GDF15 neutralizing antibody and use thereof

Abstract

The present invention provides a GDF15-binding antibody or an antigen-binding fragment thereof. The antibody or the antigen-binding fragment thereof comprises: CDR sequences selected from at least one of the following or amino acid sequences having at least 66% identity with same: heavy chain variable region CDR sequences: SEQ ID NO: 1-34 and SEQ ID NO: 74-76; and light chain variable region CDR sequences: SEQ ID NO: 36-73 and SEQ ID NO: 77-82. According to embodiments of the present invention, the antibody or the antigen-binding fragment thereof can specifically bind to GDF15, can effectively block the binding of GFRAL and GDF15, and can also effectively inhibit Treg differentiation, and therefore can be used for preventing and / or treating cancers and cachexia.

Description

GDF15 neutralizing antibody and its uses Technical Field

[0001] This invention belongs to the field of biopharmaceutical technology. Specifically, this invention relates to a GDF15 neutralizing antibody and its use. More specifically, this invention relates to an antibody or its antigen-binding fragment, nucleic acid molecules, expression vectors, recombinant cells, pharmaceutical compositions and their uses, and kits and their uses. Background Technology

[0002] Cachexia, also known as dementia, is a multifactorial syndrome characterized by persistent skeletal muscle loss (with or without adipose tissue loss), which cannot be completely relieved by conventional nutritional support and gradually leads to functional impairment. Cachexia can occur during the progression of many chronic diseases, with cancer cachexia being the most common. It is characterized by the wasting of muscle in bones and internal organs, accompanied by various clinical manifestations such as decreased appetite, anorexia, bloating, weight loss, muscle atrophy, fatigue, anemia, edema, and hypoproteinemia. It can be divided into pre-cachexia, cachexia, and refractory cachexia.

[0003] Among malignant tumors, digestive system tumors have the highest incidence of cachexia, with pancreatic cancer at 71%, gastric and esophageal cancer at 65%, colorectal cancer at 56%, and liver and bile duct cancers at 40%. The incidence of cachexia also varies at different stages of the same tumor, with a higher incidence in patients with advanced-stage tumors. Among the top ten most common cancers, lung cancer, colorectal cancer, gastric cancer, liver cancer, esophageal cancer, and pancreatic cancer are frequently associated with cachexia.

[0004] Currently, only one drug is approved in Japan for the treatment of cachexia, launched on April 1, 2021. This drug is indicated for the treatment of cachexia associated with non-small cell lung cancer, gastric cancer, pancreatic cancer, or colorectal cancer. However, results show that while this drug can increase patient weight and alleviate symptoms such as anorexia, it does not improve grip strength. No other drugs have been approved for the treatment of cancer cachexia.

[0005] Currently, the best approach to treating cancer cachexia may involve single or combined strategies, including pharmacological intervention, nutritional intervention, exercise guidance, and psychological intervention. For pharmacological treatment of cancer cachexia, progesterone-based drugs (Class 1A recommendation) are the first choice to stimulate appetite. However, the use of these drugs also carries many risks, including contraindications, adverse reactions, or limited efficacy. Therefore, there is a need to develop a drug that can effectively improve cancer cachexia.

[0006] Summary of the Invention

[0007] This invention aims to address at least one of the technical problems existing in the prior art to a certain extent. To this end, this invention provides a GDF15 neutralizing antibody that specifically binds to GDF15 and effectively blocks the binding of GFRAL and GDF15, while also effectively inhibiting the differentiation of regulatory T cells (Treg cells or Tregs), which can be used for the prevention and / or treatment of cancer and cachexia.

[0008] This invention is based on the following discoveries of the inventors:

[0009] Among all therapeutic targets for cachexia, GDF15 and its receptor GFRAL are currently the most promising and have seen the most rapid progress. GDF15, also known as macrophage inhibitory cytokine-1 (MIC-1), is a member of the transforming growth factor β (TGFβ) superfamily. GDF15 is also known as nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), prostate-derived factor (PDF), placental bone morphogenetic protein (PLAB), placental transforming growth factor beta (PTGFB), and nonsteroidal anti-inflammatory drug-regulated gene-1 (NRG-1). GDF15 exists in cells in the form of a precursor polypeptide. After hydrolysis and removal of the amino-terminal propeptide, a mature 25 kDa homodimer is secreted extracellularly to exert its effects.

[0010] Current research has identified GFRAL as a high-affinity receptor for GDF15. GFRAL is an orphan receptor, a transmembrane protein with a short cytoplasmic domain, relatively enriched in the substantia nigra, hippocampus, and posterior regions of the central nervous system. GDF15, binding to GFRAL, forms a heterodimeric complex with the transmembrane tyrosine kinase co-receptor RET, subsequently activating an intracellular signaling pathway consistent with GDNF signaling. This pathway plays a central role in mechanisms of reduced food intake and weight loss, making it a hot topic in research on obesity, diabetes, and cachexia.

[0011] In addition to its metabolic associations with cachexia, anorexia, and vomiting, GDF15 molecules also possess a variety of other functions. In recent years, the most frequently reported function of GDF15 is its immunosuppressive and anti-inflammatory effects.

[0012] However, no drug currently possesses both therapeutic effects for cachexia and tumor immunotherapy. For example, Pfizer's Ponsegromab has excellent GFRAL blocking function, but its ability to inhibit Treg differentiation and enhance tumor immunity is not high. CaltalYM's visugromab and the candidate antibody from the Fourth Military Medical University of the Chinese People's Liberation Army have been reported in the literature to have good tumor immunotherapy function, but their GFRAL blocking function is weak.

[0013] However, the inventors unexpectedly discovered through experiments that the GDF15 neutralizing antibody of the present invention can not only achieve good GFRAL blocking function, but also show in vitro experiments that it has a high function of inhibiting Treg differentiation. In particular, the GDF15 neutralizing antibody of the present invention has a stronger function of inhibiting Treg differentiation than Ponsegromab, and this has been verified at the cellular and in vivo levels, proving that it has superior tumor immune activity.

[0014] In one aspect of the invention, an antibody or antigen-binding fragment thereof is provided. According to embodiments of the invention, the antibody or antigen-binding fragment thereof comprises: a CDR sequence selected from at least one of the following or an amino acid sequence having at least 66% identity with it: heavy chain variable region CDR sequence: SEQ ID NO: 1–34 and SEQ ID NO: 74–76; light chain variable region CDR sequence: SEQ ID NO: 36–73 and SEQ ID NO: 77–82. According to embodiments of the invention, the antibody or antigen-binding fragment thereof can specifically bind to GDF15 and effectively block the binding of GFRAL and GDF15, while also effectively inhibiting Treg differentiation, and can be used for the prevention and / or treatment of cancer and cachexia.

[0015] According to embodiments of the present invention, the antibody or antigen-binding fragment may further include at least one of the following technical features:

[0016] According to an embodiment of the present invention, the antibody comprises: a heavy chain variable region CDR1 composed of amino acids selected from any one of SEQ ID NO:1, SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:12, SEQ ID NO:15, SEQ ID NO:23, and SEQ ID NO:32; a heavy chain variable region CDR2 composed of amino acids selected from any one of SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:10, SEQ ID NO:13, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:33, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76; and a heavy chain variable region CDR2 composed of amino acids selected from any one of SEQ ID NO:3, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:11, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:76, SEQ ID NO:8, SEQ ID NO:11, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:76, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:8, SEQ ID NO:11, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:12, SEQ ID NO:15, SEQ ID NO:23, and SEQ ID NO:76. Heavy chain variable region CDR3 represented by amino acids selected from any one of SEQ ID NO:22, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:34; light chain variable region CDR1 represented by amino acids selected from any one of SEQ ID NO:36, SEQ ID NO:39, SEQ ID NO:43, SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO:52, SEQ ID NO:55, SEQ ID NO:58, SEQ ID NO:63, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:77, SEQ ID NO:78, and SEQ ID NO:79; light chain variable region CDR1 represented by amino acids selected from any one of SEQ ID NO:37, SEQ ID NO:40, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:56, SEQ ID NO:59 ... The light chain variable region CDR2 represented by any of the amino acids NO:61, SEQ ID NO:64 and SEQ ID NO:71;Alternatively, the light chain variable region CDR3 represented by an amino acid selected from any one of SEQ ID NO:38, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:51, SEQ ID NO:54, SEQ ID NO:57, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:72, SEQ ID NO:80, SEQ ID NO:81, and SEQ ID NO:82.

[0017] According to embodiments of the present invention, the antibody comprises: heavy chain variable region CDR1, CDR2, CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:1, 2, and 3, respectively; or, heavy chain variable region CDR1, CDR2, CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, respectively; or, heavy chain variable region CDR1, CDR2, CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:7, 5, and 8, respectively; or, heavy chain variable region CDR1, CDR2, CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:9, 10, and 11, respectively; or, heavy chain variable region CDR1, CDR2, CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:12, 13, and 14, respectively; or, heavy chain variable region CDR1, CDR2, CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:15, 16, and 14, respectively; or, heavy chain variable region CDR1, CDR2, CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:15, 16, and 14, respectively; or, heavy chain variable region CDR1, CDR2, CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:12, 13 ... The heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:15, 19, and 20; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:4, 21, and 22; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:23, 24, and 25; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:12, 26, and 27; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:7, 28, and 29 ... The heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:7, 5, and 30; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:7, 5, and 31; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:32, 33, and 34; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 74, and 11; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 75, and 11; or, the heavy chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 76, and 11.

[0018] According to embodiments of the present invention, the antibody comprises: light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:36, 37, and 38, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:39, 40, and 41, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:39, 40, and 42, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:43, 44, and 45, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:46, 47, and 48, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:49, 50, and 51, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:36, 37, and 38, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:39, 40, and 41, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:39, 40, and 42, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:36, 37, and 38, respectively; or, light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:39, 50, and The light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:52, 53, and 54; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:49, 47, and 51; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:55, 56, and 57; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:58, 59, and 60; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:49, 61, and 62; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:63, 64, and 65; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:63, 64, and 65; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:54, 55, 56, and 57; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:55, 56, and 57; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:58, 59, and 60; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:64, 65, and 66; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid The light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:66, 40, and 67; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:68, 40, and 69; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:70, 71, and 72; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:77, 53, and 54; or, the light chain variable region CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:78, 53, and 54.Alternatively, the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:79, 53, and 54, respectively; or the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 80, respectively; or the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 81, respectively; or the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 82, respectively; or the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:73, 53, and 54, respectively.

[0019] The CDRs of the different neutralizing antibodies screened in this invention were determined and annotated using the Kabat coding system, wherein the amino acid sequences, such as those shown in SEQ ID NO:1 to 82, are shown in Table 1.

[0020] Table 1

[0021] Those skilled in the art will recognize that the CDRs determined by the same antibody using different coding systems are not entirely identical. It should be noted that the CDRs in this invention (especially in the claims) are determined and annotated using the Kabat coding system. For the neutralizing antibodies screened by this invention, determining the CDRs using other coding systems is also within the scope of protection of this application. Other coding systems include, but are not limited to, IMGT, Chothia, or North coding systems.

[0022] For example, the CDRs of the neutralizing antibodies screened by this invention, determined using coding systems such as IMGT, Chothia, North, Abm, or Contact, are shown in Table 2.

[0023] Table 2

[0024] According to embodiments of the present invention, the antibody comprises: heavy chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:1, 2, and 3, respectively, and light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:36, 37, and 38, respectively; or, heavy chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, respectively, and light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:39, 40, and 41, respectively; or, heavy chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:7, 5, and 8, respectively, and light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:39, 40, and 42, respectively; or, as shown in the amino acid sequences of SEQ ID NO:36, 37, and 3 ...6, 37, and 38, respectively, and light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:36, 37, and 38, respectively, and light chain variable regions CDR1, CDR2, and CDR3 sequences as shown in the amino acid sequences of SEQ ID NO:36, 37, and 38, respectively The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences NO:9, 10, and 11, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:43, 44, and 45, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:12, 13, and 14, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:46, 47, and 48, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:15, 16, and 14, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:49, 50, and 51, respectively; or, the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:49, 50, and 51, respectively. The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences NO:1, 17, and 18, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:52, 53, and 54, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:15, 19, and 20, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:49, 47, and 51, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:4, 21, and 22, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:55, 56, and 57, respectively.Alternatively, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:23, 24, and 25, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:58, 59, and 60, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:12, 26, and 27, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:49, 61, and 62, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:7, 28, and 29, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:63, 64, and 65, respectively; or, the sequences shown in the amino acid sequences of SEQ ID NO:23, 24, and 25, respectively, and the sequences shown in the amino acid sequences of SEQ ID NO:63, 64, and 65, respectively; or, the sequences shown in the amino acid sequences of SEQ ID NO:23, 24, and 25, respectively, and the sequences shown in the amino acid sequences of SEQ ID NO:63, 64, and 65, respectively. The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences NO:7, 5, and 30, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:66, 40, and 67, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:7, 5, and 31, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:68, 40, and 69, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:32, 33, and 34, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:70, 71, and 72, respectively; or, the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in amino acid sequences SEQ ID NO:72, 33, and 34, respectively; or, ... The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 74, and 11, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:43, 44, and 45, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 75, and 11, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:43, 44, and 45, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 76, and 11, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:43, 44, and 45, respectively.Alternatively, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:77, 53, and 54, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:78, 53, and 54, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:79, 53, and 54, respectively; or, the .... The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 80, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 81, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 82, respectively; or, the heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 80, respectively. The amino acid sequences of NO:73, 53, and 54 show the CDR1, CDR2, and CDR3 sequences of the light chain variable region.

[0025] According to an embodiment of the present invention, the antibody or its antigen-binding fragment specifically recognizes GDF15.

