Anti-chitinase-3-like protein 1 antibody

Abstract

The anti-chitinase-3-like protein 1 antibody or antigen-binding fragment thereof of the present invention comprises a light chain variable region comprising the CDRs of Table 1 and a heavy chain variable region comprising the CDRs of Table 2.

Description

[Technical field]

[0001] The present invention relates to an anti-chitinase-3-like protein 1 antibody. More specifically, the present invention relates to an antibody that can specifically bind to chitinase-3-like protein 1 (CHI3L1) and can be used to prevent or treat CHI3L1-related diseases, or to diagnose the diseases. [Background technology]

[0002] Chitinase-3-like protein 1 (CHI3L1) is known to promote cancer metastasis, suppress immune activity, and inhibit cell death, and is known to be very importantly involved in the onset and progression of cancer diseases, such as inflammatory responses and angiogenesis processes.

[0003] Although CHI3L1 expression is low under normal conditions, it has been reported that its expression is significantly increased in the blood and tissues of patients with cancer or inflammatory diseases, and its potential as a diagnostic indicator for various types of diseases is emerging.

[0004] Therefore, the present inventors attempted to develop an antibody or an antibody-related molecule that can specifically bind to the above-mentioned CHI3L1 and thereby be used for the prevention, treatment or diagnosis of CHI3L1-associated diseases.

[0005] Related prior art documents include U.S. Patent No. 7,670,599. Summary of the Invention [Problem to be solved by the invention]

[0006] The main object of the present invention is to provide a novel antibody capable of specifically binding to chitinase-3-like protein 1 (CHI3L1).

[0007] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating CHI3L1-related diseases, a composition for diagnosing the diseases, a kit for diagnosing the diseases, and a method for providing information for diagnosing the diseases, by using the antibodies.

[0008] It is yet another object of the present invention to provide polynucleotides, vectors and cells that can be used to produce the antibodies. [Means for solving the problem]

[0009] According to one aspect of the present invention, the present invention provides an anti-chitinase-3-like protein 1 (anti-CHI3L1) antibody or an antigen-binding fragment thereof, comprising a light chain variable region comprising CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3, and a heavy chain variable region comprising CDR1 of SEQ ID NO: 31, CDR2 of SEQ ID NO: 32, and CDR3 of SEQ ID NO: 33; a light chain variable region comprising CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 6, and a heavy chain variable region comprising CDR1 of SEQ ID NO: 34, CDR2 of SEQ ID NO: 35, and CDR3 of SEQ ID NO: 36. a heavy chain variable region comprising a CDR1 of SEQ ID NO: 7, a CDR2 of SEQ ID NO: 8, and a CDR3 of SEQ ID NO: 9, and a heavy chain variable region comprising a CDR1 of SEQ ID NO: 37, a CDR2 of SEQ ID NO: 38, and a CDR3 of SEQ ID NO: 39; a light chain variable region comprising a CDR1 of SEQ ID NO: 10, a CDR2 of SEQ ID NO: 11, and a CDR3 of SEQ ID NO: 12, and a heavy chain variable region comprising a CDR1 of SEQ ID NO: 40, a CDR2 of SEQ ID NO: 41, and a CDR3 of SEQ ID NO: 42; a light chain variable region comprising a CDR1 of SEQ ID NO: 13, a CDR2 of SEQ ID NO: 14, and a CDR3 of SEQ ID NO: 15, and a heavy chain variable region comprising a CDR1 of SEQ ID NO: 43, a CDR2 of SEQ ID NO: 44 and a CDR3 of SEQ ID NO: 45; a light chain variable region comprising a CDR1 of SEQ ID NO: 16, a CDR2 of SEQ ID NO: 17 and a CDR3 of SEQ ID NO: 18 and a heavy chain variable region comprising a CDR1 of SEQ ID NO: 46, a CDR2 of SEQ ID NO: 47 and a CDR3 of SEQ ID NO: 48; a light chain variable region comprising a CDR1 of SEQ ID NO: 19, a CDR2 of SEQ ID NO: 20 and a CDR3 of SEQ ID NO: 21 and a CDR1 of SEQ ID NO: 49, a CDR2 of SEQ ID NO: 50 and a CDR3 of SEQ ID NO: 51; and a heavy chain variable region comprising a CDR1 of SEQ ID NO:22, a CDR2 of SEQ ID NO:23 and a CDR3 of SEQ ID NO:24 and a heavy chain variable region comprising a CDR1 of SEQ ID NO:52, a CDR2 of SEQ ID NO:53 and a CDR3 of SEQ ID NO:54; a light chain variable region comprising a CDR1 of SEQ ID NO:25, a CDR2 of SEQ ID NO:26 and a CDR3 of SEQ ID NO:27 and a heavy chain variable region comprising a CDR1 of SEQ ID NO:55, a CDR2 of SEQ ID NO:56 and a CDR3 of SEQ ID NO:57;The present invention provides an antibody or antigen-binding fragment thereof, comprising a light chain variable region comprising CDR2 of SEQ ID NO:29 and CDR3 of SEQ ID NO:30, and a heavy chain variable region comprising CDR1 of SEQ ID NO:58, CDR2 of SEQ ID NO:59 and CDR3 of SEQ ID NO:60.

