Anti-IL-13 antibodies and uses thereof

Abstract

The present application provides anti-IL-13 antibodies and their use in the diagnosis and treatment of IL-13 related disorders.

Description

Technical Field

[0001] The present invention relates to the field of antibodies, in particular to human anti-IL-13 antibodies, especially those that can neutralize the activity of IL-13. The present invention further relates to the use of anti-IL-13 antibodies in the preparation of drugs for diagnosing or treating IL-13 related diseases or disorders, especially asthma and atopic dermatitis. Background Art

[0002] Interleukin (IL)-13 is a cytokine that is mainly secreted by Th2 CD4+ lymphocytes, but can also be produced by Th1 CD4+T cells, CD8+T lymphocytes, NK cells, and non-T-cell populations such as mast cells, basophils, eosinophils, macrophages, monocytes, and airway smooth muscle cells. IL-13 is composed of 114 amino acids and has a molecular weight of approximately 12kDa. IL-13 and IL-4 are both Th2 cytokines, have 30% sequence similarity at the amino acid level, and are closely related in function. The human IL-13 gene is adjacent to the IL-4 gene and is co-located on chromosome 5q31.

[0003] IL-13 binds to the receptor IL-13Rα1, which in turn recruits the IL-4Rα receptor to form the IL-13Rα1 / IL-4Rα functional receptor complex, thereby activating the JAK-STAT6 signaling pathway. At the same time, IL-13 can also bind to the receptor IL-13Rα2, but the cytoplasmic tail of IL-13Rα2 is short and lacks a known signal motif, acting as an attractant receptor for IL-4Rα to regulate its own IL-13 level. The IL-13Rα1 / IL-4Rα receptor complex is expressed on human B cells, mast cells, monocytes / macrophages, dendritic cells, eosinophils, basophils, fibroblasts, endothelial cells, skin tissue epithelial cells, respiratory epithelial cells, and respiratory smooth muscle cells.

[0004] Asthma, also known as bronchial asthma, is a common inflammatory disease of the respiratory system. Its main pathological features are variable and recurrent symptoms, airway airflow obstruction and bronchospasm. There are as many as 300 million asthma patients worldwide, and more than 30 million in China. At present, mild to moderate asthma can usually be controlled by inhaled corticosteroids in combination with β-agonists or leukotriene inhibitors. For severe patients, higher doses of corticosteroids can no longer effectively control symptoms, and long-term oral corticosteroids can lead to side effects such as osteoporosis, weight gain, endocrine disorders, and reduced growth rate in children. New treatments are urgently needed. The cause of asthma is believed to be an inflammatory response mediated by Th2 lymphocytes. The levels of IL-13 in bronchial biopsy specimens, sputum and bronchoalveolar lavage (BAL) cells of asthma patients are higher than those of healthy people. IL-13 is an emerging target in the field of targeted treatment of asthma, especially for patients with non-eosinophilic phenotypes (accounting for 50% of asthma patients) who currently have no effective biological therapy.

[0005] Atopic dermatitis (AD) is a type of autoimmune disease and one of the most common inflammatory skin diseases. The main symptoms are dry skin, chronic eczematous lesions and severe itching, which seriously affect the quality of life of patients. In the past two decades, the global incidence has continued to rise, and the incidence rates in children and adults have reached 10-20% and 5-10%, respectively. In 2014, the prevalence of atopic dermatitis in urban children aged 1-7 in my country reached 12.94%. Th2 inflammation is the basic feature of AD. IL-13 is one of the important cytokines that mediate the pathogenesis of AD. Its high expression is positively correlated with the severity of atopic dermatitis. Blocking IL-13 can improve the clinical symptoms of atopic dermatitis. In conventional treatment methods, for mild and moderate patients, TCS (topical corticosteroids) / TCI (topical calcineurin inhibitors) can be selected for symptomatic treatment according to the skin lesions and locations. Oral antihistamines, wet packs, or ultraviolet therapy can be used when necessary. For severe patients, immunosuppressants and short-term systemic glucocorticoids can be used to control acute severe and stubborn skin lesions. However, the above methods are not suitable for long-term use due to poor tolerability. The biological agent Dupilumab has been written into the 2020 edition of the Chinese Atopic Dermatitis Diagnosis and Treatment Guidelines with good safety and efficacy, providing a new treatment option for moderate and severe patients. Dupilumab monoclonal antibody targets IL-4Rα and can inhibit both IL-4 and IL-13 signaling pathways; however, clinical trial data have shown that Tralokinumab and Lebrikizumab, which simply target the IL-13 signaling pathway, can achieve similar efficacy to Dupilumab, but the incidence of conjunctivitis, a side effect, is significantly reduced. Compared with simultaneously targeting the IL-4 and IL-13 signaling pathways, targeting IL-13 alone can provide the advantage of a linear PK curve, thereby reducing the dosage and frequency of administration, indicating that blocking the IL-13 signaling pathway alone can provide considerable improvement and more specific targeting effects in AD. Summary of the invention

[0006] The present invention provides a group of novel antibodies against IL-13. The present invention also provides a pharmaceutical composition containing the anti-IL-13 antibody of the present invention, and the use of the antibody in preparing a drug for diagnosing or treating atopic dermatitis and asthma.

[0007] Specifically, the present invention provides anti-IL-13 antibodies. A preferred embodiment of the present invention is an antibody or antigen-binding fragment that specifically binds to IL-13, comprising heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3, wherein the heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 are at least 80%, preferably at least 90%, and more preferably at least 95% identical to the heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 sequences of an antibody selected from the group consisting of FWB03, FWB05, FWB09, FWB10, FWB11, FWB12, FWB13, FWB14, FWB15, FWB16, FWB17 and FWB19, respectively. Most preferably, the present invention relates to an antibody or antigen-binding fragment that specifically binds to IL-13, which comprises the heavy chain CDR1, CDR2 and CDR3 and the light chain CDR1, CDR2 and CDR3 of an antibody selected from the group consisting of FWB03, FWB05, FWB09, FWB10, FWB11, FWB12, FWB13, FWB14, FWB15, FWB16, FWB17 and FWB19.

