Anti-NMI monoclonal antibodies or their antigen-binding fragments and their use

Abstract

This invention provides an anti-NMI monoclonal antibody or its antigen-binding fragment and its use. The antibody or its antigen-binding fragment has good binding activity to the NMI protein and high affinity for the NMI protein, and is used to detect the presence or level of the NMI protein in a sample, to diagnose, assist in diagnosis or assess prognosis of diseases or conditions associated with abnormally high levels and / or active NMI, to remove the NMI protein from body fluids, and to prevent or treat diseases or conditions associated with abnormally high levels and / or active NMI.

Description

Technical Field

[0001] The present invention belongs to the field of antibody technology, and specifically relates to an anti-NMI monoclonal antibody or an antigen-binding fragment thereof and its use.

Background Art

[0002] When tissues are infected or damaged, molecules of a type called damage associated molecular patterns (DAMPs) are released. Such molecules can regulate the immune response, trigger an inflammatory response, thereby resist infection, and promote tissue repair. However, if DAMPs cause an overly strong or persistent inflammatory response, it may lead to damage to tissue organs and cause various acute and chronic inflammatory diseases including sepsis, pneumonia, rheumatoid arthritis, multiple sclerosis, etc.

[0003] The inventors recently discovered the IFP35 family of proteins, which includes two homologous protein molecules, IFP35 and NMI (N-myc Interacting protein), a novel family of DAMPs (Damage-Associated Molecular Patterns) proteins. In the absence of infection, injury, or interferon induction, intracellular NMI expression levels are low. When infection, injury, or interferon induction occurs in the body, the expression levels of such DAMP molecules increase significantly and they can be secreted extracellularly into bodily fluids such as blood and urine. This DAMP family of inflammatory factors is released by various immune cells (such as macrophages) in various disease models, such as salmonella infection, LPS-induced sepsis, and APAP (acetaminophen)-induced liver damage disease models, and has a pro-inflammatory effect, promoting the expression of pro-inflammatory factors such as TNF and IL-6. The inventors further found that in the case of infection induction, the release of such DAMPs is much faster than the release of HMGB1 (a previously discovered DAMP molecule) (1 hour vs. >3 hours). Research has revealed that the cell surface receptor for such novel DAMP molecules may be Toll-like receptor 4 (TLR4), and that binding to TLR4 activates the intracellular NF-κB signaling pathway, causing immune cells such as macrophages and other cells (epithelial cells, nerve cells, glial cells, etc.) to release large amounts of inflammatory cytokines, thereby promoting an improved immune response. Excessive secretion of such DAMP molecules can induce pyometra, several chronic inflammatory diseases, or autoimmune diseases (e.g., arthritis, inflammatory bowel disease, psoriasis, various encephalitis, hepatitis, multiple sclerosis, Alzheimer's disease, lupus erythematosus, pneumonia, nephritis, neurogenic inflammation, etc.). The onset and progression of these inflammatory diseases are closely related to the expression and secretion levels of such DAMPs (Zhikai Xiahou, Xiangli Wang, Juan Shen, Xiaoxiao Zhu, Feng Xu, Rong Hu, Deyin Guo, Henan Li, Yong Tian, ​​Yingfang Liu*,Huanhuan Liang* NMI and IFP35 serve as proinflammatory DAMPs during cellular infection and injury. Nat Commun. 2017; 8: 950. Published online 2017 Oct 16. doi: 10.1038 / s41467-017-00930-9. Yang Yu, Na Xu Qi Cheng, Fei Deng, Meiqin Liu, Airu Zhu, Yuan-Qin Min, Dan Zhu, Wenbo Huang, Xu Feng, Xizhong Jing, Ying Chen, Daoyuan Yue, Yawei Fan, Chang Shu, Qing Guan, Zifeng Yang, Jincun Zhao, Wenjun Song, Deyin Guo, Huanliang Liu, Jindong Zhao, Ping Lan*, Zhengli Shi*, Yingfang Liu1*, Xiaoping Chen* and Huanhuan Liang*. IFP35 as a promising biomarker and therapeutic target for the two syndromes induced by SARS-CoV-2 or influenza virus. Cell Reports. 2021 Dec 21;37(12):110126. doi: 10.1016 / j.celrep.2021.110126.、Xizhong Jing, Yongjie Yao, Danning Wu, Hao Hong, Feng Xu, Na Xu, Yingfang Liu*, Huanhuan Liang*. IFP35 family proteins promote neuroinflammation and multiple sclerosis. Proc Natl Acad Sci US A. 2021 Aug 10;118(32):e2102642118. doi: 10.1073 / pnas.2102642118.PMID: 34362845).

[0004] The development of detection kits for NMI is of significant value in meeting clinical detection needs, such as detecting the status and progression of various types of acute and chronic inflammatory diseases and autoimmune diseases caused by infection, assessing the effectiveness of treatment, and determining disease prognosis. Similar detection reagents are also urgently needed for related basic medical research. Therefore, it is necessary to develop anti-NMI monoclonal antibodies or their antigen-binding fragments. [Overview of the project]

[0005] A first aspect of the present invention aims to provide an anti-NMI antibody or an antigen-binding fragment thereof.

[0006] A second aspect of the present invention aims to provide recombinant proteins.

[0007] A third aspect of the present invention aims to provide a biomaterial related to an antibody or antigen-binding fragment thereof according to the first aspect of the present invention, or a recombinant protein according to the second aspect.

[0008] A fourth aspect of the present invention aims to provide a conjugate comprising an antibody or an antigen-binding fragment thereof according to the first aspect of the present invention.

[0009] A fifth aspect of the present invention aims to provide the use of an antibody or antigen-binding fragment thereof according to the first aspect of the present invention, a recombinant protein according to the second aspect, a biomaterial according to the third aspect, and / or a conjugate according to the fourth aspect in the manufacture of a product.

[0010] A sixth aspect of the present invention aims to provide a kit comprising an antibody or antigen-binding fragment thereof according to the first aspect of the present invention and / or a conjugate according to the sixth aspect of the present invention.

[0011] A seventh aspect of the present invention aims to provide a drug comprising an antibody or antigen-binding fragment thereof according to the first aspect of the present invention and / or a conjugate according to the sixth aspect of the present invention.

[0012] The eighth aspect of the present invention aims to provide a method for preparing an antibody or an antigen-binding fragment thereof according to the first aspect of the present invention.

[0013] A ninth aspect of the present invention aims to provide a method for detecting the presence or level of NMI.

[0014] A tenth aspect of the present invention aims to provide a method for diagnosing, assisting in the diagnosis of, or evaluating the prognosis of diseases or conditions associated with abnormally high levels and / or active NMI.

[0015] An eleventh aspect of the present invention aims to provide a method for removing NMI proteins from body fluids.

[0016] To achieve the above objective, the present invention employs the following technical approach.

[0017] According to a first aspect of the present invention, an anti-NMI antibody or an antigen-binding fragment thereof is provided, wherein the antibody or antigen-binding fragment is 94C4, B-8, 240B10-1, 98G10, or 39B4, and the antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region. The heavy chain variable region of 94C4 is one of a1) to a2) (preferably a1), a1) Including CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:4, a2) The amino acid sequence of SEQ IDNO:4 is substituted with 1, 2, 3, 4, or 5 (preferably 1 or 2) amino acids, and includes CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence having the same function as the protein shown in SEQ IDNO:4, The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The light chain variable region of 94C4 is one of b1) to b2) (preferably b1), b1) Including CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence shown in SEQ IDNO:21, b2) The amino acid sequence of SEQ IDNO:21 is substituted with 1, 2, 3, 4, or 5 (preferably 1 or 2) amino acids, and includes CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region having the same function as the protein shown in SEQ IDNO:21, The substituted amino acids are amino acids in CDR, and the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, and D97 in SEQ IDNO:21. The heavy chain variable region of B-8 is one of c1) to c2) (preferably c1), c1) Including CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence shown in SEQ IDNO:32, c2) The amino acid sequence of SEQ IDNO:32 is substituted with 1, 2, 3, 4, or 5 (preferably 1 or 2) amino acids, and includes CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence having the same function as the protein shown in SEQ IDNO:32, The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:32. The light chain variable region of B-8 is one of d1) to d2) (preferably d1), d1) Including CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence shown in SEQ IDNO:49, d2) The amino acid sequence of SEQ IDNO:49 is substituted with 1, 2, 3, 4, or 5 (preferably 1 or 2) amino acids, and includes CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region having the same function as the protein shown in SEQ IDNO:49, The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The heavy chain variable region of 240B10-1 is one of e1) to e2) (preferably e1), e1) Including CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence shown in SEQ IDNO:60, e2) The amino acid sequence of SEQ IDNO:60 is substituted with 1, 2, 3, 4, or 5 (preferably 1 or 2) amino acids, and includes CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence having the same function as the protein shown in SEQ IDNO:60, The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The light chain variable region of 240B10-1 is one of f1) to f2) (preferably f1), f1) Including CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence shown in SEQ IDNO:77, f2) The amino acid sequence of SEQ IDNO:77 is substituted with 1, 2, 3, 4, or 5 (preferably 1 or 2) amino acids, and includes CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region having the same function as the protein shown in SEQ IDNO:77, The replaced amino acids are amino acids in the CDR, and the replaced amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ ID NO: 77. The heavy chain variable region of the 98G10 is any one of g1) to g2) (preferably g1), g1) including CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence shown in SEQ ID NO: 88; g2) including CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of an amino acid sequence in which the amino acid sequence of SEQ ID NO: 88 is substituted with 1, 2, 3, 4, or 5 (preferably 1 or 2) amino acids and has the same function as the protein shown in SEQ ID NO: 88; The replaced amino acids are amino acids in the CDR, and the replaced amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D (110), I111, and Y112 in SEQ ID NO: 88. The light chain variable region of the 98G10 is any one of h1) to h2) (preferably h1), h1) including CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence shown in SEQ ID NO: 105; h2) including CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of an amino acid sequence in which the amino acid sequence of SEQ ID NO: 105 is substituted with 1, 2, 3, 4, or 5 (preferably 1 or 2) amino acids and has the same function as the protein shown in SEQ ID NO: 105; The replaced amino acids are amino acids in the CDR, and the replaced amino acids are selected from amino acids other than K53 in SEQ ID NO: 105. The heavy chain variable region of the 39B4 is any one of i1) to i2) (preferably i1), i1) comprising CDR-H1, CDR-H2 and CDR-H3 of the heavy chain variable region of the amino acid sequence shown in SEQ ID NO: 116, i2) comprising CDR-H1, CDR-H2 and CDR-H3 of the heavy chain variable region of an amino acid sequence in which the amino acid sequence of SEQ ID NO: 116 is substituted with 1, 2, 3, 4 or 5 (preferably 1 or 2) amino acids and has the same function as the protein shown in SEQ ID NO: 116, where the substituted amino acids are amino acids in the CDR, and the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, Y112 in SEQ ID NO: 116, The light chain variable region of the 39B4 is any one of j1) to j2) (preferably j1)), j1) comprising CDR-L1, CDR-L2 and CDR-L3 of the light chain variable region shown in SEQ ID NO: 132, j2) comprising CDR-L1, CDR-L2 and CDR-L3 of the light chain variable region of an amino acid sequence in which the amino acid sequence of SEQ ID NO: 132 is substituted with 1, 2, 3, 4 or 5 (preferably 1 or 2) amino acids and has the same function as the protein shown in SEQ ID NO: 132, where the substituted amino acids are amino acids in the CDR, and the substituted amino acids are selected from amino acids other than S28, N31, Y93, S96 in SEQ ID NO: 132.

[0018] Preferably, the above CDR refers to CDR-1, CDR-2 and / or CDR-3. Taking the CDR in the heavy chain variable region of 94C4 as an example, it refers to CDR-H1, CDR-H2 and / or CDR-H3. Taking the CDR in the light chain variable region of 94C4 as an example, it refers to CDR-L1, CDR-L2 and / or CDR-L3.

[0019] Preferably, the two heavy chain variable regions and two light chain variable regions of the antibody or its antigen-binding fragment (94C4, B-8, 240B10-1, 98G10, or 39B4) can be arbitrarily combined. For example, with respect to 94C4, the combination of its heavy chain variable region and light chain variable region may be a1) and b1), a1) and b2), etc.

[0020] Preferably, the combinations of the heavy chain variable region and the light chain variable region of the antibody or its antigen-binding fragment (94C4, B-8, 240B10-1, 98G10, or 39B4) are, in order, a1) and b1), c1) and d1), e1) and f1), g1) and h1), and i1) and j1).

[0021] Preferably, the substituted amino acid sequence relates to the number, position, and number of amino acids in the CDR. Here, the substituted amino acid sequence also corresponds to the selection of substituted amino acids, so there are many substituted amino acid sequences, all of which are within the scope of protection of this application, and therefore, each amino acid sequence will not be listed individually here.

[0022] The applicant requested protection of the above substituted amino acid sequences for a1), b1), c1), d1), e1), f1), g1), h1), i1), and j1) because the applicant requested that the amino acids that bind to and recognize the antigen NMI be some of the amino acids in the CDR of a1), b1), c1), d1), e1), f1), g1), h1), i1), and j1) (referred to here as important amino acids, a2), b2), c2), d2), e2), We found that the sites other than those substituted in f2), g2), h2), i2), and j2) correspond to, for example, F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105) in a2), and therefore, modifying (substituting) amino acids other than the important amino acids does not affect the function of the antibody or its antigen-binding fragment.

[0023] An anti-NMI antibody or its antigen-binding fragment, wherein the antibody or its antigen-binding fragment is 94C4, B-8, 240B10-1, 98G10, or 39B4, and the antibody or its antigen-binding fragment includes a heavy chain variable region and a light chain variable region. The 94C4 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 5, a112) SEQ IDNO:5 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:5, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:6, a212) SEQ IDNO:6 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:6, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:7, a312) SEQ IDNO:7 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:7, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:22, a412) SEQ IDNO:22 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:22, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO:23, a512) SEQ IDNO:23 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:23, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:24, a612) SEQ IDNO:24 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:24, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or When defined using the IMGT definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 8, a112) SEQ IDNO:8 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:8, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:9, a212) SEQ IDNO:9 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:9, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:10, a312) SEQ IDNO:10 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:10, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:25, a412) SEQ IDNO:25 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:25, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) RVS, a512) An amino acid sequence in which RVS is replaced by one or two (preferably one) amino acids and has the same function as RVS, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:24, a612) SEQ IDNO:24 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:24, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or When defined using Chothia's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 11, a112) SEQ IDNO:11 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:11, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 12, a212) SEQ IDNO:12 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:12, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:7, a312) SEQ IDNO:7 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:7, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:22, a412) SEQ IDNO:22 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:22, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO:23, a512) SEQ IDNO:23 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:23, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:24, a612) SEQ IDNO:24 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:24, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or When defined in the Contact definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 13, a112) SEQ IDNO:13 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:13, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 14, a212) SEQ IDNO:14 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:14, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 15, a312) SEQ IDNO:15 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:15, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:26, a412) SEQ IDNO:26 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:26, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO:27, a512) SEQ IDNO:27 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:27, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:28, a612) SEQ IDNO:28 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQIDNO:28, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or When defined using the Abm definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 16, a112) SEQ IDNO:16 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:16, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 17, a212) SEQ IDNO:17 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:17, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:7, a312) SEQ IDNO:7 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:7, wherein the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:4. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:22, a412) SEQ IDNO:22 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:22, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO:23, a512) SEQ IDNO:23 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:23, wherein the substituted amino acid is selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:24, a612) SEQ IDNO:24 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQ IDNO:24, wherein the substituted amino acid is selected from amino groups other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or The B-8 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO:33, a112) SEQ IDNO:33 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:33, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from Y33 in SEQ IDNO:32), The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:34, a212) SEQ IDNO:34 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:34, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from Y61 in SEQ IDNO:32), The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:35, a312) SEQ IDNO:35 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:35, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from F111 in SEQ IDNO:32), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 50, a412) SEQ IDNO:50 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:50, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 51, a512) SEQ IDNO:51 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:51, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 52, a612) SEQ IDNO:52 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:52, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49 (preferably the substituted amino acid is selected from S91 and Y93 in SEQ IDNO:49), or, When defined using the IMGT definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO:36, a112) SEQ IDNO:36 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:36, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from Y33 in SEQ IDNO:32), The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:37, a212) SEQ IDNO:37 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:37, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:32. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:38, a312) SEQ IDNO:38 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:38, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from F111 in SEQ IDNO:32), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 53, a412) SEQ IDNO:53 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:53, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) GAS, a512) An amino acid sequence in which GAS is replaced by one or two (preferably one) amino acids and has the same function as GAS, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 52, a612) SEQ IDNO:52 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:52, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49 (preferably the substituted amino acid is selected from S91 and Y93 in SEQ IDNO:49), or, When defined using Chothia's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO:39, a112) SEQ IDNO:39 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:39, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:32. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:40, a212) SEQ IDNO:40 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:40, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:32. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:35, a312) SEQ IDNO:35 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:35, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from F111 in SEQ IDNO:32), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 50, a412) SEQ IDNO:50 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:50, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 51, a512) SEQ IDNO:51 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:51, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 52, a612) SEQ IDNO:52 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:52, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49 (preferably the substituted amino acid is selected from S91 and Y93 in SEQ IDNO:49), or, When defined in the Contact definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 41, a112) SEQ IDNO:41 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:41, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from Y33 in SEQ IDNO:32), The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:42, a212) SEQ IDNO:42 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:42, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:32. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 43, a312) SEQ IDNO:43 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:43, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from F111 in SEQ IDNO:32), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 54, a412) SEQ IDNO:54 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:54, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 55, a512) SEQ IDNO:55 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:55, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 56, a612) SEQ IDNO:56 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:56, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49 (preferably the substituted amino acid is selected from S91 and Y93 in SEQ IDNO:49), or, When defined using the Abm definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 44, a112) SEQ IDNO:44 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:44, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from Y33 in SEQ IDNO:32), The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:45, a212) SEQ IDNO:45 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:45, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:32. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:35, a312) SEQ IDNO:35 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:35, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from F111 in SEQ IDNO:32), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 50, a412) SEQ IDNO:50 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:50, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 51, a512) SEQ IDNO:51 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:51, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 52, a612) SEQ IDNO:52 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:52, wherein the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:49 (preferably the substituted amino acid is selected from S91 and Y93 in SEQ IDNO:49), or, The 240B10-1 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 61, a112) SEQ IDNO:61 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:61, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 62, a212) SEQ IDNO:62 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:62, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 63, a312) SEQ IDNO:63 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:63, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 78, a412) SEQ IDNO:78 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:78, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 79, a512) SEQ IDNO:79 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:79, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 80, a612) SEQ IDNO:80 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQIDNO:80, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or When defined using the IMGT definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 64, a112) SEQ IDNO:64 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:64, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 65, a212) SEQ IDNO:65 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:65, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 66, a312) SEQ IDNO:66 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:66, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 81, a412) SEQ IDNO:81 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:81, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SAS, a512) An amino acid sequence in which SAS is replaced by one or two (preferably one) amino acids and has the same function as SAS, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 80, a612) SEQ IDNO:80 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQIDNO:80, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or When defined using Chothia's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 67, a112) SEQ IDNO:67 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:67, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 68, a212) SEQ IDNO:68 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:68, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 63, a312) SEQ IDNO:63 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:63, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 78, a412) SEQ IDNO:78 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:78, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 79, a512) SEQ IDNO:79 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:79, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 80, a612) SEQ IDNO:80 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQIDNO:80, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or When defined in the Contact definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 69, a112) SEQ IDNO:69 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:69, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 70, a212) SEQ IDNO:70 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:70, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 71, a312) SEQ IDNO:71 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:71, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 82, a412) SEQ IDNO:82 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:82, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 83, a512) SEQ IDNO:83 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:83, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 84, a612) SEQ IDNO:84 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:84, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or When defined using the Abm definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 72, a112) SEQ IDNO:72 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:72, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:73, a212) SEQ IDNO:73 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:73, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 63, a312) SEQ IDNO:63 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:63, wherein the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:60. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 78, a412) SEQ IDNO:78 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:78, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 79, a512) SEQ IDNO:79 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:79, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 80, a612) SEQ IDNO:80 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQIDNO:80, wherein the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or The 98G10 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 89, a112) SEQ IDNO:89 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:89, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, Y112 in SEQ IDNO:88 (preferably the substituted amino acid is selected from W34 in SEQ IDNO:88), The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:90, a212) SEQ IDNO:90 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:90, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:91, a312) SEQ IDNO:91 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:91, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88 (preferably the substituted amino acid is selected from Y112 in SEQ IDNO:88), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 106, a412) SEQ IDNO:106 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:106, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 107, a512) SEQ IDNO:107 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:107, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 108, a612) SEQ IDNO:108 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:108, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105 (preferably the substituted amino acid is selected from Y93 in SEQID NO:108), or When defined using the IMGT definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO:92, a112) SEQ IDNO:92 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:92, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, Y112 in SEQ IDNO:88 (preferably the substituted amino acid is selected from W34 in SEQ IDNO:88), The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:93, a212) SEQ IDNO:93 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:93, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:94, a312) SEQ IDNO:94 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:94, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88 (preferably the substituted amino acid is selected from Y112 in SEQ IDNO:88), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 109, a412) SEQ IDNO:109 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:109, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) TAS, a512) The TAS is substituted with one or two (preferably one) amino acids, and the amino acid sequence has the same function as the TAS, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 108, a612) SEQ IDNO:108 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:108, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105 (preferably the substituted amino acid is selected from Y93 in SEQID NO:108), or When defined using Chothia's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO:95, a112) SEQ IDNO:95 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:95, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:96, a212) SEQ IDNO:96 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:96, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:91, a312) SEQ IDNO:91 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:91, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88 (preferably the substituted amino acid is selected from Y112 in SEQ IDNO:88), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 106, a412) SEQ IDNO:106 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:106, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 107, a512) SEQ IDNO:107 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:107, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 108, a612) SEQ IDNO:108 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:108, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105 (preferably the substituted amino acid is selected from Y93 in SEQID NO:108), or When defined in the Contact definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO:97, a112) SEQ IDNO:97 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:97, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88 (preferably the substituted amino acid is selected from W34 in SEQ IDNO:88), The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO:98, a212) SEQ IDNO:98 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:98, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:99, a312) SEQ IDNO:99 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:99, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88 (preferably the substituted amino acid is selected from Y112 in SEQ IDNO:88), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 110, a412) SEQ IDNO:110 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:110, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 111, a512) SEQ IDNO:111 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:111, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 112, a612) SEQ IDNO:112 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:112, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105 (preferably the substituted amino acid is selected from Y93 in SEQID NO:108), or, When defined using the Abm definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 100, a112) SEQ IDNO:100 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:100, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88 (preferably the substituted amino acid is selected from W34 in SEQ IDNO:88), The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 101, a212) SEQ IDNO:101 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:101, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:91, a312) SEQ IDNO:91 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:91, wherein the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:88 (preferably the substituted amino acid is selected from Y112 in SEQ IDNO:88), The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 106, a412) SEQ IDNO:106 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:106, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 107, a512) SEQ IDNO:107 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:107, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 108, a612) SEQ IDNO:108 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:108, wherein the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:105 (preferably the substituted amino acid is selected from Y93 in SEQ ID NO:108), or, The 39B4 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 117, a112) SEQ IDNO:117 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:117, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 118, a212) SEQ IDNO:118 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:118, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 119, a312) SEQ IDNO:119 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:119, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 133, a412) SEQ IDNO:133 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:133, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 134, a512) SEQ IDNO:134 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:134, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 135, a612) SEQ IDNO:135 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:135, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132, or When defined using the IMGT definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 120, a112) SEQ IDNO:120 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:120, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 121, a212) SEQ IDNO:121 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQIDNO:121, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 122, a312) SEQ IDNO:122 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:122, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 136, a412) SEQ IDNO:136 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:136, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SAS, a512) An amino acid sequence in which SAS is replaced by one or two (preferably one) amino acids and has the same function as SAS, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 135, a612) SEQ IDNO:135 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:135, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132, or When defined using Chothia's definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 120, a112) SEQ IDNO:120 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:120, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 123, a212) SEQ IDNO:123 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:123, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 119, a312) SEQ IDNO:119 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:119, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 133, a412) SEQ IDNO:133 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:133, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 134, a512) SEQ IDNO:134 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:134, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 135, a612) SEQ IDNO:135 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:135, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132, or When defined in the Contact definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 117, a112) SEQ IDNO:117 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:117, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 124, a212) SEQ IDNO:124 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:124, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 125, a312) SEQ IDNO:125 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:125, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 137, a412) SEQ IDNO:137 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:137, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 138, a512) SEQ IDNO:138 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQID NO:138, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 139, a612) SEQ IDNO:139 is substituted with 1, 2, or 3 (preferably 1) amino acids, and has the same function as the protein shown in SEQIDNO:139, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132, or When defined using the Abm definition scheme, The CDR-H1 is one of the following types: a111) to a112) a111) SEQ ID NO: 126, a112) SEQ IDNO:126 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:126, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H2 is one of the following types: a211) to a212) a211) SEQ ID NO: 127, a212) SEQ IDNO:127 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:127, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 128, a312) SEQ IDNO:128 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQID NO:128, wherein the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:116. The aforementioned CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 133, a412) SEQ IDNO:133 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQIDNO:133, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 134, a512) SEQ IDNO:134 is substituted with 1, 2, or 3 (preferably 1) amino acids, and is an amino acid sequence having the same function as the protein shown in SEQID NO:134, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132. The aforementioned CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 135, a612) SEQ IDNO:135 is an amino acid sequence in which one, two, or three (preferably one) amino acids are substituted, and which has the same function as the protein shown in SEQID NO:135, wherein the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132.