[0010] According to another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a CHI3L1-associated disease, comprising the antibody or antigen-binding fragment of the present invention.

[0011] According to yet another aspect of the present invention, there is provided a composition for diagnosing a CHI3L1-associated disease, comprising the antibody or antigen-binding fragment thereof of the present invention.

[0012] According to yet another aspect, the present invention provides a diagnostic kit for a CHI3L1-associated disease, comprising the diagnostic composition of the present invention.

[0013] According to yet another aspect of the present invention, the present invention provides a method for providing information for diagnosing a CHI3L1-related disease, comprising the steps of contacting an antibody or its antigen-binding fragment of the present invention with a sample isolated from a test individual, and measuring a complex of the antibody or its antigen-binding fragment and CHI3L1 formed by the contact.

[0014] According to yet another aspect of the invention, the invention provides a polynucleotide encoding the antibody or antigen-binding fragment thereof of the invention.

[0015] According to yet another aspect of the present invention, there is provided a vector comprising a polynucleotide of the present invention.

[0016] According to yet another aspect of the present invention, there is provided a cell transformed with the vector of the present invention. Effect of the Invention

[0017] The antibody or antigen-binding fragment thereof of the present invention can specifically bind to chitinase-3-like protein 1 (CHI3L1) and can be used to prevent or treat CHI3L1-related diseases and to diagnose the diseases. Therefore, the composition, kit, and information provision method of the present invention can be used to effectively prevent, treat, or diagnose CHI3L1-related diseases. Furthermore, the polynucleotide, vector, and cell of the present invention can be used to efficiently produce the antibody or antigen-binding fragment thereof of the present invention having the above-mentioned excellent effects. [Brief description of the drawings]

[0018] [Figure 1] Figure 1A is a schematic diagram showing the process of selecting antibodies that show significant binding ability to human CHI3L1 (hCHI3L1) through phage display, and Figures 1B to 1D show the results of panning titration for Fab-I and Fab-II, respectively. [Diagram 2] Figure 2 shows the results of an investigation into the amino acid length distribution of the heavy chain CDR3 (HCDR3) of 10 antibodies against hCHI3L1 (A5, A7, D2, F2, E7, F4, H1, 1E12, C5 and H7) selected from phage display. [Diagram 3] Figure 3A shows the results of SDS-PAGE to confirm IgG production from 10 clones (A5, A7, D2, F2, E7, F4, H1, 1E12, C5 and H7) containing antibodies against hCHI3L1, and Figure 3B shows the results of measuring the amount of IgG produced. [Figure 4] 4A to 4B show the results of measuring the EC50 values ​​by ELISA for 10 antibodies against hCHI3L1. [Diagram 5] Figure 5 shows the results of measuring the number of migrated cells after treating the A549 cell line with candidate antibodies against hCHI3L1, namely A5, A7, D2, F2, E7, F4, H1, 1E12, C5 and H7. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The antibody or antigen-binding fragment thereof of the present invention was discovered through phage display panning using chitinase-3-like protein 1 (CHI3L1) as an antigen, and can specifically bind to CHI3L1.

[0020] CHI3L1, also known as YKL-40, is known to be involved in various cancers, cancer metastasis, immune function and cell death.