[0008] A more preferred embodiment of the present invention is an antibody or antigen-binding fragment that specifically binds to IL-13, which comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region have at least 85% identity, preferably at least 90% identity, more preferably 95% identity, and most preferably 98% identity with the heavy chain variable region and light chain variable region sequences of an antibody selected from the group consisting of FWB03, FWB05, FWB09, FWB10, FWB11, FWB12, FWB13, FWB14, FWB15, FWB16, FWB17, and FWB19. Most preferably, the present invention relates to an antibody or antigen-binding fragment thereof that specifically binds to IL-13, which comprises the heavy chain variable region and light chain variable region sequences of an antibody selected from the group consisting of FWB03, FWB05, FWB09, FWB10, FWB11, FWB12, FWB13, FWB14, FWB15, FWB16, FWB17 and FWB19.

[0009] A further preferred embodiment of the present invention is an antibody or antigen-binding fragment that specifically binds to IL-13, which comprises a heavy chain and a light chain, wherein the heavy chain and the light chain have at least 80%, preferably at least 85%, more preferably 90%, and most preferably at least 95% identity with the heavy chain and light chain sequences of an antibody selected from the following group: FWB03, FWB05, FWB09, FWB10, FWB11, FWB12, FWB13, FWB14, FWB15, FWB16, FWB17 and FWB19, respectively. Most preferably, the present invention relates to an antibody or antigen-binding fragment that specifically binds to IL-13, which comprises the heavy chain and light chain sequences of an antibody selected from the group consisting of FWB03, FWB05, FWB09, FWB10, FWB11, FWB12, FWB13, FWB14, FWB15, FWB16, FWB17 and FWB19.

[0010] A particularly preferred embodiment of the invention is an antibody comprising the three heavy chain CDRs and the three light chain CDRs of the antibody molecule referred to herein as FWB13.

[0011] The present invention also provides an isolated nucleic acid encoding the antibody or antigen-binding fragment of the present invention. The present invention also provides an expression vector comprising the isolated nucleic acid. The present invention also provides a host cell comprising the nucleic acid or expression vector of the present invention, preferably the host cell is a eukaryotic host cell, more preferably the host cell is a mammalian host cell. The present invention also provides a composition comprising a first nucleic acid and a second nucleic acid, wherein the first nucleic acid encodes the heavy chain of the antibody of the present invention, and the second nucleic acid encodes the light chain of the antibody of the present invention.

[0012] The present invention provides a pharmaceutical composition for treating an IL-13-related disease or disorder, comprising the antibody or antigen-binding fragment thereof, isolated nucleic acid, expression vector, or host cell of the present invention, and further comprising a pharmaceutically acceptable carrier. Preferably, the IL-13-related disease or disorder is asthma or atopic dermatitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The results of PAS-stained positive cells in mouse lung tissue pathological sections are shown as described in Example 3. The purple-red area indicated by the arrow represents PAS-stained cells

[0014] Figure 2 The clinical scoring results of the inhibitory effect of the anti-IL-13 antibody on atopic dermatitis in male mice as described in Example 4 are shown.

[0015] Figure 3The phenotype of the inhibitory effect of the anti-IL-13 antibody described in Example 4 on atopic dermatitis in male mice is shown.

[0016] Figure 4 The clinical scoring results of the inhibitory effect of the anti-IL-13 antibody described in Example 4 on atopic dermatitis in female mice are shown.

[0017] Figure 5 The phenotype of the inhibitory effect of the anti-IL-13 antibody described in Example 4 on atopic dermatitis in female mice at day 14 is shown.

[0018] Figure 6 The results of measuring the TEWL value of female mice using the anti-IL-13 antibody as described in Example 4 are shown.

[0019] Figure 7 The binding affinity of the anti-IL-13 antibodies FWB13 and FWB13B described in Example 5 to IL-13 is shown.

[0020] Figure 8 The binding affinity of the anti-IL-13 antibodies FWB03 and FWB03B described in Example 5 to IL-13 is shown.

[0021] Fig. 9 The binding affinity of the anti-IL-13 antibodies FWB09 and FWB09B described in Example 5 to IL-13 is shown.

[0022] Fig.10 The binding affinity of the anti-IL-13 antibodies FWB11 and FWB11B described in Example 5 to IL-13 is shown.

[0023] Fig.11 The binding affinity of the anti-IL-13 antibodies FWB12 and FWB12B described in Example 5 to IL-13 is shown.

[0024] Fig.12 The binding affinity of the anti-IL-13 antibodies FWB16 and FWB16B described in Example 5 to IL-13 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0025] Unless otherwise specified, the terms used in this application have the commonly used meanings known in the art.

[0026] It should be noted that, unless otherwise indicated, interleukin-13 (IL-13) referred to herein generally refers to human IL-13. In several places herein, it also refers to "antigen". The present invention provides antibodies against human IL-13, specifically human antibodies that are cross-reactive with non-human primate IL-13 including macaque IL-13 and rhesus monkey IL-13, and mouse IL-13. The antibodies described in the present invention can recognize IL-13 variants obtained by replacing the arginine residue at amino acid position 130 with glutamine. Other aspects and embodiments of the present invention provide specific binding members against mouse IL-13, especially against mouse IL-13.

[0027] The anti-IL-13 antibody molecule can be a human-effective, human, humanized, CDR-grafted, chimeric, mutated, affinity-matured, deimmunized, synthetic, or in vitro generated antibody molecule. In one embodiment, the IL-13 antibody is a humanized antibody.

