr Asn Tyr Ala

1 5

<210> 34

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 34

Gly Tyr Thr Phe Thr Asn Tyr Gly

1 5

<210> 35

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 35

Gly Tyr Thr Phe Thr Arg Tyr Thr

1 5

<210> 36

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 36

Gly Tyr Thr Phe Thr Ser Tyr Asp

1 5

<210> 37

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 37

Gly Tyr Thr Phe Thr Ser Tyr Gly

1 5

<210> 38

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 38

Ser Gly Ser Ile Ser Ser Ser Ile Trp

1 5

<210> 39

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 39

Met Asn Pro Asn Ser Gly Asn Thr

1 5

<210> 40

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 40

Ile Tyr Trp Ser Asp Asp Lys

1 5

<210> 41

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 41

Ile Tyr Gln Ser Gly Ser Thr

1 5

<210> 42

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 42

Ile Tyr His Ser Gly Ser Thr

1 5

<210> 43

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 43

Ile Tyr His Ser Gly Asn Thr

1 5

<210> 44

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 44

Ile Tyr His Ser Gly Asp Thr

1 5

<210> 45

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 45

Ile Tyr His Gly Gly Ser Thr

1 5

<210> 46

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 46

Ile Ser Trp Asn Ser Gly Ser Ile

1 5

<210> 47

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 47

Ile Ser Ser Ser Gly Thr Thr Ile

1 5

<210> 48

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 48

Ile Ser His Asn Gly Ser Thr

1 5

<210> 49

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 49

Ile Ser Gly Ser Asp Ser Thr Ile

1 5

<210> 50

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 50

Ile Ser Ala Tyr Ser Gly Asp Lys

1 5

<210> 51

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 51

Ile Ser Ala Tyr Asn Gly Tyr Thr

1 5

<210> 52

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 52

Ile Ser Ala Tyr Asn Gly Asn Thr

1 5

<210> 53

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 53

Ile Ser Ala Tyr Asn Gly His Thr

1 5

<210> 54

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 54

Ile Asn Pro Asn Ser Gly Gly Thr

1 5

<210> 55

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 55

Ile Asn Pro Asn Ser Gly Ala Thr

1 5

<210> 56

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 56

Ile Asn Pro Asn Asn Gly Asp Thr

1 5

<210> 57

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 57

Ile Asn His Ser Gly Asn Thr

1 5

<210> 58

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 58

Ile Asn His Asn Gly Ser Thr

1 5

<210> 59

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 59

Ile Asn Ala Gly Asn Gly Asn Thr

1 5

<210> 60

<211> 10

<212> PRT

<213> Artificial Sequence

<400> 60

Ile Lys Ser Lys Ala Asp Gly Gly Thr Ile

1 5 10

<210> 61

<211> 10

<212> PRT

<213> Artificial Sequence

<400> 61

Ile Lys Arg Lys Thr Asp Gly Gly Thr Thr

1 5 10

<210> 62

<211> 8

<212> PRT

<213> Artificial Sequence

<400> 62

Ile Lys Gln Asp Gly Ser Glu Lys

1 5

<210> 63

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 63

Ile His His Ser Gly Asn Thr

1 5

<210> 64

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 64

Ile Phe Trp Asn Asp Asp Lys

1 5

<210> 65

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 65

Ile Phe His Ser Gly Thr Thr

1 5

<210> 66

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 66

Cys Val Arg Ser Gly Asp Trp His Cys Phe Asp Tyr Trp

1 5 10

<210> 67

<211> 17

<212> PRT

<213> Artificial Sequence

<400> 67

Cys Val Lys Asp Tyr Tyr Gly Ser Gly Ser Tyr Gly Asp Ile Gln His

1 5 10 15

Trp

<210> 68

<211> 14

<212> PRT

<213> Artificial Sequence

<400> 68

Cys Val Ile Trp Phe Gly Glu Leu Leu Ser Phe Asp Tyr Trp

1 5 10

<210> 69

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 69

Cys Val Gly Gly Gly Tyr Asp Ala Phe Asp Ile Trp

1 5 10

<210> 70

<211> 15

<212> PRT

<213> Artificial Sequence

<400> 70

Cys Val Ala Tyr Val Ser Gly Thr Tyr Tyr Asn Phe Asp Tyr Trp

1 5 10 15

<210> 71

<211> 16

<212> PRT

<213> Artificial Sequence

<400> 71

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

1 5 10 15

<210> 72

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 72

Cys Thr Ser Asp Tyr Gly Asp Tyr Trp

1 5

<210> 73

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 73

Cys Thr Ser Ala Ala Arg Arg Gly Tyr Phe Asp Ile Trp

1 5 10

<210> 74

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 74

Cys Thr Arg Glu Ala Gly Pro Phe Asp Tyr Trp

1 5 10

<210> 75

<211> 14

<212> PRT

<213> Artificial Sequence

<400> 75

Cys Thr His Arg Pro Gly Tyr Thr Tyr Gly Tyr Gly Tyr Trp

1 5 10

<210> 76

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 76

Cys Ser Arg Glu Gly Gly Asn Ala Phe Phe Asp Tyr Trp

1 5 10

<210> 77

<211> 15

<212> PRT

<213> Artificial Sequence

<400> 77

Cys Ala Thr Leu Pro Gly Tyr Ser Ser Gly Trp Phe Asp Ser Trp

1 5 10 15

<210> 78

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 78

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

1 5 10

<210> 79

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 79

Cys Ala Ser Glu Asp Phe Asp Tyr Trp

1 5

<210> 80

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 80

Cys Ala Arg Tyr Ser Thr Pro Phe Phe Asp Tyr Trp

1 5 10

<210> 81

<211> 14

<212> PRT

<213> Artificial Sequence

<400> 81

Cys Ala Arg Val Val Val Ala Ser Tyr Tyr Phe Asp Asn Trp

1 5 10

<210> 82

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 82

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

1 5 10

<210> 83

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 83

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

1 5 10

<210> 84

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 84

Cys Ala Arg Thr Gly Pro Ile Val Thr Thr Glu Tyr Trp

1 5 10

<210> 85

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 85

Cys Ala Arg Ser Gly Thr Thr His Thr Phe Asp Ile Trp

1 5 10

<210> 86

<211> 19

<212> PRT

<213> Artificial Sequence

<400> 86

Cys Ala Arg Ser Gly Leu Tyr Glu Trp Glu Leu Gln Tyr Tyr Tyr Met

1 5 10 15

Asp Val Trp

<210> 87

<211> 15

<212> PRT

<213> Artificial Sequence

<400> 87

Cys Ala Arg Met Gly Tyr Tyr Tyr Gly Ser Gly Ser Asp Tyr Trp

1 5 10 15

<210> 88

<211> 16

<212> PRT

<213> Artificial Sequence

<400> 88

Cys Ala Arg Lys Gly Tyr Asn Trp Asn Tyr Asp Tyr Phe Asp Tyr Trp

1 5 10 15

<210> 89

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 89

Cys Ala Arg Gly Gly Thr Thr Phe Asp Tyr Trp

1 5 10

<210> 90

<211> 18

<212> PRT

<213> Artificial Sequence

<400> 90

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

1 5 10 15

Ser Trp

<210> 91

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 91

Cys Ala Arg Gly Gly Ala Val Ala Leu Asp Tyr Trp

1 5 10

<210> 92

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 92

Cys Ala Arg Gly Asp Val Leu Leu Trp Phe Gly

1 5 10

<210> 93

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 93

Cys Ala Arg Gly Asp Ile Leu Leu Trp Phe Gly

1 5 10

<210> 94

<211> 17

<212> PRT

<213> Artificial Sequence

<400> 94

Cys Ala Arg Glu Trp Phe Gly Glu Leu Trp Gln Ile Phe Phe Asp Tyr

1 5 10 15

Trp

<210> 95

<211> 14

<212> PRT

<213> Artificial Sequence

<400> 95