[0021] The present invention provides ten types of antibodies or antigen-binding fragments thereof.

[0022] The 10 types are named "A5," "A7," "D2," "F2," "E7," "F4," "H1," "1E12," "C5," and "H7," respectively, as shown in Tables 1 to 4, and each type of antibody or antigen-binding fragment thereof is characterized in that the amino acid sequences of CDR1, CDR2, and CDR3 of the light chain variable region (represented as "CDRL1," "CDRL2," and "CDRL3," respectively, in Table 1, meaning the CDRs of the light chain variable region) are as shown in Table 1, and the amino acid sequences of CDR1, CDR2, and CDR3 of the heavy chain variable region (represented as "CDRH1," "CDRH2," and "CDRH3," respectively, in Table 2, meaning the CDRs of the heavy chain variable region) are as shown in Table 2.

[0023] In one embodiment, each type of antibody or antigen-binding fragment thereof has an amino acid sequence of the variable region of its light chain as shown in Table 3 and an amino acid sequence of the variable region of its heavy chain as shown in Table 4.

[0024] The antibody or antigen-binding fragment thereof of the present invention may be in various forms that satisfy the above-mentioned conditions, for example, it may be an antibody selected from the group consisting of IgG, IgA, IgM, IgE, and IgD, or a fragment selected from the group consisting of Fab (fragment antigen binding), Fab', F(ab')2, scFv, scFv-Fc, diabody, minibody, and triabody.

[0025] The antibodies or antigen-binding fragments thereof of the present invention may be detectably labeled, in which case labeling may consist, for example, of direct or indirect binding of a detectable labeling substance.

[0026] It has been demonstrated through experiments that the antibody or antigen-binding fragment thereof of the present invention can specifically bind to CHI3L1 with high avidity, and therefore the antibody or antigen-binding fragment thereof of the present invention may be used to prevent or treat CHI3L1-associated diseases, or may be used to diagnose CHI3L1-associated diseases.

[0027] Thus, the present invention provides a pharmaceutical composition for preventing or treating a CHI3L1-associated disease, comprising the antibody or antigen-binding fragment thereof of the present invention.

[0028] The present invention also provides a composition for diagnosing a CHI3L1-associated disease, comprising the antibody or antigen-binding fragment thereof of the present invention.

[0029] The present invention also provides a diagnostic kit for a CHI3L1-associated disease, comprising the antibody or antigen-binding fragment thereof of the present invention, or the diagnostic composition of the present invention.

[0030] The present invention also relates to a method for detecting a CHI3L1-associated disease, the method comprising the steps of contacting an antibody or an antigen-binding fragment thereof of the present invention with a sample isolated from a test individual, and measuring a complex between the antibody or an antigen-binding fragment thereof and chitinase-3-like protein 1 formed by the contact. Provide a method for providing information for diagnosis.

[0031] In one embodiment of the present invention, the CHI3L1-related disease is, but is not limited to, cancer, cancer metastasis, arthritis or dementia. In one embodiment, the CHI3L1-related disease is lung cancer metastasis.

[0032] The pharmaceutical composition for preventing or treating a CHI3L1-related disease of the present invention is characterized by comprising the antibody or antigen-binding fragment thereof of the present invention as described above. The pharmaceutical composition of the present invention may comprise at least one type of the antibody or antigen-binding fragment thereof of the present invention, or may comprise all 10 types. The pharmaceutical composition of the present invention may be in the form of the antibody or antigen-binding fragment thereof itself, or a mixture with a pharma- ceutical acceptable carrier. The pharmaceutical composition of the present invention may be administered orally or parenterally during clinical administration, and may be used in the form of a general pharmaceutical formulation. The pharmaceutical composition of the present invention may be used alone or in combination with surgery, radiation therapy, hormone therapy, chemotherapy, and methods using biological response modifiers. The pharmaceutical composition of the present invention may be administered at the same dosage as a conventional antibody formulation based on the antibody or antigen-binding fragment thereof contained therein. For example, the antibody or antigen-binding fragment thereof may be administered at about 1 to 10 mg per kg of body weight based on the antibody or antigen-binding fragment thereof of the present invention, but the range may vary depending on the body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity of the subject. For clinical administration, the composition may be formulated into various oral or parenteral formulations, in which case commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants may be used.