[0024] Preferably, CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of different definition schemes for the above-mentioned antibody or its antigen-binding fragment (94C4, B-8, 240B10-1, 98G10, or 39B4) can be arbitrarily combined. For example, using the Kabat definition scheme for 94C4, combinations of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 may be a111), a211), a311), a411), a511), and a611), and so on, which will not be listed here individually.

[0025] Preferably, the substituted amino acid or inserted amino acid is alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid This includes, but is not limited to, 2-aminopimelic acid, 2,4-diaminobutyric acid, lysine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylaspartic acid, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isolidine, allo-isoleucine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, and ornithine, and may be any amino acid present in the prior art.

[0026] Preferably, the substituted amino acid sequence relates to the number and position of the substituted amino acids and the number of amino acids in the corresponding CDR (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and / or CDR-L3). Here, the substituted amino acid sequence also corresponds to the selection of the substituted amino acids, so there are many substituted amino acid sequences, all of which are within the scope of protection of this application, and therefore, each amino acid sequence will not be listed individually here.

[0027] The applicant requested protection for the above-mentioned substituted amino acid sequences (i.e., a112), a212), a312), a412), a512), a611) for a111), a211), a311), a312), a412), a512), a612)) because the applicant found that the amino acids that bind to and recognize the antigen NMI are some of the amino acids in a111), a211), a311), a411), a511), a611) (referred to here as important amino acids), and therefore, substituting amino acids other than these (important amino acids) does not affect the function of the monoclonal antibody or its antigen-binding fragment.

[0028] Preferably, the amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 94C4 are shown in SEQ IDNO: 5, 6, 7, 22, 23, and 24, respectively, and the CDRs are defined according to the Kabat definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of 94C4 are shown in SEQ IDNO: 8, 9, 10, 25, and 24, respectively, the amino acid sequence of CDR-L2 is RVS, and the CDRs are defined according to the IMGT definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of the aforementioned 94C4 are shown in SEQ IDNO: 11, 12, 7, 22, 23, and 24, respectively, and the CDRs are defined according to Chothia's definition scheme, or, The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of the aforementioned 94C4 are shown in SEQ IDNO: 13, 14, 15, 26, 27, and 28, respectively, and the CDRs are defined according to the Contact definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 94C4 are shown in SEQ IDNO: 16, 17, 7, 22, 23, and 24, respectively, and the CDRs are defined according to the Abm definition scheme.

[0029] Preferably, the amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 61, 62, 63, 78, 79, and 80, respectively, and the CDRs are defined according to the Kabat definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 64, 65, 66, 81, and 80, respectively, the amino acid sequence of CDR-L2 is SAS, and the CDRs are defined according to the IMGT definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 67, 68, 63, 78, 79, and 80, respectively, and the CDRs are defined according to Chothia's definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 69, 70, 71, 82, 83, and 84, respectively, and the CDRs are defined according to the Contact definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 72, 73, 63, 78, 79, and 80, respectively, and the CDRs are defined according to the Abm definition scheme.

[0030] Preferably, the amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 39B4 are shown in SEQ IDNO: 117, 118, 119, 133, 134, and 135, respectively, and the CDRs are defined according to the Kabat definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of 39B4 are shown in SEQ IDNO: 120, 121, 122, 136, and 135, respectively, the amino acid sequence of CDR-L2 is SAS, and CDR is defined according to the IMGT definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 39B4 are shown in SEQ IDNO: 120, 123, 119, 133, 134, and 135, respectively, and the CDRs are defined according to Chothia's definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 39B4 are shown in SEQ IDNO: 117, 124, 125, 137, 138, and 139, respectively, and the CDRs are defined in the Contact definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 39B4 are shown in SEQ IDNO: 126, 127, 128, 133, 134, and 135, respectively, and the CDRs are defined according to the Abm definition scheme.

[0031] Preferably, m1) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8 are shown in SEQ IDNO: 33, 34, 35, 50, 51, and 52, respectively, and the CDRs are defined according to the Kabat definition scheme (corresponding to B-8 in Table 17-8), or, m2) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m1), have the following mutations: a Y33E mutation in SEQ ID NO:32 (i.e., the 33rd Y in SEQ ID NO:32 is mutated to E (i.e., the 33rd Y is replaced with E, and so on), the 4th Y in CDR-H1 is mutated to E, the other CDRs remain unchanged, corresponding to the B-8-3 mutant in Table 17-8), and the CDRs are defined according to the Kabat definition scheme, or, m3) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m1), have the following mutations: a Y61E mutation in SEQ ID NO:32 (i.e., the 61st Y in SEQ ID NO:32 mutates to E, the 12th Y in CDR-H2 mutates to E, other CDRs remain unchanged, corresponding to the B-8-4 mutant in Table 17), the CDRs are defined according to the Kabat definition scheme, or, m4) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m1, have the following mutations: a mutation of F111A in SEQ ID NO:32 (i.e., the 111th F in SEQ ID NO:32 mutates to A, the 13th F in CDR-H3 mutates to A, the other CDRs remain unchanged, corresponding to the B-8-5 mutant in Table 17-8), the CDRs are defined according to the Kabat definition scheme, or, m5) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m1), have the following mutations: a Y93E mutation in SEQ ID NO:49 (i.e., the 93rd Y in SEQ ID NO:49 mutates to E, the 5th Y in CDR-L3 mutates to E, other CDRs remain unchanged, corresponding to the B-8-1 mutant in Table 17-8), the CDRs are defined according to the Kabat definition scheme, or, m6) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m1), have the following mutations: a mutation of S91R in SEQ ID NO:49 (i.e., the 91st S mutates to R in SEQ ID NO:49, the 3rd S mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the B-8-2 mutant in Table 17-8), the CDRs are defined according to the Kabat definition scheme, or, m7) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of B-8 are shown in SEQ IDNO: 36, 37, 38, 53, and 52, respectively, the amino acid sequence of CDR-L2 is GAS, and the CDR is defined according to the IMGT definition scheme (corresponding to B-8 and B-8-4 in Table 17-8), or, m8) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m7), have the following mutations: a Y33E mutation in SEQ ID NO:32 (i.e., the 33rd Y in SEQ ID NO:32 mutates to E, the 9th Y in CDR-H1 mutates to E, the other CDRs remain unchanged, corresponding to the B-8-3 mutant in Table 17-8), the CDRs are defined according to the IMGT definition scheme, or, m9) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m7), have the following mutations: a mutation of F111A in SEQ ID NO:32 (i.e., the 111th F in SEQ ID NO:32 mutates to A, the 15th F in CDR-H3 mutates to A, the other CDRs remain unchanged, corresponding to the B-8-5 mutant in Table 17-8), the CDRs are defined according to the IMGT definition scheme, or, m10) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m7), have the following mutations: a Y93E mutation in SEQ ID NO:49 (i.e., the 93rd Y in SEQ ID NO:49 mutates to E, the 5th Y in CDR-L3 mutates to E, other CDRs remain unchanged, corresponding to the B-8-1 mutant in Table 17-8), the CDRs are defined according to the IMGT definition scheme, or, m11) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m7), have the following mutations: a mutation of S91R in SEQ ID NO:49 (i.e., the 91st S mutates to R in SEQ ID NO:49, the 3rd S mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the B-8-2 mutant in Table 17-8), the CDRs are defined according to the IMGT definition scheme, or, m12) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8 are shown in order as SEQ IDNO: 50, 51, 52, 67, 68, and 63, respectively, and the CDRs are defined according to Chothia's definition scheme (corresponding to B-8, B-8-3, and B-8-4 in Table 17-8), or, m13) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m12), have the following mutations: a mutation of F111A in SEQ ID NO:32 (i.e., the 111th F in SEQ ID NO:32 mutates to A, the 13th F in CDR-H3 mutates to A, the other CDRs remain unchanged, corresponding to the B-8-5 mutant in Table 17-8), the CDRs are defined according to Chothia's definition scheme, or, m14) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m12), have the following mutations: a Y93E mutation in SEQ ID NO:49 (i.e., the 93rd Y in SEQ ID NO:49 mutates to E, the 5th Y in CDR-L3 mutates to E, the other CDRs remain unchanged, corresponding to the B-8-1 mutant in Table 17-8), the CDRs are defined according to Chothia's definition scheme, or, m15) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m12), have the following mutations: a mutation of S91R in SEQ ID NO:49 (i.e., the 91st S mutates to R in SEQ ID NO:49, the 3rd S mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the B-8-2 mutant in Table 17-8), the CDRs are defined according to Chothia's definition scheme, or, m16) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8 are shown in order as SEQ IDNO: 41, 42, 43, 54, 55, and 56, respectively, and the CDRs are defined in the Contact definition scheme (corresponding to B-8 and B-8-4 in Table 17-8), or, m17) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m16), have the following mutations: a Y33E mutation in SEQ ID NO:32 (i.e., the 33rd Y in SEQ ID NO:32 mutates to E, the 5th Y in CDR-H1 mutates to E, the other CDRs remain unchanged, corresponding to the B-8-3 mutant in Table 17-8), the CDRs are defined in the Contact definition scheme, or, m18) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m16), have the following mutations: a mutation of F111A in SEQ ID NO:32 (i.e., the 111th F in SEQ ID NO:32 mutates to A, the 15th F in CDR-H3 mutates to A, the other CDRs remain unchanged, corresponding to the B-8-5 mutant in Table 17-8), the CDRs are defined in the Contact definition scheme, or, m19) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m16), have the following mutations: a Y93E mutation in SEQ ID NO:49 (i.e., the 93rd Y in SEQ ID NO:49 mutates to E, the 5th Y in CDR-L3 mutates to E, the other CDRs remain unchanged, corresponding to the B-8-1 mutant in Table 17-8), the CDRs are defined in the Contact definition scheme, or, m20) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m16), have the following mutations: a mutation of S91R in SEQ ID NO:49 (i.e., the 91st S mutates to R in SEQ ID NO:49, the 3rd S mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the B-8-2 mutant in Table 17-8), the CDRs are defined in the Contact definition scheme, or, m21) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8 are shown in SEQ IDNO: 44, 45, 35, 50, 51, and 52, respectively, and the CDRs are defined according to the Abm definition scheme (corresponding to B-8 and B-8-4 in Table 17-8), or, m22) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m21), have the following mutations: a Y33E mutation in SEQ ID NO:32 (i.e., the 33rd Y in SEQ ID NO:32 mutates to E, the 9th Y in CDR-H1 mutates to E, the other CDRs remain unchanged, corresponding to the B-8-3 mutant in Table 17-8), the CDRs are defined according to the Abm definition scheme, or, m23) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m21), have the following mutations: a mutation of F111A in SEQ ID NO:32 (i.e., the 111th F in SEQ ID NO:32 mutates to A, the 13th F in CDR-H3 mutates to A, the other CDRs remain unchanged, corresponding to the B-8-5 mutant in Table 17-8), the CDRs are defined in the Abm definition scheme, or, m24) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m21), have the following mutations: a Y93E mutation in SEQ ID NO:49 (i.e., the 93rd Y in SEQ ID NO:49 mutates to E, the 5th Y in CDR-L3 mutates to E, the other CDRs remain unchanged, corresponding to the B-8-1 mutant in Table 17-8), the CDRs are defined according to the Abm definition scheme, or, m25) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in m21), have the following mutations: a mutation of S91R in SEQ ID NO:49 (i.e., the 91st S mutates to R in SEQ ID NO:49, the 3rd S mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the B-8-2 mutant in Table 17-8), and the CDRs are defined according to Abm's definition scheme.

[0032] Preferably, n1) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10 are shown in SEQ IDNO: 89, 90, 91, 106, 107, and 108, respectively, and the CDRs are defined according to the Kabat definition scheme (corresponding to 98G10 in Table 17-6), or, n2) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: a W34H mutation in SEQ ID NO:88 (i.e., the 34th W in SEQ ID NO:88 mutates to H, the 4th W in CDR-H1 mutates to H, the other CDRs remain unchanged, corresponding to the 98G10-H-1 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n3) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: a W34Y mutation in SEQ ID NO:88 (i.e., the 34th W mutates to Y in SEQ ID NO:88, the 4th W mutates to Y in CDR-H1, the other CDRs remain unchanged, corresponding to the 98G10-H-2 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n4) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: a Y112R mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to R, the 13th Y in CDR-H3 mutates to R, other CDRs remain unchanged, corresponding to the 98G10-H-3 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n5) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: a Y112S mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to S, the 13th Y in CDR-H3 mutates to S, the other CDRs remain unchanged, corresponding to the 98G10-H4 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n6) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: a Y112E mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to E, the 13th Y in CDR-H3 mutates to E, other CDRs remain unchanged, corresponding to the 98G10-H-5 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n7) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: a Y112Q mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to Q, the 13th Y in CDR-H3 mutates to Q, other CDRs remain unchanged, corresponding to the 98G10-H-6 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n8) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: mutations of W34R and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to R, the 112th Y mutates to R, the 4th W mutates to R in CDR-H1, the 13th Y mutates to R in CDR-H3, the other CDRs remain unchanged, corresponding to the 98G10-H-7 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n9) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: mutations of W34D and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to D and the 112th Y mutates to R, in CDR-H1 the 4th W mutates to D, in CDR-H3 the 13th Y mutates to R, with the other CDRs remaining unchanged, corresponding to the 98G10-H-8 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n10) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: mutations in W34H and Y112L in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to L, in CDR-H1 the 4th W mutates to H, in CDR-H3 the 13th Y mutates to L, other CDRs remain unchanged, corresponding to the 98G10-H-9 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n11) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: W34T and Y112R mutations in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to T and the 112th Y mutates to R, in CDR-H1 the 4th W mutates to T, in CDR-H3 the 13th Y mutates to R, and the other CDRs remain unchanged, corresponding to the 98G10-H-10 mutants in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n12) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: mutations at W34H and Y112R in SEQ ID NO:88 (i.e., the 34th W mutates to H and the 112th Y mutates to R in SEQID NO:88, the 4th W mutates to H in CDR-H1, and the 13th Y mutates to R in CDR-H3, with the other CDRs remaining unchanged, corresponding to the 98G10-H-11 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n13) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: mutations in W34H and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to S; in CDR-H1, the 4th W mutates to H; in CDR-H3, the 13th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-12 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n14) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: mutations of W34K and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to K and the 112th Y mutates to S; in CDR-H1, the 4th W mutates to K; in CDR-H3, the 13th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-13 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n15) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: mutations of W34D and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to D and the 112th Y mutates to S; in CDR-H1, the 4th W mutates to D; in CDR-H3, the 13th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-14 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n16) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: a Y93R mutation in SEQ ID NO:105 (i.e., the 93rd Y mutates to R in SEQ ID NO:105, the 5th Y mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the 98G10-L-1 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n17) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: a Y93S mutation in SEQ ID NO:105 (i.e., the 93rd Y in SEQ ID NO:105 mutates to S, the 5th Y in CDR-L3 mutates to S, other CDRs remain unchanged, corresponding to the 98G10-L-2 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n18) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n1), have the following mutations: a Y93Q mutation in SEQ ID NO:105 (i.e., the 93rd Y in SEQ ID NO:105 mutates to Q, the 5th Y in CDR-L3 mutates to Q, other CDRs remain unchanged, corresponding to the 98G10-L-3 mutant in Table 17-6), the CDRs are defined according to the Kabat definition scheme, or, n20) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of 98G10 are shown in SEQ IDNO: 92, 93, 94, 109, and 108, respectively, the amino acid sequence of CDR-L2 is TAS, and the CDR is defined according to the IMGT definition scheme (corresponding to 98G10 in Table 17-6), or, n21) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: a W34H mutation in SEQ ID NO:88 (i.e., the 34th W mutates to H in SEQ ID NO:88, the 9th W mutates to H in CDR-H1, the other CDRs remain unchanged, corresponding to the 98G10-H-1 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n22) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations, which are W34Y mutations in SEQ ID NO:88 (i.e., the 34th W mutates to Y in SEQ ID NO:88, the 9th W mutates to Y in CDR-H1, the other CDRs remain unchanged, corresponding to the 98G10-H-2 mutant in Table 17-6), and the CDRs are defined according to the IMGT definition scheme, or, n23) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: a Y112R mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to R, the 15th Y in CDR-H3 mutates to R, other CDRs remain unchanged, corresponding to the 98G10-H-3 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n24) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: a Y112S mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to S, the 15th Y in CDR-H3 mutates to S, other CDRs remain unchanged, corresponding to the 98G10-H-4 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n25) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: a Y112E mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to E, the 15th Y in CDR-H3 mutates to E, the other CDRs remain unchanged, corresponding to the 98G10-H-5 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n26) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: a Y112Q mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to Q, the 15th Y in CDR-H3 mutates to Q, other CDRs remain unchanged, corresponding to the 98G10-H-6 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n27) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: mutations of W34R and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to R, the 112th Y mutates to R, in CDR-H1 the 9th W mutates to R, in CDR-H3 the 15th Y mutates to R, other CDRs remain unchanged, corresponding to the 98G10-H-7 mutant in Table 17-6), the CDRs are defined in the IMGT definition scheme, or, n28) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: mutations of W34D and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to D and the 112th Y mutates to R, in CDR-H1 the 9th W mutates to D, in CDR-H3 the 15th Y mutates to R, and the other CDRs remain unchanged, corresponding to the 98G10-H-8 mutant in Table 17-6), the CDRs are defined in the IMGT definition scheme, or, n29) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: mutations at W34H and Y112L in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to L; in CDR-H1, the 9th W mutates to H; in CDR-H3, the 15th Y mutates to L, while other CDRs remain unchanged, corresponding to the 98G10-H-9 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n30) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: W34T and Y112R mutations in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to T and the 112th Y mutates to R, in CDR-H1 the 9th W mutates to T, in CDR-H3 the 15th Y mutates to R, and the other CDRs remain unchanged, corresponding to the 98G10-H-10 mutant in Table 17-6), the CDRs are defined in the IMGT definition scheme, or, n31) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: mutations at W34H and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to R, in CDR-H1 the 9th W mutates to H, in CDR-H3 the 15th Y mutates to R, with the other CDRs remaining unchanged, corresponding to the 98G10-H-11 mutant in Table 17-6), the CDRs are defined in the IMGT definition scheme, or, n32) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: mutations of W34H and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to S, in CDR-H1 the 9th W mutates to H, in CDR-H3 the 15th Y mutates to S, and the other CDRs remain unchanged, corresponding to the 98G10-H-12 mutant in Table 17-6), the CDRs are defined in the IMGT definition scheme, or, n33) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: mutations of W34K and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to K and the 112th Y mutates to S; in CDR-H1, the 9th W mutates to K; in CDR-H3, the 15th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-13 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n34) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: mutations of W34D and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to D and the 112th Y mutates to S; in CDR-H1, the 9th W mutates to D; in CDR-H3, the 15th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-14 mutant in Table 17-6), the CDRs are defined in the IMGT definition scheme, or, n35) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: a Y93R mutation in SEQ ID NO:105 (i.e., the 93rd Y mutates to R in SEQ ID NO:105, the 5th Y mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the 98G10-L-1 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n36) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: a Y93S mutation in SEQ ID NO:105 (i.e., the 93rd Y in SEQ ID NO:105 mutates to S, the 5th Y in CDR-L3 mutates to S, the other CDRs remain unchanged, corresponding to the 98G10-L-2 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n37) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n20), have the following mutations: a Y93Q mutation in SEQ ID NO:105 (i.e., the 93rd Y mutates to Q in SEQ ID NO:105, the 5th Y mutates to Q in CDR-L3, the other CDRs remain unchanged, corresponding to the 98G10-L-3 mutant in Table 17-6), the CDRs are defined according to the IMGT definition scheme, or, n39) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10 are shown in SEQ IDNO: 95, 96, 91, 106, 107, and 108, respectively, and the CDRs are defined according to Chothia's definition scheme (corresponding to 98G10, 98G10-H-1, and 98G10-H-2 in Table 17-6), or, n40) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n39), show the following mutations: a Y112R mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to R, the 13th Y in CDR-H3 mutates to R, and the other CDRs remain unchanged, corresponding to the 98G10-H-3, 98G10-H-7, 98G10-H-8, 98G10-H-10, and 98G10-H-11 mutants in Table 17-6), the CDRs are defined according to Chothia's definition scheme, or, n41) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n39), have the following mutations: a Y112S mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to S, the 13th Y in CDR-H3 mutates to S, and the other CDRs remain unchanged, corresponding to the 98G10-H-4, 98G10-H-12, 98G10-H-13, and 98G10-H-14 mutants in Table 17-6), the CDRs are defined according to Chothia's definition scheme, or, n42) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n39), have the following mutations: a Y112E mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to E, the 13th Y in CDR-H3 mutates to E, the other CDRs remain unchanged, corresponding to the 98G10-H-5 mutant in Table 17-6), the CDRs are defined according to Chothia's definition scheme, or, n43) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n39), have the following mutations: a Y112Q mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to Q, the 13th Y in CDR-H3 mutates to Q, other CDRs remain unchanged, corresponding to the 98G10-H-6 mutant in Table 17-6), the CDRs are defined according to Chothia's definition scheme, or, n44) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n39), have the following mutations: a Y112L mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to L, the 13th Y in CDR-H3 mutates to L, other CDRs remain unchanged, corresponding to the 98G10-H-9 mutant in Table 17-6), the CDRs are defined according to Chothia's definition scheme, or, n45) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n39), have the following mutations: a Y93R mutation in SEQ ID NO:105 (i.e., the 93rd Y mutates to R in SEQ ID NO:105, the 5th Y mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the 98G10-L-1 mutant in Table 17-6), the CDRs are defined according to Chothia's definition scheme, or, n46) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n39), have the following mutations: a Y93S mutation in SEQ ID NO:105 (i.e., the 93rd Y mutates to S in SEQ ID NO:105, the 5th Y mutates to S in CDR-L3, the other CDRs remain unchanged, corresponding to the 98G10-L-2 mutant in Table 17-6), the CDRs are defined according to Chothia's definition scheme, or, n47) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n39), have the following mutations: a Y93Q mutation in SEQ ID NO:105 (i.e., the 93rd Y mutates to Q in SEQ ID NO:105, the 5th Y mutates to Q in CDR-L3, the other CDRs remain unchanged, corresponding to the 98G10-L-3 mutant in Table 17-6), the CDRs are defined according to Chothia's definition scheme, or, n48) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10 are shown in order as SEQ IDNO: 97, 98, 99, 110, 111, and 112, respectively, and the CDRs are defined in the Contact definition scheme (corresponding to 98G10 in Table 17-6), or, n49) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: a W34H mutation in SEQ ID NO:88 (i.e., the 34th W mutates to H in SEQ ID NO:88, the 5th W mutates to H in CDR-H1, the other CDRs remain unchanged, corresponding to the 98G10-H-1 mutant in Table 17-6), the CDRs are defined in the Contact definition scheme, or, n50) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: a W34Y mutation in SEQ ID NO:88 (i.e., the 34th W mutates to Y in SEQ ID NO:88, the 5th W mutates to Y in CDR-H1, the other CDRs remain unchanged, corresponding to the 98G10-H-2 mutant in Table 17-6), the CDRs are defined in the Contact definition scheme, or, n51) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: a Y112R mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to R, the 15th Y in CDR-H3 mutates to R, other CDRs remain unchanged, corresponding to the 98G10-H-3 mutant in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n52) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: a Y112S mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to S, the 15th Y in CDR-H3 mutates to S, the other CDRs remain unchanged, corresponding to the 98G10-H-4 mutant in Table 17-6), the CDRs are defined in the Contact definition scheme, or, n53) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: a Y112E mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to E, the 15th Y in CDR-H3 mutates to E, other CDRs remain unchanged, corresponding to the 98G10-H-5 mutant in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n54) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: a Y112Q mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to Q, the 15th Y in CDR-H3 mutates to Q, other CDRs remain unchanged, corresponding to the 98G10-H-6 mutant in Table 17-6), the CDRs are defined in the Contact definition scheme, or, n55) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: mutations of W34R and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to R, the 112th Y mutates to R, the 5th W mutates to R in CDR-H1, the 15th Y mutates to R in CDR-H3, the other CDRs remain unchanged, corresponding to the 98G10-H-7 mutant in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n56) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: mutations of W34D and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to D and the 112th Y mutates to R, in CDR-H1 the 5th W mutates to D, in CDR-H3 the 15th Y mutates to R, with the other CDRs remaining unchanged, corresponding to the 98G10-H-8 mutant in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n57) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: mutations at W34H and Y112L in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to L, in CDR-H1 the 5th W mutates to H, in CDR-H3 the 15th Y mutates to L, other CDRs remain unchanged, corresponding to the 98G10-H-9 mutant in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n58) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: mutations of W34T and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to T and the 112th Y mutates to R, in CDR-H1 the 5th W mutates to T, in CDR-H3 the 15th Y mutates to R, and the other CDRs remain unchanged, corresponding to the 98G10-H-10 mutants in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n59) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: mutations at W34H and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to R, in CDR-H1 the 5th W mutates to H, in CDR-H3 the 15th Y mutates to R, with the other CDRs remaining unchanged, corresponding to the 98G10-H-11 mutant in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n60) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: mutations of W34H and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to S, in CDR-H1 the 5th W mutates to H, in CDR-H3 the 15th Y mutates to S, with the other CDRs remaining unchanged, corresponding to the 98G10-H-12 mutant in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n61) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: mutations of W34K and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to K and the 112th Y mutates to S; in CDR-H1, the 5th W mutates to K; in CDR-H3, the 15th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-13 mutant in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n62) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: mutations of W34D and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to D and the 112th Y mutates to S; in CDR-H1, the 5th W mutates to D; in CDR-H3, the 15th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-14 mutant in Table 17-6), the CDRs are defined in Contact's definition scheme, or, n63) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: a Y93R mutation in SEQ ID NO:105 (i.e., the 93rd Y mutates to R in SEQ ID NO:105, the 5th Y mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the 98G10-L-1 mutant in Table 17-6), the CDRs are defined in the Contact definition scheme, or, n64) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: a Y93S mutation in SEQ ID NO:105 (i.e., the 93rd Y in SEQ ID NO:105 mutates to S, the 5th Y in CDR-L3 mutates to S, other CDRs remain unchanged, corresponding to the 98G10-L-2 mutant in Table 17-6), the CDRs are defined in the Contact definition scheme, or, n65) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n48), have the following mutations: a Y93Q mutation in SEQ ID NO:105 (i.e., the 93rd Y in SEQ ID NO:105 mutates to Q, the 5th Y in CDR-L3 mutates to Q, other CDRs remain unchanged, corresponding to the 98G10-L-3 mutant in Table 17-6), the CDRs are defined in the Contact definition scheme, or, n66) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10 are shown in SEQ IDNO: 100, 101, 91, 106, 107, and 108, respectively, and the CDRs are defined according to the Abm definition scheme (corresponding to 98G10 in Table 17-6), or, n67) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: a W34H mutation in SEQ ID NO:88 (i.e., the 34th W mutates to H in SEQ ID NO:88, the 9th W mutates to H in CDR-H1, the other CDRs remain unchanged, corresponding to the 98G10-H-1 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n68) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: a W34Y mutation in SEQ ID NO:88 (i.e., the 34th W mutates to Y in SEQ ID NO:88, the 9th W mutates to Y in CDR-H1, the other CDRs remain unchanged, corresponding to the 98G10-H-2 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n69) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: a Y112R mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to R, the 13th Y in CDR-H3 mutates to R, other CDRs remain unchanged, corresponding to the 98G10-H-3 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n70) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: a Y112S mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to S, the 13th Y in CDR-H3 mutates to S, the other CDRs remain unchanged, corresponding to the 98G10-H-4 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n71) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: a Y112E mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to E, the 13th Y in CDR-H3 mutates to E, the other CDRs remain unchanged, corresponding to the 98G10-H-5 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n72) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: a Y112Q mutation in SEQ ID NO:88 (i.e., the 112th Y in SEQ ID NO:88 mutates to Q, the 13th Y in CDR-H3 mutates to Q, other CDRs remain unchanged, corresponding to the 98G10-H-6 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n73) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: mutations of W34R and Y112R in SEQ IDNO:88 (i.e., in SEQ IDNO:88, the 34th W mutates to R, the 112th Y mutates to R, the 9th W mutates to R in CDR-H1, the 13th Y mutates to R in CDR-H3, the other CDRs remain unchanged, corresponding to the 98G10-H-7 mutant in Table 17-6), and the CDRs are defined according to the Abm definition scheme, or, n74) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: mutations of W34D and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to D and the 112th Y mutates to R, in CDR-H1 the 9th W mutates to D, in CDR-H3 the 13th Y mutates to R, with the other CDRs remaining unchanged, corresponding to the 98G10-H-8 mutant in Table 17-6), the CDRs are defined in the Abm definition scheme, or, n75) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: mutations at W34H and Y112L in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to L; in CDR-H1, the 9th W mutates to H; in CDR-H3, the 13th Y mutates to L, while other CDRs remain unchanged, corresponding to the 98G10-H-9 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n76) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: the W34T and Y112R mutations in SEQ ID NO:88 (i.e., the 34th W mutates to T and the 112th Y mutates to R in SEQID NO:88, the 9th W mutates to T in CDR-H1, and the 13th Y mutates to R in CDR-H3, with the other CDRs remaining unchanged, corresponding to the 98G10-H-10 mutants in Table 17-6), and the CDRs are defined according to Abm's definition scheme, or, n77) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: mutations at W34H and Y112R in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to R, in CDR-H1 the 9th W mutates to H, in CDR-H3 the 13th Y mutates to R, with the other CDRs remaining unchanged, corresponding to the 98G10-H-11 mutant in Table 17-6), the CDRs are defined in the Abm definition scheme, or, n78) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: mutations of W34H and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to H and the 112th Y mutates to S; in CDR-H1, the 9th W mutates to H; in CDR-H3, the 13th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-12 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n79) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: mutations of W34K and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to K and the 112th Y mutates to S; in CDR-H1, the 9th W mutates to K; in CDR-H3, the 13th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-13 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n80) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: mutations of W34D and Y112S in SEQ ID NO:88 (i.e., in SEQID NO:88, the 34th W mutates to D and the 112th Y mutates to S; in CDR-H1, the 9th W mutates to D; in CDR-H3, the 13th Y mutates to S, while other CDRs remain unchanged, corresponding to the 98G10-H-14 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n81) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: a Y93R mutation in SEQ ID NO:105 (i.e., the 93rd Y mutates to R in SEQ ID NO:105, the 5th Y mutates to R in CDR-L3, the other CDRs remain unchanged, corresponding to the 98G10-L-1 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n82) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: a Y93S mutation in SEQ ID NO:105 (i.e., the 93rd Y in SEQ ID NO:105 mutates to S, the 5th Y in CDR-L3 mutates to S, other CDRs remain unchanged, corresponding to the 98G10-L-2 mutant in Table 17-6), the CDRs are defined according to the Abm definition scheme, or, n83) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 in n66), have the following mutations: a Y93Q mutation in SEQ ID NO:105 (i.e., the 93rd Y in SEQ ID NO:105 mutates to Q, the 5th Y in CDR-L3 mutates to Q, the other CDRs remain unchanged, corresponding to the 98G10-L-3 mutant in Table 17-6), and the CDRs are defined according to Abm's definition scheme.