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

1 5 10

<210> 96

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 96

Cys Ala Arg Glu Asp Tyr Tyr Tyr Met Asp Val Trp

1 5 10

<210> 97

<211> 16

<212> PRT

<213> Artificial Sequence

<400> 97

Cys Ala Arg Asp Trp Glu Gly Phe Gly Glu Ser Ile Gly Asp Tyr Trp

1 5 10 15

<210> 98

<211> 15

<212> PRT

<213> Artificial Sequence

<400> 98

Cys Ala Arg Asp Trp Ala Gly Asp Arg Tyr Tyr Phe Asp Tyr Trp

1 5 10 15

<210> 99

<211> 15

<212> PRT

<213> Artificial Sequence

<400> 99

Cys Ala Arg Asp Trp Ala Gly Asp His Tyr Tyr Phe Asp Tyr Trp

1 5 10 15

<210> 100

<211> 17

<212> PRT

<213> Artificial Sequence

<400> 100

Cys Ala Arg Asp Ser Ser Thr Trp Tyr Glu Gly Asn Tyr Phe Asp Tyr

1 5 10 15

Trp

<210> 101

<211> 19

<212> PRT

<213> Artificial Sequence

<400> 101

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

1 5 10 15

Asp Tyr Trp

<210> 102

<211> 16

<212> PRT

<213> Artificial Sequence

<400> 102

Cys Ala Arg Asp Gln Asp Tyr Tyr Gly Ser Gly Asn Phe Tyr Tyr Trp

1 5 10 15

<210> 103

<211> 17

<212> PRT

<213> Artificial Sequence

<400> 103

Cys Ala Arg Asp Gln Ala Asp Tyr Phe Gly Ser Gly Asn Tyr Val Tyr

1 5 10 15

Trp

<210> 104

<211> 18

<212> PRT

<213> Artificial Sequence

<400> 104

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

1 5 10 15

Tyr Trp

<210> 105

<211> 10

<212> PRT

<213> Artificial Sequence

<400> 105

Cys Ala Arg Asp Pro Pro Ser Asp Tyr Trp

1 5 10

<210> 106

<211> 16

<212> PRT

<213> Artificial Sequence

<400> 106

Cys Ala Arg Asp Glu Asp Tyr Tyr Gly Ser Gly Asn Tyr Tyr His Trp

1 5 10 15

<210> 107

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 107

Cys Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp

1 5 10

<210> 108

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 108

Cys Ala Gln Tyr Asn Trp Asn Ser Ser Phe Asp Tyr Trp

1 5 10

<210> 109

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 109

Cys Ala Asn Glu Asp Phe Asp Tyr Trp

1 5

<210> 110

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 110

Cys Ala Lys Ser Gly Thr Tyr Gly Tyr Phe Asp Tyr Trp

1 5 10

<210> 111

<211> 16

<212> PRT

<213> Artificial Sequence

<400> 111

Cys Ala Lys Asp Lys Gly Ile Met Val Arg Gly Gly Pro Asp Tyr Trp

1 5 10 15

<210> 112

<211> 10

<212> PRT

<213> Artificial Sequence

<400> 112

Cys Ala His Tyr Ser Asn Tyr Asp Tyr Trp

1 5 10

<210> 113

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 113

Cys Ala Gly Glu Asp Thr Gly Trp Pro Phe Asp Phe Trp

1 5 10

<210> 114

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 114

Cys Ala Glu Thr Ser Thr Ile Thr Thr Asn Tyr Trp

1 5 10

<210> 115

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 115

His Gly Ser Ser Thr Tyr

1 5

<210> 116

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 116

Gln Asp Ile Asn Thr Tyr

1 5

<210> 117

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 117

Gln Asp Ile Ser Asp Tyr

1 5

<210> 118

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 118

Gln Asp Ile Ser Asn Tyr

1 5

<210> 119

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 119

Gln Gly Ile Arg Asn Asp

1 5

<210> 120

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 120

Gln Gly Ile Trp Asn Asp

1 5

<210> 121

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 121

Gln Ser Ile Ser Asn Trp

1 5

<210> 122

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 122

Gln Ser Ile Ser Asn Tyr

1 5

<210> 123

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 123

Gln Ser Ile Ser Ser Trp

1 5

<210> 124

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 124

Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr

1 5 10

<210> 125

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 125

Gln Ser Leu Val Tyr Arg Asp Gly Asn Thr Phe

1 5 10

<210> 126

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 126

Gln Ser Leu Val Tyr Ser Asp Gly Asp Thr Tyr

1 5 10

<210> 127

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 127

Gln Ser Leu Val Tyr Ser Asp Gly His Thr Ser

1 5 10

<210> 128

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 128

Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Phe

1 5 10

<210> 129

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 129

Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Asn

1 5 10

<210> 130

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 130

Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr

1 5 10

<210> 131

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 131

Gln Ser Thr Ser Ser Tyr

1 5

<210> 132

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 132

Gln Ser Val Phe Tyr Ser Ser Asn Ser Arg Asn Tyr

1 5 10

<210> 133

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 133

Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr

1 5 10

<210> 134

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 134

Gln Ser Val Ser Gly Asp Tyr

1 5

<210> 135

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 135

Gln Ser Val Ser Gly Asn Tyr

1 5

<210> 136

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 136

Gln Ser Val Ser Gly Ser Tyr

1 5

<210> 137

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 137

Gln Ser Val Ser Ser Gly Tyr

1 5

<210> 138

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 138

Gln Ser Val Ser Ser Asn

1 5

<210> 139

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 139

Gln Ser Val Ser Ser Asn Tyr

1 5

<210> 140

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 140

Gln Ser Val Ser Ser Arg Tyr

1 5

<210> 141

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 141

Gln Ser Val Ser Ser Ser Tyr

1 5

<210> 142

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 142

Gln Ser Val Ser Ser Thr Tyr

1 5

<210> 143

<211> 6

<212> PRT

<213> Artificial Sequence

<400> 143

Gln Thr Ile Ser Ser Tyr

1 5

<210> 144

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 144

Gln Thr Val Ser Gly Asn Tyr

1 5

<210> 145

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 145

Gln Thr Val Ser Ser Ser Tyr

1 5

<210> 146

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 146

Thr Val Ser

1

<210> 147

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 147

Lys Val Ser

1

<210> 148

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 148

Gly Ala Ser

1

<210> 149

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 149

Trp Ala Ser

1

<210> 150

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 150

Glu Val Ser

1

<210> 151

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 151

Met Ala Ser

1

<210> 152

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 152

Gly Thr Ser

1

<210> 153

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 153

Leu Gly Ser

1

<210> 154

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 154

Asp Ala Ser

1

<210> 155

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 155

Ala Ala Ser

1

<210> 156

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 156

Trp Thr Ser

1

<210> 157

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 157

Asp Ala Phe

1

<210> 158

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 158

Gln Val Ser

1

<210> 159

<211> 3

<212> PRT

<213> Artificial Sequence

<400> 159

Lys Ala Ala

1

<210> 160

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 160