[0026] According to an embodiment of the present invention, the antibody further comprises at least one of a heavy chain framework region sequence and a light chain framework region sequence; wherein at least a portion of at least one of the heavy chain framework region sequence and the light chain framework region sequence is derived from at least one of a murine antibody, a human antibody, a primate antibody, or a mutant thereof.

[0027] .

[0028] According to an embodiment of the present invention, at least a portion of the heavy chain framework region sequence and the light chain framework region sequence are derived from human antibodies or mutants thereof.

[0029] According to embodiments of the present invention, the antibody has a heavy chain variable region of an amino acid sequence as shown in any one of SEQ ID NO:83-100, SEQ ID NO:124-127, SEQ ID NO:132-135, SEQ ID NO:140-141 and SEQ ID NO:144-145.

[0030] G2-CH1 VH:

[0031] QVTLKESGPGILQPSQTLSLTCSFSGFSLSTYGIGVGWIRQPSGKGLEWLAHIWWNNNKYFNTALKSRLTISKDTSNN QVFLKIASVDTADSATYYCARMGYDIMDYWGQGTSVTVSS(SEQ ID NO:83, where the underlined parts are, in order, the heavy chain variable regions CDR1, CDR2, and CDR3 determined by the Kabat coding system);

[0032] G2-CH2 VH:

[0033] G2-CH3 VH:

[0034] G2-CH5 VH:

[0035] G2-CH6 VH:

[0036] G2-CH7 VH:

[0037] G2-CH8 VH:

[0038] G2-CH9 VH:

[0039] G2-CH10 VH:

[0040] G2-CH12 VH:

[0041] G2-CH13 VH:

[0042] G2-CH14 VH:

[0043] G2-CH16 VH:

[0044] G2-CH17 VH:

[0045] G2-CH23 VH:

[0046] G2-CH5-VH-P1:

[0047] G2-CH5-VH-P2:

[0048] G2-CH5-VH-P3:

[0049] G2-H1-VH_2(4-39):

[0050] G2-H1-VH_3(4-39):

[0051] G2-H1-VH_2(3-23):

[0052] G2-H1-VH_3(3-23):

[0053] G2-H5-VH_1:

[0054] G2-H5-VH_2:

[0055] G2-H5-VH_3:

[0056] G2-H5-VH_4:

[0057] G2-H8-VH_1:

[0058] G2-H8-VH_2:

[0059] G2-H8-VH1(gsm):

[0060] G2-H8-VH2(gsm):

[0061] According to embodiments of the present invention, the antibody has a light chain variable region of the amino acid sequence shown in any one of SEQ ID NO:102-122, SEQ ID NO:128-131, SEQ ID NO:136-139, SEQ ID NO:142-143 and SEQ ID NO:146-147.

[0062] G2-CH1 VL:

[0063] G2-CH2 VL:

[0064] G2-CH3 VL:

[0065] G2-CH5 VL:

[0066] G2-CH6 VL:

[0067] G2-CH7 VL:

[0068] G2-CH8 VL:

[0069] G2-CH9 VL:

[0070] G2-CH10 VL:

[0071] G2-CH12 VL:

[0072] G2-CH13 VL:

[0073] G2-CH14 VL:

[0074] G2-CH16 VL:

[0075] G2-CH17 VL:

[0076] G2-CH23 VL:

[0077] G2-CH8-VL-P1:

[0078] G2-CH8-VL-P2:

[0079] G2-CH8-VL-P3:

[0080] G2-CH2-VL-P1:

[0081] G2-CH2-VL-P2:

[0082] G2-CH2-VL-P3:

[0083] G2-H1-VL_2(1-39):

[0084] G2-H1-VL_3(1-39):

[0085] G2-H1-VL_2(3-15):

[0086] G2-H1-VL_3(3-15):

[0087] G2-H5-VL_1:

[0088] G2-H5-VL_2:

[0089] G2-H5-VL_3:

[0090] G2-H5-VL_4:

[0091] G2-H8-VL_1:

[0092] G2-H8-VL_2:

[0093] G2-H8-VL1(gsm):

[0094] G2-H8-VL2(gsm):

[0095] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:83 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:102.

[0096] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:84 and a light chain variable region as shown in SEQ ID NO:103.

[0097] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:85 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:104.

[0098] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:86 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:105.

[0099] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:87 and a light chain variable region as shown in SEQ ID NO:106.

[0100] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:88 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:107.

[0101] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:89 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:108.

[0102] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:90 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:109.

[0103] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:91 and a light chain variable region as shown in SEQ ID NO:110.

[0104] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:92 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:111.

[0105] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:93 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:112.

[0106] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:94 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:113.

[0107] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:95 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:114.

[0108] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:96 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:115.

[0109] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:97 and a light chain variable region as shown in SEQ ID NO:116.

[0110] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:98 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:105.

[0111] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:99 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:105.

[0112] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:100 and a light chain variable region as shown in SEQ ID NO:105.

[0113] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:89 and a light chain variable region as shown in SEQ ID NO:117.

[0114] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:89 and a light chain variable region as shown in SEQ ID NO:118.

[0115] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:89 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:119.

[0116] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:84 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:120.

[0117] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:84 and a light chain variable region as shown in SEQ ID NO:121.

[0118] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:84 and a light chain variable region as shown in SEQ ID NO:122.

[0119] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:124 and a light chain variable region as shown in SEQ ID NO:128.

[0120] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:124 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:129.

[0121] Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:124 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:130.

[0122] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:124 and a light chain variable region as shown in SEQ ID NO:131.

[0123] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:125 and a light chain variable region as shown in SEQ ID NO:128.

[0124] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:125 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:129.

[0125] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:125 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:130.

[0126] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:125 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:131.

[0127] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:126 and a light chain variable region as shown in SEQ ID NO:128.

[0128] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:126 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:129.

[0129] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:126 and a light chain variable region as shown in SEQ ID NO:130.

[0130] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:126 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:131.

[0131] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:127 and a light chain variable region as shown in SEQ ID NO:128.

[0132] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:127 and a light chain variable region as shown in SEQ ID NO:129.

[0133] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:127 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:130.

[0134] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:127 and a light chain variable region as shown in SEQ ID NO:131.

[0135] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:132 and a light chain variable region as shown in SEQ ID NO:136.

[0136] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:133 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:136.

[0137] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:134 and a light chain variable region as shown in SEQ ID NO:136.

[0138] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:135 and a light chain variable region as shown in SEQ ID NO:136.

[0139] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:132 and a light chain variable region as shown in SEQ ID NO:137.

[0140] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:133 and a light chain variable region as shown in SEQ ID NO:137.

[0141] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:134 and a light chain variable region as shown in SEQ ID NO:137.

[0142] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:135 and a light chain variable region as shown in SEQ ID NO:137.

[0143] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:132 and a light chain variable region as shown in SEQ ID NO:138.

[0144] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:133 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:138.

[0145] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:134 and a light chain variable region as shown in SEQ ID NO:138.

[0146] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:135 and a light chain variable region as shown in SEQ ID NO:138.

[0147] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:132 and a light chain variable region as shown in SEQ ID NO:139.

[0148] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:133 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO:139.

[0149] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:134 and a light chain variable region as shown in SEQ ID NO:139.

[0150] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:135 and a light chain variable region as shown in SEQ ID NO:139.

[0151] According to an embodiment of the present invention, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:140 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:142.

[0152] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:141 and a light chain variable region as shown in SEQ ID NO:142.

[0153] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:140 and a light chain variable region as shown in SEQ ID NO:143.

[0154] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:141 and a light chain variable region as shown in SEQ ID NO:143.

[0155] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:144 and a light chain variable region as shown in SEQ ID NO:146.

[0156] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:144 and a light chain variable region as shown in SEQ ID NO:147.

[0157] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:145 and a light chain variable region as shown in SEQ ID NO:146.

[0158] According to an embodiment of the present invention, the antibody has a heavy chain variable region as shown in SEQ ID NO:145 and a light chain variable region as shown in SEQ ID NO:147.

[0159] According to an embodiment of the present invention, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:144, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:146.

[0160] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:83, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:102.

[0161] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:84, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:103.

[0162] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:85, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:104.

[0163] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:86, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:105.

[0164] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:87, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:106.

[0165] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:88, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:107.

[0166] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:89, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:108.

[0167] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:90, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:109.

[0168] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:91, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:110.

[0169] Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:92 and a light chain variable region of the amino acid sequence shown in SEQ ID NO:111.

[0170] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:93, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:112.

[0171] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:94, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:113.

[0172] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:95, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:114.

[0173] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:96, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:115.

[0174] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:97, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:116.

[0175] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:98, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:105.

[0176] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:99, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:105.

[0177] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:100, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:105.

[0178] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:89, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:117.

[0179] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:89, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:118.

[0180] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:89, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:119.

[0181] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:84, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:120.

[0182] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:84, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:121.

[0183] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:84, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:122.

[0184] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:124, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:128.

[0185] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:124, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:129.

[0186] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:124, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:130.

[0187] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:124, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:131.

[0188] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:125, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:128.

[0189] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:125, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:129.

[0190] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:125, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:130.

[0191] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:125, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:131.

[0192] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:126, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:128.

[0193] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:126, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:129.

[0194] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:126, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:130.

[0195] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:126, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:131.

[0196] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:127, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:128.

[0197] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:127, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:129.

[0198] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:127, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:130.

[0199] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:127, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:131.

[0200] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:132, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:136.

[0201] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:133, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:136.

[0202] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:134, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:136.

[0203] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:135, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:136.

[0204] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:132, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:137.

[0205] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:133, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:137.

[0206] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:134, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:137.

[0207] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:135, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:137.

[0208] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:132, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:138.

[0209] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:133, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:138.

[0210] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:134, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:138.

[0211] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:135, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:138.

[0212] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:132, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:139.

[0213] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:133, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:139.

[0214] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:134, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:139.

[0215] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:135, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:139.

[0216] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:140, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:142.

[0217] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:141, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:142.

[0218] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:140, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:143.

[0219] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:141, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:143.

[0220] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:144, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:147.

[0221] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:145, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:146.

[0222] Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:145, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:147.

[0223] The aforementioned CDR sequence also contains an amino acid sequence that is at least 66% identical to it. The aforementioned CDR was determined according to the Kabat, IMGT, Chothia, and North numbering system.

[0224] According to an embodiment of the present invention, the antibody contains at least one of a heavy chain constant region and a light chain constant region, and at least a portion of at least one of the heavy chain constant region and the light chain constant region is derived from at least one of a mouse antibody, a human antibody, a primate antibody or a mutant thereof.

[0225] According to an embodiment of the present invention, both the light chain constant region and the heavy chain constant region are derived from human IgG antibodies or their mutants.

[0226] According to an embodiment of the present invention, the heavy chain constant region is a human IgG mutant.

[0227] According to an embodiment of the present invention, the heavy chain constant region, compared to the heavy chain constant region of the human wild-type IgG1 antibody, has at least one of the following site mutations: L234A, L235A, G237A, K447, with K447 preferably deleted. Alternatively, it may have...

[0228] Therefore, the Fc effect of the antibody can be further eliminated through L234A, L235A, and G237A mutations, and antibody heterogeneity can be avoided through K447 mutations. Alternatively, substitutions at sites such as K214 / R214, E356, M358 / D356, and L358 can be performed. K447 mutation is preferably a deletion of this site.

[0229] For example, according to an embodiment of the present invention, the heavy chain constant region has an amino acid sequence as shown in SEQ ID NO:148, namely hIgG1(LALAGA,-K).

[0230] For example, according to an embodiment of the present invention, the heavy chain constant region has an amino acid sequence as shown in SEQ ID NO:228, namely hIgG1'(LALAGA,-K).

[0231] According to an embodiment of the present invention, the light chain constant region has an amino acid sequence as shown in SEQ ID NO:149.

[0232] According to an embodiment of the present invention, the antibody has a heavy chain as shown in any one of the amino acid sequences of SEQ ID NO: 150-164, 166-182, 229 or a light chain as shown in any one of the amino acid sequences of SEQ ID NO: 183-197, 199-217.

[0233] G2-CH1 H:

[0234] G2-CH2 H:

[0235] G2-CH3H:

[0236] G2-CH5 H:

[0237] G2-CH6 H:

[0238] G2-CH7 H:

[0239] G2-CH8 H:

[0240] G2-CH9 H:

[0241] G2-CH10 H:

[0242] G2-CH12 H:

[0243] G2-CH13 H:

[0244] EVLLQQSGPELVKPGASVKITCKASGYTFTDYNMNWVKQSHGKSLEWIGDINPYNGGIIYNQKFRGKATLTIDKSSSTAYMELRSLTSEDTAVYYCAREVRRGSFFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:160);

[0245] G2-CH14 H:

[0246] G2-CH16 H:

[0247] G2-CH17 H:

[0248] G2-CH23 H:

[0249] G2-CH5-P1 H:

[0250] G2-CH5-P2 H:

[0251] G2-CH5-P3 H:

[0252] G2-CH8 H (same as G2-CH8-P1 H, G2-CH8-P2 H, and G2-CH8-P3 H):

[0253] G2-CH2 H (same as G2-CH2-P1 H, G2-CH2-P2 H, and G2-CH2-P3 H):

[0254] G2-H1-H_2(4 - 39):

[0255] G2-H1-H_3(4 - 39):

[0256] G2-H1-H_2(3 - 23):

[0257] G2-H1-H_3(3 - 23):

[0258] G2-H5-H_1:

[0259] G2-H5-H_2:

[0260] G2-H5-H_3:

[0261] G2-H5-H_4:

[0262] G2-H8-H_1:

[0263] G2-H8-H_2:

[0264] G2-H8-H1(gsm)’:

[0265] G2-H8-H1(gsm):

[0266] G2-H8-H2(gsm):

[0267] G2-CH1 L:

[0268] G2-CH2 L:

[0269] G2-CH3 L:

[0270] G2-CH5 L:

[0271] G2-CH6 L:

[0272] G2-CH7 L:

[0273] G2-CH8 L:

[0274] G2-CH9 L:

[0275] G2-CH10 L:

[0276] G2-CH12 L:

[0277] G2-CH13 L:

[0278] G2-CH14 L:

[0279] G2-CH16 L:

[0280] G2-CH17 L:

[0281] G2-CH23 L:

[0282] G2-CH5 L (same as G2-CH5-P1 L, G2-CH5-P2 L, and G2-CH5-P3 L):

[0283] G2-CH8-P1 L:

[0284] G2-CH8-P2 L:

[0285] G2-CH8-P3 L:

[0286] G2-CH2-P1 L:

[0287] G2-CH2-P2 L:

[0288] G2-CH2-P3 L:

[0289] G2-H1-L_2(1-39):

[0290] G2-H1-L_3(1-39):

[0291] G2-H1-L_2(3-15):

[0292] G2-H1-L_3(3-15):

[0293] G2-H5-L_1:

[0294] G2-H5-L_2:

[0295] G2-H5-L_3:

[0296] G2-H5-L_4:

[0297] G2-H8-L_1:

[0298] G2-H8-L_2:

[0299] G2-H8-L_1(gsm):

[0300] G2-H8-L_2(gsm):

[0301] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:150 and a light chain as shown in the amino acid sequence SEQ ID NO:183.