[0028] In one embodiment, the IL-13 antibody molecule comprises a heavy chain and a light chain of the following sequence. The heavy chain and light chain of the anti-IL-13 antibody molecule can be substantially full-length (e.g., the antibody molecule comprises at least one, preferably two heavy chains and at least one, preferably two light chains) or comprise an antigen binding fragment (e.g., Fab, Fv, or single-chain Fv fragment). In another embodiment, the antibody molecule has a heavy chain constant region selected from the following heavy chain constant regions such as IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE, particularly the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4, more particularly the heavy chain constant region of IgG4 (e.g., human IgG4). The heavy chain constant region is generally human or a modified form of a human constant region. In another embodiment, the antibody molecule has a light chain constant region selected from, for example, a Lambda or Kappa (preferably Lambda, such as human Lambda) light chain constant region. In one embodiment, the constant region is altered (e.g., mutated) to modify the properties of the antibody molecule (e.g., to increase or decrease one or more of the following Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, function of effector cells, or function of complement). For example, the human IgG4 constant region can be mutated at one or more residues (e.g., heavy chain residue 228 of human IgG4).

[0029] The sequences of the six CDRs of the antibodies described herein are listed in Tables 1 and 2

[0030] Table 1. Sequences of the heavy chain CDRs of the preferred antibodies herein

[0031]

[0032]

[0033] Table 2. Sequences of the light chain CDRs of the preferred antibodies herein

[0034]

[0035]

[0036] Table 3. Sequences of the heavy chain variable region and light chain variable region of the preferred antibodies herein

[0037]

[0038]

[0039]

[0040]

[0041] Table 4. Sequences of the heavy and light chains of the preferred antibodies herein

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] Example 1 Preparation of antibodies using genetic engineering methods

[0051] The amino acid mutations in the CDR regions of the heavy and light chains were modified. The amino acid sequences of the framework regions and variable regions of the heavy chain variable regions and the framework regions and variable regions of the light chain variable regions of the 20 candidate antibodies after modification are shown below. All antibodies are human IgG4 S228P antibodies, i.e., the 228th amino acid is proline.

[0052] Table 5. Sequences of heavy chain CDRs and FRs of the antibodies of Example 1

[0053]

[0054]

[0055]

[0056] The heavy chain constant region CH of all antibodies is:

[0057] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0058] Table 6. Sequences of light chain CDRs and FRs of the antibodies of Example 1

[0059]

[0060]

[0061] The light chain constant regions of all antibodies are:

[0062] GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

[0063] Gene sequences were synthesized according to the amino acid sequences, cloned into expression vectors, transfected into HEK293 cells, and the transformed HEK293 cells expressed antibodies, and the antibodies were collected and purified. 20 candidate antibodies were screened by ELISA to obtain candidate antibodies with high IL-13 binding activity.

[0064] Example 2 Screening of candidate antibodies by in vitro experiments

[0065] 2.1 Determination of the affinity of anti-IL-13 antibodies to human, monkey and mouse IL-13 by ELISA

[0066] First, the 96-well ELISA plate was incubated with 50 μl of 1 μg / ml streptavidin at 4°C overnight, and incubated with 250 μl of blocking solution (3% BSA in TBST) at 37°C for 2 hours, and then washed 3 times with PBST. 50 μl of biotin-labeled human IL-13 (obtained from Shanghai Ruizhi Chemical Research Co., Ltd., with the sequence of SEQ ID NO: 181: GPVPPS TALRELIEEL VNITQNQKAP LCNGSMVWSI NLTAGMYCAA LESLINVSGC SAIEKTQRMLSGFCPHKVSA GQFSSLHVRD TKIEVAQFVK DLLLHLKKLF REGRFN) (1 μg / ml) was added to each ELISA experimental well and incubated for 1 hour, followed by washing the plate 3 times with PBST. The 20 antibodies to be tested were serially diluted 5-fold from 2 μg / ml, with a total of 8 concentration points (including blank control), and the serially diluted antibodies were added to the ELISA wells, incubated at 37°C for 1 hour, and then washed 3 times with PBST. The secondary antibody conjugated with horseradish peroxidase was added and incubated at 37°C for 1 hour, and finally the plate was washed 3 times with PBST and 50 μl TMB was added for 15 minutes. The color reaction can be terminated with 1N hydrochloric acid (50 μl), and the absorbance value at 450 nm is detected on a plate reader (M5) to calculate the affinity (EC50) of each antibody for IL-13. Finally, FWB03, 09, 11, 12, 13, 14, 15, 16 and FWB19 with strong binding activity to human, monkey and mouse IL-13 but no binding to human IL-4 were screened out for further experiments.

[0067] Table 7. Affinity of the antibodies of the present invention to human, monkey, mouse IL-13, human IL-4, and human IL-13R130Q

[0068]

[0069]

[0070] “--” indicates no binding activity.

[0071] 2.2 Determination of the activity of antibodies blocking the binding of IL-13 ligand to cell surface receptor hIL-13Rα by flow cytometry

[0072] The antibodies to be tested were FWB03, 09, 11, 12, 13, 14, 15, 16 and FWB19. 3 × 10 5The cells (HEK293 / hIL-13Rα / hIL-4Rα) were centrifuged and resuspended in PBS containing 2% FBS. The antibody was diluted 5-fold with an initial concentration of 10 μg / mL. 100 μl of the antibody or blank control of the corresponding concentration was added to each well of cells. Three replicate wells were set up and incubated at 4°C for 0.5 hour. Then, 100 μl of 0.32 μg / mL biotin-coupled human IL-13 protein was added and incubated at 4°C for 1 hour. The cells were washed twice with PBS containing 2% FBS, and Alexa 488 streptavidin was added. The cells were incubated at 4°C in the dark for 0.5 hour. The cells were washed twice with PBS containing 2% FBS, and then resuspended with 100 μl PBS containing 2% FBS. Finally, the fluorescence signal on the cell surface was detected by flow cytometry. During the detection, 2×10 4 The results are shown in Table 8. FWB03, 09, 11, 12, 13 and FWB16 were screened out to be able to strongly block the binding of human IL-13 to IL-13 receptor hIL-13Rα and continued the experiment.