[0033] Preferably, the amino acid sequence of the heavy chain variable region of 94C4 is: a1111) SEQ IDNO:4, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in a2111) and a1111), and having the same function as the protein of the amino acid sequence described in a1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in a3111) and / or, and having the same function as the protein of the amino acid sequence described in a1111), The amino acid sequence of the 94C4 light chain variable region is: b1111) SEQ IDNO:21, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in b2111) and b1111), and having the same function as the protein of the amino acid sequence described in b1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in b3111) and has the same function as the protein of the amino acid sequence described in b1111).

[0034] Preferably, the amino acid sequence of the heavy chain variable region of B-8 is c1111) SEQ IDNO:32, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in c2111) and c1111), and having the same function as the protein of the amino acid sequence described in c1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in c3111) and / or, and having the same function as the protein of the amino acid sequence described in c1111), and / or The amino acid sequence of the light chain variable region B-8 is: d1111) SEQ IDNO:49, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in d2111) and d1111), and having the same function as the protein of the amino acid sequence described in d1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in d3111) and has the same function as the protein of the amino acid sequence described in d1111).

[0035] Preferably, the amino acid sequence of the heavy chain variable region of B-8 is c1111) SEQ IDNO:32, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in c2111) and c1111), and having the same function as the protein of the amino acid sequence described in c1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in c3111) and / or, and having the same function as the protein of the amino acid sequence described in c1111), and / or The amino acid sequence of the light chain variable region B-8 is: Compared to d1111)SEQ IDNO:49, the amino acid sequence has a Y93E mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in d2111) and d1111), and having the same function as the protein of the amino acid sequence described in d1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in d3111) and has the same function as the protein of the amino acid sequence described in d1111).

[0036] Preferably, the amino acid sequence of the heavy chain variable region of B-8 is c1111) SEQ IDNO:32, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in c2111) and c1111), and having the same function as the protein of the amino acid sequence described in c1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in c3111) and / or, and having the same function as the protein of the amino acid sequence described in c1111), and / or The amino acid sequence of the light chain variable region B-8 is: Compared to d1111)SEQ IDNO:49, the amino acid sequence has the S91R mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in d2111) and d1111), and having the same function as the protein of the amino acid sequence described in d1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in d3111) and has the same function as the protein of the amino acid sequence described in d1111).

[0037] Preferably, the amino acid sequence of the heavy chain variable region of B-8 is Compared to c1111)SEQ IDNO:32, the amino acid sequence has a Y33E mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in c2111) and c1111), and having the same function as the protein of the amino acid sequence described in c1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in c3111) and / or, and having the same function as the protein of the amino acid sequence described in c1111), and / or The amino acid sequence of the light chain variable region B-8 is: d1111) SEQ IDNO:49, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in d2111) and d1111), and having the same function as the protein of the amino acid sequence described in d1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in d3111) and has the same function as the protein of the amino acid sequence described in d1111).

[0038] Preferably, the amino acid sequence of the heavy chain variable region of B-8 is Compared to c1111)SEQ IDNO:32, the amino acid sequence has a Y61E mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in c2111) and c1111), and having the same function as the protein of the amino acid sequence described in c1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in c3111) and / or, and having the same function as the protein of the amino acid sequence described in c1111), and / or The amino acid sequence of the light chain variable region B-8 is: d1111) SEQ IDNO:49, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in d2111) and d1111), and having the same function as the protein of the amino acid sequence described in d1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in d3111) and has the same function as the protein of the amino acid sequence described in d1111).

[0039] Preferably, the amino acid sequence of the heavy chain variable region of B-8 is Compared to c1111)SEQ IDNO:32, the amino acid sequence having the F111A mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in c2111) and c1111), and having the same function as the protein of the amino acid sequence described in c1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in c3111) and / or, and having the same function as the protein of the amino acid sequence described in c1111), and / or The amino acid sequence of the light chain variable region B-8 is: d1111) SEQ IDNO:49, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in d2111) and d1111), and having the same function as the protein of the amino acid sequence described in d1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in d3111) and has the same function as the protein of the amino acid sequence described in d1111).

[0040] Preferably, the amino acid sequence of the heavy chain variable region of 240B10-1 is: e1111) SEQ IDNO:60, or, An amino acid sequence having the same function as the protein of the amino acid sequence described in e2111)e1111), obtained by substituting and / or deleting and / or adding one or more amino acids, or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in e3111)e1111), and / or, an amino acid sequence having the same function as the protein of the amino acid sequence described in e1111), and / or The amino acid sequence of the light chain variable region of 240B10-1 is: f1111) SEQ IDNO:77, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in f2111) and f1111), and having the same function as the protein of the amino acid sequence described in f1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in f3111) and has the same function as the protein of the amino acid sequence described in f1111).

[0041] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: g1111) SEQ IDNO:88, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0042] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has a W34H mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0043] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has a W34Y mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0044] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has a Y112R mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0045] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has the Y112S mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0046] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has a Y112E mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0047] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has a Y112Q mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0048] Preferably, the amino acid sequence of the heavy chain variable region of the 98G10 is g1111) an amino acid sequence having mutations of W34R and Y112R as compared with SEQ ID NO: 88, or g2111) an amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g1111) and having the same function as the protein of the amino acid sequence described in g1111), or g3111) an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g1111) and having the same function as the protein of the amino acid sequence described in g1111), and / or Preferably, the amino acid sequence of the light chain variable region of the 98G10 is h1111) SEQ ID NO: 105, or h2111) an amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h1111) and having the same function as the protein of the amino acid sequence described in h1111), or h3111) an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h1111) and having the same function as the protein of the amino acid sequence described in h1111).

[0049] Preferably, the amino acid sequence of the heavy chain variable region of the 98G10 is g1111) an amino acid sequence having mutations of W34D and Y112R as compared with SEQ ID NO: 88, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0050] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has mutations in W34H and Y112L, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0051] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has mutations in W34T and Y112R, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0052] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has mutations in W34H and Y112R, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0053] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has mutations in W34H and Y112S, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0054] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: Compared to g1111)SEQ IDNO:88, the amino acid sequence has mutations in W34K and Y112S, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It has an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111)g1111), and has the same function as the protein of the amino acid sequence described in g1111), and / or, The amino acid sequence of the light chain variable region of the 98G10 is h1111)SEQ IDNO:105, or h2111)An amino acid sequence in which one or more amino acids are substituted and / or deleted and / or added to the amino acid sequence described in h1111), and has the same function as the protein of the amino acid sequence described in h1111), or h3111)It includes an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h1111), and has the same function as the protein of the amino acid sequence described in h1111).

[0055] Preferably, the amino acid sequence of the heavy chain variable region of the 98G10 is An amino acid sequence having mutations of W34D and Y112S compared with g1111)SEQ IDNO:88, or g2111)An amino acid sequence in which one or more amino acids are substituted and / or deleted and / or added to the amino acid sequence described in g1111), and has the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: h1111) SEQ IDNO:105, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0056] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: g1111) SEQ IDNO:88, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: Compared to h1111)SEQ IDNO:105, the amino acid sequence has a Y93R mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0057] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: g1111) SEQ IDNO:88, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: Compared to h1111)SEQ IDNO:105, the amino acid sequence has the Y93S mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0058] Preferably, the amino acid sequence of the heavy chain variable region of 98G10 is: g1111) SEQ IDNO:88, or, An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g2111) and g1111), and having the same function as the protein of the amino acid sequence described in g1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in g3111) and / or, and having the same function as the protein of the amino acid sequence described in g1111), and / or The amino acid sequence of the light chain variable region of the aforementioned 98G10 is: Compared to h1111)SEQ IDNO:105, the amino acid sequence has a Y93Q mutation, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h2111) and h1111), and having the same function as the protein of the amino acid sequence described in h1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in h3111) and has the same function as the protein of the amino acid sequence described in h1111).

[0059] Preferably, the amino acid sequence of the heavy chain variable region of 39B4 is: i1111) SEQ IDNO:116, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in i2111) and i1111), and having the same function as the protein of the amino acid sequence described in i1111), or It contains an amino acid sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in i3111) and / or, and having the same function as the protein of the amino acid sequence described in i1111), The amino acid sequence of the light chain variable region 39B4 is: j1111) SEQ IDNO:132, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in j2111) and j1111), and having the same function as the protein of the amino acid sequence described in j1111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the amino acid sequence described in j3111) and has the same function as the protein of the amino acid sequence described in j1111).

[0060] Preferably, the antibody or its antigen-binding fragment comprises at least one of the following: full-length antibody, Fab, Fab', F(ab')2, Fv, scFv, bispecific antibody, or multispecific antibody.

[0061] Preferably, the antibody is a fully human antibody or a humanized antibody.

[0062] Preferably, the heavy chain variable region of the antibody or its antigen-binding fragment further comprises a heavy chain signal peptide and / or The light chain variable region of the antibody or its antigen-binding fragment further comprises a light chain signal peptide.

[0063] Preferably, the amino acid sequence of the 94C4 heavy chain signal peptide is: a11111) Amino acid sequence consisting of amino acids 1-19 of SEQ IDNO:3, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in a21111) and a11111), and having the same function as the protein of the amino acid sequence described in a11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in a31111) and has the same function as the protein of the amino acid sequence described in a11111).

[0064] Preferably, the amino acid sequence of the 94C4 light chain signal peptide is: b11111) Amino acid sequence consisting of amino acids 1-23 of SEQ IDNO:20, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in b21111) and b11111), and having the same function as the protein of the amino acid sequence described in b11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in b31111) and b11111), and has the same function as the protein of the amino acid sequence described in b11111).

[0065] Preferably, the amino acid sequence of the heavy chain signal peptide B-8 is: c11111) SEQ IDNO:31, consisting of amino acids from positions 1 to 19, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in c21111) and c11111), and having the same function as the protein of the amino acid sequence described in c11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in c31111) and has the same function as the protein of the amino acid sequence described in c11111).

[0066] Preferably, the amino acid sequence of the light chain signal peptide B-8 is: d11111) Amino acid sequence consisting of amino acids 1-22 of SEQ IDNO:48, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in d21111) and d11111), and having the same function as the protein of the amino acid sequence described in d11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in d31111) and has the same function as the protein of the amino acid sequence described in d11111).

[0067] Preferably, the amino acid sequence of the 240B10-1 heavy chain signal peptide is: (e11111) Amino acid sequence consisting of amino acids 1-19 of SEQ IDNO:59, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in e21111) and e11111), and having the same function as the protein of the amino acid sequence described in e11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in e31111)e11111), and has the same function as the protein of the amino acid sequence described in e11111).

[0068] Preferably, the amino acid sequence of the 240B10-1 light chain signal peptide is f11111) Amino acid sequence consisting of amino acids 1-23 of SEQ IDNO:76, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in f21111) and f11111), and having the same function as the protein of the amino acid sequence described in f11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in f31111)f11111), and has the same function as the protein of the amino acid sequence described in f11111).

[0069] Preferably, the amino acid sequence of the 98G10 heavy chain signal peptide is: (g11111) Amino acid sequence consisting of amino acids 1-19 of SEQ IDNO:87, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in g21111) and g11111), and having the same function as the protein of the amino acid sequence described in g11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in g31111) and has the same function as the protein of the amino acid sequence described in g11111).

[0070] Preferably, the amino acid sequence of the 98G10 light chain signal peptide is: (h11111) The amino acid sequence consisting of the 1st to 22nd amino acids of SEQ IDNO:104, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in h21111) and having the same function as the protein of the amino acid sequence described in h11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in h31111) and has the same function as the protein of the amino acid sequence described in h11111).

[0071] Preferably, the amino acid sequence of the 39B4 heavy chain signal peptide is: i11111) Amino acid sequence consisting of amino acids 1-19 of SEQ IDNO:115, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in i21111) and having the same function as the protein of the amino acid sequence described in i11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in i31111) and has the same function as the protein of the amino acid sequence described in i11111).

[0072] Preferably, the amino acid sequence of the 39B4 light chain signal peptide is: j11111) Amino acid sequence consisting of amino acids 1-22 of SEQ IDNO:131, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in j21111) and j11111), and having the same function as the protein of the amino acid sequence described in j11111), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in j31111) and has the same function as the protein of the amino acid sequence described in j11111).

[0073] Preferably, the amino acid sequence of the NMI is k1) The amino acid sequence with registration number Gene ID:9111, or An amino acid sequence obtained by substituting and / or deleting and / or adding one or more amino acids to the amino acid sequence described in k2) and k1), and having the same function as the protein of the amino acid sequence described in k1), or It contains an amino acid sequence that has 99%, 98%, 97%, 96%, 95%, 94%, or 93% homology to the amino acid sequence described in k3)k1), and has the same function as the protein of the amino acid sequence described in k1).

[0074] A second aspect of the present invention provides a recombinant protein comprising an antibody or antigen-binding fragment thereof according to the first aspect of the present invention, and a tag sequence that optionally assists in expression and / or purification.

[0075] Preferably, the tag sequence is at least one selected from the group consisting of His tags, GGGS sequences, and FLAG tags.

[0076] A third aspect of the present invention provides a biomaterial relating to an antibody or antigen-binding fragment thereof according to the first aspect of the present invention, or a recombinant protein according to the second aspect of the present invention, comprising at least one of l1) to l16). l1) A nucleic acid molecule encoding an antibody or antigen-binding fragment thereof according to the first aspect of the present invention, or a recombinant protein according to the second aspect of the present invention, Expression cassette containing nucleic acid molecules as described in l2) l1), A vector containing nucleic acid molecules as described in l3) l1), A vector containing the expression cassette described in l4) l2), Transgenic cell lines containing nucleic acid molecules as described in l5) l1), Transgenic cell lines containing the expression cassette described in l6) l2), Transgenic cell lines containing the vectors described in l7) l3), Transgenic cell lines containing the vectors described in l8) l4), Microorganisms containing nucleic acid molecules as described in l9) l1), Microorganisms containing the expression cassette described in l10) l2), Microorganisms containing the vectors described in l11) l3), Microorganisms containing the vectors described in l12) l4), Viruses containing nucleic acid molecules as described in l13) l1), Viruses containing the expression cassette described in l14) l2), Viruses containing vectors as described in l15) l3), A virus containing the vector described in l16) l4).

[0077] Preferably, the transgenic cell line does not contain any reproductive material.