[0033] The diagnostic composition for CHI3L1-related disease of the present invention is characterized by comprising the antibody or antigen-binding fragment thereof of the present invention as described above. As in the case of the pharmaceutical composition, the diagnostic composition of the present invention may also comprise at least one type of the antibody or antigen-binding fragment thereof of the present invention, or may comprise all 10 types. The diagnostic composition of the present invention may also comprise an antibody or antigen-binding fragment thereof other than the antibody or antigen-binding fragment thereof of the present invention. In addition, the diagnostic composition of the present invention may further comprise a substance, such as a reagent, necessary for the binding reaction between the antibody or antigen-binding fragment thereof of the present invention and the antigen. In addition, the diagnostic composition of the present invention may further comprise a substance necessary for detecting this binding, a substance for stabilizing the antibody or antigen-binding fragment thereof of the present invention, etc.

[0034] A diagnostic kit for a CHI3L1-associated disease of the present invention is characterized by comprising the diagnostic composition of the present invention. The diagnostic kit of the present invention may further comprise, in addition to the diagnostic composition of the present invention, reagents, instruments, etc. required for diagnosing a CHI3L1-associated disease using the diagnostic composition of the present invention, such as reagents, instruments, etc. required for detecting the binding of the antibody or antigen-binding fragment thereof to an antigen of the present invention.

[0035] The information providing method for diagnosing a CHI3L1-related disease of the present invention is characterized by comprising a step of contacting the antibody or its antigen-binding fragment with a sample isolated from a test individual, and a step of measuring a complex of the antibody or its antigen-binding fragment and CHI3L1 formed by the contact. In the information providing method of the present invention, the test individual may be a mammal, preferably a human. In the information providing method of the present invention, the sample may be a biological sample, for example, a sample of tissue, cell, body fluid, etc., separated from the test individual, or may be blood or serum. In the information providing method of the present invention, the measurement of the complex may be achieved using a conventional method used to measure a binding complex between an antibody or an antibody-related molecule and an antigen.

[0036] The present invention also provides polynucleotides encoding the antibodies or antigen-binding fragments thereof of the present invention.

[0037] In one embodiment, the polynucleotide of the present invention has a base sequence in the light chain variable region coding region CDR1, CDR2, and CDR3 (represented in Table 5 as "CDRL1," "CDRL2," and "CDRL3," meaning the CDRs of the light chain variable region) as shown in Table 5, and a base sequence in the heavy chain variable region coding region CDR1, CDR2, and CDR3 (represented in Table 6 as "CDRH1," "CDRH2," and "CDRH3," meaning the CDRs of the heavy chain variable region) as shown in Table 6.

[0038] In one embodiment, a polynucleotide encoding each type of antibody or antigen-binding fragment thereof of the present invention has a coding base sequence for the light chain variable region as shown in Table 7 and a coding base sequence for the heavy chain variable region as shown in Table 8.

[0039] The present invention also provides a vector comprising the polynucleotide of the present invention. In one embodiment, the vector of the present invention is configured so that the antibody or antigen-binding fragment thereof encoded by the polynucleotide is expressed in a host cell. In one embodiment, the vector of the present invention comprises a replication origin, a promoter, a selection marker, etc. suitable for replication and expression in a host cell.

[0040] The present invention also provides a cell transformed with the vector of the present invention. In one embodiment, the cell of the present invention is a cell capable of expressing an antibody or an antigen-binding fragment thereof encoded by a polynucleotide contained in the vector of the present invention and capable of replicating the vector of the present invention.

[0041] The above-mentioned amino acid sequence and nucleotide sequence information related to the antibody or antigen-binding fragment thereof of the present invention, and the polynucleotide, vector, or cell of the present invention can be used to produce the antibody or antigen-binding fragment thereof of the present invention.

[0042] [Table 1]

[0043] [Table 2]

[0044] [Table 3]

[0045] [Table 4]

[0046] [Table 5]

[0047] [Table 6]

[0048] [Table 7]

[0049] [Table 8]

[0050] The present invention will be described in more detail with reference to the following examples. These examples are merely for the purpose of illustrating the present invention, and therefore the scope of the present invention should not be construed as being limited by these examples.