[0073] Table 8. IC50 of the antibodies of the present invention blocking human IL-13 ligand binding

[0074] Antibody ID <![CDATA[IC of human IL-13 ligand binding blockade 50 (nM)]]> FWB03 1.036 FWB09 1.083 FWB11 0.8327 FWB12 0.9479 FWB13 0.9807 FWB14 1.246 FWB15 1.473 FWB16 1.182 FWB19 2.709 Tralokinumab 1.105

[0075] 2.3 Determination of the inhibitory effect of antibodies on TF-1 cell proliferation

[0076] The antibodies to be tested were FWB03, 09, 11, 12, 13 and FWB16. The growth and proliferation of TF-1 cells (human myeloid leukemia cells, purchased from ATCC) depend on IL-13. TF-1 cells were cultured in RPMI1640 medium containing 10% fetal bovine serum (FBS) and 2 ng / mL granulocyte-macrophage colony stimulating factor (GM-CSF) was added. 2×10 cells were collected in each well of a 96-well plate. 5 TF-1 cells were cultured in 50 μL of RPMI1640 medium containing 2% FBS. Human IL-13 antigen was premixed with FWB03, 09, 11, 12, 13 or FWB16 antibodies. 50 μL of antigen-antibody mixture of corresponding concentration was added to each well, the final concentration of antigen was 10 ng / mL, and the final concentration of antibody was 10 μg / mL, 2 μg / mL, 0.4 μg / mL, 0.08 μg / mL, 16 ng / mL, 3.2 ng / mL, 0.64 ng / mL, 0.128 ng / mL, 0.0256 ng / mL. After 37°C 5% CO2 incubator culture for 3 days, 50 μL Cell-Titer Glo was added to each well, and the fluorescence intensity was detected on a plate reader (M5). The antibody concentration required to obtain a 50% inhibitory effect is the IC50 value.

[0077] Table 9. TF-1 proliferation assay IC50

[0078]

[0079]

[0080] 2.4 Analysis of the affinity of anti-IL-13 antibodies to human IL-13 by BIAcore

[0081] The affinity of FWB03, FWB09, FWB11, FWB12, FWB13, and FWB16 as human anti-IL-13 IgG4 antibodies to human IL-13 was determined by surface plasmon resonance using BIAcore 2000 Biosensor (BIAcore AB). Briefly, the antibody was coupled to a CM5 sensor chip using an amine coupling kit (BIAcore) with a surface density of approximately 500Ru, and IL-13 was serially diluted with HBS-EP buffer, and the resulting serial dilutions (50nM-0.78nM) were passed through the sensor chip surface. The sensor recordings obtained above were evaluated using BIA Evaluation 3.1 software to obtain kinetic data.

[0082] Table 10. Human IL-13 BIAcore Kd of the antibodies of the present invention

[0083] Antibody ID <![CDATA[Human IL-13 BIAcore K d (M)]]> FWB03 9.6E-11 FWB09 1.3E-10 FWB11 7.3E-11 FWB12 6.9E-11 FWB13 7.0E-11 FWB16 7.4E-11 Tralokinumab 1.3E-10

[0084] Example 3 Efficacy of anti-IL-13 antibody in mouse asthma model

[0085] This example evaluates the in vivo pharmacodynamics of FWB13 in a Balb / c mouse respiratory response model induced by intratracheal injection of human recombinant IL-13.

[0086] The 29 mice were divided into 5 groups:

[0087] 1. G1) Naive, n = 5;

[0088] 2. G2) IL-13+human IgG4 group (antibodies that cannot specifically recognize and bind to IL-13), 3 mpk, n=8;

[0089] 3. G3) IL-13 + Tralokinumab group, 3 mpk, n = 8;

[0090] 4. G4) IL-13+FWB13 group, 3 mpk, n=8;

[0091] The mice in the G2, G3, and G4 groups were intraperitoneally injected with 0.2 mL of the test antibody at a concentration of 3 mg / kg on the first and third days. Human recombinant IL-13 was intratracheally administered on the second and fourth days, with each mouse receiving 25 μg dissolved in PBS in a volume of 50 μL. The mice in the G1 Naive control group were sprayed with PBS through the trachea without IL-13 or the test antibody.

[0092] In vivo experiments:

[0093] On the fifth day of the experiment, the mice were stimulated by aerosol inhalation with increasing concentrations of acetylcholine (0 mg / mL, 1.25 mg / mL, 2.5 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL and 40 mg / mL), and their lung function was tested. Penh (enhanced pause) is a dimensionless indicator that is commonly used to evaluate changes in the pattern of airflow in and out of the respiratory tract. Penh has been widely accepted as a method for evaluating changes in lung function and for evaluating airway responsiveness. The measured Penh values ​​are shown in Table 11. The results showed that after stimulation with 20 mg / mL of acetylcholine, the model groups G2 and G1 There was a statistically significant difference between the two groups (P<0.001), indicating that the model of respiratory tract response induced by human recombinant IL-13 in mice was successfully established. When the concentration of acetylcholine increased to 40 mg / mL, the Penh value of the positive control antibody administration group G3 was significantly reduced compared with the model group G2 (P<0.001). At the same time, the Penh value of the test antibody FWB13 G4 group was also significantly reduced compared with the model group G2 (P<0.001), indicating that FWB13 had a significant inhibitory effect on the penh value of respiratory tract response induced by high concentrations of acetylcholine in mice in the in vivo experiment.

[0094] Table 11: Penh values ​​of mouse respiratory response (mean ± SEM)

[0095]

[0096]

[0097] Two way ANOVA analysis***p<0.001,****p<0.0001NS means no significant difference

[0098] Pathological experiments:

[0099] On the sixth day, the mice were euthanized and their lung tissues were fixed in 10% neutral formalin and preserved. After being embedded in paraffin, they were cut into 5 μm thick sections for PAS staining and pathological analysis.