[0078] Preferably, the nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to the first aspect of the present invention comprises a nucleic acid molecule encoding the heavy chain variable region of the antibody or antigen-binding fragment thereof according to the first aspect of the present invention, and a nucleic acid molecule encoding the light chain variable region of the antibody or antigen-binding fragment thereof according to the first aspect of the present invention.

[0079] Preferably, the nucleotide sequence of the nucleic acid molecule encoding the heavy chain variable region of the antibody or its antigen-binding fragment 94C4 according to the first aspect of the present invention is: m1) SEQ IDNO: The nucleotide sequence shown in 1 or 2, or A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in m2)m1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in m1), or m3)m1) contains a nucleotide sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology to the nucleotide sequence described in m3)m1), and / or a nucleotide sequence having the same function as the nucleic acid molecule of the nucleotide sequence described in m1), and / or The nucleotide sequence of the nucleic acid molecule encoding the light chain variable region of the antibody or its antigen-binding fragment 94C4 according to the first aspect of the present invention is: n1) Nucleotide sequence shown in SEQ IDNO: 18 or 19, or A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in n2)n1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in n1), or n3) contains a nucleotide sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the nucleotide sequence described in n1), and has the same function as the nucleic acid molecule of the nucleotide sequence described in n1).

[0080] Preferably, the nucleotide sequence of the nucleic acid molecule encoding the heavy chain variable region of the antibody or its antigen-binding fragment B-8 in the first aspect of the present invention is: o1) Nucleotide sequence shown in SEQ IDNO:29 or 30, or A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in o2)o1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in o1), or o3)o1) contains a nucleotide sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the nucleotide sequence described in o1), and / or, The nucleotide sequence of the nucleic acid molecule encoding the light chain variable region of the antibody or its antigen-binding fragment B-8 in the first aspect of the present invention is: p1) Nucleotide sequence shown in SEQ IDNO:46 or 47, or A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in p2) and p1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in p1), or The nucleotide sequence contains nucleotide sequences that have 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the nucleotide sequence described in p3)p1), and that have the same function as the nucleic acid molecule of the nucleotide sequence described in p1).

[0081] Preferably, the nucleotide sequence of the nucleic acid molecule encoding the heavy chain variable region of the antibody or its antigen-binding fragment 240B10-1 in the first aspect of the present invention is: q1) The nucleotide sequence shown in SEQ IDNO: 57 or 58, or q2) A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in q1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in q1), or q3) A nucleotide sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the nucleotide sequence described in q1), and / or a nucleotide sequence having the same function as the nucleic acid molecule of the nucleotide sequence described in q1), The nucleotide sequence of the nucleic acid molecule encoding the light chain variable region of the antibody or its antigen-binding fragment 240B10-1 according to the first aspect of the present invention is: r1) Nucleotide sequence shown in SEQ IDNO:74 or 75, or A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in r2)r1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in r1), or The nucleotide sequence contains a nucleotide sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the nucleotide sequence described in r3)r1), and has the same function as the nucleic acid molecule of the nucleotide sequence described in r1).

[0082] Preferably, the nucleotide sequence of the nucleic acid molecule encoding the heavy chain variable region of the antibody or its antigen-binding fragment 98G10 in the first aspect of the present invention is: s1) Nucleotide sequence shown in SEQ IDNO:85 or 86, or A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in s2)s1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in s1), or s3)s1) comprises a nucleotide sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the nucleotide sequence described in s1), and / or a nucleotide sequence having the same function as the nucleic acid molecule of the nucleotide sequence described in s1), The nucleotide sequence of the nucleic acid molecule encoding the light chain variable region of the antibody or its antigen-binding fragment 98G10 according to the first aspect of the present invention is: t1) Nucleotide sequence shown in SEQ IDNO:102 or 103, or A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in t2)t1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in t1), or The nucleotide sequence contains a nucleotide sequence that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the nucleotide sequence described in t3)t1), and has the same function as the nucleic acid molecule of the nucleotide sequence described in t1).

[0083] Preferably, the nucleotide sequence of the nucleic acid molecule encoding the heavy chain variable region of the antibody or its antigen-binding fragment 39B4 in the first aspect of the present invention is: u1) Nucleotide sequence shown in SEQ IDNO:113 or 114, or A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in u2) and u1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in u1), or u3)u1) contains a nucleotide sequence having 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the nucleotide sequence described in u1), and / or, The nucleotide sequence of the nucleic acid molecule encoding the light chain variable region of the antibody or its antigen-binding fragment 39B4 according to the first aspect of the present invention is: v1) Nucleotide sequence shown in SEQ IDNO:129 or 130, or A nucleotide sequence obtained by substituting and / or deleting and / or adding one or more nucleotides to the nucleotide sequence described in v2)v1), and having the same function as the nucleic acid molecule of the nucleotide sequence described in v1), or The nucleotide sequence contains nucleotide sequences that have 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 70%, 60%, 50%, 40%, 35%, or 30% or more homology with the nucleotide sequence described in v3)v1), and that have the same function as the nucleic acid molecule of the nucleotide sequence described in v1).

[0084] In a fourth aspect of the present invention, at least one of the antibody or antigen-binding fragment thereof according to the first aspect of the present invention and the recombinant protein according to the second aspect of the present invention, The present invention provides a conjugate comprising a conjugate moiety containing at least one of the following: a detectable labeling substance, a drug, a toxin, or a cytokine.

[0085] Preferably, the conjugate portion contains a detectable labeling substance.

[0086] Preferably, the conjugate portion contains at least one of a drug, a toxin, or a cytokine.

[0087] Preferably, the detectable labeling substance is a fine particle (e.g., gold colloid and colored latex), a fluorescent label (e.g., fluorescein (e.g., 5-fluorescein, 6-carboxyfluorescein, 3'6-carboxyfluorescein, 5(6)-carboxyfluorescein, 6-hexachlorofluorescein, 6-tetrachlorofluorescein, fluorescein isothiocyanate, etc.)), rhodamine, phycoerythrin, phycocyanin, allophycocyanin, phthalaldehyde and fluorescamin), a redox molecular label (e.g., ferrocene, ruthenium complex, viologen, quinone, It ion, Cs ion, diimide, 1,4-benzoquinone, hydroquinone), a chemiluminescent label (e.g., acridinium ester, luminol, isoluminol, phena Labeling is selected from the following: (e.g., iondidinium esters), radioactive labels (e.g., 3H, 14C, 32P, 33P, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho, and 153Sm), enzyme labels (e.g., β-glucuronidase, β-glucosidase, urease, peroxidase (horseradish peroxidase) or alkaline phosphatase, acetylcholinesterase, glucose oxidase, hexokinase and GDPase, RNase, glucose oxidase and luciferase, phosphofructokinase, phosphoenolpyruvate carboxylase, aspartate aminotransferase, phosphoenolpyruvate decarboxylase, and β-lactamase), ligand labels (e.g., biotin and its derivatives), or any combination thereof.

[0088] A fifth aspect of the present invention provides the use of an antibody or antigen-binding fragment thereof according to the first aspect of the present invention, a recombinant protein according to the second aspect, a biomaterial according to the third aspect, and / or a conjugate according to the fourth aspect in the manufacture of a product. The aforementioned product includes at least one of the following: drugs, reagents, test strips, detection plates, kits, detection chips, adsorbents, and medical devices.

[0089] Preferably, the drug can prevent or treat diseases or conditions associated with abnormally high levels and / or active NMI.

[0090] Preferably, the target population for administration of the drug is mammals.

[0091] Preferably, the reagent, test strip, detection plate, detection chip, or kit has at least one of the functions of w1) to w3). w1) Detection of the presence or level of NMI protein in the sample. w2) Diagnosis, diagnostic assistance, or prognosis assessment of diseases or conditions associated with abnormally high levels and / or active NMI. w3) Screening for drugs to prevent or treat diseases or conditions associated with abnormally high levels and / or active NMI.

[0092] Preferably, the reagent, test strip, detection plate, detection chip, or kit is used in one or more detection methods selected from the group consisting of radiolabeled immunoassay (RIA), enzyme immunoassay (EIA or ELISA), fluorescence immunoassay (FIA), luminescence immunoassay, protein immunoblotting, physicochemical methods, and biochip methods.

[0093] Preferably, the test sample for the reagent, test strip, detection plate, detection chip, or kit is at least one selected from the body fluids, tissues, cells, or excretions to be measured.

[0094] Preferably, the subject of measurement is a mammal.

[0095] Preferably, the adsorbent and medical device are used to remove NMI proteins from body fluids and reduce the occurrence of abnormal immune responses caused by NMI proteins.

[0096] Preferably, the body fluids include serum, plasma, whole blood, urine, sputum, pleural fluid, cerebrospinal fluid, synovial fluid, ascites, saliva, tears, lymph, and fluids accumulated in body cavities.

[0097] Preferably, the bodily fluids are of mammalian origin.

[0098] Preferably, the disease or condition associated with the abnormally high levels and / or active NMI includes at least one of inflammation, infection, sepsis, organ injury, and autoimmune disease, and further includes at least one of sepsis and autoimmune disease.

[0099] Preferably, the autoimmune disease includes at least one of the following: arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis, neurological disorders, vitiligo, asthma, inflammatory bowel disease, peritonitis, lung injury, pneumonia, nephritis, neurogenic inflammation, and hepatitis.

[0100] Preferably, the neurological disease includes at least one of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, encephalitis, brain tumor, traumatic brain injury, and autoimmune brain disease.

[0101] Preferably, the encephalitis includes at least one of fungal encephalitis, bacterial encephalitis, viral encephalitis, and anti-N-methyl-D-aspartate receptor encephalitis.

[0102] Preferably, the mammal is a human.

[0103] Preferably, the antibody or antigen-binding fragment of the first embodiment of the present invention may be one, two, three, four, or five of 94C4, B-8, 240B10-1, 98G10, and 39B4.

[0104] A sixth aspect of the present invention provides a product comprising at least one of x1) to x3). x1) An antibody or antigen-binding fragment thereof according to a first aspect of the present invention, x2) Recombinant protein according to a second aspect of the present invention, x3) ​​A conjugate according to a fourth aspect of the present invention.

[0105] The aforementioned product includes at least one of the following: reagents, test strips, detection plates, kits, detection chips, adsorbents, and medical devices.

[0106] Preferably, the reagent, test strip, detection plate, detection chip, or kit has at least one of the functions of w1) to w3). w1) Detection of the presence or level of NMI protein in the sample. w2) Diagnosis, diagnostic assistance, or prognosis assessment of diseases or conditions associated with abnormally high levels and / or active NMI. w3) Screening for drugs to prevent or treat diseases or conditions associated with abnormally high levels and / or active NMI.

[0107] Preferably, the reagent, test strip, detection plate, detection chip, or kit is used in one or more detection methods selected from the group consisting of radiolabeled immunoassay (RIA), enzyme immunoassay (EIA or ELISA), fluorescence immunoassay (FIA), luminescence immunoassay, protein immunoblotting, physicochemical methods, and biochip methods.

[0108] Preferably, the test sample for the reagent, test strip, detection plate, detection chip, or kit is at least one selected from the body fluids, tissues, cells, or excretions to be measured.

[0109] Preferably, the subject of measurement is a mammal.

[0110] Preferably, the adsorbent and medical device are used to remove NMI proteins from body fluids and reduce the occurrence of abnormal immune responses caused by NMI proteins.

[0111] Preferably, the body fluids include serum, plasma, whole blood, urine, sputum, pleural fluid, cerebrospinal fluid, synovial fluid, ascites, saliva, tears, lymph, and fluids accumulated in body cavities.

[0112] Preferably, the bodily fluids are of mammalian origin.

[0113] Preferably, the disease or condition associated with the abnormally high levels and / or active NMI includes at least one of inflammation, infection, sepsis, organ injury, and autoimmune disease, and further includes at least one of sepsis and autoimmune disease.

[0114] Preferably, the autoimmune disease includes at least one of the following: arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis, neurological disorders, vitiligo, asthma, inflammatory bowel disease, peritonitis, lung injury, pneumonia, nephritis, neurogenic inflammation, and hepatitis.

[0115] Preferably, the neurological disease includes at least one of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, encephalitis, brain tumor, traumatic brain injury, and autoimmune brain disease.

[0116] Preferably, the encephalitis includes at least one of fungal encephalitis, bacterial encephalitis, viral encephalitis, and anti-N-methyl-D-aspartate receptor encephalitis.

[0117] Preferably, the mammal is a human.

[0118] Preferably, the antibody or antigen-binding fragment of the first embodiment of the present invention may be one, two, three, four, or five of 94C4, B-8, 240B10-1, 98G10, and 39B4.

[0119] Preferably, a double antibody sandwich ELISA kit comprising a coated antibody and a detection antibody, wherein at least one of the coated antibody and the detection antibody comprises an antibody according to the first embodiment of the present invention or an antigen-binding fragment thereof.

[0120] Preferably, the coating antibody and the detection antibody are each for different antigenic epitopes of NMI.

[0121] Preferably, the coated antibody binds to the solid support.

[0122] Preferably, the solid-phase support comprises at least one of magnetic particles, latex particles, and microplates, and is further a microplate, and further a highly bonded microplate made of polystyrene material.

[0123] Preferably, the detection antibody is labeled with a detectable labeling substance.

[0124] Preferably, the detectable labeled substance is at least one selected from enzyme labels (e.g., β-glucuronidase, β-glucosidase, urease, peroxidase (horseradish peroxidase) or alkaline phosphatase, acetylcholinesterase, glucose oxidase, hexokinase and GDPase, RNase, glucose oxidase and luciferase, phosphofructokinase, phosphoenolpyruvate carboxylase, aspartate aminotransferase, phosphoenolpyruvate decarboxylase, and β-lactamase), ligand labels (e.g., biotin and its derivatives), and is further ligand-labeled, and further biotin.

[0125] Preferably, if the detectable labeling substance is selected from ligand (e.g., biotin) labeling, the double antibody sandwich ELISA kit further comprises an enzyme-labeled receptor (e.g., horseradish peroxidase-labeled streptavidin).

[0126] Preferably, the coated antibody and the detection antibody are any two selected from the antibodies or antigen-binding fragments thereof according to the first aspect of the present invention, and more preferably, the coated antibody contains B-8 and the detection antibody contains 94C4, or the coated antibody contains 94C4 and the detection antibody contains B-8.

[0127] Preferably, the double antibody sandwich ELISA kit further comprises at least one of the following: a sample diluent, a washing solution, a blocking solution, a chromogenic solution, a stop solution, and a calibrator.

[0128] In this application, the sample buffer, washing solution, blocking solution, color developer, and stop solution are commonly used reagents in the art and can be selected and used as needed by those skilled in the art.

[0129] Preferably, the sample diluent is PBS containing BSA and Tween-20.

[0130] Preferably, the washing solution is PBS containing Tween-20.

[0131] Preferably, the blocking solution is PBS containing BSA.

[0132] Preferably, the color-developing solution is TMB color-developing solution.

[0133] Preferably, the stop solution is sulfuric acid.

[0134] Preferably, the coating concentration of the coating antibody bound to the solid support is 0.25 to 5 μg / mL, and more preferably 0.25 to 1 μg / mL.

[0135] Preferably, the concentration of the detection antibody used is 0.25 to 1 μg / mL.

[0136] Preferably, the concentration of the enzyme-labeled receptor used is 50 to 200 ng / mL.

[0137] Preferably, when using the kit, the incubation time between the sample and the coated antibody is 45 min to 1.5 h.

[0138] A chemiluminescence detection kit comprising a coated antibody and a detection antibody, wherein at least one of the coated antibody and the detection antibody comprises an antibody according to the first aspect of the present invention or an antigen-binding fragment thereof.

[0139] Preferably, the coating antibody and the detection antibody are each for different antigenic epitopes of NMI.

[0140] Preferably, the coated antibody binds to the solid support.

[0141] Preferably, the solid-phase support comprises at least one of magnetic particles, latex particles, and microplates, and further comprises magnetic particles.

[0142] Preferably, the detection antibody is labeled with a detectable labeling substance.

[0143] Preferably, the detectable labeling substance is selected from chemiluminescent labels (e.g., acridinium esters, luminols, isoluminols, phenanthidinium esters, etc.), and further selected from acridinium esters.

[0144] Preferably, the coated antibody and the detection antibody are any two selected from the antibodies or antigen-binding fragments thereof according to the first aspect of the present invention, and more preferably, the coated antibody comprises B-8 and the detection antibody comprises 98G10, or the coated antibody comprises 98G10 and the detection antibody comprises B-8.

[0145] Preferably, the chemiluminescence detection kit further comprises at least one of a reaction buffer, an NMI calibrator, and a luminescent substrate.

[0146] Preferably, the luminescent substrate includes a pre-excitation solution and an excitation solution.

[0147] An immunochromatography test strip comprising a base plate, a sample pad, a labeling pad, a chromatography membrane, and a water-absorbing pad attached to the base plate, wherein the labeling pad is coated with anti-NMI antibody I labeled with a labeling substance, a test line is provided on the chromatography membrane, the test line is coated with anti-NMI antibody II, and at least one of anti-NMI antibody I and anti-NMI antibody II comprises an antibody according to the first embodiment of the present invention or an antigen-binding fragment thereof.

[0148] Preferably, the anti-NMI antibody I and the anti-NMI antibody II are each against different antigenic epitopes of NMI.

[0149] Preferably, the anti-NMI antibody I and the anti-NMI antibody II are any two selected from the antibodies or antigen-binding fragments thereof according to the first embodiment of the present invention, and more preferably, the anti-NMI antibody I contains B-8 and the anti-NMI antibody II contains 94C4, or the anti-NMI antibody I contains 94C4 and the anti-NMI antibody II contains B-8.

[0150] Preferably, the chromatography membrane can be a conventional NC membrane (nitrocellulose membrane).

[0151] Preferably, the labeling substance is a gold colloid.

[0152] Preferably, the chromatographic membrane is further provided with a control line.

[0153] Preferably, the control line is coated with anti-NMI antibody I, and further coated with goat anti-rabbit IgG antibody.

[0154] Preferably, an adsorbent comprising a carrier matrix and an antibody or antigen-binding fragment thereof according to the first aspect of the present invention.

[0155] Preferably, the antibody or its antigen-binding fragment is linked to the carrier matrix.

[0156] Preferably, the support matrix is ​​at least one selected from agarose gel particles, cellulose gel particles, dextran gel particles, magnetic particles, silica gel particles, activated carbon, resin particles, Protein A agarose particles, and Protein G agarose particles.

[0157] Preferably, a medical device comprising an antibody or antigen-binding fragment thereof according to the first aspect of the present invention, and at least one of the adsorbents described above.

[0158] A seventh aspect of the present invention provides a drug comprising at least one of y1) to y4). y1) An antibody or antigen-binding fragment thereof according to a first aspect of the present invention, y2) Recombinant protein according to a second aspect of the present invention, y3) A biomaterial according to a third aspect of the present invention, y4) A conjugate according to a fourth aspect of the present invention.

[0159] Preferably, the drug further comprises a pharmaceutically acceptable carrier.

[0160] Preferably, the drug can prevent or treat diseases or conditions associated with abnormally high levels and / or active NMI.

[0161] Preferably, the disease or condition associated with the abnormally high levels and / or active NMI includes at least one of inflammation, infection, sepsis, organ injury, and autoimmune disease, and further includes at least one of sepsis and autoimmune disease.

[0162] Preferably, the autoimmune disease includes at least one of the following: arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis, neurological disorders, vitiligo, asthma, inflammatory bowel disease, peritonitis, lung injury, pneumonia, nephritis, neurogenic inflammation, and hepatitis.

[0163] Preferably, the neurological disease includes at least one of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, encephalitis, brain tumor, traumatic brain injury, and autoimmune brain disease.

[0164] Preferably, the encephalitis includes at least one of fungal encephalitis, bacterial encephalitis, viral encephalitis, and anti-N-methyl-D-aspartate receptor encephalitis.

[0165] Preferably, the target population for administration of the drug is mammals.

[0166] Preferably, the mammal is a human.

[0167] Preferably, the antibody or antigen-binding fragment of the first embodiment of the present invention may be one, two, three, four, or five of 94C4, B-8, 240B10-1, 98G10, and 39B4.

[0168] An eighth aspect of the present invention provides a method for preparing an antibody according to the first aspect of the present invention or its antigen-binding fragment, or a recombinant protein according to the second aspect, obtained by culturing a transgenic cell line, microorganism, or virus according to the third aspect of the present invention.

[0169] A ninth aspect of the present invention provides a method for detecting the presence or level of NMI, comprising the step of using a reagent, test strip, detection plate, kit, or detection chip according to the sixth aspect of the present invention.

[0170] A tenth aspect of the present invention provides a method for diagnosing, assisting in the diagnosis of, or assessing the prognosis of a disease or condition associated with abnormally high levels and / or active NMI, comprising the step of using a reagent, test strip, detection plate, kit, or detection chip according to the sixth aspect of the present invention.

[0171] Preferably, the method includes the step of detecting the presence or level of NMI in a test sample using a reagent, test strip, detection plate, kit, or detection chip according to a sixth aspect of the present invention.

[0172] Preferably, the method further includes a step of diagnosing, assisting in diagnosis, or assessing prognosis of a disease or condition associated with abnormally high levels and / or active NMI, based on the presence or level of NMI in the test sample.

[0173] Preferably, the test sample is at least one selected from the body fluids, tissues, cells, and excretions to be measured.

[0174] Preferably, the subject of measurement is a mammal.

[0175] An eleventh aspect of the present invention provides a method for removing NMI proteins from body fluids, comprising the step of using an adsorbent or medical device according to the sixth aspect of the present invention.

[0176] Preferably, the method includes the step of treating a body fluid with an adsorbent or medical device according to a sixth aspect of the present invention to remove NMI proteins from the body fluid.

[0177] The beneficial effects of this invention are as follows: The present invention provides an anti-NMI antibody or its antigen-binding fragment, which has good binding activity to NMI protein and high affinity for NMI protein, and is used to detect the presence or level of NMI protein in a sample, to diagnose, assist in diagnosis or assess prognosis of diseases or conditions associated with abnormally high levels and / or active NMI, to remove NMI protein from body fluids, and to prevent or treat diseases or conditions associated with abnormally high levels and / or active NMI. [Brief explanation of the drawing]

[0178]

Figure 1

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[0179] The present invention will be described in more detail below with reference to specific examples, but the provided examples are intended to provide a more thorough understanding of the present invention and to fully convey its scope to those skilled in the art.

[0180] These examples are merely illustrative of the present invention and should not be used to limit its scope.

[0181] In the specification and claims, terms are used to refer to specific components. A person skilled in the art should understand that the same component may be referred to by different nouns. This specification and claims do not distinguish based on differences in nouns, but on differences in function. For example, the terms "includes" or "contains" as used in the specification and claims are open terms and should be interpreted as "includes, but not limited to." The subsequent descriptions in the specification are preferred embodiments for carrying out this application, but are intended to give an overview of the general principles of the specification and do not limit the scope of this application. The scope of protection of this application is defined primarily by the claims.

[0182] The scientific and technical terms used herein have the same meanings as those commonly understood by those skilled in the art, and in case of any conflict, the definitions provided herein shall prevail.

[0183] In general, the terms used herein have the following meanings:

[0184] In this specification, “monoclonal antibody” refers to an antibody obtained from a substantially homologous population of antibodies, that is, each antibody constituting the population is identical and / or bound to the same epitope, except for possible variant antibodies (including naturally occurring variants or variants arising during the production process of the monoclonal antibody product), such variants are usually present in trace amounts. Unlike polyclonal antibody products, which typically contain different antibodies against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody product is against a single determinant on an antigen. Therefore, the modifier “monoclonal” indicates that the antibody is obtained from a substantially homologous population of antibodies and should not be interpreted as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies according to the present invention can be prepared by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods using transgenic animals containing all or part of a human immunoglobulin locus, and such methods and other exemplary methods for preparing monoclonal antibodies are described herein.