[0051] [Example] Example 1. Selection of Fab antibody clones against CHI3L1 To screen for antibodies that specifically bind to CHI3L1, we performed immunotube and magnetic bead-based phage display panning using CHI3L1 as an antigen, and then performed monoclonal phage ELISA to select clones that specifically bind to CHI3L1 (Figure 1).

[0052] A total of 10 Fab clones were selected from the clones that were positive in the monoclonal phage ELISA through nucleotide and amino acid sequence analysis. The length distribution of the heavy chain CDR3 (HCDR3) of the selected Fab clones was examined, and it was confirmed that 70% of the clones had 8 residues, and 10% of the clones had 6, 7, or 11 residues (Figure 2).

[0053] Example 2. Expression and purification of antibodies in the IgG form The clones selected in Example 1 were converted to human IgG antibodies and an experiment was conducted to verify the conversion. The 10 anti-CHI3L1 antibodies were co-transfected into ExpiCHO-S cells and cultured, and the IgG was purified using a Protein A resin column. The molecular weight and purity of the purified IgG antibody were confirmed by SDS-PAGE (Figure 3).

[0054] Example 3. ELISA analysis of antibodies EC for each antibody via ELISA 50 We performed an experiment to measure the antigen affinity by examining the EC value. As a result, it was confirmed that all ten antibodies bind to the CHI3L1 antigen protein. 50 Looking at the values, the C5, F4, and 1E12 antibodies in particular showed excellent binding strength (Figure 4).

[0055] Example 4. Anti-cancer efficacy analysis of antibodies We conducted an experiment to confirm whether treatment of lung cancer cell lines with antibodies against CHI3L1 has the effect of suppressing cancer metastasis. Migration of the human lung cancer cell line, A549 cell line, was quantitatively performed using a permeable insert. As a result, we confirmed that the number of migrated cells in the A549 cell line was reduced when treated with 10 antibodies against human CHI3L1 (hCHI3L1) compared to the control group (Figure 5).

Claims

1. As the anti-chitinase-3-like protein 1 antibody or an antigen-binding fragment thereof, a light chain variable region comprising CDR1 of SEQ ID NO:1, CDR2 of SEQ ID NO:2 and CDR3 of SEQ ID NO:3, and a heavy chain variable region comprising CDR1 of SEQ ID NO:31, CDR2 of SEQ ID NO:32 and CDR3 of SEQ ID NO:33; a light chain variable region comprising CDR1 of SEQ ID NO:4, CDR2 of SEQ ID NO:5 and CDR3 of SEQ ID NO:6, and a heavy chain variable region comprising CDR1 of SEQ ID NO:34, CDR2 of SEQ ID NO:35 and CDR3 of SEQ ID NO:36; a light chain variable region comprising CDR1 of SEQ ID NO:7, CDR2 of SEQ ID NO:8 and CDR3 of SEQ ID NO:9, and a heavy chain variable region comprising CDR1 of SEQ ID NO:37, CDR2 of SEQ ID NO:38 and CDR3 of SEQ ID NO:39; a light chain variable region comprising CDR1 of SEQ ID NO: 10, CDR2 of SEQ ID NO: 11 and CDR3 of SEQ ID NO: 12, and a heavy chain variable region comprising CDR1 of SEQ ID NO: 40, CDR2 of SEQ ID NO: 41 and CDR3 of SEQ ID NO: 42; a light chain variable region comprising CDR1 of SEQ ID NO: 13, CDR2 of SEQ ID NO: 14 and CDR3 of SEQ ID NO: 15, and a heavy chain variable region comprising CDR1 of SEQ ID NO: 43, CDR2 of SEQ ID NO: 44 and CDR3 of SEQ ID NO: 45; a light chain variable region comprising CDR1 of SEQ ID NO: 16, CDR2 of SEQ ID NO: 17 and CDR3 of SEQ ID NO: 18, and a heavy chain variable region comprising CDR1 of SEQ ID NO: 46, CDR2 of SEQ ID NO: 47 and CDR3 of SEQ ID NO: 48; a light chain variable region comprising CDR1 of SEQ ID NO: 19, CDR2 of SEQ ID NO: 20 and CDR3 of SEQ ID NO: 21, and a heavy chain variable region comprising CDR1 of SEQ ID NO: 49, CDR2 of SEQ ID NO: 50 and CDR3 of SEQ ID NO: 51; a light chain variable region comprising CDR1 of SEQ ID NO:22, CDR2 of SEQ ID NO:23 and CDR3 of SEQ ID NO:24 and a heavy chain variable region comprising CDR1 of SEQ ID NO:52, CDR2 of SEQ ID NO:53 and CDR3 of SEQ ID NO:54; a light chain variable region comprising CDR1 of SEQ ID NO:25, CDR2 of SEQ ID NO:26 and CDR3 of SEQ ID NO:27, and a heavy chain variable region comprising CDR1 of SEQ ID NO:55, CDR2 of SEQ ID NO:56 and CDR3 of SEQ ID NO:57; or An antibody or antigen-binding fragment thereof, comprising a light chain variable region comprising CDR1 of SEQ ID NO:28, CDR2 of SEQ ID NO:29, and CDR3 of SEQ ID NO:30, and a heavy chain variable region comprising CDR1 of SEQ ID NO:58, CDR2 of SEQ ID NO:59, and CDR3 of SEQ ID NO:

60.

2. comprising the light chain variable region of SEQ ID NO: 61 and the heavy chain variable region of SEQ ID NO: 71; comprising a light chain variable region of SEQ ID NO:62 and a heavy chain variable region of SEQ ID NO:72; comprising a light chain variable region of SEQ ID NO: 63 and a heavy chain variable region of SEQ ID NO: 73; comprising a light chain variable region of SEQ ID NO:64 and a heavy chain variable region of SEQ ID NO:74; comprising a light chain variable region of SEQ ID NO:65 and a heavy chain variable region of SEQ ID NO:75; comprising a light chain variable region of SEQ ID NO:66 and a heavy chain variable region of SEQ ID NO:76; comprising a light chain variable region of SEQ ID NO:67 and a heavy chain variable region of SEQ ID NO:77; comprising the light chain variable region of SEQ ID NO:68 and the heavy chain variable region of SEQ ID NO:78; comprising the light chain variable region of SEQ ID NO:69 and the heavy chain variable region of SEQ ID NO:79; or The antibody or antigen-binding fragment thereof according to claim 1, which comprises a light chain variable region of SEQ ID NO: 70 and a heavy chain variable region of SEQ ID NO:

80.

3. A pharmaceutical composition for preventing or treating a chitinase-3-like protein 1-associated disease, comprising the antibody or antigen-binding fragment thereof according to claim 1 or 2.

4. The pharmaceutical composition according to claim 3, wherein the chitinase-3-like protein 1 associated disease is cancer, cancer metastasis, arthritis or dementia.

5. The pharmaceutical composition of claim 4, wherein the chitinase-3-like protein 1 associated disease is lung cancer metastasis.

6. A diagnostic composition for chitinase-3-like protein 1-associated diseases, comprising the antibody or antigen-binding fragment thereof according to claim 1 or 2.

7. The composition according to claim 6, wherein the chitinase-3-like protein 1 associated disease is cancer, cancer metastasis, arthritis or dementia.

8. A diagnostic kit for chitinase-3-like protein 1-associated diseases, comprising the composition according to claim 6.

9. The kit according to claim 8, wherein the chitinase-3-like protein 1 associated disease is cancer, cancer metastasis, arthritis or dementia.

10. contacting the antibody or antigen-binding fragment thereof of claim 1 or 2 with a sample isolated from a test individual; measuring a complex formed by said contacting between said antibody or antigen-binding fragment thereof and chitinase-3-like protein 1; A method for providing information for diagnosing a chitinase-3-like protein 1-associated disease, comprising:

11. The method for providing information according to claim 10, wherein the chitinase-3-like protein 1-associated disease is cancer, cancer metastasis, arthritis or dementia.