[0100] PAS (Periodic Acid-Schiff stain) is the periodic acid-Schiff reaction. The basic process of its chemical reaction is to expose the aldehyde group of polysaccharide through the oxidation of periodic acid. The aldehyde group reacts with colorless basic fuchsin to form a new purple-red complex at the site where the polysaccharide exists. Through microscopic observation, the chemical components such as glycogen, glycoprotein or mucopolysaccharide in tissue cells are located, qualitatively and quantitatively studied. For the asthma (airway inflammation) model, inflammation leads to increased mucopolysaccharide secretion, and a positive PAS reaction indicates that the airway at that site has induced an inflammatory response.

[0101] The staining results were analyzed using ImageScope software to calculate the proportion of PAS-positive cells, i.e., goblet cells and columnar epithelial cells stained red, in a single terminal bronchiole.

[0102] Tissue sections showed that PAS staining of G1 in the control group was negative, while inflammatory cells in the model group were clearly stained, and the amount of mucus secretion in the bronchioles was also significantly increased ( Figure 1 ).

[0103] As shown in Table 13, the PAS staining of group G1 (blank control group) was completely negative; the strongest signal (mucus secretion) appeared in group G2 (with inducer IL-13 but without neutralizing antibody, PAS positive cells accounted for 28.39%); compared with the disease model group (group G2), the mucus secretion of the Tralokinumab group (group G3) and the FWB13 group (group G4) decreased significantly, and the PAS positive cells accounted for 15.09% and 13.36%, respectively. The results of pathological experiments showed that FWB13 (group G4) could significantly inhibit the increase in the number of PAS positive cells.

[0104] Table 12. PAS staining results

[0105]

[0106] t-test statistical analysis ***p<0.001, NA means not applicable

[0107] Example 4 Efficacy of anti-IL-13 antibody in a mouse atopic dermatitis model

[0108] This example evaluates the in vivo efficacy of FWB13 in a mouse dermatitis model that can induce overexpression of IL-13. R26-(2xIns-TRE-CMV-Il13-SV40-pA) F1 generation (constructed in-house) was mated with the transgenic mouse strain Tg(KRT5-rtTA) (purchased from JAX), and the offspring mice completed the identification of IL-13+ and KRT5+ double positive Tg(+) 6 weeks ago. IL-13 overexpression in epidermal tissue can be induced by feeding water containing Doxycycline (DOX, 1 mg / mL), thereby causing atopic dermatitis symptoms.

[0109] The transgenic mouse strain R26-(2xIns-TRE-CMV-Il13-SV40-pA) was constructed in-house. First, ROSA26-(2xIns-TRE-CMV- IL13 -SV40-pA) donor homologous recombination vector. The vector is site-specifically integrated into the intron of the ROSA26 gene of the mouse C57 BL / 6J genome through a pair of homologous recombination arms, and overexpresses the IL-13 gene under the drive of the tetracycline response element (TRE) and the CMV fusion promoter. The expression vector is injected into F0 generation mice through fertilized eggs, and further mated with wild mice after identification to obtain F1 generation mice. F1 generation mice are mated with skin tissue specific (keratin5, keratin promoter) transgenic mouse strain Tg (KRT5-rtTA) (FVB background), and the offspring mice can be fed with Doxycycline to specifically drive the IL-13 gene to be expressed in the skin epidermal tissue.

[0110] Tg(+) male mice and female mice were used as two models for drug efficacy evaluation.

[0111] 4.1 Evaluation of the efficacy of FWB13 in Tg(+) male mice

[0112] Forty-eight Tg(+) male mice were divided into six groups:

[0113] 1. Normal group, n = 8;

[0114] 2. Vehicle group, PBS, ip, BIW (twice a week), n=8;

[0115] 3. Tralokinumab, 3 mg / kg group (positive control low-dose group), ip, BIW, n=8;

[0116] 4. Tralokinumab, 10 mg / kg group (positive control high-dose group), ip, BIW, n=8;

[0117] 5. FWB13, 3 mg / kg group (low-dose group of the antibody to be tested), ip, BIW, n=8;

[0118] 6. FWB13, 10 mg / kg group (high-dose group of the antibody to be tested), ip, BIW, n=8;

[0119] On the 1st, 4th, 8th and 11th days, the antibody drug was intraperitoneally injected into the experimental groups 3-6, and PBS was intraperitoneally injected into the vehicle group. From the 1st day, all groups of mice except the normal group were continuously fed with Doxycycline (1 mg / mL) aqueous solution, and the feeding of Doxycycline aqueous solution was stopped on the 13th day. The Normal group was fed with sterile drinking water. Phenotypic scoring was performed on the 7th, 11th, 13th and 15th days, including the sum of erythema (0-3 points), crusting (0-3 points) and thickness (0-3 points), with a total score of 0-9 points. Two way ANOVA was used for statistical analysis. Scoring ( Figure 2 ) showed that there was no significant difference in the score between the low-dose group of the positive control antibody drug Tralokimumab 3mg / kg and the vehicle group, and the high-dose group 10mg / kg had significant differences compared with the vehicle group on the 7th and 10th days, and the scores could be reduced by 56% and 27% respectively relative to the vehicle group. Therefore, the dose of the positive control antibody used in the experiment of Example 4.2 below was determined to be 10mg / kg. The low-dose group of the test antibody FWB13 3mg / kg had significant differences compared with the vehicle group on the 7th, 11th and 15th days, and the scores could be reduced by 59%, 25% and 22% respectively. It can be seen that at a dose of 3mg / kg, the efficacy of FWB13 is better than that of the positive control antibody drug Tralokinumab. The high-dose group of 10 mg / kg showed significant differences compared with the vehicle group on days 7, 11 and 15, and the scores were reduced by 72%, 33% and 23% respectively; however, the efficacy was similar to that of the 3 mg / kg group and there was no significant difference. Therefore, the highest dose of the antibody used in the experiment of Example 4.2 below was determined to be 3 mg / kg. The phenotypes of the mice in each group on days 11 and 15 were as follows: Figure 3 shown.