[0302] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:151 and a light chain as shown in the amino acid sequence SEQ ID NO:184.

[0303] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:152 and a light chain as shown in the amino acid sequence SEQ ID NO:185.

[0304] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:153 and a light chain as shown in the amino acid sequence SEQ ID NO:186.

[0305] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:154 and a light chain as shown in the amino acid sequence SEQ ID NO:187.

[0306] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:155 and a light chain as shown in the amino acid sequence SEQ ID NO:188.

[0307] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:156 and a light chain as shown in the amino acid sequence SEQ ID NO:189.

[0308] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:157 and a light chain as shown in the amino acid sequence SEQ ID NO:190.

[0309] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:158 and a light chain as shown in the amino acid sequence SEQ ID NO:191.

[0310] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:159 and a light chain as shown in the amino acid sequence SEQ ID NO:192.

[0311] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:160 and a light chain as shown in the amino acid sequence SEQ ID NO:193.

[0312] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:161 and a light chain as shown in the amino acid sequence SEQ ID NO:194.

[0313] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:162 and a light chain as shown in the amino acid sequence SEQ ID NO:195.

[0314] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:163 and a light chain as shown in the amino acid sequence SEQ ID NO:196.

[0315] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:166 and a light chain as shown in the amino acid sequence SEQ ID NO:199.

[0316] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:167 and a light chain as shown in the amino acid sequence SEQ ID NO:199.

[0317] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:168 and a light chain as shown in the amino acid sequence SEQ ID NO:199.

[0318] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:169 and a light chain as shown in the amino acid sequence SEQ ID NO:200.

[0319] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:169 and a light chain as shown in the amino acid sequence SEQ ID NO:201.

[0320] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:169 and a light chain as shown in the amino acid sequence SEQ ID NO:202.

[0321] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:170 and a light chain as shown in the amino acid sequence SEQ ID NO:203.

[0322] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:170 and a light chain as shown in the amino acid sequence SEQ ID NO:204.

[0323] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:170 and a light chain as shown in the amino acid sequence SEQ ID NO:205.

[0324] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:171 and a light chain as shown in the amino acid sequence SEQ ID NO:206.

[0325] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:171 and a light chain as shown in the amino acid sequence SEQ ID NO:207.

[0326] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:171 and a light chain as shown in the amino acid sequence SEQ ID NO:208.

[0327] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:171 and a light chain as shown in the amino acid sequence SEQ ID NO:209.

[0328] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:172 and a light chain as shown in the amino acid sequence SEQ ID NO:206.

[0329] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:172 and a light chain as shown in the amino acid sequence SEQ ID NO:207.

[0330] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:172 and a light chain as shown in the amino acid sequence SEQ ID NO:208.

[0331] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:172 and a light chain as shown in the amino acid sequence SEQ ID NO:209.

[0332] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:173 and a light chain as shown in the amino acid sequence SEQ ID NO:206.

[0333] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:173 and a light chain as shown in the amino acid sequence SEQ ID NO:207.

[0334] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:173 and a light chain as shown in the amino acid sequence SEQ ID NO:208.

[0335] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:173 and a light chain as shown in the amino acid sequence SEQ ID NO:209.

[0336] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:174 and a light chain as shown in the amino acid sequence SEQ ID NO:206.

[0337] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:174 and a light chain as shown in the amino acid sequence SEQ ID NO:207.

[0338] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:174 and a light chain as shown in the amino acid sequence SEQ ID NO:208.

[0339] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:174 and a light chain as shown in the amino acid sequence SEQ ID NO:209.

[0340] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:175 and a light chain as shown in the amino acid sequence SEQ ID NO:210.

[0341] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:175 and a light chain as shown in the amino acid sequence SEQ ID NO:211.

[0342] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:175 and a light chain as shown in the amino acid sequence SEQ ID NO:212.

[0343] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:175 and a light chain as shown in the amino acid sequence SEQ ID NO:213.

[0344] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:176 and a light chain as shown in the amino acid sequence SEQ ID NO:210.

[0345] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:176 and a light chain as shown in the amino acid sequence SEQ ID NO:211.

[0346] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:176 and a light chain as shown in the amino acid sequence SEQ ID NO:212.

[0347] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:176 and a light chain as shown in the amino acid sequence SEQ ID NO:213.

[0348] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:177 and a light chain as shown in the amino acid sequence SEQ ID NO:210.

[0349] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:177 and a light chain as shown in the amino acid sequence SEQ ID NO:211.

[0350] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:177 and a light chain as shown in the amino acid sequence SEQ ID NO:212.

[0351] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:177 and a light chain as shown in the amino acid sequence SEQ ID NO:213.

[0352] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:178 and a light chain as shown in the amino acid sequence SEQ ID NO:210.

[0353] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:178 and a light chain as shown in the amino acid sequence SEQ ID NO:211.

[0354] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:178 and a light chain as shown in the amino acid sequence SEQ ID NO:212.

[0355] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:178 and a light chain as shown in the amino acid sequence SEQ ID NO:213.

[0356] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:179 and a light chain as shown in the amino acid sequence SEQ ID NO:214.

[0357] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:179 and a light chain as shown in the amino acid sequence SEQ ID NO:215.

[0358] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:180 and a light chain as shown in the amino acid sequence SEQ ID NO:214.

[0359] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:180 and a light chain as shown in the amino acid sequence SEQ ID NO:215.

[0360] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:181 and a light chain as shown in the amino acid sequence SEQ ID NO:216.

[0361] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:229 and a light chain as shown in the amino acid sequence SEQ ID NO:216.

[0362] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:181 and a light chain as shown in the amino acid sequence SEQ ID NO:217.

[0363] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:182 and a light chain as shown in the amino acid sequence SEQ ID NO:216.

[0364] According to an embodiment of the present invention, the antibody comprises a heavy chain as shown in the amino acid sequence SEQ ID NO:182 and a light chain as shown in the amino acid sequence SEQ ID NO:217.

[0365] According to embodiments of the present invention, the antibody includes at least one selected from monoclonal antibodies, polyclonal antibodies, multimeric antibodies, and CDR transplantation antibodies.

[0366] In this document, the term "monoclonal antibody" refers to an antibody that recognizes only one specific antigenic epitope. Common monoclonal antibodies consist of two lighter light chains and two heavier heavy chains, linked by disulfide bonds to form a tetrapeptide molecule. The amino-terminal (N-terminus) amino acid sequence of this heavy or light chain varies considerably and is called the variable region (V-terminus), while the carboxyl-terminus (C-terminus) of the heavy or light chain is relatively stable and varies little, and is called the constant region (C-terminus). The V-termini of the L-chain and H-chain are called VL and VH, respectively. Furthermore, the monoclonal antibody also includes, but is not limited to, single-chain antibodies, Fab antibodies, Fv antibodies, single-domain antibodies, and at least one of the smallest recognition units.

[0367] In this document, the terms "CDR-transplanted antibody" and "modified antibody" both refer to the transplantation of the CDR of a monoclonal antibody from one species to the variable region of an antibody from another species. For example, the CDR of a murine monoclonal antibody can be transplanted to the variable region of a human antibody to replace the human antibody's CDR, thereby giving the human antibody the antigen-binding specificity of the murine monoclonal antibody while reducing its heterologousness. It should be noted that both polyclonal antibodies and monoclonal antibodies in this application can be CDR-transplanted antibodies.

[0368] According to embodiments of the present invention, the antigen-binding fragment includes at least one of the following: Fab fragment, (Fab)2 fragment, scFv-Fc fusion protein, scFv-Fv fusion protein, Fv fragment, and minimum recognition unit.

[0369] In another aspect of the invention, a nucleic acid molecule is proposed. According to embodiments of the invention, the nucleic acid molecule encodes the antibody or antigen-binding fragment of the aforementioned claim. The nucleic acid molecule according to embodiments of the invention encodes the aforementioned antibody or antigen-binding fragment.

[0370] According to an embodiment of the present invention, the nucleic acid molecule is DNA.

[0371] It should be noted that those skilled in the art will understand that the nucleic acid molecules mentioned herein actually include any one or both of the complementary double strands. For convenience, although only one strand is given in most cases in this specification and claims, the other complementary strand is also disclosed. Furthermore, the nucleic acid sequences in this application include DNA or RNA forms; disclosure of one implies that the other is also disclosed.

[0372] In another aspect, the present invention provides an expression vector. According to an embodiment of the present invention, the expression vector carries the aforementioned nucleic acid molecule. When the aforementioned nucleic acid molecule is ligated to the vector, the nucleic acid molecule can be directly or indirectly linked to control elements on the vector, as long as these control elements can control the translation and expression of the nucleic acid molecule. Of course, these control elements can be directly derived from the vector itself or can be exogenous, i.e., not derived from the vector itself. Of course, the nucleic acid molecule and the control elements can be operably linked. In this document, "operably linked" means ligating a foreign gene to the vector so that the control elements within the vector, such as transcription control sequences and translation control sequences, can perform their intended function of regulating the transcription and translation of the foreign gene. Commonly used vectors can be, for example, plasmids, bacteriophages, etc. After the expression vector of some specific embodiments of the present invention is introduced into suitable recipient cells, the aforementioned antibody or antigen-binding fragments can be effectively expressed under the mediation of a regulatory system, thereby achieving the large-scale acquisition of antibody or antigen-binding fragments in vitro.

[0373] According to embodiments of the present invention, the expression vector is a eukaryotic expression vector or a prokaryotic expression vector, preferably a plasmid expression vector.

[0374] In another aspect, the present invention provides a recombinant cell. According to embodiments of the invention, the recombinant cell: carries the aforementioned nucleic acid molecule; or expresses the aforementioned antibody or its antigen-binding fragment. Using this recombinant cell, under suitable conditions, the aforementioned antibody or antigen-binding fragment can be effectively expressed intracellularly.

[0375] It should be noted that the "suitable conditions" mentioned in this application specification refer to conditions suitable for the expression of the antibody or antigen-binding fragment described in this invention. Those skilled in the art will readily understand that suitable conditions for the expression of the antibody or antigen-binding fragment include, but are not limited to, suitable transformation or transfection methods, suitable transformation or transfection conditions, healthy host cell state, suitable host cell density, suitable cell culture environment, and suitable cell culture time. The term "suitable conditions" is not particularly limited, and those skilled in the art can optimize the optimal conditions for the expression of the antibody or antigen-binding fragment according to the specific environment of their laboratory.

[0376] According to an embodiment of the present invention, the recombinant cells are obtained by introducing the aforementioned expression vector into host cells.

[0377] According to an embodiment of the present invention, the recombinant cells are eukaryotic cells.

[0378] According to an embodiment of the present invention, the recombinant cell is a mammalian cell.

[0379] In another aspect, the present invention provides a pharmaceutical composition. According to embodiments of the present invention, the pharmaceutical composition comprises: the aforementioned antibody or its antigen-binding fragment; the aforementioned nucleic acid molecule; the aforementioned expression vector; or the aforementioned recombinant cells. The pharmaceutical composition of the present invention can specifically bind to GDF15 and effectively block the binding of GFRAL and GDF15, while also effectively inhibiting Treg differentiation, and can be used for the prevention and / or treatment of cancer and cachexia.

[0380] According to embodiments of the present invention, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0381] In another aspect, the present invention provides a combination drug or kit. According to embodiments of the present invention, the combination drug or kit comprises: the aforementioned antibody or its antigen-binding fragment or the aforementioned pharmaceutical composition as a first active ingredient; and an anti-PDL1 drug as a second active ingredient. The combination drug or kit of the present invention can effectively block the binding of GFRAL and GDF15, and can also effectively inhibit Treg differentiation, and can be used for the prevention and / or treatment of cancer and cachexia.

[0382] In this article, the term "anti-PDL1 drug" refers to a drug that can be used to inhibit PDL1 expression or activity, for example, by inhibiting PDL1 activity to block the PD1 / PDL1 pathway. "Anti-PDL1 drug" includes, but is not limited to, anti-PDL1 antibodies.

[0383] For example, the anti-PDL1 drug is atezolizumab (Tecentriq).

[0384] In another aspect of the invention, the invention provides the use of the aforementioned antibody or antigen-binding fragment thereof, the aforementioned nucleic acid molecule, the aforementioned expression vector, the aforementioned recombinant cell, the aforementioned pharmaceutical composition or the aforementioned combination of pharmaceutical or cassette in the preparation of a medicament for the prevention and / or treatment of cancer and cachexia.