Cys Met Gln Gly Thr His Trp Pro Trp Thr Phe

1 5 10

<210> 161

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 161

Cys Gln Gln Tyr Gly Ser Ser Pro Phe Thr Phe

1 5 10

<210> 162

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 162

Cys Gln Gln Tyr Tyr Ser Thr Pro Leu Thr Phe

1 5 10

<210> 163

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 163

Cys Met Gln Gly Thr His Trp Pro Pro Thr Phe

1 5 10

<210> 164

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 164

Cys Gln Gln Tyr Asn Ser Tyr Ser Leu Thr Phe

1 5 10

<210> 165

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 165

Cys Gln Gln Tyr Gly Thr Ser Pro Ile Thr Phe

1 5 10

<210> 166

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 166

Cys Met Gln Ala Leu Gln Thr Pro Tyr Thr Phe

1 5 10

<210> 167

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 167

Cys Gln Gln Tyr Asp Asp Leu Pro Leu Thr Phe

1 5 10

<210> 168

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 168

Cys Gln Gln Tyr Gly Ser Ser Pro Leu Thr Phe

1 5 10

<210> 169

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 169

Cys Gln Gln Tyr Asp Asn Leu Pro Ile Thr Phe

1 5 10

<210> 170

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 170

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

1 5 10

<210> 171

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 171

Cys Met Gln Val Leu Gln Thr Pro Tyr Thr Phe

1 5 10

<210> 172

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 172

Cys Met Gln Gly Thr His Trp Pro Arg Thr Phe

1 5 10

<210> 173

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 173

Cys Gln Gln Tyr Gly Ser Ser Met Phe Thr Phe

1 5 10

<210> 174

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 174

Cys Met Gln Ala Leu Gln Thr Pro Leu Thr Phe

1 5 10

<210> 175

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 175

Cys Leu Gln His Asn Ser Tyr Pro Trp Thr Phe

1 5 10

<210> 176

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 176

Cys Gln Gln Tyr Tyr Ser Ser Pro Trp Thr Phe

1 5 10

<210> 177

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 177

Cys Gln Gln Tyr Asn Asn Trp Pro Leu Thr Phe

1 5 10

<210> 178

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 178

Cys Gln Gln Tyr Asp Ile Leu Pro Tyr Thr Phe

1 5 10

<210> 179

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 179

Cys Gln Gln Tyr Tyr Ser Thr Pro Tyr Thr Phe

1 5 10

<210> 180

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 180

Cys Gln Gln Tyr Tyr Ser Ile Pro Leu Thr Phe

1 5 10

<210> 181

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 181

Cys Gln Gln Tyr Gly Asn Ser Pro Leu Thr Phe

1 5 10

<210> 182

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 182

Cys Gln Gln Tyr Gly Ser Ser Pro Ile Thr Phe

1 5 10

<210> 183

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 183

Cys Gln Gln Tyr Gly Ser Leu Pro Leu Thr Phe

1 5 10

<210> 184

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 184

Cys Gln Gln Tyr Ser Ser Ser Pro Ile Thr Phe

1 5 10

<210> 185

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 185

Cys Leu Gln Tyr Gly Ser Ser Pro Leu Thr Phe

1 5 10

<210> 186

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 186

Cys Gln Gln Tyr Gly Arg Ser Pro Leu Thr Phe

1 5 10

<210> 187

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 187

Cys Gln Gln Thr Tyr Ser Ile Pro Ile Thr Phe

1 5 10

<210> 188

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 188

Cys Gln Gln Tyr Gly Asn Ser Pro Ile Thr Phe

1 5 10

<210> 189

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 189

Cys Gln Gln Tyr Asp Asn Leu Pro Phe Thr Phe

1 5 10

<210> 190

<211> 13

<212> PRT

<213> Artificial Sequence

<400> 190

Cys Met Gln Gly Thr His Trp Pro Pro Ala Leu Thr Phe

1 5 10

<210> 191

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 191

Cys Gln Gln Phe Gly Ser Ser Pro Leu Thr Phe

1 5 10

<210> 192

<211> 10

<212> PRT

<213> Artificial Sequence

<400> 192

Cys Gln Gln Tyr Asp Asn Leu Ile Thr Phe

1 5 10

<210> 193

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 193

Cys Gln Gln Ser Tyr Ser Ile Pro Ile Thr Phe

1 5 10

<210> 194

<211> 10

<212> PRT

<213> Artificial Sequence

<400> 194

Cys Gln Gln Tyr Tyr Asp Tyr Trp Thr Phe

1 5 10

<210> 195

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 195

Cys Leu Gln Tyr Asn Asn Tyr Pro Leu Thr Phe

1 5 10

<210> 196

<211> 12

<212> PRT

<213> Artificial Sequence

<400> 196

Cys His Gln Tyr Asn Asn Trp Pro Pro Trp Thr Phe

1 5 10

<210> 197

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 197

Cys Gln Gln Tyr Gly Ser Leu Pro Ile Thr Phe

1 5 10

<210> 198

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 198

Cys Gln Gln Ser Tyr Asn Asn Pro Leu Thr Phe

1 5 10

<210> 199

<211> 11

<212> PRT

<213> Artificial Sequence

<400> 199

Cys Gln Gln Tyr Asn Asn Tyr Thr Phe Thr Phe

1 5 10

<210> 200

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 200

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Val Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Asn His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Asn Leu Ser Thr Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 201

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 201

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Thr Val Ser Tyr Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Gly

85 90 95

Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 202

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 202

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

1 5 10 15

Thr Leu Ser Leu Ser Cys Ala Phe Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Asn His Ser Gly Asn Thr Ser Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Arg Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 203

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 203

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Thr Val Ser Tyr Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Gly

85 90 95

Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 204

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 204

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Ser Phe Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Leu Ser

65 70 75 80

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

85 90 95

Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 205

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 205

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly

85 90 95

Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 206

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 206

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Ser His Asn Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 207

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 207

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Gly

85 90 95

Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 208

<211> 120

<212> PRT

<213> Artificial Sequence

<400> 208

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

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

35 40 45

Gly Trp Ile Ser Ala Tyr Ser Gly Asp Lys Lys Tyr Glu Gln Lys Phe

50 55 60

Gln Gly Arg Val Ser Val Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Trp Ala Gly Asp His Tyr Tyr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 209