[0185] In this specification, “affinity” represents the sum of the non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, “binding affinity” as used herein refers to the intrinsic binding affinity that reflects the 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can usually be expressed by the equilibrium dissociation constant (KD). Affinity can be measured by common methods known in the art.

[0186] In this specification, human NMI refers to a protein of human origin.

[0187] In this specification, "anti-human NMI monoclonal antibody" means a monoclonal antibody that can bind to human NMI proteins with sufficient affinity to identify / detect human NMI proteins.

[0188] In this specification, "enzyme-linked immunosorbent assay (EILSA)" refers to a detection method that utilizes the characteristic that antibody molecules can specifically bind to antigen molecules to bind a free heteroprotein to a target protein bound to a solid support, and then performs qualitative or quantitative analysis using a special labeling substance. The principle is that the antigen or antibody is physically adsorbed to the solid surface and retains its immunoactivity, and the antigen or antibody forms an enzyme complex by covalent bonding with an enzyme, while retaining its respective immunoactivity or enzyme activity. After the enzyme complex binds to the corresponding antigen or antibody, the occurrence of an immune response can be identified by a color reaction when a substrate is added, and the depth of the color reaction is proportional to the amount of the corresponding antigen or antibody in the sample. Various types of detection methods can be designed depending on the substance to be detected and the detection conditions, and the double antibody sandwich method is the most common method for detecting antigens. This method involves adsorbing antiserum containing known antibodies onto wells on a microtiter plate, washing it once, adding the test antigen, and if both are specific, binding occurs. Then, excess antibodies are washed away, and an enzyme-conjugated antibody that specifically reacts with the test antigen is added to form a "sandwich." The substrate to which this enzyme is added shows the presence of the corresponding antigen when a colored enzymatic degradation product is observed.

[0189] In this specification, "avidin" is a type of glycoprotein consisting of four subunits per molecule, capable of intimately binding to four biotin molecules. Streptavidin extracted from Streptomyces is often used.

[0190] In this specification, "biotin" is also referred to as vitamin H. Biotin-hydroxysuccinimide (BNHS), a derivative produced by chemical methods, can form biotinylated products with various types of large and small molecules, including proteins, sugars, and enzymes. The binding of avidin and biotin is not an immunoreaction, but it exhibits strong specificity and affinity, and the binding of the two molecules is extremely stable. Since one avidin molecule has four binding sites for biotin molecules, it is possible to link more biotinylated molecules and form a lattice-like complex. Therefore, combining avidin and biotin with ELISA can significantly improve the sensitivity of the ELISA.

[0191] Biotin-avidin systems can be used in various ways in ELISA, including indirectly for coating or for final reaction amplification. In conventional ELISA, the enzyme-labeled antibody can be replaced with a biotinylated antibody, and then the avidin-enzyme conjugate can be attached to amplify the reaction signal. [Examples]

[0192] In the following examples, experimental methods for which specific conditions are not explicitly stated shall generally follow standard conditions or conditions suggested by the manufacturer. Unless otherwise specified, the materials, reagents, etc., used in these examples are commercially available.

[0193] The biotin-labeled monoclonal antibody in this example is prepared as follows: Take 2.0 mg of antibody, add 27 μL of 10 mM biotin solution, mix thoroughly, and rotate in a freezer at 2-8°C for 18 ± 2 hours in the dark to mix thoroughly. Transfer the conjugation solution to a 50 kD ultrafiltration centrifuge tube, centrifuge at 8000 rpm for 10 min, discard the filtrate, add 200 μL of PBS buffer, centrifuge at 8000 rpm for 10 min, repeat the procedure 5 times, invert the centrifuge tube filtration membrane, centrifuge at 3000 rpm for 1 min to collect the concentrated biotin-labeled antibody, add 100 μL of PBS buffer, let stand for 3 min, invert the centrifuge tube filtration membrane again, centrifuge at 3000 rpm for 1 min, detect the concentration of the biotin-labeled antibody with Nanodrop, and adjust the volume to 2 mg / mL.

[0194] Example 1: Screening and identification of anti-NMI monoclonal antibodies Rabbits were immunized with human NMI (GeneID:9111; hereafter, unless otherwise specified, the corresponding registration number is GeneID:9111) protein, antibodies were prepared using hybridoma cells, and rabbit monoclonal antibodies were screened using the Elisa method (for specific methods, refer to the examples section of Patent Document CN115698058A; the difference is that in this example, the coating protein is human NMI, and the secondary antibody is anti-rabbit IgG conjugated with horseradish peroxidase). The only condition is that it is an Fc secondary antibody and is diluted 1:30000. The indirect Elisa detection results for each positive monoclonal antibody are shown in Tables 1-4 and Figures 1-2. Monoclonal antibodies with clone numbers 94C4, 39B4, 8D1, 65G6, 98G10, 295D9-1, B-8, 240B10-1, B-2, and 71F3-3 were selected and subjected to binding epitope analysis. As shown in Table 5, the epitopes of 39B4, 8D1, 65G6, and 295D9-1 are the same, the epitopes of 240B10-1 and B-2 are the same, the epitope of 71F3-3 is unknown, and the epitopes of the remaining monoclonal antibodies are different from each other.

[0195] [Table 1] JPEG2026515753000002.jpg153170

[0196] [Table 2]

[0197] [Table 3]

[0198] [Table 4]

[0199] [Table 5]

[0200] Finally, we selected 94C4, B-8, 240B10-1, 98G10, and 39B4 (which have different epitopes) and measured their heavy chain variable region and light chain variable region sequences. The results are as follows.

[0201] The nucleotide sequence of the heavy chain variable region (including the signal peptide) of 94C4 is ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGT CAGTCGTTGGAGGAGTCCGGGGGAGGCCTGGTCCAGCCTGAGGGATCCCTGACACTCACCTGCAAAGCCTCTGGATTCGACTTCAGTAGCAATGCAATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTAGTAGTGCTAGTAGTGGTAGTAGTGGTAGCACTTACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACATGGCCACCTATTTCTGTGCGAGAGATGGTTACGACTTGTGGGGCCCAGGCACCCTGGTCACCGTCTCCTCA (SEQ ID NO:1) Here, the italicized part is the signal peptide sequence, and the underlined part is the nucleotide sequence of the heavy chain variable region (SEQ ID NO:2), and the corresponding amino acid sequence is METGLRWLLLVAVLKGVQC QSLEESGGGLVQPEGSLTLTCKASGFDFSSNAMCWVRQAPGKGLEWIACISSASSGSSGSTYYASWAKGRFTISKTSSTTVTLQMTSLTAADMATYFCARDGYDLWGPGTLVTVSS (SEQ ID NO:3) is the signal peptide sequence, and the underlined portion is the amino acid sequence of the heavy chain variable region (SEQ ID NO:4). Table 6 shows the CDR-H1, CDR-H2, and CDR-H3 based on different CDR definition schemes in the heavy chain variable region.

[0202] [Table 6]

[0203] The nucleotide sequence of the 94C4 light chain variable region (including the signal peptide) is ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCC CAAGTGCTGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGTCAGTCCAGTCCGAGTGTTTATAATAACTACTTATCCTGGTTTCAGCAGAAACCAGGGCAGTCTCCCAAGCTCCTGATCTACAGGGTATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTATTACTGTGCAGGCGGTTATGATAGCGCTAGTGATACATATGTTTTCGGCGGAGGGACCGAGGTGGTGGTCAAA (SEQ ID NO:18) Here, the italicized part is the signal peptide sequence, and the underlined part is the nucleotide sequence of the light chain variable region (SEQ ID NO:19), and the corresponding amino acid sequence is MDTRAPTQLLGLLLLWLPGATFA QVLTQTPSSVSAAVGGTVTISCQSSPSVYNNYLSWFQQKPGQSPKLLIYRVSTLASGVPSRFSGSGSGTQFTLTISGVQCDDAATYYCAGGYDSASDTYVFGGGTEVVVK (SEQ ID NO:20) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the amino acid sequence of the light chain variable region (SEQ ID NO:21). The CDR-L1, CDR-L2, and CDR-L3 based on different CDR definition schemes in the light chain variable region are shown in Table 7.

[0204] [Table 7]

[0205] The nucleotide sequence of the heavy chain variable region (including the signal peptide) of B-8 is ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGT CAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCTTTAGTAGCAGCTACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGCTGGTAGTAGTGGTAGCACTTACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAGATGACCAGTCTGACAGCCGCGGACACGGCCACTTATTTCTGTGCGAGGGAGTATAGCTACGATGACTATGGTGATTTCTGGGGTTTTAACTTGTGGGGCCCAGGCACCCTGGTCACCGTCTCCTCA (SEQ ID NO:29) Here, the italicized part is the signal peptide sequence, and the underlined part is the nucleotide sequence of the heavy chain variable region (SEQ ID NO:30), and the corresponding amino acid sequence is METGLRWLLLVAVLKGVQC QSLEESGGDLVKPGASLTLTCTASGFSFSSSYYMCWVRQAPGKGLEWIACIYAGSSGSTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCAREYSYDDYGDFWGFNLWGPGTLVTVSS (SEQ ID NO:31) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the amino acid sequence of the heavy chain variable region (SEQ ID NO:32). The CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable region, based on different CDR definition schemes, are shown in Table 8.

[0206] [Table 8]

[0207] The nucleotide sequence of the light chain variable region (including the signal peptide) of B-8 is ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGT GCCCTTGTGATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTCAGAACATTTACACCAATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCAATCTGGAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAATACACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTATTACTGTCAAAGTTCTTTGTATAGTCGTATTGCTGACCGGGCTAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAA (SEQ ID NO:46) Here, the italicized part is the signal peptide sequence, and the underlined part is the nucleotide sequence of the light chain variable region (SEQ ID NO:47), and its corresponding amino acid sequence is MDTRAPTQLLGLLLLWLPGARC ALVMTQTPSSVSAAVGGTVTINCQASQNIYTNLAWYQQKPGQPPKLLIYGASNLESGVPSRFKGSGSGTEYTLTISDLECDDAATYYCQSSLYSRIADRANAFGGGTEVVVK (SEQ ID NO:48) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the amino acid sequence of the light chain variable region (SEQ ID NO:49). The CDR-L1, CDR-L2, and CDR-L3 based on different CDR definition schemes in the light chain variable region are shown in Table 9.

[0208] [Table 9]

[0209] The nucleotide sequence of the heavy chain variable region (including the signal peptide) of 240B10-1 is ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAGAGGTGTCCAGTGT CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGAGGATCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCTATACAATGGGCTGGGTCCGCCAGGCTCCAGGGAAGGGACTTGAATACATCGGAATCATTAGTGGTGGTGGTAGGACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAGTGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAATATATACCTTGTGGGGCCAAGGCACCCTGGTCACCGTCTCCTCG (SEQ ID NO:57) Here, the italicized part is the signal peptide sequence, and the underlined part is the nucleotide sequence of the heavy chain variable region (SEQ ID NO:58), and the corresponding amino acid sequence is METGLRWLLLVAVLRGVQC QSLEESGGRLVTPGGSLTLTCTVSGIDLSSYTMGWVRQAPGKGLEYIGIISGGGRTYYASWAKGRFTISKTSSTTVDLKVTSLTTEDTATYFCARIYTLWGQGTLVTVSS (SEQ ID NO: 59) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the amino acid sequence of the heavy chain variable region (SEQ ID NO: 60). Table 10 shows the CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable region according to different CDR definition schemes.

[0210] [Table 10]

[0211] The nucleotide sequence of the light chain variable region (including the signal peptide) of 240B10-1 is ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCC CAAGTGCTGACCCAGACTCTAGCCTCCGTGTCTGCGGCTGTTGGAGGCACAGTCACCATCAATTGCCAGTCCAGTCAGAGTGTTTATAATAACGACTACCTAGCCTGGTTTCAGCAGAAATCAGGGCAGCCTCCCAAGCAACTGATCCATTCTGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAACGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGGTTATGATTGTTATAGTGCTGATTGTAATGTTTTCGGCGGAGGGACCGAGGTGGTGGTCAAA (SEQ ID NO:74) Here, the italicized part is the signal peptide sequence, and the underlined part is the nucleotide sequence of the light chain variable region (SEQ ID NO:75), and the corresponding amino acid sequence is MDTRAPTQLLGLLLLWLPGATFA QVLTQTLASVSAAVGGTVTINCQSSQSVYNNDYLAWFQQKSGQPPKQLIHSASKLASGVPSRFKGSGSGTQFTLTINDVQCDDAATYYCLGGYDCYSADCNVFGGGTEVVVK (SEQ ID NO:76) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the amino acid sequence of the light chain variable region (SEQ ID NO:77). The CDR-L1, CDR-L2, and CDR-L3 based on different CDR definition schemes in the light chain variable region are shown in Table 11.

[0212] [Table 11]

[0213] The nucleotide sequence of the heavy chain variable region (including the signal peptide) of 98G10 is ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGT CAGGAGCAGCTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGAGGGATCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCTTCAGTGCCAGCTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGCCTGGAGTGGATCGCATGCATTTATGGTGGTAGTAGTGGTAGCGCTTACTACGCGAGCTGGGCGAAGGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACTTATTTCTGTGCGAGAGCCGGTTACTATAATTATGGTAGTGCTGGTGATATTTATCCTAGTTCCTTTAAGTTGTGGGGCCCAGGCACCCTGGTCACCGTCTCCTCA (SEQ ID NO:85) Here, the italicized part is the signal peptide sequence, and the underlined part is the nucleotide sequence of the heavy chain variable region (SEQ ID NO:86), and the corresponding amino acid sequence is METGLRWLLLVAVLKGVQC QEQLEESGGDLVKPEGSLTLTCTASGFSFSASYWICWVRQAPGKGLEWIACIYGGSSGSAYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARAGYYNYGSAGDIYPSSFKLWGPGTLVTVSS (SEQ ID NO:87) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the amino acid sequence of the heavy chain variable region (SEQ ID NO:88). Table 12 shows the CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable region according to different CDR definition schemes.

[0214] [Table 12]

[0215] The nucleotide sequence of the light chain variable region (including the signal peptide) of 98G10 is ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTACTGCTCTGGCTCCCAGGTGCCAGATGT GACATTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTCAGAGCATTAGCACTGCATTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATACTGCATCCAAGGTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAACTATTATTATAGTAGTAGTAGTATTACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAA (SEQ ID NO:102) Here, the italicized part is the signal peptide sequence, and the underlined part is the nucleotide sequence of the light chain variable region (SEQ ID NO:103), and its corresponding amino acid sequence is MDTRAPTQLLGLLLLWLPGARC DIVMTQTPASVEAAVGGTVTINCQASQSISTALAWYQQKPGQPPKLLIYTASKVASGVPSRFSGSGSGTQFTLTISDLECADAATYYCQNYYYSSSSITFGGGTEVVVK (SEQ ID NO:104) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the amino acid sequence of the light chain variable region (SEQ ID NO:105). The CDR-L1, CDR-L2, and CDR-L3 based on different CDR definition schemes in the light chain variable region are shown in Table 13.

[0216] [Table 13]

[0217] The nucleotide sequence of the heavy chain variable region (including the signal peptide) of 39B4 is ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGT CAGGAGCAGCTGGTGGAGTCCGGGGGAGGCCTGGTCCAGCCTGAGGGATCCCTGACACTCACCTGCACAGCTTCTGGATTCTCCTTCAGTAGTAGTTATTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGCTGGTACTAGTGGTAGCACTTACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACTGTGGATCTTCAAATGAACAGTCTGACAGCGGCGGACACGGCCACCTATTTCTGTGCGAGAGCCGGTTACTATACTTATGGTGCTGGTGTTTATATTTATCCTAGTTCCTTTAAGTTGTGGGGCCCAGGCACCCTGGTCACCGTCTCCTCA (SEQ ID NO:113) Here, the italicized part is the signal peptide sequence, and the underlined part is the nucleotide sequence of the heavy chain variable region (SEQ ID NO:114), and the corresponding amino acid sequence is METGLRWLLLVAVLKGVQC QEQLVESGGGLVQPEGSLTLTCTASGFSFSSSYWICWVRQAPGKGLEWIACIYAGTSGSTYYASWAKGRFTISKTSSTTVDLQMNSLTAADTATYFCARAGYYTYGAGVYIYPSSFKLWGPGTLVTVSS (SEQ ID NO:115) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the amino acid sequence of the heavy chain variable region (SEQ ID NO:116). The CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable region, based on different CDR definition schemes, are shown in Table 14.

[0218] [Table 14]

[0219] The nucleotide sequence of the light chain variable region (including the signal peptide) of 39B4 is ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTACTGCTCTGGCTCCCAGGTGCCAGATGT GATGTCGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAGCATTGGCAATGCATTAGCCTGGTATCAGCAGAAACCAGGACAGCCTCCCAAGCTCCTGATCTATTCTGCATCCAATCTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAGCTATTATTATAGTAGTAGTAGTATTACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAA (SEQ ID NO:129) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the nucleotide sequence of the light chain variable region (SEQ ID NO:130). The corresponding amino acid sequence is MDTRAPTQLLGLLLLWLPGARC DVVMTQTPASVEAAVGGTVTIKCQASESIGNALAWYQQKPGQPPKLLIYSASNLASGVPSRFSGSGSGTQFTLTISDLECADAATYYCQSYYYSSSSITFGGGTEVVVK (SEQ ID NO:131) Here, the italicized portion is the signal peptide sequence, and the underlined portion is the amino acid sequence of the light chain variable region (SEQ ID NO:132). The CDR-L1, CDR-L2, and CDR-L3 based on different CDR definition schemes in the light chain variable region are shown in Table 15.

[0220] [Table 15]

[0221] Example 2: Verification of the effect of an anti-NMI monoclonal antibody 1. The method for preparing antibodies is as follows: (1) Cell transfection: Cell density 4.0 × 10 6 Once the cell / mL reaches the target, transfection can be performed. Before transfection, it is necessary to remove the original medium by centrifugation and then add fresh medium. The following example uses transfection of 100 mL of cells. 1) The antibody plasmid was added to 5 mL of serum-free medium in a heavy chain:light chain ratio of 1:2, totaling 100 μg, and incubated at room temperature for 5 minutes. 2) PEI was added to 5 mL of serum-free medium in a plasmid:PEI ratio of 1:3, totaling 300 μg, and incubated at room temperature for 5 minutes. 3) The incubated plasmid and PEI were uniformly mixed, incubated for 15 minutes, and then added to the cells. (2) Antibody purification: Six days after cell transfection, the culture supernatant was collected according to the cell culture status. 1) The cell culture supernatant was collected after centrifuging 2000g at 4°C for 20 minutes. 2) Protein G beads or Protein A beads treated with conjugation buffer (20 mM sodium phosphate, pH 7.0) were added to the supernatant and rotated incubated at 4°C for 2 hours to allow sufficient antibody to bind to the beads. 3) The beads were collected by centrifugation at 3000 rpm and 4°C, and the beads were washed three times with binding buffer to remove contaminating proteins. 4) Finally, the antibodies on the beads were eluted using elution buffer (0.1M glycine-HCl, pH 2.9), and the pH was adjusted by adding 100 μL of 1M Tris-HCl (pH 9.0) per 1 mL of eluate to obtain the antibodies (the SDS-PAGE results after antibody B8, 94C4 preparation are shown in Figure 3).

[0222] 2. Affinity test The affinity of 94C4, B-8, 240B10-1, 98G10, and 39B4 was measured using the I-Elisa method. Specifically, 1) Antigen coating: The antigen, e.g., hNMI, was diluted to 1 μg / mL in PBS, added to an Elisa plate, and coated overnight at 4°C with 100 μL / well. 2) Blocking: The antigen solution was discarded, washed four times with 250 μL / well of PBST, incubated for 3 minutes each time, the remaining solution was thoroughly removed by tapping, 5% BSA prepared in PBS was added at 200 μL / well, sealed with a blocking membrane, and blocked at 37°C for 2 hours. 3) Primary antibody incubation: Discard the blocking solution, wash four times with 250 μL / well PBST, add 100 μL / well of primary antibody solution (initial concentration of 2.5 μg / mL, 2-fold gradient dilution to create a total of 12 gradients, dilution in PBS, 1×PBS as negative control), seal with a blocking membrane, and incubate at 37°C for 1 hour. 4) Secondary antibody incubation: Discard the primary antibody solution, wash four times with 250 μL / well PBST, add the corresponding HRP-labeled secondary antibody diluent (anti-rabbit IgGHRP-Linked antibody, 1:3000) in 100 μL / well, seal with a blocking membrane, and incubate at 37°C for 1 hour. 5) Chromogenic development: Discard the secondary antibody diluent, wash six times with 250 μL / well PBST, remove any remaining solution by tapping, add 90 μL / well TMB, and incubate for 20 minutes under light shielding. 6) Final reading: Add 2 mol / LH2SO4 in 50 μL / well, and read the OD450 value with a microplate reader. The results are shown in Table 16. The logarithm of the antibody concentration is used as the x-coordinate, and the OD measured at each dilution is shown. 450 The values ​​were used as the vertical axis, and nonlinear regression analysis was performed on the above data. As shown in Figure 5 and Table 17, the EC50 values ​​of 94C4, B-8, 240B10-1, 98G10, and 39B4 were 30-70 ng / mL (here, the results differed significantly from Example 1, which may be due to the antibodies being stored at -20°C for one year and the use of a different brand of chromogenic reagent than in Example 1). In particular, 94C4 had the strongest affinity for the antigen, with an EC50 value of 32.72 ng / mL.

[0223] The inventors performed structural analysis using AlphaFold and discovered, as shown in Figure 9-13, that the amino acids bound to and recognized by the antigen hNMI were some of the amino acids (referred to here as important amino acids) of the above monoclonal antibodies (94C4, B-8, 240B10-1, 98G10, or 39B4). Among these, the important sites of monoclonal antibody 39B4 are E2 (E2 refers to the second amino acid E in the heavy chain variable region of monoclonal antibody 39B4, and the same applies hereafter), G26, F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, Y112 in the heavy chain variable region, and S28, N31, Y93, S96 in the light chain variable region. The important sites of monoclonal antibody B-8 are S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in the heavy chain variable region, and Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in the light chain variable region. The important sites for monoclonal antibody 240B10-1 are D27, L28, S29, S30, Y31, T32, S51, G52, G53, G54, K70, S72, and S73 in the heavy chain variable region, and Y29, N30, D32, Y33, S51, K54, C75, and Y76 in the light chain variable region. The important sites for monoclonal antibody 98G10 are F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, K74, S76, S77, Y102, N104, S107, A108, G109, D110, I111, and Y112 in the heavy chain variable region, and K53 in the light chain variable region.The important sites of the monoclonal antibody 94C4 are Q1, F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in the heavy chain variable region, and Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, and D97 in the light chain variable region. Those skilled in the art are well aware that the amino acid that binds to and recognizes the antigen hNMI in a monoclonal antibody is its CDR. Therefore, in conjunction with the results of the AlphaFold structural analysis described above, the following important sites of the monoclonal antibodies (94C4, B-8, 240B10-1, 98G10, or 39B4) were identified. The important sites of monoclonal antibody 39B4 are G26 (G26 refers to the 26th amino acid G in the heavy chain variable region of monoclonal antibody 39B4, and the same applies hereinafter), F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in the heavy chain variable region, and S28, N31, Y93, and S96 in the light chain variable region. The important sites of monoclonal antibody B-8 are S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in the heavy chain variable region, and Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in the light chain variable region. The important sites for monoclonal antibody 240B10-1 are D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in the heavy chain variable region, and Y29, N30, D32, Y33, S51, K54, C75, and Y76 in the light chain variable region. The important sites for monoclonal antibody 98G10 are F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in the heavy chain variable region, and K53 in the light chain variable region.The important sites of the monoclonal antibody 94C4 are F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in the heavy chain variable region, and Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, and D97 in the light chain variable region.