[0385] In another aspect, the present invention provides a method for preventing and / or treating cancer and cachexia. According to embodiments of the present invention, the method comprises administering to a subject a pharmaceutically acceptable amount of the aforementioned antibody or antigen-binding fragment, the aforementioned pharmaceutical composition, or the aforementioned combination drug or kit. The method of the present invention can effectively prevent and / or treat cancer and cachexia.

[0386] The effective amount of the antibody or antigen-binding fragment or pharmaceutical composition described in this invention can vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0387] The antibodies or antigen-binding fragments or pharmaceutical compositions of the present invention can be incorporated into drugs suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These drugs can be prepared in various forms, such as liquids, semi-solids, and solid dosage forms, including but not limited to liquid solutions (e.g., injection solutions and infusion solutions) or lyophilized powders. Typical drugs are in the form of injection solutions or infusion solutions. The aforementioned antibodies or antigen-binding fragments or pharmaceutical compositions can be administered by intravenous infusion or injection, or by intramuscular or subcutaneous injection.

[0388] In another aspect, the present invention provides a kit. According to embodiments of the present invention, the kit comprises: the aforementioned antibody or its antigen-binding fragment; the aforementioned nucleic acid molecule; the aforementioned expression vector; or the aforementioned recombinant cells. The antibody or antigen-binding fragment in the kit provided by the present invention can effectively bind to GDF15. Furthermore, under suitable conditions, the nucleic acid molecule, expression vector, or recombinant cells can all express the antibody or antigen-binding fragment. Further, the kit containing the above substances can effectively bind to GDF15 and can be used for the effective detection of GDF15. The kit can be used for scientific research, such as qualitative or quantitative detection of GDF15 in biological samples, and can also be used to assess individual status, such as determining whether an individual's GDF15 level is too high or too low than normal after obtaining the individual's GDF15 level. The biological sample can be cells, tissues, blood, etc.

[0389] In another aspect of the invention, the invention provides the use of the aforementioned antibody or its antigen-binding fragment, the aforementioned nucleic acid molecule, the aforementioned expression vector or the aforementioned recombinant cell in the preparation of a kit for detecting GDF15.

[0390] In another aspect, the present invention provides a method for detecting GDF15. According to an embodiment of the present invention, the method includes: detecting the sample to be tested using the aforementioned antibody or its antigen-binding fragment, or the aforementioned kit. As is known prior, the aforementioned antibody or antigen-binding fragment can effectively bind to GDF15. Therefore, the method of the present invention can effectively detect GDF15, such as for qualitative or quantitative detection of GDF15 in biological samples, and can also be used to assess an individual's condition, such as determining whether the individual's GDF15 level is too high or too low than normal after obtaining the individual's GDF15 level. The biological sample can be cells, tissues, blood, etc.

[0391] According to an embodiment of the present invention, the antibody or its antigen-binding fragment forms an immune complex with GDF15 in the sample to be tested; the presence of the immune complex is detected, and the presence of GDF15 in the sample to be tested is determined based on the presence of the immune complex.

[0392] According to an embodiment of the present invention, the presence of the immune complex indicates the presence of GDF15 in the sample to be tested.

[0393] According to an embodiment of the present invention, the immune complex further includes a second antibody, which binds to the antibody.

[0394] According to an embodiment of the present invention, the immune complex further includes a second antibody that binds to GDF15.

[0395] The method for detecting the GDF15 can be any method known to those skilled in the art, such as detecting the GDF15 with an additional antibody against the GDF15 (which is usually labeled with a signaling substance, or detected with a secondary antibody labeled with a signaling substance) after the GDF15 has been contacted with the solid-phase support (double antibody sandwich).

[0396] Alternatively, conventional antibodies can be used as antibodies coated on a solid phase and co-incubated with the GDF15 to be detected, and the immunoglobulin can be used as a free detection antibody (which is usually labeled with a signal substance, or detected by a secondary antibody labeled with a signal substance).

[0397] Alternatively, the solid-phase carrier can be used in combination with the immunoglobulin to detect GDF15, in which case the two are paired antibodies.

[0398] The signaling substance can be any one of the following: fluorescent substance, quantum dot, digoxigenin-labeled probe, biotin, radioactive isotope, radioactive contrast agent, paramagnetic ion fluorescent microsphere, electron-dense material, chemiluminescent label, ultrasound contrast agent, photosensitizer, colloidal gold, or enzyme. In some embodiments, the signaling substance is colloidal gold, fluorescein, fluorescent microsphere, acrid ester, horseradish peroxidase, alkaline phosphatase, or β-galactosidase.

[0399] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0400] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0401] Figure 1 shows the detection results of the binding activity of each anti-GDF15 neutralizing antibody to human GDF15 protein in Test Example 1 of the present invention;

[0402] Figure 2 shows the detection results of the binding activity of each anti-GDF15 neutralizing antibody to mouse GDF15 protein in Test Example 1 of the present invention;

[0403] Figure 3 shows the detection results of the binding activity of each anti-GDF15 neutralizing antibody to the GDF15 protein of cynomolgus monkey in Test Example 1 of the present invention;

[0404] Figure 4 shows the results of the neutralizing activity detection of each anti-GDF15 neutralizing antibody in the reporter gene cell line (mGFRAL) in Test Example 1 of the present invention;

[0405] Figure 5 shows the detection results of the inhibitory activity of each anti-GDF15 neutralizing antibody on Treg differentiation in Test Example 1 of the present invention;

[0406] Figure 6 shows the reporter gene assay results of the anti-GDF15 neutralizing antibody modified with PTMs in Test Example 2 of the present invention.

[0407] Figure 7 shows the detection results of the anti-GDF15 neutralizing antibody after PTMs modification inhibiting Treg differentiation in Test Example 2 of the present invention (Day 2);

[0408] Figure 8 shows the detection results of the anti-GDF15 neutralizing antibody after PTMs modification inhibiting Treg differentiation in Test Example 2 of the present invention (Day 5, 7);

[0409] Figure 9 is a summary bar chart of the results of the inhibition of Treg differentiation by the anti-GDF15 neutralizing antibody after PTMs modification in Test Example 2 of the present invention;

[0410] Figure 10 shows the detection results of the affinity kinetics between the humanized anti-GDF15 neutralizing antibody and GDF15 in Test Example 3 of the present invention;

[0411] Figure 11 shows the detection results of the affinity kinetics between the humanized anti-GDF15 neutralizing antibody and GDF15 in Test Example 3 of the present invention;

[0412] Figure 12 shows the detection results of the affinity kinetics between the humanized anti-GDF15 neutralizing antibody and GDF15 in Test Example 3 of the present invention;

[0413] Figure 13 shows the detection results of the affinity kinetics between the humanized anti-GDF15 neutralizing antibody and GDF15 in Test Example 3 of the present invention;

[0414] Figure 14 shows the detection results of the affinity kinetics between the humanized anti-GDF15 neutralizing antibody and GDF15 in Test Example 3 of the present invention;

[0415] Figure 15 shows the detection results of the affinity kinetics between the humanized anti-GDF15 neutralizing antibody and GDF15 in Test Example 3 of the present invention;

[0416] Figure 16 shows the detection results of the affinity kinetics between the humanized anti-GDF15 neutralizing antibody and GDF15 in Test Example 3 of the present invention;

[0417] Figure 17 shows the detection results of the affinity kinetics between the humanized anti-GDF15 neutralizing antibody and GDF15 in Test Example 3 of the present invention;

[0418] Figure 18 shows the detection results of the affinity kinetics between the humanized anti-GDF15 neutralizing antibody and GDF15 in Test Example 3 of the present invention;

[0419] Figure 19 shows the reporter gene assay results of the humanized anti-GDF15 neutralizing antibody in Test Example 3 of the present invention.

[0420] Figure 20 shows the reporter gene assay results of the humanized anti-GDF15 neutralizing antibody in Test Example 3 of the present invention.

[0421] Figure 21 shows the results of the reporter gene assay for detecting the activity of the humanized anti-GDF15 neutralizing antibody and the control antibody in Test Example 3 of the present invention;

[0422] Figure 22 is a bar chart showing the inhibition of Treg differentiation by the humanized anti-GDF15 neutralizing antibody in Test Example 3 of the present invention;

[0423] Figure 23 shows the results of the anti-GDF15 antibody reversing cachexia effect in the HT1080 cachexia model in Test Example 3 of the present invention, wherein Figure 23A shows the weight change and Figure 23B shows the weight change rate.

[0424] Figure 24 shows the forelimb (Figure 24A) and limb gripping force results (Figure 24B) of the HT1080 cachexia model in Test Example 3 of this invention, demonstrating the effect of anti-GDF15 antibody on reversing cachexia.

[0425] Figure 25 shows the results of the anti-GDF15 antibody reversing cachexia effect in the HT1080 cachexia model in Test Example 3 of the present invention, wherein Figure 25A shows the change in fat content and Figure 25B shows the change in muscle content.

[0426] Figure 26 shows the results of the anti-GDF15 antibody reversing cachexia effect in the HT1080 cachexia model in Test Example 3 of the present invention. Figure 26A shows the serum free GDF15 level of the animals before administration, and Figure 26B shows the serum free GDF15 level of the animals after administration.

[0427] Figure 27 shows the results of the anti-GDF15 antibody reversal effect on cachexia in the LNCaP cachexia model in Test Example 3 of the present invention, wherein Figure 27A shows the change in body weight and Figure 27B shows the rate of change in body weight.

[0428] Figure 28 shows the results of the anti-GDF15 antibody reversing cachexia effect in the LNCaP cachexia model in Test Example 3 of the present invention. In Figure 28A, the change in fat content is shown; Figure 28B, the change in muscle content is shown; Figure 28C, the rate of change in fat content is shown; and Figure 28D, the rate of change in muscle content is shown.

[0429] Figure 29 shows the weight change results of the MKN45 cachexia model in Test Example 3 of the present invention after reversing cachexia with anti-GDF15 antibody;

[0430] Figure 30 shows the results of the anti-GDF15 antibody reversing cachexia effect in the MKN45 cachexia model in Test Example 3 of the present invention. In Figure 30A, the change in fat content is shown; Figure 30B, the change in muscle content is shown; Figure 30C, the rate of change in fat content is shown; and Figure 30D, the rate of change in muscle content is shown.

[0431] Figure 31 shows the results of the anti-GDF15 antibody reversing cachexia effect in the MKN45 cachexia model in Test Example 3 of the present invention;

[0432] Figure 31A shows the serum free GDF15 level of the animals at the experimental endpoint, and Figure 31B shows the serum total GDF15 level of the animals at the experimental endpoint.

[0433] Figure 32 shows the survival curves of groups G1-G9 in test example 3 of the present invention;

[0434] Figure 33 shows the tumor volume and TGI results of G1-G7 in Test Example 3 of this invention. Detailed Implementation

[0435] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0436] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0437] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this invention, but do not exclude other aspects.

[0438] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0439] In this document, the amino acid numbers of the IgG1 portion are based on the EU numbering system. For example, position 334 refers to position 334 according to the EU numbering system; L234A means that leucine at position 234 according to the EU numbering system is replaced by alanine; L235A means that leucine at position 235 according to the EU numbering system is replaced by alanine; G237A means that glycine at position 237 according to the EU numbering system is replaced by alanine; and "K447" means that lysine at position 447 according to the EU numbering system is deleted.

[0440] In this article, the term "antibody" generally refers to an antibody that can recognize one or more antigenic epitopes, including but not limited to monoclonal antibodies, polyclonal antibodies, multimeric antibodies, and CDR transplantation antibodies.

[0441] In this article, the term "Fab antibody" generally refers to an antibody containing only Fab molecules, which consists of the VH and CH1 of the heavy chain and the complete light chain, linked by a disulfide bond.

[0442] In this article, the term "Fv antibody" generally refers to an antibody composed only of a light chain variable region (VL) and a heavy chain variable region (VH) linked by non-covalent bonds. It is the smallest functional fragment of an antibody that retains the complete antigen-binding site.

[0443] In this paper, the terms “single-domain antibody,” “nanobody,” and “VHH antibody” are used interchangeably. The antibody was originally described as an antigen-binding immunoglobulin (variable) domain of a “heavy chain antibody” (i.e., “antibody lacking light chains”) containing only the heavy chain variable region (VH) and the conventional CH2 and CH3 regions, which binds specifically to the antigen through the heavy chain variable region.

[0444] In this article, the term "single-chain antibody" generally refers to an antibody composed of a heavy chain variable region (VH) and a light chain variable region (VL) linked by a linker peptide.

[0445] In this article, the terms "minimum recognition unit" and "MRU" both refer to antibodies consisting of only one CDR, which have a very small molecular weight and account for only about 1% of the complete antibody.

[0446] In this paper, the terms “identity,” “homology,” or “similar phase” are used to describe the percentage of identical amino acids or nucleotides between two amino acid sequences or nucleic acid sequences relative to a reference sequence, determined by conventional methods, for example, see Ausubel et al., eds. (1995), Current Protocols in Molecular Biology, Chapter 19 (Greene Publishing and Wiley-Interscience, New York); and the ALIGN procedure (Dayhoff (1978), Atlas of Protein Sequence and Structure 5: Suppl. 3 (National Biomedical Research Institute)). Foundation, Washington, DC). There are many algorithms for aligning sequences and determining sequence identity, including: Needleman et al. (1970) J. Mol. Biol. 48: 443, a homology alignment algorithm; Smith et al. (1981) Adv. Appl. Math. 2: 482, a local homology algorithm; Pearson et al. (1988) Proc. Natl. Acad. Sci. 85: 2444, a similarity search method; and the Smith-Waterman algorithm (Meth. Mol. Biol). .70:173-187 (1997); and the BLASTP, BLASTN, and BLASTX algorithms (see Altschul et al. (1990) J.Mol.Biol. 215:403-410). Computer programs utilizing these algorithms are also available, including but not limited to: ALIGN or Megalign (DNASTAR) software, or WU-BLAST-2 (Altschul et al., Meth.Enzym., 266:460-480 (1996)); or GAP, BESTFIT, BLAST Altschul et al., above, FASTA, and TFASTA, available in Genetics Computing Group (GCG) package, version 8, Madison, Wisconsin, USA; and CLUSTAL in the PC / Gene program provided by Intelligenetics, Mountain View, California.