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 209

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 210

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 210

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

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Lys Ser Gly Thr Tyr Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 211

<211> 113

<212> PRT

<213> Artificial Sequence

<400> 211

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

Ser Asn Asn Lys Asn Tyr Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

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

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

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

100 105 110

Lys

<210> 212

<211> 117

<212> PRT

<213> Artificial Sequence

<400> 212

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Arg Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Val Gly Gly Gly Tyr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met

100 105 110

Val Thr Val Ser Ser

115

<210> 213

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 213

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asn Thr Tyr Leu Ile Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Glu Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly

85 90 95

Thr His Trp Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 214

<211> 117

<212> PRT

<213> Artificial Sequence

<400> 214

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Val Gly Gly Gly Tyr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met

100 105 110

Val Thr Val Ser Ser

115

<210> 215

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 215

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Arg

20 25 30

Asp Gly Asn Thr Phe Leu Phe Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

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

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly

85 90 95

Thr His Trp Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 216

<211> 115

<212> PRT

<213> Artificial Sequence

<400> 216

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

1 5 10 15

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

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Asn Pro Asn Asn Gly Asp Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Gly Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Pro Pro Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 217

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 217

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Trp

20 25 30

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

35 40 45

Tyr Met Ala Ser Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 218

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 218

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Phe Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Ser Ile Leu Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Thr Thr His Thr Phe Asp Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 219

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 219

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Thr Ser Phe Arg Ala Thr Gly Ile Pro Asp Asn Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 220

<211> 122

<212> PRT

<213> Artificial Sequence

<400> 220

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

1 5 10 15

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

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Tyr Tyr Val Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 221

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 221

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

1 5 10 15

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

20 25 30

Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Arg Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 222

<211> 123

<212> PRT

<213> Artificial Sequence

<400> 222

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Ala Asp Gly Gly Thr Ile Asp Tyr Ala Ala

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 223

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 223

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 Gln Ala Ser Gln Asp Ile Ser Asp Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Arg

100 105

<210> 224

<211> 120

<212> PRT

<213> Artificial Sequence

<400> 224

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

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

35 40 45

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

50 55 60

Gln Gly Arg Val Ser Val Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Trp Ala Gly Asp Arg Tyr Tyr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 225

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 225

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 226

<211> 120

<212> PRT

<213> Artificial Sequence

<400> 226

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

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser

20 25 30

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

35 40 45

Trp Leu Ala Leu Ile Tyr Trp Ser Asp Asp Lys Arg Tyr Ser Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val

65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr

85 90 95

Cys Thr His Arg Pro Gly Tyr Thr Tyr Gly Tyr Gly Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 227

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 227

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asn Thr Phe Leu His Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Leu Tyr Tyr Cys Met Gln Gly

85 90 95

Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 228

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 228

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Ser His Asn Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 229

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 229

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 Gln Ala Ser Gln Asp Ile Ser Asn Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 230

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 230

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 231

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 231

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 232

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 232

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Val Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Asn His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Asn Leu Ser Thr Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 233

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 233

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 Gln Ala Ser Gln Asp Ile Ser Asp Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Arg

100 105

<210> 234

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 234

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Asn His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Asn Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 235

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 235

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Thr Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ala Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Gly