[0120] 4.2 Evaluation of the efficacy of FWB13 in Tg(+) female mice

[0121] Forty-seven Tg(+) female mice were divided into five groups:

[0122] 1. Normal group, n=7;

[0123] 2.Vehicle group, PBS, IP, BIW, n=10;

[0124] 3. Tralokinumab group (positive control dose group), 10 mg / kg, ip, BIW, n = 10;

[0125] 4. FWB13 group, 1 mg / kg (low-dose group of the antibody to be tested), ip, BIW, n=10;

[0126] 5. FWB13 group, 3 mg / kg (high-dose group of the antibody to be tested), ip, BIW, n=10;

[0127] On days 0, 3, 6, 10, 13 and 17, the antibody drug was intraperitoneally injected into the experimental groups 3-5, and PBS was intraperitoneally injected into the vehicle group. From day 1 to day 12, all groups of mice except the normal group were continuously fed with Doxycycline (1 mg / mL) aqueous solution every day, and the feeding of Doxycycline aqueous solution was stopped on day 13. The Normal group was fed with sterile drinking water. Phenotypic scoring was performed on days 3, 5, 7, 10, 12, 14, 17 and 20, including the sum of erythema (0-3 points), crusting (0-3 points) and thickness (0-3 points), with a total score of 0-9 points. Two-way ANOVA was used for statistical analysis. Scoring ( Figure 4 ) showed that the positive control high-dose group Tralokinumab 10mg / kg had a significant difference compared with the vehicle group on the 10th day, which could reduce the score by 29%, but there was no significant difference at other time points as the symptoms worsened. The low-dose FWB13 group 1mg / kg had significant differences compared with the vehicle group on the 10th, 12th, 14th, 17th and 20th days, which could reduce the score by 28%, 17%, 22%, 16% and 22% respectively. The high-dose FWB13 group 3mg / kg also had a significant difference compared with the vehicle group on the 10th, 12th, 14th, 17th and 20th days, which could reduce the score by 36%, 32%, 33%, 33% and 32%. The efficacy of the FWB13 1 mg / kg dose group was similar to that of the positive control antibody high-dose group Tralokinumab 10 mg / kg. The efficacy of the FWB13 3 mg / kg dose group was significantly better than that of the positive control Tralokinumab 10 mg / kg dose group on days 12, 14, 17 and 20.

[0128] On day 14, the phenotype of mice was Figure 5 In addition to the scoring, the transepithelial water loss (TEWL) values ​​were measured on days 3, 7, 10, 12, and 14, as shown in the figure below. Figure 6 As shown in the results, after two-way ANOVA statistical analysis, there was no significant difference between Tralokinumab 10mg / kg and the vehicle group. FWB13 1mg / kg showed a significant difference compared with the vehicle group on day 10, reducing TEWL by 36%; FWB13 3mg / kg significantly reduced TEWL by 59%, 63% and 47% on days 7, 10 and 20 compared with the vehicle group. Compared with the Tralokinumab 10mg / kg group, the FWB13 3mg / kg dose group can more significantly improve the condition of epidermal water loss.

[0129] Example 5 Determination of the affinity of anti-IL-13 antibodies to human IL-13 by ELISA

[0130] First, human IL13 (Sino10369-HNAC, purchased from Beijing Sino Biological, with an amino acid sequence of SEQ ID NO: 182: MALLLTTVIA LTCLGGFASP GPVPPSTALR ELIEELVNIT QNQKAPLCNGSMVWSINLTA GMYCAALESL INVSGCSAIE KTQRMLSGFC PHKVSAGQFS SLHVRDTKIE VAQFVKDLLLHLKKLFREGR FN) was diluted to 1 μg / mL with coating solution (PBS), and 50 μL was added to each well and incubated overnight at 4°C. Then the antigen solution was removed by aspiration, and 200 μL of 3% BSA solution was added to each well and incubated at room temperature for 1 hour; the plate was then washed 3 times with PBST. The 12 test antibodies shown in Table 13 (whose heavy chain constant region and light chain constant region and the framework region of the heavy chain and light chain variable region are the same) were diluted 10 times from 50 μg / mL, with a total of 8 concentration points (including blank controls), and the serially diluted antibodies were added to the ELISA wells, incubated at 37°C for 1 hour, and then washed 3 times with PBST. Horseradish peroxidase-conjugated secondary antibody was added and incubated at 37°C for 1 hour, and finally the plate was washed 3 times with PBST and 50 μL TMB was added for 15 minutes. The color reaction can be terminated with 1N hydrochloric acid (50 μl), and the absorbance value at 450 nm is detected on a plate reader (M5) to calculate the affinity (EC50) of each antibody for IL-13. The experimental results are shown in Table 14 and Figure 7-12 The experimental results show that the affinity of FWB1313 to human IL-13 antigen is higher than that of FWB1313B.