[0447] In this paper, the term "at least 66% identity" refers to an identity of at least 66% with each reference sequence, which may be 66%, 67%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%.

[0448] In this document, the term "expression vector" generally refers to a nucleic acid molecule capable of self-replication within a suitable host, transferring the inserted nucleic acid molecule to host cells and / or between host cells. The expression vector may include vectors primarily for inserting DNA or RNA into cells, vectors primarily for replicating DNA or RNA, and expression vectors primarily for transcription and / or translation of DNA or RNA. The expression vector also includes vectors having multiple of the aforementioned functions. The expression vector may be a polynucleotide capable of being transcribed and translated into a polypeptide when introduced into a suitable host cell. Typically, by culturing suitable host cells containing the expression vector, the expression vector can produce the desired expression product.

[0449] In this document, the term "recombinant cell" generally refers to a cell in which the genetic material of a host cell is modified or recombined using genetic engineering or cell fusion techniques to obtain a unique trait with stable inheritance. The term "host cell" refers to a prokaryotic or eukaryotic cell into which a recombinant expression vector can be introduced. The terms "transformed" or "transfected" as used herein refer to the introduction of nucleic acids (e.g., vectors) into cells using various techniques known in the art. Suitable host cells can be transformed or transfected with the DNA sequences of this invention and can be used for the expression and / or secretion of target proteins. Examples of suitable host cells that can be used in this invention include immortalized hybridoma cells, NS / O myeloma cells, 293 cells, Chinese hamster ovary (CHO) cells, HeLa cells, Cap cells (cells derived from human amniotic fluid), and CoS cells.

[0450] In this document, the term "pharmaceutical composition" generally refers to a unit dose form and can be prepared by any method well known in the pharmaceutical industry. All methods involve the step of combining the active ingredient with a carrier constituting one or more adjunct components. Typically, compositions are prepared by uniformly and adequately combining an active antibody or its antigen-binding fragment with a liquid carrier, a finely fragmented solid carrier, or both.

[0451] In this document, the term "pharmaceuticalally acceptable excipient" may include any solvent, solid excipient, diluent, or other liquid excipient, etc., suitable for a particular target dosage form. The use of any conventional excipients, except for those incompatible with the antibody or its antigen-binding fragment of the present invention, for example, for any adverse biological effects or harmful interactions with any other component of the pharmaceutically acceptable composition, is also within the scope of this invention.

[0452] In this document, the term "administration" refers to the introduction of a predetermined amount of a substance into a patient in a suitable manner. The antibody or antigen-binding fragment or pharmaceutical composition of the present invention can be administered via any common route, as long as it can reach the intended tissue. Various routes of administration are foreseeable, including peritoneal, intravenous, intramuscular, subcutaneous, etc., but the present invention is not limited to these exemplified routes of administration.

[0453] In this document, the term "treatment" refers to the administration of a drug or antibody or its antigen-binding fragment to an individual to treat, cure, alleviate, improve, reduce, or suppress an individual's disease, including but not limited to administering a drug containing an antibody or its antigen-binding fragment described herein.

[0454] In this article, "anti-GDF15 neutralizing monoclonal antibody", "anti-GDF15 neutralizing antibody", "GDF15 neutralizing antibody" and "GDF15 antibody" are synonymous.

[0455] This invention proposes an antibody, a nucleic acid molecule, an expression vector, a recombinant cell, a pharmaceutical composition and its uses, and a kit and its uses, which will be described in detail below.

[0456] Antibody

[0457] In this article, the term "antibody" refers to an immunoglobulin molecule capable of binding to a specific antigen. It consists of two lighter chains (H chains) and two heavier chains (L chains), linked by disulfide bonds to form a tetrapeptide molecule. The amino acid sequence at the N-terminus of the peptide chain varies considerably and is called the variable region (V region), while the carboxyl terminus (C-terminus) is relatively stable and changes very little, called the constant region (C region). The V regions of the L and H chains are referred to as VL and VH, respectively.

[0458] Within the variable region, certain areas exhibit a higher degree of variation in amino acid composition and sequence, known as hypervariable regions (HVRs). These hypervariable regions are the sites where antigens and antibodies bind, and are therefore also called complementarity-determining regions (CDRs). Both the heavy chain and light chain variable regions have three CDRs.

[0459] This invention utilizes human or murine GDF15 tagged with hFc or his as an antigen to immunize BALB / c, A / J, and C57bl / 6 female mice. Fifteen murine antibodies specifically binding to human GDF15 protein were screened using hybridoma fusion technology. These antibody fragments can block the binding of GDF15 and GFRAL, and the antibodies also exhibit Treg differentiation inhibition, demonstrating superior tumor immunomodulatory activity. Therefore, this antibody can effectively prevent and treat cancer and cachexia.

[0460] In some embodiments, the present invention provides an antibody or antigen-binding fragment thereof comprising: a CDR sequence selected from at least one of the following: or an amino acid sequence having at least 66% identity with: heavy chain variable region CDR sequence: SEQ ID NO: 1-34 and SEQ ID NO: 74-76; light chain variable region CDR sequence: SEQ ID NO: 36-73 and SEQ ID NO: 77-82. In other embodiments, the antibody or antigen-binding fragment provided by the present invention has conserved amino acid substitutions compared to the above-described heavy and light chains. "Antigen-binding fragment" refers to an antibody fragment that maintains the ability to specifically bind antigens. Examples of antigen-binding fragments include, but are not limited to, at least one of the following: Fv fragments, disulfide-stabilized Fv fragments (dsFv), Fab fragments, (Fab)2, scFv-Fc fusion proteins, scFv-Fv fusion proteins, Fv-Fc fusion proteins, multispecific antibodies formed from antigen-binding fragments, single-domain antibodies, bivalent domain antibodies, VHH nanobodies, or minimum recognition units. "Conservative amino acid substitution" refers to the substitution of an amino acid by another amino acid with biologically, chemically, or structurally similar residues. Biological similarity means that the substitution does not impair the biological activity of the GDF15 antibody or the GDF15 antigen. Structural similarity means that the amino acids have side chains of similar length, such as alanine, glycine, or serine, or side chains of similar size. Chemical similarity means that the amino acids have the same charge or are both hydrophilic or hydrophobic. For example, hydrophobic residues such as isoleucine, valine, leucine, or methionine can be substituted for each other. Alternatively, polar amino acids can be used, such as arginine replacing lysine, glutamic acid replacing aspartic acid, glutamine replacing asparagine, serine replacing threonine, etc.

[0461] In some embodiments, the present invention provides an antibody or antigen-binding fragment having a heavy chain variable region having an amino acid sequence as shown in any one of SEQ ID NO: 83–100, SEQ ID NO: 124–127, SEQ ID NO: 132–135, SEQ ID NO: 140–141, and SEQ ID NO: 144–145; or, the antibody having a light chain variable region having an amino acid sequence as shown in any one of SEQ ID NO: 102–122, SEQ ID NO: 128–131, SEQ ID NO: 136–139, SEQ ID NO: 142–143, and SEQ ID NO: 146–147. The inventors can obtain the CDR regions (as shown in SEQ ID NO: 1–34 and SEQ ID NO: 74–76) of the heavy chain variable region sequence and the CDR regions (as shown in SEQ ID NO: 36–73 and SEQ ID NO: 77–82) of the light chain variable region sequence of the above-mentioned antibody using an antibody sequence alignment database (KABAT) or related software. In some embodiments, the heavy chain variable region sequence of the antibody or antigen-binding fragment has conserved amino acid substitutions compared to the amino acid sequences shown in any one of SEQ ID NO: 83–100, SEQ ID NO: 124–127, SEQ ID NO: 132–125, SEQ ID NO: 140–141, and SEQ ID NO: 144–145. In some embodiments, the light chain variable region sequence of the antibody or antigen-binding fragment has conserved amino acid substitutions compared to the amino acid sequences shown in any one of SEQ ID NO: 102–122, SEQ ID NO: 128–131, SEQ ID NO: 136–139, SEQ ID NO: 142–143, and SEQ ID NO: 146–147. Of course, these conserved amino acid substitutions do not alter the biological function of the antibody or antigen-binding fragment. In some specific embodiments, these conserved amino acid substitutions may occur on amino acids in the heavy and light chain variable regions other than the CDR region.

[0462] In some preferred embodiments, the present invention provides an antibody having a heavy chain as shown in any one of the amino acid sequences of SEQ ID NO: 150-164, 166-182, 229 and a light chain as shown in any one of the amino acid sequences of SEQ ID NO: 183-197, 199-217.

[0463] Nucleic acid molecules, expression vectors, recombinant cells

[0464] In the process of preparing or obtaining these antibodies or their antigen-binding fragments, nucleic acid molecules expressing these antibodies or their antigen-binding fragments can be linked to different vectors and then expressed in different cells to obtain the corresponding antibodies or their antigen-binding fragments.

[0465] Therefore, the present invention also provides an isolated nucleic acid molecule that encodes the antibody or its antigen-binding fragment described above.

[0466] In some preferred embodiments, the nucleic acid molecules are species-optimized for easier expression in prokaryotic and mammalian cells. For those skilled in the art, designing nucleotide sequences using known antibody amino acid sequences and selecting appropriate codons according to the needs of the expression vector is a conventional genetic engineering technique.

[0467] This invention also provides an expression vector comprising the isolated nucleic acid molecule described above. When linking the isolated polynucleotide to the vector, the polynucleotide can be directly or indirectly linked to control elements on the vector, as long as these control elements can control the translation and expression of the polynucleotide. These control elements can be derived directly from the vector itself or be exogenous, i.e., not originating from the vector itself. Of course, the operative linking of the polynucleotide to the control elements is sufficient.

[0468] In this article, "operable ligation" refers to ligating a foreign gene into a vector so that the control elements within the vector, such as transcriptional and translational control sequences, can perform their intended functions of regulating the transcription and translation of the foreign gene. Of course, the polynucleotides encoding the antibody heavy and light chains can be inserted independently into different vectors, but it is more common to insert them into the same vector. Commonly used vectors include plasmids and phages.

[0469] This invention also provides a recombinant cell containing the expression vector. The expression vector can be introduced into mammalian cells to construct recombinant cells, which can then be used to express the antibody or antigen-binding fragment provided by this invention. The corresponding antibody can be obtained by culturing these recombinant cells. These usable mammalian cells can be, for example, CHO, 293, 293T, BHK cells, etc.

[0470] Pharmaceutical compositions, combination drugs or kits, reagent kits and pharmaceutical uses and uses in the preparation of reagent kits

[0471] The present invention also provides a pharmaceutical composition comprising the above-mentioned antibody or its antigen-binding fragment, and may further comprise the above-mentioned nucleic acid molecule, expression vector, and recombinant cell.

[0472] The GDF15 antibody described herein can be incorporated into pharmaceutical compositions suitable for administration to subjects. Typically, these pharmaceutical compositions include the GDF15 antibody described herein.

[0473] In some embodiments, these pharmaceutical compositions further include a pharmaceutically acceptable carrier suitable for a specific target dosage form. The use of any conventional excipients that are incompatible with the antibodies or antigen-binding fragments of the present invention, such as any adverse biological effects or harmful interactions with any other component of the pharmaceutically acceptable composition, is also within the scope of this invention. For example, the antibodies of the present invention can be incorporated into pharmaceutical compositions suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These pharmaceutical compositions can be prepared in various forms, such as liquid, semi-solid, and solid dosage forms, including but not limited to liquid solutions (e.g., injection solutions and infusion solutions), dispersants or suspensions, tablets, pills, powders, liposomes, and suppositories. Typical pharmaceutical compositions are in the form of injection solutions or infusion solutions. The antibodies can be administered by intravenous infusion or injection, or by intramuscular or subcutaneous injection.

[0474] The present invention also provides a combination drug or kit. According to an embodiment of the present invention, the combination drug or kit comprises: the aforementioned antibody or its antigen-binding fragment or the aforementioned pharmaceutical composition as a first active ingredient; and an anti-PDL1 drug as a second active ingredient.

[0475] Of course, the GDF15 antibody described herein can also be incorporated into kits or other diagnostic reagents as needed. According to embodiments of the present invention, a kit comprising the aforementioned GDF15 antibody is also provided. The kit provided by the present invention can be used, for example, in kits involving the detection of GDF15 antigen and antibody specific binding properties, such as immunoblotting and immunoprecipitation. These kits may contain any one or more of the following: antagonist, GDF15 antibody or pharmaceutical reference material; protein purification column; immunoglobulin affinity purification buffer; cell assay diluent; instructions or literature, etc. The GDF15 antibody can be used in various types of diagnostic tests, such as detecting the presence of various diseases, drugs, toxins, or other proteins in vitro or in vivo. For example, GDF15 can be tested by examining the serum or blood of a subject.

[0476] The present invention relates to GDF15 antibodies and / or drugs containing GDF15 antibodies, which can prevent and / or treat cachexia or cancer, wherein cachexia is caused by tumors or other chronic diseases or injuries. These cancers (or tumors) can be any unregulated cell growth. Specifically, they can be lung cancer, colorectal cancer, gastric cancer, liver cancer, esophageal cancer, pancreatic cancer, non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, head and neck cancer, kidney cancer, bladder cancer, breast cancer, ovarian cancer, bile duct cancer or sarcoma, acute myeloid leukemia, large cell neuroendocrine carcinoma, neuroblastoma, prostate cancer, neuroblastoma, melanoma, head and neck squamous cell carcinoma or gastric cancer, etc.; other chronic diseases include but are not limited to renal failure, AIDS, malabsorption and severe sepsis, etc.; injuries include but are not limited to severe trauma, postoperative, massive blood loss, etc.