85 90 95

Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 236

<211> 120

<212> PRT

<213> Artificial Sequence

<400> 236

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

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

35 40 45

Gly Trp Ile Ser Ala Tyr Ser Gly Asp Lys Lys Tyr Glu Gln Lys Phe

50 55 60

Gln Gly Arg Val Ser Val Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Trp Ala Gly Asp His Tyr Tyr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 237

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 237

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 238

<211> 124

<212> PRT

<213> Artificial Sequence

<400> 238

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Phe Tyr Cys

85 90 95

Ala Arg Ser Gly Leu Tyr Glu Trp Glu Leu Gln Tyr Tyr Tyr Met Asp

100 105 110

Val Trp Gly Ile Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 239

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 239

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Val Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 240

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 240

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Ser Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 241

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 241

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Val Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 242

<211> 123

<212> PRT

<213> Artificial Sequence

<400> 242

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

1 5 10 15

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

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr

65 70 75 80

Met Asp Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 243

<211> 110

<212> PRT

<213> Artificial Sequence

<400> 243

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Gly Ser Pro

85 90 95

Pro Leu Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 244

<211> 124

<212> PRT

<213> Artificial Sequence

<400> 244

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Phe Tyr Cys

85 90 95

Ala Arg Ser Gly Leu Tyr Glu Trp Glu Leu Gln Tyr Tyr Tyr Met Asp

100 105 110

Val Trp Gly Ile Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 245

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 245

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

1 5 10 15

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

20 25 30

Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Phe Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Val

85 90 95

Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 246

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 246

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

1 5 10 15

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

20 25 30

Phe Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asn Pro Asn Ser Gly Ala Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Val Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Asp Leu Ser Arg Leu Arg Phe Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Glu Ala Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 247

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 247

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly His Thr Ser Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Leu Glu Ala Glu Asp Val Gly Val Tyr Cys Cys Met Gln Gly

85 90 95

Thr His Trp Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 248

<211> 123

<212> PRT

<213> Artificial Sequence

<400> 248

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Asn Trp Trp Gly Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr Gln Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Pro Tyr Gly Ser Gly Thr Tyr Tyr Arg Leu Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Ile Leu Val Thr Val Ser Ser

115 120

<210> 249

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 249

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Met

85 90 95

Phe Thr Phe Gly Pro Gly Thr Asn Val Asp Ile Lys

100 105

<210> 250

<211> 121

<212> PRT

<213> Artificial Sequence

<400> 250

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

1 5 10 15

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

20 25 30

Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asn Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Lys Gly Tyr Asn Trp Asn Tyr Asp Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 251

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 251

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

1 5 10 15

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

20 25 30

Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

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

100 105 110

<210> 252

<211> 115

<212> PRT

<213> Artificial Sequence

<400> 252

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

1 5 10 15

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

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala His Tyr Ser Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 253

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 253

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 254

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 254

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

1 5 10 15

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

20 25 30

Phe Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asn Pro Asn Ser Gly Ala Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Val Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Asp Leu Ser Arg Leu Arg Phe Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Glu Ala Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 255

<211> 113

<212> PRT

<213> Artificial Sequence

<400> 255

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Val Phe Tyr Ser

20 25 30

Ser Asn Ser Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

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

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Leu Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

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

100 105 110

Lys

<210> 256

<211> 122

<212> PRT

<213> Artificial Sequence

<400> 256

Gln Val Gln Leu Val His Ser 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 Ile Gly Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Thr Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Glu Trp Phe Gly Glu Leu Trp Gln Ile Phe Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 257

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 257

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

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

35 40 45

Phe Gly Ala Ser Thr Arg Ala Thr Gly Thr Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 258

<211> 121

<212> PRT

<213> Artificial Sequence

<400> 258

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

1 5 10 15

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

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Asp Lys Gly Ile Met Val Arg Gly Gly Pro Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 259

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 259

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ile Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 260

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 260

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

1 5 10 15

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

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ser Arg Glu Gly Gly Asn Ala Phe Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 261

<211> 113

<212> PRT

<213> Artificial Sequence

<400> 261

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln

85 90 95

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

100 105 110

Lys

<210> 262

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 262

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Thr Tyr Val Thr Asp Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 263

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 263

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 264

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 264

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 265

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 265

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 266

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 266

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 267

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 267

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 268

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 268

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 269

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 269

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 270

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 270

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Ser Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 271

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 271

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Val Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 272

<211> 123

<212> PRT

<213> Artificial Sequence

<400> 272

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Ala Asp Gly Gly Thr Ile Asp Tyr Ala Ala

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 273

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 273

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Thr Ser Phe Arg Ala Thr Gly Ile Pro Asp Asn Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 274

<211> 117

<212> PRT

<213> Artificial Sequence

<400> 274

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Val Gly Ala Asn Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 275

<211> 113

<212> PRT

<213> Artificial Sequence

<400> 275

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

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

35 40 45

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

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

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

100 105 110

Lys

<210> 276

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 276

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Val Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Asn His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Asn Leu Ser Thr Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 277

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 277

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Thr Ser Phe Arg Ala Thr Gly Ile Pro Asp Asn Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 278

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 278

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Gly

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Arg Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Val Arg Ser Gly Asp Trp His Cys Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 279

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 279

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 280

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 280

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Asp Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Val Ser

65 70 75 80

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

85 90 95

Ala Arg Gly Asp Ile Leu Leu Trp Phe Gly Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 281

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 281

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Met Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 282

<211> 121

<212> PRT

<213> Artificial Sequence

<400> 282

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

1 5 10 15

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

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Glu Asp Tyr Tyr Gly Ser Gly Asn Tyr Tyr His Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 283

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 283

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr Gly Ser Leu Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Thr Lys

100 105

<210> 284

<211> 121

<212> PRT

<213> Artificial Sequence

<400> 284

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

1 5 10 15

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

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr Cys

85 90 95

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

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 285

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 285

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 286

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 286

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Ser Gln Ile Ser

65 70 75 80

Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Val Leu Leu Trp Phe Gly Gly Arg Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 287

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 287

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Ser Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Thr Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 288

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 288

Gln Val Gln Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Lys Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Val Leu Leu Trp Phe Gly Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 289

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 289

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Trp Ala Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 290

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 290

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Thr Thr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 291

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 291

Glu Ile Val Leu Met Gln Tyr Pro Gly Thr Leu Ser Leu Ser Ser Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Asn Arg Ala Ser Gly Met Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 292