12. A polynucleotide encoding the antibody or antigen-binding fragment thereof according to claim 1 or 2.

13. a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:81, a CDR2 coding sequence of SEQ ID NO:82 and a CDR3 coding sequence of SEQ ID NO:83, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:111, a CDR2 coding sequence of SEQ ID NO:112 and a CDR3 coding sequence of SEQ ID NO:113; a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:84, a CDR2 coding sequence of SEQ ID NO:85 and a CDR3 coding sequence of SEQ ID NO:86, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:114, a CDR2 coding sequence of SEQ ID NO:115 and a CDR3 coding sequence of SEQ ID NO:116; a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:87, a CDR2 coding sequence of SEQ ID NO:88 and a CDR3 coding sequence of SEQ ID NO:89, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:117, a CDR2 coding sequence of SEQ ID NO:118 and a CDR3 coding sequence of SEQ ID NO:119; a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:90, a CDR2 coding sequence of SEQ ID NO:91 and a CDR3 coding sequence of SEQ ID NO:92, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:120, a CDR2 coding sequence of SEQ ID NO:121 and a CDR3 coding sequence of SEQ ID NO:122; a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:93, a CDR2 coding sequence of SEQ ID NO:94 and a CDR3 coding sequence of SEQ ID NO:95, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:123, a CDR2 coding sequence of SEQ ID NO:124 and a CDR3 coding sequence of SEQ ID NO:125; a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:96, a CDR2 coding sequence of SEQ ID NO:97 and a CDR3 coding sequence of SEQ ID NO:98, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:126, a CDR2 coding sequence of SEQ ID NO:127 and a CDR3 coding sequence of SEQ ID NO:128; a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:99, a CDR2 coding sequence of SEQ ID NO:100 and a CDR3 coding sequence of SEQ ID NO:101, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO:129, a CDR2 coding sequence of SEQ ID NO:130 and a CDR3 coding sequence of SEQ ID NO:131; a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO: 102, a CDR2 coding sequence of SEQ ID NO: 103 and a CDR3 coding sequence of SEQ ID NO: 104, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO: 132, a CDR2 coding sequence of SEQ ID NO: 133 and a CDR3 coding sequence of SEQ ID NO: 134; a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO: 105, a CDR2 coding sequence of SEQ ID NO: 106 and a CDR3 coding sequence of SEQ ID NO: 107, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO: 135, a CDR2 coding sequence of SEQ ID NO: 136 and a CDR3 coding sequence of SEQ ID NO: 137; or 13. The polynucleotide of claim 12, comprising a light chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO: 108, a CDR2 coding sequence of SEQ ID NO: 109 and a CDR3 coding sequence of SEQ ID NO: 110, and a heavy chain variable region coding sequence comprising a CDR1 coding sequence of SEQ ID NO: 138, a CDR2 coding sequence of SEQ ID NO: 139 and a CDR3 coding sequence of SEQ ID NO:

140.

14. comprising a light chain variable region coding sequence of SEQ ID NO: 141 and a heavy chain variable region coding sequence of SEQ ID NO: 151; comprising a light chain variable region coding sequence of SEQ ID NO: 142 and a heavy chain variable region coding sequence of SEQ ID NO: 152; comprising a light chain variable region coding sequence of SEQ ID NO: 143 and a heavy chain variable region coding sequence of SEQ ID NO: 153; comprising a light chain variable region coding sequence of SEQ ID NO: 144 and a heavy chain variable region coding sequence of SEQ ID NO: 154; comprising a light chain variable region coding sequence of SEQ ID NO: 145 and a heavy chain variable region coding sequence of SEQ ID NO: 155; comprising a light chain variable region coding sequence of SEQ ID NO: 146 and a heavy chain variable region coding sequence of SEQ ID NO: 156; comprising a light chain variable region coding sequence of SEQ ID NO: 147 and a heavy chain variable region coding sequence of SEQ ID NO: 157; It comprises a light chain variable region coding sequence of SEQ ID NO:148 and a heavy chain variable region coding sequence of SEQ ID NO:

158. comprising a light chain variable region coding sequence of SEQ ID NO: 149 and a heavy chain variable region coding sequence of SEQ ID NO: 159; or 14. The polynucleotide of claim 13, comprising a light chain variable region coding sequence of SEQ ID NO: 150 and a heavy chain variable region coding sequence of SEQ ID NO:

160.

15. A vector comprising the polynucleotide of claim 12.

16. A cell transformed with the vector described in claim 15.

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