[0477] When treating the above-mentioned diseases using the GDF15 antibody provided by this invention, the GDF15 antibody provided by this invention can be provided to the subject. Therefore, this invention provides a method for treating the above-mentioned diseases, comprising administering the antibody or its antigen-binding fragment, pharmaceutical composition, or combination drug or kit provided by this invention to a subject in need.

[0478] cell line model

[0479] The cachexia tumor cell line models mentioned in this article can include various tumor cell lines, including but not limited to HT1080 (human fibrosarcoma), LNCAP (human prostate cancer) cell line, MKN45 (human gastric cancer) cell line, K562 (human myeloid leukemia) cell line, A549, HeLa, MCF-7, HCT-116, Panc-1, T24, BT16, A498, etc.

[0480] There are various ways to establish a model, the purpose of which is to simulate cachexia symptoms caused by tumors or other chronic diseases or injuries. As an example, human tumor cell lines can be inoculated into an immunodeficient animal model to induce cachexia symptoms, such as weight loss and reduced food intake. The administration mode is SC and / or IP, and the recommended administration frequency is 5-30 mg / kg. Optional frequencies include 10 mg / kg / Q3D, 20 mg / kg / Q6D, 10 mg / kg / Q7D, and 20 mg / kg / Q3D.

[0481] It should be noted that mg / kg / QnD refers to a dosage that is administered once every n days. For example, 10 mg / kg / Q3D means that the dosage is 10 mg / kg, administered once every three days.

[0482] The observation indicators are changes in animal body weight, changes in fat and muscle mass, and serum GDF15 concentration; the animals include, but are not limited to, monkeys, mice, and rats, and monkeys include, but are not limited to, cynomolgus monkeys and rhesus monkeys.

[0483] Overall, the experimentally related antibody molecules in this invention, compared with the blank control, significantly reversed the trend of weight loss in animals, such as significantly reversing the loss of fat and / or muscle. The activity of the experimentally related antibody molecules in this invention is similar to that of the control antibody. By detecting the binding of free GDF15 antibody to total GDF15 content, both the experimentally related antibody molecules in this invention and the control antibody were able to occupy the target site well, with a target occupancy rate of over 90%.

[0484] Furthermore, the present invention also conducted a tumor suppression experiment to detect the size of the tumor and observe its growth.

[0485] In vivo efficacy verification

[0486] The antibody molecules involved in this invention are used to verify in vivo efficacy. Cell lines including, but not limited to, HT1080 (human fibrosarcoma), LNCAP (human prostate cancer), MKN45 (human gastric cancer), K562 (human myeloid leukemia), A549, HeLa, MCF-7, HCT-116, Panc-1, T24, BT16, and A498 are inoculated into animals, including but not limited to mice, rats, cynomolgus monkeys, and rhesus monkeys, to establish animal models and test anti-tumor activity. The effect on tumors is verified by detecting indicators such as tumor volume and survival rate.

[0487] Drugability verification

[0488] The antibody molecules involved in this invention were used to prepare formulations, which were then incubated under different conditions at specific temperatures, including but not limited to 20-50°C and 30-45°C (e.g., 40°C), for one to five weeks (e.g., four weeks). Stability was assessed through thermostability and repeated freeze-thaw cycles (e.g., five cycles at -80°C / 4°C). The stability was also tested with PBS, 529, and His buffers. Detection methods included Tm, Tagg, SEC, NR-CE-SDS, icIEF, and mass spectrometry. The results showed that the antibody molecules involved in this invention exhibited good drug-like properties.

[0489] In a rat pharmacokinetic (PK) experiment, the antibody drug was injected into rats, blood samples were collected at specific sites, and the blood drug concentration was measured. The pharmacokinetic (PK) ratio of the drug in the rats was calculated. The results showed that the half-life of the antibody molecule involved in this invention was close to that of the control antibody (e.g., GDAb2), both within the normal range, meeting the quality requirements of the finished drug. Furthermore, no significant decrease in activity was observed when the drug was placed at 37°C. The results demonstrate that the antibody molecule involved in this invention has good drug-like properties. Of course, the PK experiment is not limited to rats; it can also be performed on model organisms commonly used in this field.

[0490] Cytokine release verification

[0491] The antibody molecules of the present invention were co-incubated with modeled cell lines, including but not limited to PBMC cells, and the release of cytokines was detected to predict the cytokine storm that the antibody may cause. The results showed no significant increase in inflammatory cytokines (exemplary, cytokines include but are not limited to IL-2, IL-4, IL-10, IL-12, TNF (TGFα, TGFβ), IFN-α, IFN-β, GM-CSF, IFNγ and VEGF, etc.).

[0492] Biomarker verification

[0493] This invention also relates to in vitro and in vivo biomarker validation. The presence of hGDF15 expression in the model can be verified by analyzing GDF15 serum concentration, thus confirming successful modeling. Biomarker validation can be used for validation of, but is not limited to, in vivo tumor immune models.

[0494] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0495] Example 1: Preparation and purification of anti-GDF15 neutralizing antibody

[0496] I. Screening of anti-GDF15 neutralizing antibodies and determination of their variable regions

[0497] 1. Mouse antigen immunization

[0498] Anti-human GDF15 neutralizing antibodies were produced by immunizing mice. Balb / C, A / J, and C57bl / 6 mice, female, 6 weeks old, were used in the experiment. Housing environment: SPF grade. After purchase, the mice were housed in a laboratory environment for one week with a 12 / 12-hour light / dark cycle, temperature 20-25℃, and humidity 40-60%. The acclimatized mice were then immunized according to the following protocol.

[0499] Human GDF15 (Accession Q99988-1, Ala197-Ile308) and mouse GDF15 (Accession Q9Z0J7, Ser189-Ala303) with hFc or his tags were used as antigens, and mice were immunized by single immunization or cross immunization.

[0500] Immunization regimen: Routine immunization was performed using complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA). For the initial immunization, the antigen-to-CFA mixture ratio was 1:1, and the injection dose was 50 μg / mouse / time. For the booster immunization, the antigen-to-IFA mixture ratio was 1:1, and the injection dose was 25 μg / mouse / time. Emulsified antigens were administered on days 0, 14, and 28. Specifically, on day 0, 50 μg / mouse of the emulsified antigen was injected intraperitoneally (IP); on day 14, 25 μg / mouse of the emulsified antigen was injected intraperitoneally (IP); and on day 28, 25 μg / mouse of the emulsified antigen was injected intraperitoneally (IP). Blood samples were collected on days 21 and 35, and serum antibody titers were determined using ELISA. After the third immunization, mice with high antibody titers in their serum that were trending towards a plateau were selected for spleen cell fusion. Three days before spleen cell fusion, a booster immunization was performed by intraperitoneal (IP) injection of 50 μg / mouse of an antigen solution prepared with physiological saline (1 mg / mL).

[0501] 2. Spleen cell fusion

[0502] Splenic lymphocytes were fused with myeloma Sp2 / 0 cells using an optimized PEG-mediated fusion procedure. Hybridoma cells were obtained by fusing CRL-8287TM. The fused hybridoma cells were then cultured at a concentration of 0.5-1 × 10⁻⁶. 6The culture medium was resuspended at a density of 1 / mL in complete medium (DMEM medium containing 20% ​​FBS, 1×HAT, and 1×OPI), and 100 μL / well was seeded into 96-well plates. After incubation at 37°C and 5% CO2 for 3-4 days, 100 μL / well of HAT complete medium was added, and the plates were cultured for another 3-4 days until pinpoint colonies formed. The supernatant was removed, and 200 μL / well of HT complete medium (RPMI-1640 medium containing 20% ​​FBS, 1×HT, and 1×OPI) was added. After incubation at 37°C and 5% CO2 for 3 days, ELISA detection was performed.

[0503] 3. Hybridoma cell screening

[0504] Based on the hybridoma cell growth density, the hybridoma culture supernatant was analyzed using a binding ELISA method. The supernatant from the positive wells detected by binding ELISA was then subjected to cell blocking experiments. Cells from both binding and blocking wells that were positive were promptly expanded, cryopreserved, and subjected to two to three subcloning processes until single-cell clones were obtained.

[0505] Each subcloned cell was subjected to GDF15 binding ELISA and GFRAL blocking assays. Hybridoma clones were obtained through these experiments, and antibodies were further prepared using serum-free cell culture. The antibodies were then purified according to the purification examples for use in the assays.

[0506] 4. Sequence determination of hybridoma positive clones

[0507] Clones from logarithmic growth phase positive hybridomas were collected, processed, and then subjected to first- or second-generation sequencing to obtain the antibody variable region sequence.

[0508] 5. Beacon filtering

[0509] Spleens were harvested from immunized mice. Plasma cells were enriched using a CD138b kit (stemcell, 18957) while maintaining optimal cell viability. The enriched cells were then loaded onto a Beacon 14K chip. Signals that simultaneously bind human GDF15, mouse GDF15, and block the interaction between GDF15 and GFRAL were analyzed to obtain target positive clones. After exporting the positive clones, the antibody variable region was obtained using single-cell sequencing technology.

[0510] 6. Sequence Analysis

[0511] Hybridoma and beacon screening, followed by sequencing and variable region sequence analysis, and removal of duplicates, yielded unique sequences. See Table 1 for the specific sequences: G2-CH1 VH, G2-CH2 VH, G2-CH3 VH, G2-CH5 VH, G2-CH6 VH, G2-CH7 VH, G2-CH8 VH, G2-CH9 VH, G2-CH10 VH, G2-CH12 VH, G2-CH13 VH, G2-CH14 VH, G2-CH16 VH, G2-CH17 VH, G2-CH23 VH, G2-CH1 VL, G2-CH2 VL, G2-CH3 VL, G2-CH5 VL, G2-CH6 VL, G2-CH7 VL, G2-CH8 VL, G2-CH9 VL, G2-CH10 VL, G2-CH12 VL, and G2-CH13 VL. The CDR sequences corresponding to VL, G2-CH14 VL, G2-CH16 VL, G2-CH17 VL and G2-CH23 VL.

[0512] II. Sequencing of murine antibodies and construction of chimeric antibodies (anti-GDF15 neutralizing antibody)

[0513] The variable region sequences of 15 antibodies were obtained (CDR annotations are shown in Table 1, heavy chain variable region: SEQ ID NO: 83-97, light chain variable region: SEQ ID NO: 102-116), fused with human IgG1 constant region mutants hIgG1(LALAGA,-K) (SEQ ID NO: 148) or hIgG1'(LALAGA,-K) (SEQ ID NO: 228). The amino acid sequence of the anti-GDF15 neutralizing antibody is shown in Table 3.

[0514] Table 3

[0515] III. Expression and Purification of Anti-GDF15 Neutralizing Antibody

[0516] The antibody coding sequence (i.e., the nucleotide sequence encoding the amino acid sequence in Table 3) was cloned into the expression vector pCDNA3.4. After sequencing to identify the correct clone, the plasmid was extracted and transfected for expression. ExpiCHO-S cells were co-transfected with the expression vector at a light-to-heavy chain plasmid ratio of 1:2, and the cell density was increased to 6 × 10⁶ cells / year. 6Transfection was performed at a ratio of 1 μg plasmid per mL of cells. After transfection, cells were cultured at 37°C and 5% CO2 for 5–7 days. The supernatant was collected by centrifugation and filtered through a 0.22 μm filter. The filtered cell culture medium was loaded onto a Protein A chromatography column equilibrated with PBS. After loading, the cells were washed with PBS, followed by washing with 100 mM citrate buffer (pH 5.0) to remove impurities. Antibody elution was achieved with 100 mM citrate buffer (pH 3.0), and the antibody sample was immediately neutralized with 1 M Tris-HCl buffer (pH 9.0). A portion of the antibody sample was then used for subsequent protein purity analysis, such as SDS-PAGE and SEC-HPLC. The results showed that 15 anti-GDF15 neutralizing antibodies were successfully purified.

[0517] Test Example 1: Detection of the activity and function of anti-GDF15 neutralizing antibody

[0518] 1. Determination of binding activity and species selectivity of anti-GDF15 neutralizing antibody

[0519] To confirm the species specificity of the candidate molecule and to select a suitable animal model, the inventors conducted a species binding assay on the anti-GDF15 neutralizing antibody (hereinafter referred to as the candidate antibody molecule) prepared in Example 1. The specific experimental steps are as follows:

[0520] Fourteen anti-GDF15 neutralizing antibodies were used to determine the binding activity of GDF15 protein in three species (human, mouse, and cynomolgus monkey) using ELISA. The specific detection steps were as follows:

[0521] [Corrected from Rule 91, 02.04.2025] 96-well ELISA plates were coated with antigen molecules hGDF-15.His, mGDF-15.hFc, and cynoGDF-15.hFc at 2 μg / mL, 100 μL / well, and incubated overnight at 4°C. The next day, after washing and blocking, serially diluted candidate antibody molecules were added and incubated at room temperature for 1 hour. After washing, diluted anti-hFc-HRP or anti-hFab-HRP was added and incubated at room temperature for 1 hour. After washing and development, the results were read using an ELISA reader. The detection results are shown in Figures 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 3C, and Table 4. The results showed that 14 anti-GDF15 neutralizing antibodies were resistant to EC5 of recombinant human GDF15 protein (ACRO, GD5-H5149). 50 (KD) values ​​were all <10 pM, and the EC50 values ​​were similar to those of the mouse GDF15 recombinant protein (Kactus, GDF-MM215). 50(KD) except for G2-CH3, G2-CH12, and G2-CH17, all others are below 0.5 nM, similar to the cynomolgus monkey cynoGDF15 recombinant protein (Kactus, GDF-CM215) EC. 50 The KD values ​​are quite similar, around 100 pM. The binding activity is comparable to that of two comparative antibodies, GDAb1 (from AVEO, WO2014100689A1) and GDAb2 (from Pfizer, ponsegromab).