[0224] To verify whether changes in key sites of monoclonal antibody 94C4 affect the function of the monoclonal antibody, the inventors performed point mutations on some key sites (specific mutation information is shown in Table 17-1; other sequences are the same as monoclonal antibody 94C4, and the mutation site is A32K as an example, in which a mutation was made only in the 32nd amino acid of the heavy chain variable region of monoclonal antibody 94C4, specifically by mutating the 32nd A to K). As a result, as shown in Table 17-1, after mutating key sites of monoclonal antibody 94C4 (for example, S29, A32, S52, D101 in the heavy chain variable region, and D97 in the light chain variable region), its function was affected (affinity with antigen NMI was significantly reduced).

[0225] To verify whether changes in key sites of monoclonal antibody B-8 affect the function of the monoclonal antibody, the inventors performed point mutations on some key sites (specific mutation information is shown in Table 17-2, while other sequences are the same as those of monoclonal antibody B-8). As a result, as shown in Table 17-2, after mutating key sites of monoclonal antibody B-8 (for example, S101 and G106 in the heavy chain variable region, and T31 in the light chain variable region), its function was affected (affinity with antigen NMI was significantly reduced).

[0226] To verify whether changes in key sites of the monoclonal antibody 240B10-1 affect the function of the monoclonal antibody, the inventors performed point mutations on some key sites (specific mutation information is shown in Table 17-3, while other sequences are the same as those of monoclonal antibody 240B10-1). As a result, as shown in Table 17-3, after mutating key sites of monoclonal antibody 240B10-1 (for example, D27, S29, S30, G52 in the heavy chain variable region and N30 in the light chain variable region), its function was affected (affinity with antigen NMI was significantly reduced).

[0227] To verify whether changes in key regions of the monoclonal antibody 98G10 affect the function of the monoclonal antibody, the inventors performed point mutations on some key regions (specific mutation information is shown in Table 17-4, while other sequences are the same as those of monoclonal antibody 98G10). As a result, as shown in Table 17-4, after mutating key regions of monoclonal antibody 98G10 (for example, G55, S56, S57, and G58 in the heavy chain variable region), its function was affected (affinity with antigen NMI was significantly reduced).

[0228] To verify whether changes in key regions of monoclonal antibody 39B4 affect the function of the monoclonal antibody, the inventors performed point mutations on some key regions (specific mutation information is shown in Table 17-5, while other sequences are the same as those of monoclonal antibody 39B4). As a result, as shown in Table 17-5, after mutating key regions of monoclonal antibody 39B4 (for example, Y102, G106, A107, V109 in the heavy chain variable region), its function was affected (affinity with antigen NMI was significantly reduced).

[0229] To verify whether changes in amino acids other than the critical site of the monoclonal antibody 98G10 (substitution, deletion, and / or insertion) affect the function of the monoclonal antibody, the inventors modified other amino acids other than the critical site of the monoclonal antibody 98G10 (specific mutation information is shown in Tables 17-6 (mutation occurs in the CDR region) and 17-7 (mutation occurs in the non-CDR region), with the other sequences being the same as monoclonal antibody 98G10, and taking W34H as an example, a mutation occurred only in the 34th amino acid of the heavy chain variable region of monoclonal antibody 98G10, specifically by mutating the 34th W to H). The results are shown in Figures 17-6 and 17-7 (the differences in the results for 98G10 in Tables 17-6 and 17-7 are due to experiments with different batches, and similarly, the differences in the results for the same antibody in this application are due to differences in experiments). It can be seen that mutating sites other than the critical site does not affect the function of the antibody and that it still has good affinity for the antigen hNMI.

[0230] To verify whether changes in amino acids other than the critical site of monoclonal antibody B8 (substitution, deletion, and / or insertion) affect the function of the monoclonal antibody, the inventors altered other amino acids other than the critical site of monoclonal antibody B8 (specific mutation information is shown in Table 17-8; other sequences are the same as monoclonal antibody B8, and as an example, the mutation site is Y93E, in which only the 93rd amino acid in the heavy chain variable region of monoclonal antibody B8 was mutated, specifically by mutating the 93rd Y to E). As shown in Figure 17-8, the results show that mutating sites other than the critical site does not affect the function of the antibody, and it still has good affinity for the antigen hNMI.

[0231] [Table 16]

[0232] [Table 17]

[0233] [Table 17-1]

[0234] [Table 17-2]

[0235] [Table 17-3]

[0236] [Table 17-4]

[0237] [Table 17-5]

[0238] [Table 17-6]

[0239] [Table 17-7]

[0240] [Table 17-8]

[0241] In Tables 17-1 to 17-8 above, the Arabic numerals at the mutation sites indicate the location of the mutation site within the heavy chain variable region or light chain variable region, the alphabet before the Arabic numeral represents the amino acid at that location before the mutation, and the alphabet after the Arabic numeral represents the amino acid at that location after the mutation; the rest of the sequence remains unchanged.

[0242] 2. Western blotting will be used to verify whether the recombinant protein and the overexpressed protein of 293T transfection are recognized. This example provides a method for detecting target proteins by following gel electrophoresis of proteins (recombinant protein (hNMI), cell lysates of 293T cells (293T-NMI-flag, 293T-NMI) into which hNMI plasmids have been introduced, and cell lysates of 293T cells (293T-flag-pcdna3.4, 293T-pcDNA3.4) into which empty vector plasmids have been introduced, followed by transfer to an NC membrane and further detection of target proteins by Western blotting. Specifically, the following steps were performed: Cell lysate of recombinant protein (hNMI), 293T cells (293T-NMI-flag) into which hNMI plasmid was introduced, and 293T cells (293T-flag-pcdna3.4) into which an empty vector plasmid was introduced. After polyacrylamide gel electrophoresis, the cells were transferred to an NC membrane, incubated with 5% skim milk at 37°C for 1 hour, and the NC membrane was washed 5 times with 1×PBST solution for 5 minutes each time. The monoclonal antibodies of the present invention (94C4 (94C4-1), B-8 (B8-1), 240B10-1, 98G10 (98G10-1), 39B4 (39B4-1)) were diluted to 1 μg / mL as primary antibodies in 1% BSA solution and incubated with the NC membrane for 4 The NC membrane was incubated at °C for 12 hours and washed five times with 1×PBST solution for 5 minutes each time. The NC membrane was incubated with an HRP-labeled secondary antibody that specifically recognizes rabbit-derived antibodies at 37°C for 1 hour, and the NC membrane was washed three times with 1×PBST solution for 5 minutes each time. After adding an HRP chromogenic substrate and developing the color using a gel imaging system, as shown in Figure 6, specific bands appeared on the membrane at the location of the cell lysates of 293T cells (293T-NMI-flag) into which recombinant protein (hnmi) and NMI plasmid had been introduced, but no specific bands appeared at the location of the cell lysates of 293T cells (293T-flag-pcdna3.4) into which an empty vector plasmid had been introduced.

[0243] 3. Matched-pair experiments with monoclonal antibodies (94C4 (94C4-1), B-8 (B8-1), 240B10-1, 98G10 (98G10-1), 39B4 (39B4-1)) The antigen detection effect of each antibody pair was detected using the bi-antibody sandwich Elisa method. Specifically, 1) Microplates were coated with 2.5 μg / mL of 94C4 (94C4-1), B-8 (B8-1), and 240B10-1 monoclonal antibodies as coating antibodies (100 μL / well, coated overnight at 4°C). 2) The coating solution was discarded, and the plates were washed 9 times using a plate washer. The washing solution was PBST, 250 μL / well, and any remaining solution was thoroughly removed by tapping. 3) The plates were blocked with 5% BSA, diluted with PBS, and incubated at 37°C for 2 hours in 150 μL / well. 4) The blocking solution was discarded, and the plates were washed 9 times using a plate washer. The final solution was PBST, 250 μL / well. 5) The antigen hNMI concentration was measured, and 0.1 μg / mL was used as the initial concentration. A 3-fold gradient dilution was performed to obtain a total of 6 gradients (specifically shown in Table 18). The diluent was PBS, 100 μL / well, and incubated at 37°C for 1 hour. 6) The antigen solution was discarded, and the plate was washed 9 times with a plate washer to obtain PBST 250 μL / well. 7) 94C4 (94C4-1), B-8 (B8-1), 240B10-1, 98G10 (98G10-1), and 39B4 (39B4-1), each labeled with 1 μg / mL of biotin, were added to prepare the detection antibodies (the detection antibodies are different from the coated antibodies), and incubated at 100 μL / well at 37°C for 1 hour. 8) The detection antibody solution was discarded, and the plate was washed 9 times with a plate washer to obtain PBST 250 μL / well. 9) Add streptavidin diluted 1:5000 with PBS as a diluent, and incubate at 37°C for 1 hour at 100 μL / well. 10) Discard the streptavidin solution, wash the plate 9 times with a plate washer, and prepare 250 μL / well of PBST. 11) Develop with TMB chromogenic solution, and incubate at 37°C for 15 minutes at 90 μL / well under light shielding. 12) Stop with 2M H2SO4, prepare at 50 μL / well, and measure OD450.As shown in Table 18, when 94C4 (94C4-1), B-8 (B8-1), and 240B10-1 were used as the coating antibodies, and biotin-labeled B-8 (B8-1), 240B10-1, 98G10 (98G10-1), 94C4 (94C4-1), and 39B4 (39B4-1) were used as the detection antibodies (the detection antibodies were different from the coating antibodies), a good detection effect was observed.

[0244] [Table 18]

[0245] The antigen detection effect of each antibody pair was detected using the double antibody sandwich Elisa method. The method was consistent with the process described above, with the only differences being the following: 1) Microplates were coated with 2.5 μg / mL B-8 (B8-1), 240B10-1, 98G10 (98G10-1), and 39B4 (39B4-1) monoclonal antibodies as coating antibodies. 5) Antigen concentrations were measured, and 50,000 pg / mL was used as the initial concentration. A 2-fold gradient dilution was performed, creating a total of 12 gradients (specifically shown in Table 19), and the dilution was PBS. 3) When 94C4 (94C4-1) labeled with 1 μg / mL and 0.5 μg / mL biotin, respectively, were used as detection antibodies, the results are shown in Table 19. When 94C4 (94C4-1) labeled with 0.5 μg / mL biotin was used as the detection antibody, and 2.5 μg / mL B-8 (B8-1), 240B10-1, 98G10 (98G10-1), and 39B4 (39B4-1) monoclonal antibodies were used as coating antibodies, the detection limits (sensitivity) were 60, 60, 60, and 40 pg / mL, respectively.

[0246] [Table 19]

[0247] IV. Detection of specificity of paired antibodies using the double antibody sandwich Elisa method. Cells for protein overexpression samples were prepared. NMI-flag refers to 293T cells (NMI-flag) into which the hNMI-flag plasmid was introduced, flag refers to 293T cells (empty vector, flag) into which the flag tag plasmid was introduced, and 293T refers to 293T cells cultured in synchronous culture (synchronous control, 293T). Overexpressed proteins in the cells were detected using the double antibody sandwich Elisa method with screened paired antibodies (B-8 (B8-1) as the coating antibody and 0.5 μg / mL of 94C4-1-biotin as the detection antibody). The specific method was as follows: 1) The coating antibody was diluted to 2.5 ug / mL in PBS and coated at 100 μL / well overnight at 4°C. 2) The coating solution was discarded, and the plate was washed 9 times with a plate washer. The washing solution was PBST, 250 μL / well, and any remaining solution was thoroughly removed by tapping. 3) Block with 5% BSA, dilute with PBS, and incubate at 37°C for 2 hours in 150 μL / well. 4) Discard the blocking solution, wash the plate 9 times with a plate washer, and prepare 250 μL / well of PBST. 5) Add the antigen solution (cell supernatant or cell lysate) and incubate at 37°C for 1 hour in 100 μL / well. 6) Discard the antigen solution, wash the plate 9 times with a plate washer, and prepare 250 μL / well of PBST. 7) Add 94C4 (94C4-1) labeled with 0.5 μg / mL biotin as the detection antibody, and incubate at 37°C for 1 hour in 100 μL / well. 6) Discard the antibody solution, wash the plate 9 times with a plate washer, and prepare 250 μL / well of PBST. 7) Add 94C4 (94C4-1) labeled with 0.5 μg / mL biotin as the detection antibody, and incubate at 37°C for 1 hour at 100 μL / well. 8) Discard the detection antibody solution, wash the plate 9 times with a plate washer, and prepare 250 μL / well of PBST. 9) Add streptavidin diluted 1:5000 with PBS as the diluent, and incubate at 37°C for 1 hour at 100 μL / well. 10) Discard the streptavidin solution, wash the plate 9 times with a plate washer, and prepare 250 μL / well of PBST.11) The cells were colored with TMB chromogenic solution and incubated at 37°C for 15 minutes at 90 μL / well under light-shielding conditions. 12) The cells were stopped with 2M H2SO4, diluted to 50 μL / well, and the OD450 was measured. As shown in Figure 4 and Table 20, NMI-flag overexpression protein (NMI-flag) was specifically detected in both the supernatant and cell lysates of 293T cells, and the OD450 was not detected in the supernatant of 293T cells with an empty vector or synchronized control. 450 All values ​​were significantly below the detection limit. On the other hand, in the cell lysates of the empty vector, the detection value was higher than that of the control supernatant, which corresponds to the phenomenon where the detection value increases due to NMI released as a result of cell damage or death caused by transfection during the transfection process.

[0248] [Table 20]

[0249] 5. Testing of natural proteins in human bodily fluids The method for detecting the effect of each antibody pair on detecting intrinsic proteins in human body fluids using the bi-antibody sandwich Elisa method is the same as the third method, with the only difference being the following: 1) Microplates were coated with 2.5 μg / mL B-8 (B8-1) monoclonal antibody as the coating antibody. 5) Antigens were measured using synovial fluid samples from arthritis patients (undiluted, 2-fold diluted undiluted (dilution PBS, 1 / 2), and PBS as a negative control (0)). 7) Using 0.5 μg / mL biotin-labeled 94C4 (94C4-1) as the detection antibody, the results, as shown in Table 21, show that NMI in synovial fluid can be detected, i.e., intrinsic proteins can be recognized, using biotin-labeled 94C4 (94C4-1) as the detection antibody and B-8 (B8-1) as the coating antibody.

[0250] [Table 21]

[0251] Example 3: Optimization of a dual antibody sandwich enzyme-coupled immunosorbent assay (ELISA) kit for NMI detection. Optimization of blocking solution 1) A dual antibody sandwich enzyme-linked immunosorbent assay (ELISA) kit for NMI detection, comprising: coated antibody B-8, polystyrene plastic plate (Corning Coster), coated antibody diluent (0.05 mol / L phosphate buffer, pH 7.5), blocking solution (PBS solution containing 5 (w / v)% BSA (pH 7.5, 0.05 M)), washing solution (PBS solution containing 0.05% Tween-20 (pH 7.5, 0.05 M)), sample diluent (PBS solution containing 5% (w / v) BSA and 0.1% (v / v) Tween-20 (pH 7.5, 0.05 M)), biotin-labeled detection antibody 94C4, streptavidin-horseradine peroxidase complex (SA-HRP), 3,3',5,5'-tetramethylbenzidine (TMB) chromogenic solution, and stop solution (2 M sulfuric acid solution). 2) A double antibody sandwich enzyme-coupled immunosorbent assay (ELISA) kit for NMI detection, which is the same as in 1) except that the blocking solution is 5 wt% skim milk powder. 3) A double antibody sandwich enzyme-coupled immunosorbent assay (ELISA) kit for NMI detection, which is the same as in 1), except that the blocking solution is a PBS solution (pH 7.5, 0.05 M) containing 5 (w / v) FBS. NMI was detected using kits 1), 2), and 3), respectively. Specifically, Coating antibody B-8 was diluted to 0.25 μg / mL with coating antibody diluent (0.05 mol / L phosphate buffer, pH 7.5), coated polystyrene plastic plates (Corning Coster), and coated with 100 μL of the solution in each well at 4°C overnight. The following day, after discarding the coating solution, the samples were blocked using the blocking solutions from kits 1), 2), and 3), respectively, and blocked at 37°C for 2 hours. After blocking, the plate was washed twice with a washing solution (PBS solution containing 0.05% Tween-20 (pH 7.5, 0.05 M)), the detection antigen (hNMI) was added, starting at 25 ng / mL, and then diluted 2-fold using the sample diluent (specifically shown in Table 22), with each well containing 100 μL. The antigen was incubated at 37°C for 1 hour to allow the reaction to occur. The plate was then washed four times with washing solution, and 100 μL of 0.25 μg / mL biotin-labeled detection antibody 94C4 was added to each well. The detection antibody was incubated at 37°C for 1 hour to allow the reaction to occur. The plate was then washed four times with washing solution, and 100 μL of 50 ng / mL streptavidin-horseradish peroxidase complex (SA-HRP) was added to each well. SA-HRP was incubated at 37°C for 15 minutes to allow the reaction to occur. The plate was then washed four times with washing solution, and 3,3',5,5'-tetramethylbenzidine (TMB) chromogenic solution was added at a rate of 100 μL / well. The color-developing solution was incubated at 37°C for 15 minutes to allow the reaction to proceed. 50 μL / well of stop solution (2M sulfuric acid solution) was added to halt the reaction, and the plate was read at 450 nm using a microplate reader. As shown in Table 22, the test results for different kits (blocking solutions) were almost identical. Based on the blankwell OD values, a PBS solution containing 5(w / v)% BSA (pH 7.5, 0.05M) was selected as the blocking solution, i.e., kit 1) was selected for subsequent experiments.

[0252] [Table 22]

[0253] Example 4: Optimization of the method for using a dual antibody sandwich enzyme-coupled immunosorbent assay (ELISA) kit for NMI detection. 1) Optimization of the concentration used for coated antibodies In Example 3, the concentration of the coated antibody was optimized using the kit from 1). The method was the same as the NMI detection method in Example 3, except that coated antibody B-8 was diluted to 0.25, 0.5, 1, 2.5, and 5 μg / mL with coated antibody diluent (0.05 mol / L phosphate buffer, pH 7.5), coated onto a polystyrene plastic plate (Corning Coster), and coated overnight at 4°C with 100 μL of each well. As shown in Table 23, the optimal concentration of the coated antibody was 0.25 μg / mL, resulting in a high overall signal value and a low background value.

[0254] [Table 23]

[0255] 2) Optimization of detection antibody concentration In Example 3, the concentration of the detection antibody was optimized using the kit from 1). The method was the same as the detection method for NMI in Example 3, except that the initial antigen concentration was 12.5 ng / mL, the antigen was incubated at 37°C for 1 hour, the plate was washed four times with washing solution, and 100 μL of biotin-labeled detection antibody 94C4 at concentrations of 0.25, 0.5, and 1.0 μg / mL were added to each well. As shown in Table 24, when comparing different detection antibody concentrations, a relatively good linear relationship was already obtained for the detection result at 0.25 μg / mL.

[0256] [Table 24]

[0257] 3) Optimization of SA-HRP detection concentration In Example 3, the concentration of the coated antibody was optimized using the kit from 1). The method was the same as the detection method for NMI in Example 3, except that the initial antigen concentration was 12.5 ng / mL, the detection antibody was incubated at 37°C for 1 hour, the plate was washed four times with washing solution, and 100 μL of streptavidin-horseradish peroxidase complex (SA-HRP) at concentrations of 50, 100, and 200 ng / mL were added to each well. As shown in Table 25, comparing different SA-HRP concentrations, the optimal SA-HRP concentration, based on the detection signal, was found to be 50 ng / mL.

[0258] [Table 25]

[0259] 4) Optimization of antigen reaction time In Example 3, the concentration of the coated antibody was optimized using the kit from 1). The method was the same as the detection method for NMI in Example 3, except that the antigen was incubated at 37°C for 45 min, 1 hour, and 1.5 hours, respectively, the plate was washed four times with washing solution, and 100 μL of 0.25 μg / mL biotin-labeled detection antibody 94C4 was added to each well. As shown in Table 26, a comprehensive analysis comparing different antigen reaction times revealed that 1 hour was optimal.

[0260] [Table 26]

[0261] Example 5 Linear range of a double antibody sandwich enzyme-conjugated immunosorbent assay (ELISA) kit for NMI detection A calibration curve was created using the kit from 1) in Example 3, and the method was the same as the NMI detection method in Example 3, except that the antigen concentration was 12 ng / mL and a 2-fold ratio dilution was performed using the sample diluent (specifically shown in Table 27). As shown in Table 27 and Figure 7, the fitting curve is y = 0.0001x + 0.0914(R 2 The coefficient was 0.9992, indicating good linearity, with a linear range of 187.5 pg / mL to 12000 pg / mL.

[0262] [Table 27]

[0263] Example 6: Detection of serum NMI content in healthy individuals and sepsis patients In Example 3, samples were collected using the kit from 1) from healthy individuals and sepsis patients. The OD values ​​were read using a microplate reader, and the NMI protein content was calculated based on the fitting equation of the calibration curve from Example 5. Using Graphpad Prism 8, we plotted the data and analyzed the difference in serum NMI (antigen 1) protein content between healthy individuals and sepsis patients using the Mann-Whitney U test. The results showed that the serum antigen 1 content in sepsis patients was significantly higher than that of the healthy group (P<0.005). Therefore, the kit manufactured according to this invention can be used to rapidly detect the antigen 1 content in serum. Simultaneously, when ROC curves were plotted and the diagnostic value of serum antigen 1 in sepsis was analyzed, serum antigen 1 was found to be effective in diagnosing sepsis (high AUC value).

[0264] Example 7: Analytical sensitivity of a dual antibody sandwich enzyme-conjugated immunosorbent assay (ELISA) kit for NMI detection As shown in Table 27, when 20 negative samples were detected using the kit from 1) in Example 3 of the same batch, the mean (X) and standard deviation (SD) of the negative wells were calculated, and the cutoff value was determined using the formula (cutoff value = X + 2SD). The calculated cutoff value was substituted into the calibration curve in Example 5, and the calculated concentration was used as the analytical sensitivity of the detection kit. As a result, the cutoff value of the kit was 0.1207, and the analytical sensitivity was 196.864 pg / mL.