[0131] Table 13. CDR sequences of the antibodies to be tested

[0132]

[0133] Table 14. Binding affinity of the antibodies of Example 5 to human IL13 (Sino10369-HNAC)

[0134] Antibody ID EC50(nM) Antibody ID EC50(nM) FWB13 2.873 FWB 1313B 5.206 FWB03 4.181 FWB 1303B 3.415 FWB09 6.229 FWB 1309B 3.364 FWB11 4.306 FWB 1311B 1.719 FWB12 4.076 FWB 1312B 3.843 FWB16 4.442 FWB 1316B 3.563 Sequence Listing <110> Shenzhen Fuwo Pharmaceutical Co., Ltd. <120> Anti-IL-13 antibodies and uses thereof <130> C21P0185 <140> 202110128204.3 <141> 2021-01-29 <150> 202011425673.3 <151> 2020-12-08 <160> 180 <170> PatentIn version 3.5 <210> 1 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 1 Ser Tyr Gly Leu Ser 1 5 <210> 2 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 2 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 3 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 3 Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu 1 5 10 <210> 4 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 4 Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 5 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 5 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 6 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 6 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 7 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 7 Ser Tyr Gly Leu Ser 1 5 <210> 8 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 8 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 9 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 9 Asp Ser Ser Ser Thr Trp Ala Arg Trp Phe Phe Asp Leu 1 5 10 <210> 10 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 10 Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 11 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 11 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 12 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 12 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 13 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 13 Ser Tyr Gly Leu Ser 1 5 <210> 14 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 14 Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Gln Lys Phe Gln 1 5 10 15 Gly <210> 15 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 15 Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu 1 5 10 <210> 16 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 16 Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 17 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 17 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 18 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 18 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 19 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 19 Ser Tyr Gly Leu Ser 1 5 <210> 20 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 20 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Lys Phe Gln 1 5 10 15 Gly <210> twenty one <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> twenty one Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu 1 5 10 <210> twenty two <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> twenty two Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> twenty three <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> twenty three Asp Asp Gly Asn Arg Pro Ser 1 5 <210> twenty four <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> twenty four Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 25 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 25 Asn Tyr Gly Met Ser 1 5 <210> 26 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 26 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 27 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 27 Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu 1 5 10 <210> 28 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 28 Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 29 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 29 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 30 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 30 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 31 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 31 Ser Tyr Gly Leu Ser 1 5 <210> 32 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 32 Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Pro Glu Phe Gln 1 5 10 15 Gly <210> 33 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 33 Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu 1 5 10 <210> 34 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 34 Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 35 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 35 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 36 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 36 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 37 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 37 Ser Tyr Gly Leu Ser 1 5 <210> 38 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 38 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 39 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 39 Asp Ser Asp Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu 1 5 10 <210> 40 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 40 Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 41 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 41 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 42 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 42 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 43 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 43 Ser Tyr Gly Leu Ser 1 5 <210> 44 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 44 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 45 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 45 Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu 1 5 10 <210> 46 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 46 Gly Gly Asn Ile Ile Gly Ser Lys Leu Leu His 1 5 10 <210> 47 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 47 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 48 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 48 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 49 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 49 Ser Tyr Gly Leu Ser 1 5 <210> 50 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 50 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 51 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 51 Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu 1 5 10 <210> 52 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 52 Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 53 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 53 Asp Asp Ser Asp Arg Pro Ser 1 5 <210> 54 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 54 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 55 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 55 Ser Tyr Gly Leu Ser 1 5 <210> 56 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 56 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 57 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 57 Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu 1 5 10 <210> 58 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 58 Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 59 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 59 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 60 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 60 Gln Val Trp Asp Thr Gly Thr Asp Pro Val Val 1 5 10 <210> 61 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 61 Ser Tyr Gly Leu Ser 1 5 <210> 62 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 62 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 63 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 63 Asp Arg Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu 1 5 10 <210> 64 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 64 Gly Gly Thr Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 65 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 65 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 66 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 66 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 67 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 67 Ser Tyr Gly Leu Ser 1 5 <210> 68 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 68 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 69 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 69 Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu 1 5 10 <210> 70 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 70 Gly Gly Asn Arg Ile Gly Ser Lys Leu Val His 1 5 10 <210> 71 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 71 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 72 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 72 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 73 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 73 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 74 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 74 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 75 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 75 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Thr Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 76 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 76 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 77 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 77 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 78 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 78 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 79 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 79 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 80 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 80 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 81 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 81 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 82 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 82 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 83 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 83 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Pro Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 84 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 84 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 85 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 85 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asp Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 86 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 86 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 87 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 87 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 88 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 88 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Leu 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 89 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 89 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 90 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 90 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 91 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 91 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 92 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 92 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Thr Asp Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 93 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 93 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 94 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 94 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 95 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 95 Gln Val Gln Leu Val Gln Ser 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 Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 96 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 96 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Arg Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 97 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 97 Gln Val Gln Leu Val Gln Ser 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 Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 98 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 98 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 99 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 99 Gln Val Gln Leu Val Gln Ser 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 Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Thr Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 100 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 100 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 101 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 101 Gln Val Gln Leu Val Gln Ser 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 Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 102 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 102 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 103 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 103 Gln Val Gln Leu Val Gln Ser 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 Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 104 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 104 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 105 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 105 Gln Val Gln Leu Val Gln Ser 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 Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 106 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 106 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 107 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 107 Gln Val Gln Leu Val Gln Ser 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 Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Pro Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 108 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 108 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 109 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 109 Gln Val Gln Leu Val Gln Ser 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 Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asp Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 110 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 110 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 111 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 111 Gln Val Gln Leu Val Gln Ser 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 Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 112 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 112 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Leu 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 113 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 113 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 114 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 114 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 115 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 115 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 116 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 116 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Thr Asp Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 117 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 117 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 118 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 118 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Thr Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 119 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 119 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 120 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 120 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Arg Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 121 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 121 Asn Tyr Gly Leu Ser 1 5 <210> 122 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 122 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 123 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 123 Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu 1 5 10 <210> 124 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 124 Gly Gly Asn Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 125 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 125 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 126 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 126 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 127 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 127 Asn Tyr Gly Leu Ser 1 5 <210> 128 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 128 Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Gln Lys Phe Gln 1 5 10 15 Gly <210> 129 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 129 Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu 1 5 10 <210> 130 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 130 Gly Gly Asn Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 131 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 131 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 132 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 132 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 133 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 133 Asn Tyr Gly Leu Ser 1 5 <210> 134 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 134 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 135 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 135 Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu 1 5 10 <210> 136 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 136 Gly Gly Asn Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 137 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 137 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 138 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 138 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 139 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 139 Asn Tyr Gly Leu Ser 1 5 <210> 140 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 140 Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 141 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 141 Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu 1 5 10 <210> 142 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 142 Gly Gly Asn Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 143 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 143 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 144 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 144 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 145 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 145 Asn Tyr Gly Leu Ser 1 5 <210> 146 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 146 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 147 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 147 Asp Ser Asp Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu 1 5 10 <210> 148 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 148 Gly Gly Asn Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 149 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 149 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 150 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 150 Gln Val Trp Asp Thr Gly Ser Asn Pro Val Val 1 5 10 <210> 151 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 151 Asn Tyr Gly Leu Ser 1 5 <210> 152 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 152 Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe Gln 1 5 10 15 Gly <210> 153 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 153 Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu 1 5 10 <210> 154 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 154 Gly Gly Asn Ile Ile Gly Ser Lys Leu Val His 1 5 10 <210> 155 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 155 Asp Asp Gly Asp Arg Pro Thr 1 5 <210> 156 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 156 Gln Val Trp Asp Thr Gly Ser Asp Pro Val Val 1 5 10 <210> 157 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 157 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 158 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 158 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 159 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 159 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 160 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 160 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 161 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 161 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 162 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 162 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 163 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 163 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 164 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 164 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 165 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 165 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asp Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 166 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 166 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 167 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 167 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 168 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 168 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asp Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 169 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 169 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 170 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 170 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 171 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 171 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 172 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 172 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 173 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 173 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 174 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 174 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys 210 <210> 175 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 175 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 176 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 176 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 177 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 177 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asp Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 178 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 178 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asn Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 179 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Artificial Sequence <400> 179 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Ser Asn Gly Asp Thr Asn Tyr Gly Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 180 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificial sequence <400> 180 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser Lys Leu Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Asp Asp Gly Asp Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly Ser Asp Pro 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to IL-13, comprising: (1) the heavy chain CDR1 set forth in SEQ ID NO:1, the heavy chain CDR2 set forth in SEQ ID NO:2, the heavy chain CDR3 set forth in SEQ ID NO:3, the light chain CDR1 set forth in SEQ ID NO:4, the light chain CDR2 set forth in SEQ ID NO:5, and the light chain CDR3 set forth in SEQ ID NO:6; or (2) the heavy chain CDR1 set forth in SEQ ID NO:13, the heavy chain CDR2 set forth in SEQ ID NO:14, the heavy chain CDR3 set forth in SEQ ID NO:15, the light chain CDR1 set forth in SEQ ID NO:16, the light chain CDR2 set forth in SEQ ID NO:17, and the light chain CDR3 set forth in SEQ ID NO:18; or (3) a heavy chain CDR1 as set forth in SEQ ID NO:25, a heavy chain CDR2 as set forth in SEQ ID NO:26, a heavy chain CDR3 as set forth in SEQ ID NO:27, a light chain CDR1 as set forth in SEQ ID NO:28, a light chain CDR2 as set forth in SEQ ID NO:29, and a light chain CDR3 as set forth in SEQ ID NO:30; or (4) the heavy chain CDR1 as shown in SEQ ID NO:31, the heavy chain CDR2 as shown in SEQ ID NO:32, the heavy chain CDR3 as shown in SEQ ID NO:33, the light chain CDR1 as shown in SEQ ID NO:34, the light chain CDR2 as shown in SEQ ID NO:35, and the light chain CDR3 as shown in SEQ ID NO:

36.

2. The antibody or antigen-binding fragment thereof that specifically binds to IL-13 according to claim 1, comprising: (1) the heavy chain variable region set forth in SEQ ID NO: 73 and the light chain variable region set forth in SEQ ID NO: 74; or (2) the heavy chain variable region set forth in SEQ ID NO: 77 and the light chain variable region set forth in SEQ ID NO: 78; or (3) the heavy chain variable region set forth in SEQ ID NO: 81 and the light chain variable region set forth in SEQ ID NO: 82; or (4) the heavy chain variable region shown in SEQ ID NO: 83 and the light chain variable region shown in SEQ ID NO:

84.

3. The antibody or antigen-binding fragment thereof that specifically binds to IL-13 according to claim 1 or 2, comprising: (1) the heavy chain set forth in SEQ ID NO:97 and the light chain set forth in SEQ ID NO:98; or (2) the heavy chain set forth in SEQ ID NO:101 and the light chain set forth in SEQ ID NO:102; or (3) the heavy chain set forth in SEQ ID NO:105 and the light chain set forth in SEQ ID NO:106; or (4) the heavy chain set forth in SEQ ID NO:107 and the light chain set forth in SEQ ID NO:

108.

4. The antibody of claim 1, wherein the antibody is IgA, IgG and IgD.

5. The antibody of claim 1 or 2, wherein the antigen-binding fragment is selected from the group consisting of a Fab fragment, a F(ab') fragment, a Fv fragment, a F(ab')2 fragment, a single-chain antibody (scFV), and a diabody.

6. An isolated nucleic acid encoding the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5.

7. An expression vector comprising the isolated nucleic acid of claim 6.

8. A host cell comprising the isolated nucleic acid of claim 6 or the expression vector of claim 7.

9. The host cell of claim 8, wherein the host cell is a eukaryotic host cell.

10. The host cell of claim 9, wherein the host cell is a mammalian host cell.

11. A pharmaceutical composition for treating an IL-13-related disease or disorder, comprising the antibody or antigen-binding fragment thereof of claims 1-5, the isolated nucleic acid of claim 6, the expression vector of claim 7, or the host cell of any one of claims 8-10, and further comprising a pharmaceutically acceptable carrier.

12. A composition comprising a first nucleic acid and a second nucleic acid, wherein the first nucleic acid encodes the heavy chain of the antibody of any one of claims 1-5, and the second nucleic acid encodes the light chain of the antibody of any one of claims 1-5.

13. Use of the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5 in the preparation of a medicament for treating an IL-13-related disease or disorder, wherein the IL-13-related disease or disorder is asthma or atopic dermatitis.

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