[0522] Table 4

[0523] Note: NA indicates not detected.

[0524] >GDAb1-VH:

[0525] >GDAb1-VL:

[0526] >GDAb2-VH:

[0527] GDAb2-VL:

[0528] 2. Receptor blocking activity of anti-GDF15 neutralizing antibody on reporter gene (mGFRAL)

[0529] The GFRAL receptor of neutralizing antibodies was detected using a reporter gene cell line stably transfected with mouse GDF15 receptor mouse GFRAL and co-receptor RET. In this example, the reporter gene cell line used was HEK293 cells co-transfected with mGDF15 receptor GFRAL and co-receptor RET. Downstream, the expression of reporter gene luciferase reflected the activation status of the GDF15 pathway.

[0530] [Corrected according to Rule 91, 02.04.2025] On the first day of the experiment, cells with a confluence of 70%-80% were collected, digested with trypsin and EDTA (0.25%), and digestion was terminated using assay buffer (DMEM + 1% FBS). 1.3 × 10 4Cells were plated at 50 μL / well and incubated overnight at 37°C. The next day, the antibody and hGDF15 (ACRO, GD5-H5149) were diluted with assay buffer. Different concentrations of antibody and GDF15 were mixed at a 1:1 volume ratio, and 100 μL / well was added to the cell plate and incubated at 37°C for 6 hours (pre-incubated at room temperature for 0.5 hours). After 6 hours, luciferase assay reagent (Promega, G7940) was added at 50 μL / well. The results are shown in Figures 4A, 4B, 4C, 4D, 4E, 4F and Table 5. The results showed that multiple antibodies, including G2-CH1, G2-CH2, G2-CH3, G2-CH5, G2-CH6, G2-CH7, G2-CH8, G2-CH9, G2-CH10, G2-CH14, and G2-CH16, exhibited neutralizing activity comparable to GDAb2 and better than GDAb1.

[0531] Table 5

[0532] Note: NA indicates not detected.

[0533] 3. Detection of Foxp3 expression level on Juramab induced by GDF15 neutralizing antibody neutralization

[0534] Based on previous research, GDF15 can induce Foxp3 expression on jurakat within 7 days. The neutralization level of Foxp3 on jurakat induced by GDF15 was detected using qPCR with selected anti-GDF15 neutralizing antibodies.

[0535] On the first day of the experiment, anti-GDF15 neutralizing antibodies against CD3 and CD28 (hereinafter referred to as antibodies) were coated into 12-well plates at 2 μg / mL each, 500 μL / well, and incubated overnight at 4°C. On the second day, after washing with PBS, 1×10⁻⁶ antibodies were seeded into each well. 6 Cells were treated with GDF15 (ACRO, GD5-H5149, 40 ng / mL) and antibody (10 μg / mL) for 7 days, with the medium changed every 2 days. After day 7, the cells were reverse-engineered into cDNA using a reverse PCR kit (Invitrogen 11750150), and the expression of Foxp3 on Jurkat cells was detected by qPCR (Vazyme Q121-03). The results are shown in Figure 5. The qPCR results showed that multiple antibodies inhibited Foxp3 expression, with G2-CH1, G2-CH2, G2-CH5, G2-CH8, G2-CH16, and G2-CH17 molecules showing inhibitory activity similar to the control antibodies GDAb1 and GDAb2.

[0536] Example 2: Modification of PTM sites in anti-GDF15 neutralizing antibody

[0537] 1. Research has found that during antibody production, various physicochemical factors can easily lead to the generation of various post-translational modification (PTM) variants, such as glycosylation, oxidation, glycation, deamidation, isomerization, and terminal cyclization. Some PTM sites often exhibit potential modifications in the primary structure of the antibody. When PTMs occur in antibodies, they usually cause antibody heterogeneity. When PTMs occur in the CDR region of the antibody, they may lead to loss of antibody activity. In antibody development, to avoid the occurrence of PTMs, potentially risky sites are usually replaced with conserved amino acids.

[0538] Through sequence analysis, the inventors discovered a risk point for NS deamidation in the light chain CDR3 of candidate antibody G2-CH2, a risk point for NG deamidation in the heavy chain CDR2 of G2-CH5, and a risk point for NG deamidation in the light chain CDR1 of G2-CH8. Therefore, the inventors modified the CDRs of these antibodies using a conserved amino acid substitution method. The modified sequences of the light chain CDR3 of G2-CH2 are shown in Table 1 as SEQ ID NO:80, SEQ ID NO:81, and SEQ ID NO:82; the modified sequences of the heavy chain CDR2 of G2-CH5 are shown in Table 1 as SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76; and the modified sequences of the light chain CDR1 of G2-CH8 are shown in Table 1 as SEQ ID NO:77, SEQ ID NO:78, and SEQ ID NO:79.

[0539] 2. Construct the PTMs-modified anti-GDF15 neutralizing antibody according to step two in Example 1, and express and purify the PTMs-modified anti-GDF15 neutralizing antibody according to step three in Example 1. The heavy chain variable region and light chain variable region, the amino acid sequence of the heavy chain and the amino acid sequence of the light chain, and the nucleotide sequence of the heavy chain and the nucleotide sequence of the light chain of the PTMs-modified anti-GDF15 neutralizing antibody are shown in Table 6.

[0540] Table 6

[0541] Test Example 2: Activity and Function Detection of PTM-Modified Anti-GDF15 Neutralizing Antibody

[0542] 1. Reporter gene assay for detecting receptor blocking activity of anti-GDF15 neutralizing antibody

[0543] The receptor-blocking activity of the nine PTMs-modified anti-GDF15 neutralizing antibodies prepared in Example 2 against GDF15 was detected using a reporter gene cell line (mGFRAL). The detection method is the same as step 2 in Test Example 1. The results are shown in Figure 6 and Table 7. The results showed that, except for G2-CH5-HP3, eight molecules, after PTM modification, still maintained receptor-blocking activity comparable to the control antibody.

[0544] Table 7

[0545] 2. Based on previous research, GDF15 can induce CD4+ T cells to differentiate into Tregs (with high expression of Foxp3 and CD25) in vitro. As shown in Figures 7 and 8, in this embodiment, after one week of Treg differentiation induced by GDF15, the proportion of Tregs reached a level close to that of the positive control TGFβ, exceeding 20%. After co-incubation of the candidate antibody molecule with GDF15, the proportion of Tregs induced by GDF15 can be significantly blocked, thus indicating that the candidate molecule may play a role in tumor immunity. Therefore, detecting this indicator can predict that the GDF15 antibody also has tumor immune activity.

[0546] However, the inventors used flow cytometry to detect the neutralizing activity of antibodies modified with G2-CH1, G2-CH2, G2-CH5, and G2-CH8 and their PTMs against GDF15. The specific experimental steps are as follows:

[0547] On the first day of the experiment, CD3 (Invitrogen 16-0037-85) and CD28 (Invitrogen 16-0289-85) antibodies were coated in 96-well plates at 2 μg / mL, 500 μL / well, and incubated overnight at 4°C. On the second day, CD4+ cells from PBMCs were sorted using CD4beads (Miltenyi Biotec MB17-R0024), and then resuspended in 1640 medium with IL2 (Acro IL2-H4113). After washing the coated 96-well plates with PBS, the cells were cultured at 2 × 10⁶ cells / well. 5Cells were seeded per well and treated with various antibodies and GDF15 / PBS (final concentration 40 ng / mL) for 7 days, with the medium changed every 2 days. After 7 days, cells were collected, stained, fixed, and permeabilized. Finally, the ratio of Foxp3+ and CD25+ in CD4T cells was detected by flow cytometry to determine the Treg-induced differentiation rate, as shown in Figure 9. As shown by flow cytometry, the horizontal axis represents each treatment group, and the vertical axis represents the Treg% percentage in the gate. Regardless of whether the molar ratio of GDF15 to antibody was 1:20 or 1:7, G2-CH1 and the PTM mutants G2-CH5-HP2-hIgG1 (LALAGA,-K) and G2-CH8-LP3-hIgG1 (LALAGA,-K) significantly downregulated the Treg differentiation rate induced by GDF15.

[0548] Example 3: Humanization of Antibodies

[0549] Humanization methods typically employ framework transplantation and protein surface amino acid humanization techniques. The humanization experimental steps are as follows:

[0550] By comparing the germline gene database of the heavy and light chain variable regions of human antibodies with molecular modeling software, germline genes of the heavy and light chain variable regions with high homology with the maternal parent were selected as templates. The CDRs of the murine antibody were transplanted into the corresponding human templates, and corresponding reversion mutations were performed according to the modeling structure. See Tables 8 and 9 for details. Among them, G2-CH1 used IGHV4-39*01, IGHV3-23*01 and IGKV1-39*01, IGKV3-15*01 as templates; G2-CH5-HP2-hIgG1(LALAGA,-K) used IGHV1-8*01 as a template. Using IGKV1-33*04 as a template, G2-CH8-LP3-hIgG1(LALAGA,-K) uses IGHV2-70*06, IGHV2-5*01, IGKV2-29*02, and IGKV2D-29*02 as templates to form a variable region sequence of FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The CDRs are then appropriately reversed, resulting in humanized antibodies like G2-H8-H1L1-hIgG1(LALAGA,-K)(gsm), which is obtained by reversing the CDRs. The amino acid residues are identified and annotated using the Kabat numbering system.

[0551] The light and heavy chain variable region sequences and light and heavy chain sequences of the humanized antibody are shown in Tables 10-11. Then, the humanized anti-GDF15 neutralizing antibody was constructed according to step two in Example 1, and the expression and purification of the humanized anti-GDF15 neutralizing antibody were carried out according to step three in Example 1. The purification results are shown in Tables 12-13.

[0552] Table 8

[0553] Table 9

[0554] Table 10

[0555] Table 11

[0556] Table 12

[0557] Table 13

[0558] Test Example 3: Activity and Function Detection of Humanized Anti-GDF15 Neutralizing Antibody

[0559] 1. Immunogenicity analysis of humanized anti-GDF15 neutralizing antibodies

[0560] To verify the potential immunogenicity of the candidate molecules, the inventors selected three candidate antibodies (see Table 14 for details, and Example 3 for specific amino acid sequences) for MHCII linear epitope prediction related to immunogenicity. This study used the publicly available website resource NETMHCIIpan-4.0 to predict MHCII epitopes of the candidate molecules. Alleles of 10 common HLA subtypes (HLA-DRB1*01, 1*03, 1*04, 1*07, 1*08, 1*11, 1*13, 1*15, 1*09, and 1*12) commonly found in Asians, Caucasians, and people of color were analyzed. Strong binding in three or more alleles, with all markers ranking in the 1% rank, was identified as epitope peptides. The prediction results are shown in Table 14. The results indicate that the three molecules have weak immunogenicity and a low risk of immunogenicity.

[0561] Table 14

[0562] 2. SPR method for detecting the affinity kinetics between humanized antibody and GDF15

[0563] The affinity of the humanized anti-GDF15 neutralizing antibody sample prepared in Example 3 for the GDF15 protein was determined by SPR using a Biacore T200 (Cytiva) analyzer. The specific steps are as follows:

[0564] The CM5 chip (Cytiva, 29104988) was pre-conjugated with an anti-hFc antibody (Cytiva, 29234600) as the detection chip, and HBS-EP+ (Cytiva, BR100669) was used as the experimental buffer. Each cycle included the capture of ligands, the injection of different concentrations of analyte, and regeneration. 1 μg / mL of antibody protein was injected into channels 1 and 2 of the chip at a flow rate of 10 μL / min for 60 s, allowing it to be captured by the anti-hFc antibody on the surface of the channel, with a solidification height of ~300 RU. Channel 1 of the chip served as the reference channel. Using a High Performance model, diluted GDF15 protein (R&D, 8146-GD) was injected sequentially into channels 1 and 2 of the chip at concentrations of 10 nM, 5 nM, 2.5 nM, 1.25 nM, 0.625 nM, 0.3125 nM, and 0 nM at a flow rate of 30 μL / min. The binding time was 300 s, and the dissociation time was 600 s. The chip was then regenerated by injecting 3 M MgCl2 at a flow rate of 30 μL / mL for 60 s. Data were analyzed using Biacore T200 software in a 1:1 binding model, with KD automatically calculated by the software. Detailed data are shown in Table 15 and Figures 10–18. The results indicate that the affinity of the 26 antibodies was comparable to GDAb2, all within 10-1. -11 ~10 -12 Order of magnitude. It should be noted that in this test case, G2-H1-hz1-hIgG1(LALAGA,-K), G2-H1-hz1-hIgG1, and G2-H1-hz1 are synonymous; the same applies to other groups. The contrast antibody GDAb2-hIgG1(LALAGA) refers to hIgG1(LALAGA,-K) without the deletion of the terminal K; the subsequent GDAb2 is synonymous with GDAb2-hIgG1(LALAGA).

[0565] Table 15

[0566] 3. Reporter gene assay for detecting receptor blocking activity of humanized antibodies

[0567] The humanized antibodies prepared in Example 3 were used to test their neutralizing activity in reporter cell lines stably transfected with hGDF15 receptor GFRAL and co-receptor RET. The specific detection method is described in step 2 of Test Example 1. The results are shown in Figures 19-20 and Table 16. The results showed that all antibodies significantly inhibited the activation of the GFRAL-RET pathway by GDF15, and the blocking activity of all antibodies was comparable to that of GDAb2.