[0265] [Table 27]

[0266] Example 8: Magnetic particle chemiluminescence detection kit for NMI detection Example 8-1 A magnetic particle chemiluminescence detection kit for NMI detection, comprising magnetic beads coated with 98G10, B-8 labeled with acridinium ester, reaction buffer, and hNMI calibrator, The method for preparing magnetic beads coated with 98G10 is as follows: 1) Activation of magnetic microspheres (magnetic beads): 20 mg of carboxyl-modified magnetic microspheres with a diameter of approximately 1 μm were aspirated into a 2 mL centrifuge tube, and magnetic separation of the magnetic microspheres and liquid was performed using a magnetic stand. The magnetic microspheres were then washed four times with 1 mL of 0.1 M pH 6.0 sodium 2-(N-morpholine)ethanesulfonate (MES). To the washed magnetic microspheres described above, 1 mL of 0.1 MpH 6.0 MES was added, followed by 10 μL of 20 mg / mL 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 50 μL of 20 mg / mL N-hydroxysuccinimide. The mixture was then shaken at room temperature for 1 hour. 2) Coupling: The activated magnetic microspheres were placed on a magnetic stand and magnetically separated from the liquid. The magnetic microspheres were washed four times with 1 mL of 0.1 M pH 6.0 2-(N-morpholine) ethanesulfonate sodium salt (MES), 0.5 mg of monoclonal antibody 98G10 was added, and 0.1 M pH 6.0 2-(N-morpholine) ethanesulfonate sodium salt (MES) was added to 1 mL to make a 1 mL volume of antibody-containing magnetic microsphere suspension. The suspension was incubated at room temperature for 15 hours with continuous rotation. 3) Blocking: 1.5% (v / v) ethanolamine was added to the magnetic microsphere suspension containing the above antibody, and the suspension was incubated at room temperature for 30 minutes with continuous rotation. The magnetic microsphere suspension containing the above antibody was placed on a magnetic stand and subjected to magnetic separation. It was then washed four times with 1 ml of 0.1 M pH 6.0 2-(N-morpholine) ethanesulfonate sodium salt (MES), and 1 ml of 0.05 M Tris-HCl buffer at pH 7.5 containing 2% (w / v) BSA and 1% (w / v) trehalose was added. The suspension was incubated at room temperature for 2 hours with continuous rotation. A magnetic microsphere suspension containing the above antibody was placed on a magnetic stand and subjected to magnetic separation. 1 mL of 0.05 M Tris-HCl buffer at pH 7.5 containing 2% (w / v) BSA and 1% (w / v) trehalose was added and the suspension was washed four times. 1 mL of 0.05 M Tris-HCl buffer at pH 7.5 containing 2% (w / v) BSA and 1% (w / v) trehalose was added to obtain magnetic microspheres coated with monoclonal antibody 98G10. Magnetic microspheres coated with the above monoclonal antibody 98G10 were diluted 1:100 with 0.05M Tris-HCl buffer at pH 7.5 containing 2% (w / v) BSA and 1% (w / v) trehalose, aliquoted, and stored in a medical refrigerator at 2-8°C. The hNMI calibrator is a lyophilized powder. It was prepared by diluting recombinant human hNMI protein to 0.00 pg / mL, 200.00 pg / mL, and 2000.00 pg / mL using 0.05 M Tris-HCl buffer at pH 7.8 containing 5% (w / v) BSA, 1% (w / v) trehalose, 0.1% (v / v) Tween-20, and 0.1% (v / v) Proclin300, then dispensing the diluted solution into 1 mL / vial and lyophilizing it. The method for preparing B-8 labeled with acridinium ester is as follows: 1) Washing: 1.0 mg of monoclonal antibody B-8 was taken, added to a 50 kD ultrafiltration tube, and concentrated by centrifugation at 4°C and 8000 rpm for 5 minutes in a high-speed cryogenic centrifuge. The waste liquid was discarded, and PB buffer containing 0.02 M disodium hydrogen phosphate and 0.002 M potassium dihydrogen phosphate at pH 6.5 was added to an ultrafiltration centrifuge tube, bringing the volume of the ultrafiltration centrifuge tube to approximately 400 μL. The sample was centrifuged in a high-speed refrigerated centrifuge at 4°C and 8000 rpm for 5 minutes, the waste liquid was discarded, and this procedure was repeated four times. The ultrafiltration centrifuge tube was inverted and centrifuged in a high-speed cryogenic centrifuge at 4°C and 3000 rpm for 1 minute. Then, 100 μL of PB buffer was added to the ultrafiltration tube, and after standing for 5 minutes, the ultrafiltration centrifuge tube was inverted again and centrifuged in a high-speed cryogenic centrifuge at 4°C and 3000 rpm for 1 minute. The antibodies from the two inverted centrifuges were collected together. 2) Coupling: 0.05 mg of acridinium salt was added to the above antibody and incubated in an incubator at 26°C for 19 ± 1 hours with light-shielding and shaking. 3) Purification: SepHadex TM Monoclonal antibody B-8 labeled with acridinium ester was purified using a G50 gel column in combination with a high-efficiency protein purification system. The eluate was PB buffer at pH 6.5. The cleanliness of the gel chromatography column was checked using the UV detection function of the purification system. After each baseline stabilized, purification was started, and the solution of the first protein peak was collected to obtain the target antibody solution. 4) Storage: The acridinium ester-labeled monoclonal antibody B-8 collected by the above purification was filtered through a 0.22 μm syringe filter, its protein concentration was measured using Nanodrop, and finally, a protein stabilizer containing 10% (v / v) glycerin and 0.1% (v / v) Procline300 was added at 1% of the total volume. Monoclonal antibody B-8 labeled with the above acridinium salt was diluted 1:400 with 0.05 M Tris-HCl buffer at pH 7.2 containing 1% (w / v) trehalose, 0.1% (v / v) Tween-20, and 1 mM disodium ethylenediaminetetraacetate, aliquoted, and stored in a medical refrigerator at 2-8°C. The reaction buffer is prepared by creating a 0.025 M Tris-HCl buffer at pH 7.2 containing 0.1% (v / v) Tween-20 and 0.1% (v / v) Proclin300.

[0267] Example 8-2 A magnetic particle chemiluminescence detection kit for NMI detection is provided, and is the same as in Example 8-1 except that 1 mg of monoclonal antibody 98G10 is added during the coupling process in the preparation method of magnetic beads coated with 98G10.

[0268] Example 8-3 This is a magnetic particle chemiluminescence detection kit for NMI detection, and the method for preparing B-8 labeled with acridinium ester is the same as in Example 8-1, except that 2.0 mg of monoclonal antibody B-8 is taken during the washing process. 1) Optimization of the amount of 98G10 used in the preparation method for magnetic beads coated with 98G10. Using the kits of Examples 8-1 and 8-2, different concentrations of hNMI were detected. As shown in Table 28, the background interference was lower when 0.5 mg of 98G10 was used in the preparation method for 98G10-coated magnetic beads (Example 8-1).

[0269] [Table 28]

[0270] 2) Optimization of the amount of B-8 used in the preparation method of B-8 labeled with acridinium ester. Using the kits of Examples 8-1 and 8-3, different concentrations of hNMI were detected, and the method was the same as in 1). As shown in Table 29, when the amount of B-8 used in the preparation method for acridinium ester-labeled B-8 is 1.0 mg (Example 8-1), background interference is lower.

[0271] [Table 29]

[0272] 3) Identifying the linear range Using the kit from Example 8-1, the antigen hNMI was detected in different concentration ranges, using the same method as in 1). The results are shown in Table 30. After comprehensive analysis, a linear range interval of 50 to 10000 pg / mL was finally selected, where the concentration points include 0, 50, 200, 1000, 4000, and 10000 pg / mL.

[0273] [Table 30]

[0274] 4) Verification of the kit's reproducibility The kit from Example 8-1 was used to detect different concentrations of the antigen hNMI and verify reproducibility. The method was the same as in 1), and as shown in Table 31, when the CV% of different concentrations of the antigen hNMI was detected using the kit from Example 8-1, all were ≤5%.

[0275] [Table 31]

[0276] 5) Accuracy verification Three samples of different concentrations were prepared by taking the same low-value sample, dividing it into three equal volumes, and adding a standard solution (10 microliters of 2000 pg / mL standard solution for sample 1, 20 microliters of 20000 pg / mL standard solution for sample 2, and 40 microliters of 20000 pg / mL standard solution for sample 3) to each low-value sample, in accordance with the requirement that the added volume be less than 10% of the original volume. These samples were then repeatedly measured using the kit from Example 8-1, and the recovery rate was calculated by taking the average value. The results, as shown in Table 32, show a recovery rate of 85% to 115%.

[0277] [Table 32]

[0278] 6) Blank and analytical sensitivity Using the kit from Example 8-1, 25 healthy serum samples were detected. The method was the same as in 1), and the mean (X) and standard deviation (SD) for each concentration were calculated. The critical value was identified using the formula (LOD=X+2SD). As shown in Table 33, the analytical sensitivity was calculated to be 16.64 pg / mL.

[0279] [Table 33]

[0280] 7) Detection of serum NMI content in healthy individuals and sepsis patients Using the kit from Example 8-1, 30 healthy samples and 15 sepsis patients were detected. As shown in Table 34, the signal values ​​of the serum samples from sepsis patients and healthy samples showed a significant difference (p<0.05), indicating that the kit from Example 8-1 has a good detection effect.

[0281] [Table 34] JPEG2026515753000045.jpg23170

[0282] Example 9: Gold colloid test strip for NMI detection A gold colloid test strip for NMI detection, as shown in Figure 8, comprises a PVC base plate, a sample pad attached to the PVC base plate, a gold colloid pad, a nitrocellulose membrane, and absorbent filter paper. The gold colloid pad is coated with gold colloid-labeled B-8, and the nitrocellulose membrane has a test line and a control line. The test line is coated with 94C4, and the control line is coated with goat anti-rabbit IgG antibody.

[0283] Example 10: Biomaterial that adsorbs NMI A biomaterial that adsorbs NMI, containing a Protein G chromatography column coupled with B-8.

[0284] While the above embodiments are preferred embodiments of the present invention, the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principles of the present invention are all within the scope of protection of the present invention.

Claims

1. An anti-NMI antibody or its antigen-binding fragment, wherein the antibody or its antigen-binding fragment is 94C4, B-8, 240B10-1, 98G10, or 39B4, and the antibody or its antigen-binding fragment includes a heavy chain variable region and a light chain variable region. The heavy chain variable region of 94C4 is one of a1) to a2), a1) Consists of CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO: 4, a2) The amino acid sequence of SEQ ID NO:4 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence having the same function as the protein shown in SEQ ID NO:4, The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The light chain variable region of 94C4 is one of the following: b1) Including CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence shown in SEQ IDNO:21, b2) The amino acid sequence of SEQ ID NO: 21 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region having the same function as the protein shown in SEQ ID NO: 21, The substituted amino acids are amino acids in CDR, and the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, and D97 in SEQ IDNO:

21. The heavy chain variable region of B-8 is one of the following: c1) Includes CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence shown in SEQ IDNO:32, c2) The amino acid sequence of SEQ ID NO: 32 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence having the same function as the protein shown in SEQ ID NO: 32, The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The light chain variable region of B-8 is one of d1) to d2), d1) Including CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence shown in SEQ IDNO:49, d2) The amino acid sequence of SEQ ID NO: 49 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence having the same function as the protein shown in SEQ ID NO: 49, The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The heavy chain variable region of 240B10-1 is one of e1) to e2), e1) Consists of CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable region of the amino acid sequence shown in SEQ IDNO:60, e2) The amino acid sequence of SEQ ID NO: 60 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence having the same function as the protein shown in SEQ ID NO: 60, The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The light chain variable region of the 240B10-1 is one of the following: f1) Includes CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence shown in SEQ IDNO:77, f2) The amino acid sequence of SEQ ID NO: 77 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence having the same function as the protein shown in SEQ ID NO:

77. The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The heavy chain variable region of 98G10 is one of g1) to g2), g1) Consists of CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable region of the amino acid sequence shown in SEQ IDNO:88, g2) The amino acid sequence of SEQ ID NO: 88 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence having the same function as the protein shown in SEQ ID NO:

88. The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The light chain variable region of the 98G10 is one of h1) to h2), h1) Including CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence shown in SEQ IDNO: 105, h2) The amino acid sequence of SEQ ID NO: 105 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence having the same function as the protein shown in SEQ ID NO:

105. The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than K53 in SEQ IDNO:

105. The heavy chain variable region of 39B4 is one of i1) to i2), i1) Including CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence shown in SEQ IDNO:116, i2) The amino acid sequence of SEQ ID NO: 116 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region of the amino acid sequence having the same function as the protein shown in SEQ ID NO: 116, The substituted amino acid is an amino acid in CDR, and the substituted amino acid is selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The light chain variable region of 39B4 is one of j1) to j2), j1) Including the light chain variable regions CDR-L1, CDR-L2, and CDR-L3 shown in SEQ IDNO: 132, j2) The amino acid sequence of SEQ ID NO: 132 is substituted with 1, 2, 3, 4, or 5 amino acids, and includes CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region of the amino acid sequence having the same function as the protein shown in SEQ ID NO:

132. The substituted amino acid is an amino acid in the CDR, and the substituted amino acid is selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132, and is an antibody or its antigen-binding fragment.

2. An anti-NMI antibody or its antigen-binding fragment, wherein the antibody or its antigen-binding fragment is 94C4, B-8, 240B10-1, 98G10, or 39B4, and the antibody or its antigen-binding fragment includes a heavy chain variable region and a light chain variable region. The 94C4 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 5, a112) SEQ IDNO:5 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:5, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 6, a212) SEQ IDNO:6 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:6, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 7, a312) SEQ IDNO:7 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:7, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 22, a412) SEQ IDNO:22 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:22, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 23, a512) SEQ IDNO:23 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:23, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 24, a612) SEQ IDNO:24 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:24, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or When defined using the IMGT definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO:8, a112) SEQ IDNO:8 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:8, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO:9, a212) SEQ IDNO:9 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:9, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 10, a312) SEQ IDNO:10 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:10, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 25, a412) SEQ IDNO:25 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:25, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L2 is one of the following types: a511) to a512) a511) RVS, a512) An amino acid sequence in which RVS is replaced by one or two amino acids and has the same function as RVS, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 24, a612) SEQ IDNO:24 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:24, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or When defined using Chothia's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 11, a112) SEQ IDNO:11 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:11, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 12, a212) SEQ IDNO:12 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:12, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 7, a312) SEQ IDNO:7 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:7, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 22, a412) SEQ IDNO:22 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:22, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 23, a512) SEQ IDNO:23 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:23, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 24, a612) SEQ IDNO:24 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:24, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or When defined using the Contact definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 13, a112) SEQ IDNO:13 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:13, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 14, a212) SEQ IDNO:14 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:14, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 15, a312) SEQ IDNO:15 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:15, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 26, a412) SEQ IDNO:26 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:26, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 27, a512) SEQ IDNO:27 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:27, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 28, a612) SEQ IDNO:28 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:28, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or When defined using the Abm definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 16, a112) SEQ IDNO:16 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:16, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 17, a212) SEQ IDNO:17 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:17, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 7, a312) SEQ IDNO:7 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:7, wherein the substituted amino acids are selected from amino acids other than F26, S29, S30, N31, A32, C49, I50, S51, S52, S54, S60, Y62, R100, D101, G102, D104, and L105 in SEQ IDNO:

4. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 22, a412) SEQ IDNO:22 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:22, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 23, a512) SEQ IDNO:23 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:23, wherein the substituted amino acids are selected from amino acids other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:

21. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 24, a612) SEQ IDNO:24 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:24, wherein the substituted amino acids are selected from amino groups other than Y29, N30, Y32, S34, L46, Y49, R50, S52, T53, L54, S56, S94, A95, D97 in SEQ IDNO:21, or The B-8 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 33, a112) SEQ IDNO:33 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:33, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 34, a212) SEQ IDNO:34 is substituted with 1, 2, or 3 amino acids, and is an amino acid sequence having the same function as the protein shown in SEQ IDNO:34, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 35, a312) SEQ IDNO:35 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:35, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:50, a412) SEQ IDNO:50 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:50, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO:51, a512) SEQ IDNO:51 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:51, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:52, a612) SEQ IDNO:52 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:52, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, R99 in SEQ IDNO:49, or When defined using the IMGT definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 36, a112) SEQ IDNO:36 is substituted with 1, 2, or 3 (preferably 1) amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:36, wherein the substituted amino acid is selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, W109 in SEQ IDNO:32 (preferably the substituted amino acid is selected from Y33 in SEQ IDNO:32), The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 37, a212) SEQ IDNO:37 is substituted with 1, 2, or 3 amino acids, and is an amino acid sequence having the same function as the protein shown in SEQ IDNO:37, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 38, a312) SEQ IDNO:38 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:38, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:53, a412) SEQ IDNO:53 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:53, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L2 is one of the following types: a511) to a512) a511) GAS, a512) A GAS is substituted with one or two amino acids and has the same function as GAS, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:52, a612) SEQ IDNO:52 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:52, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, R99 in SEQ IDNO:49, or When defined using Chothia's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 39, a112) SEQ IDNO:39 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:39, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 40, a212) SEQ IDNO:40 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:40, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 35, a312) SEQ IDNO:35 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:35, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:50, a412) SEQ IDNO:50 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:50, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO:51, a512) SEQ IDNO:51 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:51, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:52, a612) SEQ IDNO:52 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:52, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, R99 in SEQ IDNO:49, or When defined using the Contact definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 41, a112) SEQ IDNO:41 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:41, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 42, a212) SEQ IDNO:42 is substituted with 1, 2, or 3 amino acids, and is an amino acid sequence having the same function as the protein shown in SEQ IDNO:42, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 43, a312) SEQ IDNO:43 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:43, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:54, a412) SEQ IDNO:54 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:54, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO:55, a512) SEQ IDNO:55 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:55, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:56, a612) SEQ IDNO:56 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:56, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, R99 in SEQ IDNO:49, or When defined using the Abm definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 44, a112) SEQ IDNO:44 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:44, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 45, a212) SEQ IDNO:45 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:45, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 35, a312) SEQ IDNO:35 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:35, wherein the substituted amino acids are selected from amino acids other than S30, S31, Y33, Y52, S55, S56, S58, T59, Y60, K66, Y100, S101, D103, D104, Y105, G106, D107, F108, and W109 in SEQ IDNO:

32. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:50, a412) SEQ IDNO:50 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:50, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO:51, a512) SEQ IDNO:51 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:51, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, and R99 in SEQ IDNO:

49. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:52, a612) SEQ IDNO:52 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:52, wherein the substituted amino acids are selected from amino acids other than Y30, T31, N32, L92, Y93, S94, R95, I96, A97, D98, R99 in SEQ IDNO:49, or The 240B10-1 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 61, a112) SEQ IDNO:61 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:61, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 62, a212) SEQ IDNO:62 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:62, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:63, a312) SEQ IDNO:63 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:63, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:78, a412) SEQ IDNO:78 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:78, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 79, a512) SEQ IDNO:79 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:79, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:80, a612) SEQ IDNO:80 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:80, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or When defined using the IMGT definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 64, a112) SEQ IDNO:64 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:64, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 65, a212) SEQ IDNO:65 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:65, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 66, a312) SEQ IDNO:66 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:66, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:81, a412) SEQ IDNO:81 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:81, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L2 is one of the following types: a511) to a512) a511) SAS, a512) An amino acid sequence in which SAS is replaced by one or two amino acids and has the same function as SAS, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:80, a612) SEQ IDNO:80 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:80, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or When defined using Chothia's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 67, a112) SEQ IDNO:67 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:67, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 68, a212) SEQ IDNO:68 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:68, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:63, a312) SEQ IDNO:63 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:63, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:78, a412) SEQ IDNO:78 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:78, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 79, a512) SEQ IDNO:79 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:79, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:80, a612) SEQ IDNO:80 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:80, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or When defined using the Contact definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 69, a112) SEQ IDNO:69 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:69, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO:70, a212) SEQ IDNO:70 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:70, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:71, a312) SEQ IDNO:71 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:71, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:82, a412) SEQ IDNO:82 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:82, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO:83, a512) SEQ IDNO:83 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:83, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:84, a612) SEQ IDNO:84 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:84, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or When defined using the Abm definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 72, a112) SEQ IDNO:72 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:72, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 73, a212) SEQ IDNO:73 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:73, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:63, a312) SEQ IDNO:63 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:63, wherein the substituted amino acids are selected from amino acids other than D27, L28, S29, S30, Y31, T32, S51, G52, G53, and G54 in SEQ IDNO:

60. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO:78, a412) SEQ IDNO:78 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:78, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 79, a512) SEQ IDNO:79 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:79, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:

77. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO:80, a612) SEQ IDNO:80 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:80, wherein the substituted amino acids are selected from amino acids other than Y29, N30, D32, Y33, S51, K54, C75, and Y76 in SEQ IDNO:77, or The 98G10 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO:89, a112) SEQ ID NO: 89 consists of 1, 2, or 3 amino acids, selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ ID NO:

88. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO:90, a212) SEQ IDNO:90 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:90, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:91, a312) SEQ IDNO:91 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:91, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 106, a412) SEQ IDNO:106 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:106, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 107, a512) SEQ IDNO:107 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:107, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 108, a612) SEQ IDNO:108 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:108, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:105, or When defined using the IMGT definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO:92, a112) SEQ IDNO:92 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:92, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO:93, a212) SEQ IDNO:93 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:93, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:94, a312) SEQ IDNO:94 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:94, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 109, a412) SEQ IDNO:109 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:109, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L2 is one of the following types: a511) to a512) a511) TAS, a512) The TAS is an amino acid sequence in which one or two amino acids are substituted and which has the same function as the TAS, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 108, a612) SEQ IDNO:108 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:108, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:105, or When defined using Chothia's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO:95, a112) SEQ IDNO:95 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:95, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO:96, a212) SEQ IDNO:96 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:96, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:91, a312) SEQ IDNO:91 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:91, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 106, a412) SEQ IDNO:106 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:106, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 107, a512) SEQ IDNO:107 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:107, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 108, a612) SEQ IDNO:108 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:108, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:105, or When defined using the Contact definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO:97, a112) SEQ IDNO:97 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:97, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO:98, a212) SEQ IDNO:98 is an amino acid sequence in which one, two, or three amino acids are substituted, and which has the same function as the protein shown in SEQ IDNO:98, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:99, a312) SEQ IDNO:99 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:99, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 110, a412) SEQ IDNO:110 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:110, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 111, a512) SEQ IDNO:111 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:111, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 112, a612) SEQ IDNO:112 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:112, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:105, or When defined using the Abm definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 100, a112) SEQ IDNO:100 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:100, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 101, a212) SEQ IDNO:101 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:101, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO:91, a312) SEQ IDNO:91 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:91, wherein the substituted amino acids are selected from amino acids other than F29, S30, A31, Y53, G55, S56, S57, G58, S59, Y61, Y102, N104, S107, A108, G109, D110, I111, and Y112 in SEQ IDNO:

88. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 106, a412) SEQ IDNO:106 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:106, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 107, a512) SEQ IDNO:107 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:107, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:

105. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 108, a612) SEQ IDNO:108 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:108, wherein the substituted amino acids are selected from amino acids other than K53 in SEQ IDNO:105, or The 39B4 includes a heavy chain variable region and a light chain variable region, the heavy chain variable region includes CDR-H1, CDR-H2 and CDR-H3, and the light chain variable region includes CDR-L1, CDR-L2 and CDR-L3. When defined using Kabat's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 117, a112) SEQ IDNO:117 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:117, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 118, a212) SEQ IDNO:118 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:118, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 119, a312) SEQ IDNO:119 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:119, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 133, a412) SEQ IDNO:133 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:133, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 134, a512) SEQ IDNO:134 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:134, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 135, a612) SEQ IDNO:135 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:135, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132, or When defined using the IMGT definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 120, a112) SEQ IDNO:120 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:120, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 121, a212) SEQ IDNO:121 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:121, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 122, a312) SEQ IDNO:122 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:122, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 136, a412) SEQ IDNO:136 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:136, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L2 is one of the following types: a511) to a512) a511) SAS, a512) An amino acid sequence in which SAS is replaced by one or two amino acids and has the same function as SAS, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 135, a612) SEQ IDNO:135 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:135, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132, or When defined using Chothia's definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 120, a112) SEQ IDNO:120 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:120, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 123, a212) SEQ IDNO:123 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:123, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 119, a312) SEQ IDNO:119 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:119, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 133, a412) SEQ IDNO:133 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:133, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 134, a512) SEQ IDNO:134 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:134, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 135, a612) SEQ IDNO:135 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:135, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132, or When defined using the Contact definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 117, a112) SEQ IDNO:117 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:117, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 124, a212) SEQ IDNO:124 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:124, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 125, a312) SEQ IDNO:125 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:125, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 137, a412) SEQ IDNO:137 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:137, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 138, a512) SEQ IDNO:138 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:138, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 139, a612) SEQ IDNO:139 is substituted with 1, 2, or 3 amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:139, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:132, or When defined using the Abm definition scheme, The CDR-H1 is one of the following types a111) to a112): a111) SEQ ID NO: 126, a112) SEQ IDNO:126 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:126, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H2 is one of the following types a211) to a212): a211) SEQ ID NO: 127, a212) SEQ IDNO:127 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:127, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-H3 is one of the following types: a311) to a312) a311) SEQ ID NO: 128, a312) SEQ IDNO:128 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:128, wherein the substituted amino acids are selected from amino acids other than F27, S28, S30, S31, S32, Y33, Y53, T56, Y102, T104, Y105, G106, A107, G108, V109, Y110, I111, and Y112 in SEQ IDNO:

116. The CDR-L1 is one of the following types: a411) to a412) a411) SEQ ID NO: 133, a412) SEQ IDNO:133 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:133, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L2 is one of the following types: a511) to a512) a511) SEQ ID NO: 134, a512) SEQ IDNO:134 is substituted with 1, 2, or 3 amino acids, and has the same function as the protein shown in SEQ IDNO:134, wherein the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132. The CDR-L3 is one of the following types: a611) to a612) a611) SEQ ID NO: 135, a612) An antibody or its antigen-binding fragment, wherein SEQ IDNO:135 is substituted with one, two, or three amino acids, and the amino acid sequence has the same function as the protein shown in SEQ IDNO:135, and the substituted amino acids are selected from amino acids other than S28, N31, Y93, and S96 in SEQ IDNO:

132.