<211> 120

<212> PRT

<213> Artificial Sequence

<400> 292

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Ile Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Thr Leu Pro Gly Tyr Ser Ser Gly Trp Phe Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 293

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 293

Glu Ile Val Leu Met Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu

35 40 45

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

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Arg Val Glu Ile Lys

100 105

<210> 294

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 294

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Cys Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Ile Pro Gly Lys Arg Ala Gly Val

35 40 45

Asp Trp Gly Asn Leu Ser Trp Glu His Gln Leu Gln Pro Ala Pro Gln

50 55 60

Glu Ser Ser His His Ile Ser Arg Gln Val Gln Glu Pro Val Leu Pro

65 70 75 80

Glu Ala Glu Leu Cys Asp Arg Arg Gly His Asp Arg Val Leu Leu Cys

85 90 95

Glu Asn Gly Val Leu Leu Trp Phe Gly Glu Leu Leu Gly Pro Gly Asn

100 105 110

Pro Gly His Arg Leu Leu

115

<210> 295

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 295

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Phe Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Tyr Gly Ser Ser Pro

85 90 95

Leu Thr Phe Gly Arg Gly Thr Lys Val Glu Ile Lys

100 105

<210> 296

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 296

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Thr Gly Pro Thr Val Thr Thr Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 297

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 297

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Met Pro Glu Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Tyr Gly Arg Ser Pro

85 90 95

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

100 105

<210> 298

<211> 117

<212> PRT

<213> Artificial Sequence

<400> 298

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Val Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Glu Thr Ser Thr Ile Thr Thr Asn Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 299

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 299

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ser Ser Tyr

20 25 30

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

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Ile Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 300

<211> 117

<212> PRT

<213> Artificial Sequence

<400> 300

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

1 5 10 15

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

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Ala Val Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 301

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 301

Glu Ile Val Leu Thr Gln Ser Pro Gly Pro Leu Ser Leu Ser Pro Gly

1 5 10 15

Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Leu Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 302

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 302

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Asp Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Val Ser

65 70 75 80

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

85 90 95

Ala Arg Gly Asp Ile Leu Leu Trp Phe Gly Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 303

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 303

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 Gln Ala Ser Gln Asp Ile Ser Asn Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Phe Asn Leu Glu Val Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 304

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 304

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Trp Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Ser Ser

<210> 305

<211> 114

<212> PRT

<213> Artificial Sequence

<400> 305

Asp Val Val Val Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asn Thr Asn Leu Tyr Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Gln Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly

85 90 95

Thr His Trp Pro Pro Ala Leu Thr Phe Gly Gly Gly Thr Glu Val Glu

100 105 110

Ile Lys

<210> 306

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 306

Gln Val Gln Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly

1 5 10 15

Thr Leu Ser Leu Ile Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Lys Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Val Leu Leu Trp Phe Gly Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 307

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 307

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr Gly Ser Leu Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Thr Lys

100 105

<210> 308

<211> 120

<212> PRT

<213> Artificial Sequence

<400> 308

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

1 5 10 15

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

20 25 30

Asn Trp Trp Thr Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Phe His Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Asn Arg Val Thr Ile Ser Val Asp Lys Ala Lys Asn Gln Phe Ser

65 70 75 80

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

85 90 95

Val Ala Tyr Val Ser Gly Thr Tyr Tyr Asn Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 309

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 309

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Gly Ser Ser Pro

85 90 95

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

100 105

<210> 310

<211> 119

<212> PRT

<213> Artificial Sequence

<400> 310

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

1 5 10 15

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

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asp Phe Ala Gln Lys Phe

50 55 60

Gln Ala Arg Val Thr Met Thr Arg Asp Thr Ala Ile Asn Ile Val Tyr

65 70 75 80

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

85 90 95

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

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 311

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 311

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

1 5 10 15

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

20 25 30

Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

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

100 105 110

<210> 312

<211> 124

<212> PRT

<213> Artificial Sequence

<400> 312

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

1 5 10 15

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

20 25 30

Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Ile

35 40 45

Ser Tyr Ile Ser Gly Ser Asp Ser Thr Ile Tyr Tyr Glu Asp Ser Val

50 55 60

Met Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 313

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 313

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Met Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 314

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 314

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Thr Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Thr Gly Pro Ile Val Thr Thr Glu Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 315

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 315

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Gly

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 316

<211> 119

<212> PRT

<213> Artificial Sequence

<400> 316

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

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser

20 25 30

Ala Val Asn Val Gly Trp Ile Arg Gln Pro His Gly Lys Ala Leu Glu

35 40 45

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

50 55 60

Leu Lys Asn Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asp Gln Val

65 70 75 80

Val Leu Thr Met Ser Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr

85 90 95

Cys Ala Gln Tyr Asn Trp Asn Ser Ser Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 317

<211> 106

<212> PRT

<213> Artificial Sequence

<400> 317

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Asn Thr Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Phe Tyr Cys Gln Gln Tyr Asp Asn Leu Ile Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 318

<211> 120

<212> PRT

<213> Artificial Sequence

<400> 318

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

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

35 40 45

Gly Arg Ile Lys Arg Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Thr

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ala Ser Lys Asn Thr

65 70 75 80

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

85 90 95

Tyr Cys Thr Ser Ala Ala Arg Arg Gly Tyr Phe Asp Ile Trp Gly Arg

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 319

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 319

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Met Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 320

<211> 117

<212> PRT

<213> Artificial Sequence

<400> 320

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

1 5 10 15

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

20 25 30

Asn Trp Trp Thr Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Leu Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Ser Gly Ser Leu Tyr Met Asp Val Trp Gly Lys Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 321

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 321

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 Ser Cys Arg Ala Ser Gln Ser Thr Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 322

<211> 119

<212> PRT

<213> Artificial Sequence

<400> 322

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

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

35 40 45

Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Glu Gly Val Gly Ala Thr Pro Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser

115

<210> 323

<211> 106

<212> PRT

<213> Artificial Sequence

<400> 323

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asp Tyr Trp Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 324

<211> 117

<212> PRT

<213> Artificial Sequence

<400> 324

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

1 5 10 15

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

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Asn His Asn Gly Ser Thr Tyr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Asp Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 325

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 325

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Gly Ile Trp Asn Asp

20 25 30

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

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Asn Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 326

<211> 121

<212> PRT

<213> Artificial Sequence

<400> 326

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

1 5 10 15

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

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Glu Asp Tyr Tyr Gly Ser Gly Asn Tyr Tyr His Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 327

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 327

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

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

35 40 45

Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Asn Asn Trp Pro Pro

85 90 95

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

100 105

<210> 328

<211> 122

<212> PRT

<213> Artificial Sequence

<400> 328

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Tyr Ile Ser Ser Ser Gly Thr Thr Ile Tyr Cys Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Ser Ser Thr Trp Tyr Glu Gly Asn Tyr Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 329

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 329

Asp Val Val Val Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly

85 90 95

Thr His Trp Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 330

<211> 122

<212> PRT

<213> Artificial Sequence

<400> 330

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

1 5 10 15

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

20 25 30

Ser Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

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

50 55 60

Lys Ser Arg Val Ala Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 331

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 331

Glu Ile Val Leu Met Gln Tyr Pro Gly Thr Leu Ser Leu Ser Ser Gly

1 5 10 15

Glu Arg Arg Val Leu Ser Cys Arg Pro Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

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

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro

85 90 95

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

100 105

<210> 332

<211> 121

<212> PRT

<213> Artificial Sequence

<400> 332

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

1 5 10 15

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

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Ala Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Trp Glu Gly Phe Gly Glu Ser Ile Gly Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 333

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 333

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Phe Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

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

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 334

<211> 117

<212> PRT

<213> Artificial Sequence

<400> 334

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

1 5 10 15

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

20 25 30

Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Ser Thr Pro Phe Phe Asp Tyr Trp Gly Gln Gly Asn Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 335

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 335

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr

20 25 30

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

35 40 45

Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Cys Cys Gln Gln Ser Tyr Asn Asn Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 336

<211> 117

<212> PRT

<213> Artificial Sequence

<400> 336

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Ile Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Leu Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Ser Gly Ser Leu Tyr Met Asp Val Trp Gly Lys Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 337

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 337

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

1 5 10 15

Asp Arg Val Thr Ile Ser Cys Arg Ala Ser His Gly Ser Ser Thr Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 338

<211> 119

<212> PRT

<213> Artificial Sequence

<400> 338

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

1 5 10 15

Ser Met Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ala Asn Phe

20 25 30

Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Ala Tyr Asn Gly Tyr Thr Asn Tyr Ala Gln Gln Phe

50 55 60

Gln Gly Arg Ile Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Val Ile Trp Phe Gly Glu Leu Leu Ser Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 339

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 339

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly

50 55 60

Asn Gly Phe Gly Thr Asp Phe Thr Phe Pro Leu Ser Arg Met Gln Pro

65 70 75 80

Glu Asp Phe Ala Ser Ser Tyr Cys Gln Gln Tyr Asn Asn Tyr Thr Phe

85 90 95

Thr Phe Gly Arg Gly Thr Lys Val Glu Ile Lys

100 105

<210> 340

<211> 118

<212> PRT

<213> Artificial Sequence

<400> 340

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Phe Gly Asp Ser Ile Ser Ser Ser

20 25 30

Tyr Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr His Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn His Leu Ser

65 70 75 80

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

85 90 95

Ala Gly Glu Asp Thr Gly Trp Pro Phe Asp Phe Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 341