3. Preferably, the amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 94C4 are shown in SEQ IDNO: 5, 6, 7, 22, 23, and 24, respectively, and the CDRs are defined according to Kabat's definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of 94C4 are shown in SEQ IDNO: 8, 9, 10, 25, and 24, respectively, the amino acid sequence of CDR-L2 is RVS, and CDR is defined according to the IMGT definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 94C4 are shown in SEQ IDNO: 11, 12, 7, 22, 23, and 24, respectively, and the CDRs are defined according to Chothia's definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 94C4 are shown in SEQ IDNO: 13, 14, 15, 26, 27, and 28, respectively, and the CDRs are defined in the Contact definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 94C4 are shown in SEQ IDNO: 16, 17, 7, 22, 23, and 24, respectively, and the CDRs are defined according to the Abm definition scheme, or Preferably, the amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 61, 62, 63, 78, 79, and 80, respectively, and the CDRs are defined according to Kabat's definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 64, 65, 66, 81, and 80, respectively, the amino acid sequence of CDR-L2 is SAS, and CDR is defined according to the IMGT definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 67, 68, 63, 78, 79, and 80, respectively, and the CDRs are defined according to Chothia's definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 69, 70, 71, 82, 83, and 84, respectively, and the CDRs are defined in the Contact definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 240B10-1 are shown in SEQ IDNO: 72, 73, 63, 78, 79, and 80, respectively, and the CDRs are defined according to the Abm definition scheme, or Preferably, the amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 39B4 are shown in SEQ IDNO: 117, 118, 119, 133, 134, and 135, respectively, and the CDRs are defined according to Kabat's definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of 39B4 are shown in SEQ IDNO: 120, 121, 122, 136, and 135, respectively, the amino acid sequence of CDR-L2 is SAS, and CDR is defined according to the IMGT definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 39B4 are shown in SEQ IDNO: 120, 123, 119, 133, 134, and 135, respectively, and the CDRs are defined according to Chothia's definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 39B4 are shown in SEQ IDNO: 117, 124, 125, 137, 138, and 139, respectively, and the CDRs are defined in the Contact definition scheme, or The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 39B4 are shown in SEQ IDNO: 126, 127, 128, 133, 134, and 135, respectively, and the CDRs are defined according to the Abm definition scheme. Preferably, m1) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8 are shown in SEQ IDNO: 33, 34, 35, 50, 51, and 52, respectively, and the CDRs are defined according to Kabat's definition scheme, or, m2) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m1), have the following mutations: a Y33E mutation in SEQ IDNO:32, and the CDRs are defined according to Kabat's definition scheme, or m3) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m1), have the following mutations: a Y61E mutation in SEQ IDNO:32, and the CDRs are defined according to Kabat's definition scheme, or m4) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m1), have the following mutations: the F111A mutation in SEQ IDNO:32, and the CDRs are defined according to Kabat's definition scheme, or m5) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m1), have the following mutations: a Y93E mutation in SEQ IDNO: 49, and the CDRs are defined according to Kabat's definition scheme, or m6) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m1), have the following mutations: a mutation in S91R at SEQ IDNO:49, and the CDRs are defined according to Kabat's definition scheme, or m7) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of B-8 are shown in SEQ IDNO: 36, 37, 38, 53, and 52, respectively, the amino acid sequence of CDR-L2 is GAS, and CDR is defined according to the IMGT definition scheme, or m8) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m7), have the following mutations: a Y33E mutation in SEQ IDNO:32, the CDRs are defined according to the IMGT definition scheme, or m9) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m7), have the following mutations: the F111A mutation in SEQ IDNO:32, the CDRs are defined according to the IMGT definition scheme, or m10) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m7), have the following mutations: a Y93E mutation in SEQ IDNO: 49, and the CDRs are defined according to the IMGT definition scheme, or m11) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m7), have the following mutations: a mutation in S91R at SEQ IDNO:49, the CDRs are defined according to the IMGT definition scheme, or m12) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8 are shown in SEQ IDNO: 50, 51, 52, 67, 68, and 63, respectively, and the CDRs are defined according to Chothia's definition scheme, or m13) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m12), have the following mutations: the F111A mutation in SEQ IDNO:32, and the CDRs are defined according to Chothia's definition scheme, or m14) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m12), have the following mutations: a Y93E mutation in SEQ IDNO: 49, and the CDRs are defined according to Chothia's definition scheme, or m15) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m12), have the following mutations: a mutation in S91R in SEQ IDNO: 49, and the CDRs are defined according to Chothia's definition scheme, or m16) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8 are shown in SEQ IDNO: 41, 42, 43, 54, 55, and 56, respectively, and the CDRs are defined in the Contact definition scheme, or m17) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m16), have the following mutations: a Y33E mutation in SEQ IDNO:32, and the CDRs are defined according to the Contact definition scheme, or m18) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m16), have the following mutations: the F111A mutation in SEQ IDNO:32, and the CDRs are defined according to the Contact definition scheme, or m19) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m16), have the following mutations: a Y93E mutation in SEQ IDNO: 49, and the CDRs are defined according to the Contact definition scheme, or m20) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m16), have the following mutations: a mutation in S91R at SEQ IDNO:49, and the CDRs are defined according to the Contact definition scheme, or m21) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8 are shown in SEQ IDNO: 44, 45, 35, 50, 51, and 52, respectively, and the CDRs are defined according to the Abm definition scheme, or m22) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m21), have the following mutations: a Y33E mutation in SEQ IDNO:32, and the CDRs are defined according to the Abm definition scheme, or m23) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m21), have the following mutations: the F111A mutation in SEQ IDNO:32, the CDRs are defined according to the Abm definition scheme, or m24) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m21), have the following mutations: a Y93E mutation in SEQ IDNO: 49, and the CDRs are defined according to the Abm definition scheme, or m25) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of B-8, compared to m21), have the following mutations: the S91R mutation in SEQ IDNO: 49, and the CDRs are defined according to the Abm definition scheme. Preferably, n1) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10 are shown in SEQ IDNO: 89, 90, 91, 106, 107, and 108, respectively, and the CDRs are defined according to Kabat's definition scheme, or n2) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a W34H mutation in SEQ IDNO: 88, the CDRs are defined according to Kabat's definition scheme, or n3) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a W34Y mutation in SEQ IDNO: 88, and the CDRs are defined according to Kabat's definition scheme, or n4) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a Y112R mutation in SEQ IDNO: 88, the CDRs are defined according to Kabat's definition scheme, or n5) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a Y112S mutation in SEQ IDNO: 88, the CDRs are defined according to Kabat's definition scheme, or n6) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a Y112E mutation in SEQ IDNO: 88, the CDRs are defined according to Kabat's definition scheme, or n7) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a Y112Q mutation in SEQ IDNO: 88, the CDRs are defined according to Kabat's definition scheme, or n8) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: mutations in W34R and Y112R in SEQ IDNO: 88, and the CDRs are defined according to Kabat's definition scheme, or n9) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: the W34D and Y112R mutations in SEQ IDNO: 88, and the CDRs are defined according to Kabat's definition scheme, or n10) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: mutations in W34H and Y112L in SEQ IDNO: 88, and the CDRs are defined according to Kabat's definition scheme, or n11) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: W34T and Y112R mutations in SEQ IDNO: 88, and the CDRs are defined according to Kabat's definition scheme, or n12) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: mutations at W34H and Y112R in SEQ ID NO: 88, and the CDRs are defined according to Kabat's definition scheme, or n13) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: the W34H and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to Kabat's definition scheme, or n14) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: the W34K and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to Kabat's definition scheme, or n15) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: the W34D and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to Kabat's definition scheme, or n16) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a Y93R mutation in SEQ IDNO: 105, the CDRs are defined according to Kabat's definition scheme, or n17) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a Y93S mutation in SEQ IDNO: 105, the CDRs are defined according to Kabat's definition scheme, or n18) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a Y93Q mutation in SEQ IDNO: 105, and the CDRs are defined according to Kabat's definition scheme, or n20) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of 98G10 are shown in SEQ IDNO: 92, 93, 94, 109, and 108, respectively, the amino acid sequence of CDR-L2 is TAS, and CDR is defined in the IMGT definition scheme, or n21) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: a W34H mutation in SEQ IDNO: 88, the CDRs are defined according to the IMGT definition scheme, or n22) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: a W34Y mutation in SEQ IDNO: 88, the CDRs are defined according to the IMGT definition scheme, or n23) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: a Y112R mutation in SEQ IDNO: 88, the CDRs are defined according to the IMGT definition scheme, or n24) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: a Y112S mutation in SEQ IDNO: 88, the CDRs are defined according to the IMGT definition scheme, or n25) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: a Y112E mutation in SEQ IDNO: 88, the CDRs are defined according to the IMGT definition scheme, or n26) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: a Y112Q mutation in SEQ IDNO: 88, the CDRs are defined according to the IMGT definition scheme, or n27) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: mutations in W34R and Y112R in SEQ IDNO: 88, and the CDRs are defined according to the IMGT definition scheme, or n28) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: the W34D and Y112R mutations in SEQ IDNO: 88, and the CDRs are defined according to the IMGT definition scheme, or n29) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: mutations in W34H and Y112L in SEQ IDNO: 88, and the CDRs are defined according to the IMGT definition scheme, or n30) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: W34T and Y112R mutations in SEQ IDNO: 88, and the CDRs are defined according to the IMGT definition scheme, or n31) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: mutations in W34H and Y112R in SEQ IDNO: 88, and the CDRs are defined according to the IMGT definition scheme, or n32) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: the W34H and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to the IMGT definition scheme, or n33) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: the W34K and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to the IMGT definition scheme, or n34) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: the W34D and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to the IMGT definition scheme, or n35) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: a Y93R mutation in SEQ IDNO: 105, the CDRs are defined according to the IMGT definition scheme, or n36) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: a Y93S mutation in SEQ IDNO: 105, the CDRs are defined according to the IMGT definition scheme, or n37) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n20), have the following mutations: a Y93Q mutation in SEQ IDNO: 105, the CDRs are defined according to the IMGT definition scheme, or n39) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10 are shown in SEQ IDNO: 95, 96, 91, 106, 107, and 108, respectively, and the CDRs are defined according to Chothia's definition scheme, or n40) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n39), have the following mutations: a Y112R mutation in SEQ IDNO: 88, the CDRs are defined according to Chothia's definition scheme, or n41) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n39), have the following mutations: a Y112S mutation in SEQ IDNO: 88, and the CDRs are defined according to Chothia's definition scheme, or n42) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n39), have the following mutations: a Y112E mutation in SEQ IDNO: 88, and the CDRs are defined according to Chothia's definition scheme, or n43) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n39), contain the following mutations: a Y112Q mutation in SEQ IDNO: 88, and the CDRs are defined according to Chothia's definition scheme, or n44) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n39), have the following mutations: a Y112L mutation in SEQ IDNO: 88, and the CDRs are defined according to Chothia's definition scheme, or n45) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n39), have the following mutations: a Y93R mutation in SEQ IDNO: 105, the CDRs are defined according to Chothia's definition scheme, or n46) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n39), contain the following mutations: a Y93S mutation in SEQ IDNO: 105, and the CDRs are defined according to Chothia's definition scheme, or n47) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n1), have the following mutations: a Y93Q mutation in SEQ IDNO: 105, and the CDRs are defined according to Chothia's definition scheme, or n48) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10 are shown in SEQ IDNO: 97, 98, 99, 110, 111, and 112, respectively, and the CDRs are defined in the Contact definition scheme, or n49) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: a W34H mutation in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n50) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: a W34Y mutation in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n51) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: a Y112R mutation in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n52) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: a Y112S mutation in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n53) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: a Y112E mutation in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n54) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: a Y112Q mutation in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n55) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: mutations in W34R and Y112R in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n56) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: the W34D and Y112R mutations in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n57) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: mutations in W34H and Y112L in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n58) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: W34T and Y112R mutations in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n59) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: mutations in W34H and Y112R in SEQ IDNO:88, and the CDRs are defined according to the Contact definition scheme, or n60) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: the W34H and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n61) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: the W34K and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n62) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: the W34D and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to the Contact definition scheme, or n63) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: a Y93R mutation in SEQ IDNO: 105, and the CDRs are defined according to the Contact definition scheme, or n64) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: a Y93S mutation in SEQ IDNO: 105, and the CDRs are defined according to the Contact definition scheme, or n65) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n48), have the following mutations: a Y93Q mutation in SEQ IDNO: 105, and the CDRs are defined according to the Contact definition scheme, or n66) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10 are shown in SEQ IDNO: 100, 101, 91, 106, 107, and 108, respectively, and the CDRs are defined according to the Abm definition scheme, or n67) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: a W34H mutation in SEQ IDNO: 88, the CDRs are defined according to the Abm definition scheme, or n68) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: a W34Y mutation in SEQ IDNO: 88, and the CDRs are defined according to the Abm definition scheme, or n69) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: a Y112R mutation in SEQ IDNO: 88, the CDRs are defined according to the Abm definition scheme, or n70) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: a Y112S mutation in SEQ IDNO: 88, the CDRs are defined according to the Abm definition scheme, or n71) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: a Y112E mutation in SEQ IDNO: 88, the CDRs are defined according to the Abm definition scheme, or n72) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: a Y112Q mutation in SEQ IDNO: 88, the CDRs are defined according to the Abm definition scheme, or n73) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: mutations in W34R and Y112R in SEQ IDNO:88, and the CDRs are defined according to the Abm definition scheme, or n74) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: the W34D and Y112R mutations in SEQ IDNO: 88, and the CDRs are defined according to the Abm definition scheme, or n75) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: mutations in W34H and Y112L in SEQ IDNO: 88, and the CDRs are defined according to the Abm definition scheme, or n76) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: the W34T and Y112R mutations in SEQ IDNO: 88, and the CDRs are defined according to the Abm definition scheme, or n77) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: the W34H and Y112R mutations in SEQ IDNO: 88, and the CDRs are defined according to the Abm definition scheme, or n78) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: the W34H and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to the Abm definition scheme, or n79) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: the W34K and Y112S mutations in SEQ IDNO: 88, and the CDRs are defined according to the Abm definition scheme, or n80) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: the W34D and Y112S mutations in SEQ IDNO:88, and the CDRs are defined according to the Abm definition scheme, or n81) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: a Y93R mutation in SEQ IDNO: 105, the CDRs are defined according to the Abm definition scheme, or n82) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: a Y93S mutation in SEQ IDNO: 105, the CDRs are defined according to the Abm definition scheme, or n83) The amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 98G10, compared to n66), have the following mutations: a Y93Q mutation in SEQ IDNO: 105, the CDRs are defined according to the Abm definition scheme, or Preferably, the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a full-length antibody, Fab, Fab', F(ab')2, Fv, scFv, a bispecific antibody, or a multispecific antibody, as described in claim 1 or 2.

4. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, Recombinant proteins comprising a tag sequence that selectively assists in expression and / or purification.

5. A biomaterial relating to an antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, or a recombinant protein according to claim 4, The aforementioned biomaterial is 1) An antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, or a nucleic acid molecule encoding a recombinant protein according to claim 4, l2) Expression cassette containing the nucleic acid molecule described in l1), l3) A vector containing the nucleic acid molecule described in l1), l4) A vector containing the expression cassette described in l2), l5) Transgenic cell lines containing the nucleic acid molecules described in l1), l6) l2) Transgenic cell lines containing the expression cassette described above, l7) Transgenic cell lines containing the vector described in l3), Transgenic cell lines containing the vector described in l8) l4), l9) Microorganisms containing nucleic acid molecules as described in l1), Microorganisms containing the expression cassette described in l10) l2), Microorganisms containing the vector described in l11) l3), Microorganisms containing the vector described in l12) l4), l13) Viruses containing nucleic acid molecules as described in l1), Viruses containing the expression cassette described in l14) l2), Viruses containing the vectors described in l15) and l3), A biomaterial containing at least one of the viruses containing the vectors described in l16) and l4).

6. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, and at least one recombinant protein according to claim 4, A conjugate moiety comprising at least one of the following: a detectable labeled substance, drug, toxin, or cytokine, Preferably, the detectable labeling substance is a conjugate selected from fine particles, fluorescent labels, redox molecular labels, chemiluminescent labels, radioactive labels, enzyme labels, ligand labels, or any combination thereof.

7. (1) The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, (2) Recombinant protein according to claim 4, (3) The biomaterial according to claim 5, (4) Use in the manufacture of at least one product of the conjugate described in claim 6, The aforementioned product includes at least one of the following: drugs, reagents, test strips, detection plates, kits, detection chips, adsorbents, and medical devices. Preferably, the drug can prevent or treat diseases or conditions associated with abnormally high levels and / or active NMI. Preferably, the reagent, test strip, detection plate, detection chip, or kit is w1) Detection of the presence or level of NMI protein in the sample, w2) Diagnosis, diagnostic assistance, or prognosis assessment of diseases or conditions associated with abnormally high levels and / or active NMI. w3) Screening for drugs to prevent or treat diseases or conditions associated with abnormally high levels and / or active NMI, having at least one of these functions, Preferably, the reagent, test strip, detection plate, detection chip, or kit is used in one or more detection methods selected from the group consisting of radioactive labeling immunoassay, enzyme immunoassay, fluorescence immunoassay, luminescence immunoassay, protein immunoblotting, physicochemical method, and biochip method. Preferably, the test sample for the reagent, test strip, detection plate, detection chip, or kit is at least one selected from the body fluids, tissues, cells, and excretions to be measured. Preferably, the adsorbent and medical device are used to remove NMI proteins from body fluids. Preferably, the disease or condition associated with the abnormally high levels and / or active NMI includes at least one of inflammation, infection, sepsis, organ injury, and autoimmune disease.

8. x1) The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, x2) Recombinant protein according to claim 4, x3) ​​A product comprising at least one of the conjugates described in claim 6, The aforementioned product includes at least one of the following: reagents, test strips, detection plates, kits, detection chips, adsorbents, and medical devices. Preferably, the reagent, test strip, detection plate, detection chip, or kit is w1) Detection of the presence or level of NMI protein in the sample, w2) Diagnosis, diagnostic assistance, or prognosis assessment of diseases or conditions associated with abnormally high levels and / or active NMI. w3) Screening for drugs to prevent or treat diseases or conditions associated with abnormally high levels and / or active NMI, having at least one of these functions, Preferably, the reagent, test strip, detection plate, detection chip, or kit is used in one or more detection methods selected from the group consisting of radioactive labeling immunoassay, enzyme immunoassay, fluorescence immunoassay, luminescence immunoassay, protein immunoblotting, physicochemical method, and biochip method. Preferably, the test sample for the reagent, test strip, detection plate, detection chip, or kit is at least one selected from the body fluids, tissues, cells, and excretions to be measured. Preferably, the adsorbent and medical device are used to remove NMI proteins from body fluids. Preferably, the product includes at least one of the following diseases or conditions associated with the abnormally high levels and / or active NMI: inflammation, infection, sepsis, organ injury, and autoimmune disease.

9. A double antibody sandwich ELISA kit comprising a coated antibody and a detection antibody, wherein at least one of the coated antibody and the detection antibody comprises the antibody described in any one of claims 1 to 3 or an antigen-binding fragment thereof.

10. The coated antibody binds to a solid support, Preferably, the solid-phase support comprises at least one of magnetic particles, latex particles, and microplates. Preferably, the detection antibody is labeled with a detectable labeling substance. Preferably, the detectable labeling substance is at least one selected from enzyme labeling and ligand labeling. Preferably, when the detectable labeling substance is selected from ligand labeling, the bi-antibody sandwich ELISA kit further comprises an enzyme-labeled receptor. Preferably, the coated antibody and the detection antibody are any two selected from the antibodies or antigen-binding fragments described in any one of claims 1 to 3. Preferably, the coated antibody contains B-8 and the detection antibody contains 94C4, or the coated antibody contains 94C4 and the detection antibody contains B-8. Preferably, the biantibody sandwich ELISA kit according to claim 9 further comprises at least one of a sample diluent, a washing solution, a blocking solution, a chromogenic solution, a stop solution, and a calibrator.

11. A chemiluminescence detection kit comprising a coated antibody and a detection antibody, wherein at least one of the coated antibody and the detection antibody comprises the antibody or antigen-binding fragment thereof as described in any one of claims 1 to 3.

12. The coated antibody binds to a solid support, Preferably, the solid-phase support comprises at least one of magnetic particles, latex particles, and microplates. Preferably, the detection antibody is labeled with a detectable labeling substance. Preferably, the detectable labeling substance is selected from chemiluminescent labels. Preferably, the coated antibody and the detection antibody are any two selected from the antibodies or antigen-binding fragments described in any one of claims 1 to 3. Preferably, the coated antibody contains B-8 and the detection antibody contains 98G10, or the coated antibody contains 98G10 and the detection antibody contains B-8. Preferably, the chemiluminescence detection kit according to claim 11 further comprises at least one of a reaction buffer, an NMI calibrator, and a luminescent substrate.

13. An immunochromatography test strip comprising a base plate, a sample pad, a labeling pad, a chromatography membrane, and a water-absorbing pad attached to the base plate, wherein the labeling pad is coated with a label-labeled anti-NMI antibody I, a test line is provided on the chromatography membrane, and the test line is coated with anti-NMI antibody II, and at least one of the anti-NMI antibody I and the anti-NMI antibody II comprises the antibody or antigen-binding fragment thereof described in any one of claims 1 to 3.

14. The anti-NMI antibody I and the anti-NMI antibody II are any two selected from the antibodies or antigen-binding fragments described in any one of claims 1 to 3. Preferably, the anti-NMI antibody I contains B-8 and the anti-NMI antibody II contains 94C4, or the anti-NMI antibody I contains 94C4 and the anti-NMI antibody II contains B-8. Preferably, the labeling substance is a gold colloid. Preferably, the immunochromatography test strip according to claim 13 is further provided with a control line in the chromatographic membrane.

15. An adsorbent comprising a carrier matrix and an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 3.

16. The carrier matrix is ​​at least one selected from agarose gel particles, cellulose gel particles, dextran gel particles, magnetic particles, silica gel particles, activated carbon, resin particles, Protein A agarose particles, and Protein G agarose particles. Preferably, the adsorbent according to claim 15, characterized in that the antibody or its antigen-binding fragment is linked to the carrier matrix.

17. A medical device comprising at least one of the antibodies or antigen-binding fragments thereof described in any one of claims 1 to 3, and the adsorbent described in any one of claims 15 to 16.

18. y1) The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, y2) Recombinant protein according to claim 4, y3) The biomaterial according to claim 5, y4) comprising at least one of the conjugates described in claim 6, Preferably, a drug further comprising a pharmaceutically acceptable carrier.

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