<211> 108

<212> PRT

<213> Artificial Sequence

<400> 341

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 342

<211> 336

<212> PRT

<213> Artificial Sequence

<400> 342

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

1 5 10 15

Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr

20 25 30

Phe Pro Glu Ser Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser

35 40 45

Ser Val His Thr Phe Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Met

50 55 60

Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val

65 70 75 80

Thr Cys Ser Val Ala His Pro Ala Ser Ser Thr Thr Val Asp Lys Lys

85 90 95

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

100 105 110

Lys Glu Cys His Lys Cys Pro Ala Pro Asn Leu Glu Gly Gly Pro Ser

115 120 125

Val Phe Ile Phe Pro Pro Asn Ile Lys Asp Val Leu Met Ile Ser Leu

130 135 140

Thr Pro Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro

145 150 155 160

Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala

165 170 175

Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Ile Arg Val Val

180 185 190

Ser Thr Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe

195 200 205

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

210 215 220

Ile Ser Lys Ile Lys Gly Leu Val Arg Ala Pro Gln Val Tyr Ile Leu

225 230 235 240

Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys Asp Val Ser Leu Thr Cys

245 250 255

Leu Val Val Gly Phe Asn Pro Gly Asp Ile Ser Val Glu Trp Thr Ser

260 265 270

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

275 280 285

Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Met Lys Thr Ser

290 295 300

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

305 310 315 320

Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile Ser Arg Ser Pro Gly Lys

325 330 335

<210> 343

<211> 335

<212> PRT

<213> Artificial Sequence

<400> 343

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

1 5 10 15

Gly Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr

20 25 30

Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser

35 40 45

Gly Val His Thr Phe Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Leu

50 55 60

Ser Ser Ser Val Thr Val Thr Ser Asn Thr Trp Pro Ser Gln Thr Ile

65 70 75 80

Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys

85 90 95

Ile Glu Pro Arg Val Pro Ile Thr Gln Asn Pro Cys Pro Pro Leu Lys

100 105 110

Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu Gly Gly Pro Ser Val

115 120 125

Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser

130 135 140

Pro Met Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp

145 150 155 160

Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln

165 170 175

Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser

180 185 190

Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys

195 200 205

Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro Ile Glu Lys Thr Ile

210 215 220

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

225 230 235 240

Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe Ser Leu Thr Cys Met

245 250 255

Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val Asp Trp Thr Ser Asn

260 265 270

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

275 280 285

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

290 295 300

Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val Val His Glu Val Leu

305 310 315 320

His Asn His Leu Thr Thr Lys Thr Ile Ser Arg Ser Leu Gly Lys

325 330 335

<210> 344

<211> 324

<212> PRT

<213> Artificial Sequence

<400> 344

Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala

1 5 10 15

Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Glu Ser Asp Leu Tyr Thr Leu

50 55 60

Ser Ser Ser Val Thr Val Pro Ser Ser Pro Arg Pro Ser Glu Thr Val

65 70 75 80

Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys

85 90 95

Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro

100 105 110

Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

115 120 125

Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser

130 135 140

Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu

145 150 155 160

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

165 170 175

Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn

180 185 190

Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro

195 200 205

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

210 215 220

Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val

225 230 235 240

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

245 250 255

Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln

260 265 270

Pro Ile Met Asn Thr Asn Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn

275 280 285

Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val

290 295 300

Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His

305 310 315 320

Ser Pro Gly Lys

<210> 345

<211> 326

<212> PRT

<213> Artificial Sequence

<400> 345

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Ser Leu Ser Pro Gly Lys

325

<210> 346

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 346

Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu

1 5 10 15

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

20 25 30

Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg

35 40 45

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

50 55 60

Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu

65 70 75 80

Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser

85 90 95

Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys

100 105

<210> 347

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 347

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

35 40 45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

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

85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

<210> 348

<211> 327

<212> PRT

<213> Artificial Sequence

<400> 348

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro

100 105 110

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

115 120 125

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

130 135 140

Asp Val Ser Asp Glu Asp Gly Glu Val Lys Phe Asn Trp Tyr Val Asp

145 150 155 160

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

165 170 175

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

180 185 190

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

195 200 205

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

210 215 220

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

290 295 300

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

305 310 315 320

Leu Ser Leu Ser Pro Gly Lys

325

<210> 349

<211> 327

<212> PRT

<213> Artificial Sequence

<400> 349

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro

100 105 110

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

115 120 125

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

130 135 140

Asp Val Ser His Glu Asp Gly Glu Val Lys Phe Asn Trp Tyr Val Asp

145 150 155 160

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

165 170 175

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

180 185 190

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

195 200 205

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

210 215 220

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

290 295 300

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

305 310 315 320

Leu Ser Leu Ser Pro Gly Lys

325

<210> 350

<211> 326

<212> PRT

<213> Artificial Sequence

<400> 350

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Ser Leu Ser Pro Gly Lys

325

<210> 351

<211> 326

<212> PRT

<213> Artificial Sequence

<400> 351

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Ser Leu Ser Pro Gly Lys

325

Claims

1. An anti-OX 40 antibody or antigen-binding fragment thereof, wherein the anti-OX 40 antibody comprises

(1) HCDR1 as shown in SEQ ID NO. 1, HCDR2 as shown in SEQ ID NO. 2 and HCDR3 as shown in SEQ ID NO. 3, and/or a hybrid comprising LCDR1 as shown in SEQ ID NO. 4, LCDR2 as shown in SEQ ID NO. 5 and LCDR3 as shown in SEQ ID NO. 6, and

2. The anti-OX 40 antibody or antigen-binding fragment thereof of claim 1, wherein the anti-OX 40 antibody comprises HCDR1 as shown in any one of SEQ ID NOs 7-38, HCDR2 as shown in any one of SEQ ID NOs 39-65, and HCDR3 as shown in any one of SEQ ID NOs 66-114, and/or LCDR1 as shown in any one of SEQ ID NOs 115-145, LCDR2 as shown in any one of SEQ ID NOs 146-159, and LCDR3 as shown in any one of SEQ ID NOs 160-199.

3. The anti-OX 40 antibody or antigen-binding fragment thereof of claim 1, wherein the anti-OX 40 antibody comprises HCDR1, HCDR2, and HCDR3 as set forth in any one of groups a1 through a 71:

4. the anti-OX 40 antibody or antigen-binding fragment thereof of claim 1, wherein the anti-OX 40 antibody comprises the HCDR and LCDR shown in any one of groups c1 through c71 of Table 1.

5. The anti-OX 40 antibody or antigen-binding fragment thereof of any one of claims 1-4, wherein each FR region of the VH of the anti-OX 40 antibody is a FR region selected from any one of the VH shown in SEQ ID NO: 200-341 and each FR region of the VL is a FR region selected from any one of the VL shown in SEQ ID NO: 271-341; more preferably, each of the FR regions of the VH and VL of the anti-OX 40 antibody is a FR region selected from the group consisting of the VH and VL of any one of the antibodies in Table 2.

6. The anti-OX 40 antibody or antigen-binding fragment thereof of claim 1, wherein the amino acid sequence of the VH of the anti-OX 40 antibody is as set forth in any one of SEQ ID NO:200-270, and/or the amino acid sequence of the VL is as set forth in any one of SEQ ID NO: 271-341; preferably, the amino acid sequence of the VH and the amino acid sequence of the VL of the anti-OX 40 antibody are as shown in any one of the antibody numbers of Table 2, or

The anti-OX 40 antibody is a chimeric antibody or a fully human antibody; preferably fully human antibodies.

7. The anti-OX 40 antibody or antigen-binding fragment thereof of any one of claims 1-6, wherein the sequences of the CH2 domain and the CH3 domain of the heavy chain constant region are selected from:

d) Sequences derived from the CH2 and CH3 domains of human IgG2, and containing the H268D and P271G mutations within the CH2 and CH3 domains,

preferably, the amino acid sequence of the heavy chain constant region of the anti-OX 40 antibody has the sequence shown in any one of SEQ ID NO 348-351, and/or the amino acid sequence of the light chain constant region has the sequence shown in SEQ ID NO 347.

8. A pharmaceutical composition comprising an anti-OX 40 antibody or antigen-binding fragment thereof according to any one of claims 1-7 and a pharmaceutically acceptable excipient or carrier.

9. A nucleic acid molecule or a vector comprising the nucleic acid molecule selected from the group consisting of:

(1) a polynucleotide sequence encoding the anti-OX 40 antibody or antigen-binding fragment thereof of any one of claims 1-7;

(2) (1) the complement of the polynucleotide sequence.

10. Use of an anti-OX 40 antibody or antigen-binding fragment thereof of any one of claims 1-7 in the preparation of a medicament for treating a T cell related disease; preferably, the T cell-associated disease is a T cell-associated tumor or an OX 40-mediated disease; more preferably, the OX 40-mediated diseases include OX 40-mediated allergies, asthma, COPD, rheumatoid arthritis, psoriasis, autoimmune diseases and inflammation-related diseases.