[0568] Table 16

[0569] 4. Reporter gene assay was used to detect the neutralizing effect of the six humanized antibodies prepared in Example 3 and the four previously reported contrast antibodies on the GDF15-blocking GFRAL pathway. The specific detection steps are as follows:

[0570] To compare the GDF15 molecule blocking activity of the GFRAL pathway by the GDF15 antibody prepared in Example 3 and the control antibody, a reporter gene cell line (hGFRAL / RET reporter gene cell) was used to compare the blocking activity of six humanized antibodies and five previously reported control antibodies against the GDF15 / GFRAL / RET signaling pathway. The reporter gene cell line was based on HEK293 cells, co-transfected with the human GDF15 receptor GFRAL and the co-receptor RET. Downstream, the expression of reporter gene luciferase reflected the activation status of the GDF15 pathway. The results are shown in Figure 21, where the horizontal axis represents the antibody concentration after logarithmic transformation, and the vertical axis represents the fluorescence intensity detected by the reporter gene cell, representing the degree of pathway activation. Among them, the six humanized antibodies prepared in Example 3 are G2-H1-hz2-hIgG1, G2-H1-hz14-hIgG1, G2-H1-hz13-hIgG1, G2-H5-H1.2L2-hIgG1, G2-H5-H4.2L4-hIgG1 and G2-H8-H1L1-hIgG1(gsm) (where “IgG1” is “IgG1(LALAGA,-K)”); the selected positive antibodies (i.e., control antibodies) are GDAb1, GDAb2, GDAb4 (from the Fourth Military Medical University of the Chinese People's Liberation Army CN111393526B), GDAb5 (visugromab from CaltalYM) and GDAb6 (from the Kangwon National University Industry-University Cooperation Group WO2019004550A1). The results showed that the six humanized antibodies had similar activities to GDAb1 and GDAb2, and were stronger than GDAb4, GDAb5 and GDAb6.

[0571] in,

[0572] >GDAb4-VH:

[0573] GDAb4-VL:

[0574] >GDAb5-VH:

[0575] GDAb5-VL:

[0576] >GDAb6-VH:

[0577] GDAb6-VL:

[0578] 5. Flow cytometry detection of differentiation of GDF15-induced Tregs by candidate antibodies.

[0579] The GDF15 blocking activity of the humanized antibody prepared in Example 3 was tested following the steps in step 2 of Test Example 2. A bar chart was plotted with the horizontal axis representing each treatment group and the vertical axis representing the percentage of Tregs (see Figure 22). Compared with the GDF15-only treatment group, the treatment groups that simultaneously added the humanized molecule and the contrast antibodies GDAb2 and GDAb4 (see step 4 of this Test Example for details) significantly neutralized GDF15-induced Treg differentiation. Compared with GDAb2, G2-H1-hz13 (G2-H1-hz13-hIgG1), G2-H5-H4.2L1 (G2-H5-H4.2L1-hIgG1), and G2-H5-H4.2L4 (G2-H5-H4.2L4-hIgG1) showed stronger neutralizing ability. The differences in Treg percentages among the groups were statistically analyzed using one-way ANOVA.

[0580] In this test case, for example, G2-H1-hz13-hIgG1 is G2-H1-hz13-hIgG1(LALAGA,-K), and the same applies to other groups. Because there are too many groups in Figure 22 and subsequent figures to display the full name, the abbreviation hIgG1 is used in the figure instead of (LALAGA,-K).

[0581] 6. Efficacy test of anti-GDF15 antibody in reversing cachexia in the HT1080 cachexia model.

[0582] The classic cachexia model HT1080 was selected for in vivo efficacy validation. The specific experimental steps are as follows:

[0583] Female NCG mice (from Jicui Pharmaceutical) aged 6-8 weeks were used to establish the HT1080 human fibrosarcoma cachexia model. When the mice's body weight decreased to approximately 10% (day 16 after tumor inoculation), they were grouped according to their body weight. The day of grouping was defined as day D0, and drug administration began according to the experimental protocol on the day of grouping:

[0584] G1:hIgG1 blank control;

[0585] G2: Positive control GDAb2 (see step 4 of this test example for details);

[0586] G3:G2-H1-hz2-hIgG1;

[0587] G4:G2-H5-H2.2L4-hIgG1;

[0588] G5:G2-H8-H1L1-hIgG1(gsm)

[0589] (In this test example, G2-H1-hz2-hIgG1 is G2-H1-hz2-hIgG1(LALAGA,-K), G2-H5-H2.2L4-hIgG1 is G2-H5-H2.2L4-hIgG1(LALAGA,-K), and G2-H8-H1L1-hIgG1(gsm) is G2-H8-H1L1-hIgG1(LALAGA,-K)(gsm)).

[0590] Dosage volume: adjusted according to mouse body weight (mouse dosage volume = 10 μL / g × mouse body weight (g)); dosage 10 mg / kg, Q3D*6 times (i.e., once every 3 days, for a total of 6 times). After grouping, body weight was measured daily, and tumor volume was measured twice weekly. Tumor volume was calculated as: tumor volume (mm). 3 = 0.5 × tumor long diameter × tumor short diameter 2 Serum was collected before grouping and on day 18. Grasping strength was measured on day 12, and fat and muscle content were measured on day 13. The experiment ended on day 18, and the mice were euthanized. For results analysis, since animals were euthanized after day 13, data from day 0 to day 13 were used for analysis.

[0591] The experimental results are shown in Figures 23-25. The results showed that, compared to the blank control group, the weight of mice in the antibody control group and the candidate drug group gradually recovered from day one after drug treatment (as shown in Figure 23A). From D3 to D13, the weight of all drug-treated groups was significantly higher than that of the blank control group (Figure 23A shows weight change, Figure 23B shows the rate of weight change). Statistical analysis was performed using two-way ANOVA, with P < 0.05 considered statistically significant. On day 12 after grouping, the forelimb (Figure 24A) and limb grip strength (Figure 24B) of each group were measured. The data are shown in Table 17 and Figure 24. There were no significant differences between all treatment groups and the blank control group. On day 13 after grouping, DEXO was used to detect fat and muscle content. The results are shown in Table 18, Figure 25A, and Figure 25B. The drug group significantly reversed muscle mass, but no statistically significant difference was observed in fat content. Therefore, the in vivo pharmacodynamic experiments of HT1080 showed that the three test drugs G2-H1-hz2-hIgG1, G2-H5-H2.2L4-hIgG1, and G2-H8-H1L1-hIgG1 (gsm) had a good effect on cachexia symptoms in the HT1080 cachexia model.

[0592] To compare the neutralization effect of the drugs on the target GDF15, the serum free GDF15 levels of each group of animals before and after drug administration were measured (Figures 26A and 26B). Before drug administration, the GDF15 levels of each group of animals were around 4 ng / mL. After drug administration, the GDF15 level in the blank control group increased to about 20 ng / mL. After treatment with drugs GDAb2, G2-H1-hz2-hIgG1, and G2-H8-H1L1-hIgG1 (gsm), the serum free GDF15 levels were significantly decreased compared with the blank control (statistical analysis was performed using one-way ANOVA, and P < 0.05 was considered statistically significant), which corroborates the pharmacological effect of the drugs in reversing weight loss and improving cachexia symptoms after neutralizing GDF15.

[0593] Table 17 Changes in forelimb and quadriplimb gripping strength in mice of different groups

[0594] Statistical analysis of p-values ​​of forelimb and quadripleg grip strength in mice of different groups

[0595] Table 18

[0596] Changes in fat mass, muscle mass, and body fat percentage in mice of different groups

[0597] Statistical analysis of p-values ​​of fat mass, muscle mass, and body fat ratio in mice from different groups

[0598] Note: All statistical analyses here use one-way ANOVA, and P < 0.05 is considered statistically significant.

[0599] 7. Efficacy test of anti-GDF15 antibody in reversing cachexia in LNCaP cachexia model

[0600] The LNCaP cachexia model was selected for in vivo efficacy validation. The specific experimental steps are as follows:

[0601] Male CB17SCID mice (from WuXi AppTec) aged 6-8 weeks were used to establish a LNCaP-mediated human prostate cancer cachexia model. When the mice's body weight decreased to approximately 9%, they were grouped according to their body weight. The day of grouping was defined as day 0 (D0), and drug administration began on the grouping day according to the experimental protocol design.

[0602] G1: IgG1 isotype control;

[0603] G2: Control antibody GDAb2;

[0604] G3: Control antibody GDAb5;

[0605] G4: G2-H1-hz2-hIgG1;

[0606] G5: G2-H1-hz14-hIgG1;

[0607] G6: G2-H8-H1L1-hIgG1(gsm);

[0608] G7: G2-H5-H4.2L4-hIgG1;

[0609] G8: G2-H5-H1.2L2-hIgG1;

[0610] G9: G2-H1-hz13-hIgG1;

[0611] G10: NTA (animals that do not require tumor grafting).

[0612] (In this test case: G2-H5-H4.2L4-hIgG1 is equivalent to G2-H5-H4.2L4-hIgG1 (LALAGA,-K), and the same applies to other groups.)

[0613] Dosage volume: adjusted according to mouse body weight (mouse dosage volume = 10 μL / g × mouse body weight (g)); dosage 20 mg / kg, Q6D*2 times (i.e., once every 6 days, for a total of 2 doses). After grouping, body weight was measured daily, and tumor volume was measured twice weekly. Tumor volume was calculated as: tumor volume (mm²) 3 = 0.5 × tumor long diameter × tumor short diameter 2 The experimental endpoint was measured by measuring body fat percentage, fat, and muscle mass in mice. The results are shown in Figures 27 and 28 and Table 19. Figure 27 shows that, compared to the isotype control group, the weight of mice in the control antibody GDAb2 and test drug groups gradually recovered from day one after drug treatment until the end of the experiment. The control antibody GDAb5 initially showed some weight recovery, but with prolonged administration, weight gradually decreased and failed to maintain an upward trend. Subsequently, compared to the vehicle group, the weight loss in mice was not significantly alleviated. Statistical analysis of the weight at different time points in each drug administration group compared to the isotype control group is shown in Table 1 (two-way ANOVA was used for statistical analysis; P < 0.05 was considered statistically significant; P values ​​were obtained by comparing with the hIgG1 group).

[0614] The results in Figure 28 show that, compared with the isotype control group, the fat weight of the test groups (except for the GDAb5 antibody group) was statistically different from that of the control group; the muscle weight of the test groups, GDAb2, G2-H5-H4.2L4-hIgG1, G2-H5-H1.2L2-hIgG1, and G2-H1-hz13-hIgG1 were statistically different from those of the control group; the fat percentage results were similar to the fat weight results, the GDAb5 antibody showed no difference compared with the control, and all other groups showed statistical differences; the muscle percentage of each test group was lower than that of the control group.

[0615] In summary, the in vivo efficacy results of the tested drugs in LNCaP indicate that all tested drugs in each group have good efficacy in reversing weight loss due to cachexia.

[0616] Table 19

[0617] 8. Efficacy test of anti-GDF15 antibody in reversing cachexia in the MKN45 cachexia model.

[0618] The MKN45 cachexia model was selected for in vivo efficacy validation. The specific experimental steps are as follows:

[0619] Female BALB / c nude mice (from WuXi AppTec) aged 6-8 weeks were used to establish the MKN45 human gastric cancer cachexia model. When the average body weight of the mice decreased to approximately 6.6% (day 15 after tumor inoculation), they were grouped according to their body weight. The day of grouping was defined as day D0, and drug administration began according to the experimental protocol on the day of grouping:

[0620] G1: hIgG1 isotype control, dose 10 mg / kg;

[0621] G2: Positive control GDAb2, dose 1 mg / kg;

[0622] G3: Positive control GDAb2, dose 3 mg / kg;

[0623] G4: G2-H8-H1L1-hIgG1(gsm), dosage 1 mg / kg;

[0624] G5: G2-H8-H1L1-hIgG1(gsm), dosage 3mg / kg;

[0625] G6: G2-H8-H1L1-hIgG1(gsm), dose 10mg / kg;

[0626] G7: NTA (animals that do not require tumor grafting).

[0627] (In this test case, G2-H8-H1L1-hIgG1(gsm) is equivalent to G2-H8-H1L1-hIgG1(LALAGA,-K)(gsm))

[0628] Dosage volume: Adjusted according to mouse body weight (mouse dosage volume = 10 μL / g × mouse body weight (g)); dosage as above, Q3D*4 times (i.e., once every 3 days, for a total of 4 times). After grouping, weigh the mice daily and measure the tumor volume. Tumor volume is calculated as: tumor volume (mm). 3 = 0.5 × tumor long diameter × tumor short diameter 2 Tumor weight is estimated at 1g / 1000mm. 3 Body fat percentage was measured at the end of the experiment, and serum samples were collected and frozen. The changes in body weight and body fat percentage of mice in each group were measured at the end of the experiment. The results are shown in Figures 29-30 and Table 20.

[0629] Figure 29 shows the weight change results. Compared with the isotype control group, the weight of mice in the positive antibody control group and the candidate antibody group (G2-CH8-H1L1) gradually recovered from day one after drug treatment until the end of the experiment. At the end of the experiment, the weight of all experimental groups of mice returned to the baseline level (on the day of tumor inoculation). In the isotype control group, the weight of mice gradually decreased. Figure 29 shows the rate of change in weight after tumor removal. The experimental results were statistically analyzed using one-way ANOVA (P < 0.05 was considered statistically significant).

[0630] The results of body fat percentage in Figure 30 and Table 1 show that, compared with the isotype control group, all experimental groups of mice had significant differences in fat weight, muscle weight, and fat percentage, while there was no significant difference in muscle percentage.

[0631] Therefore, the results of Figures 29 and 30 show that the candidate antibody of this application demonstrates a good ability to reverse the weight loss in MKN45 cachexia model mice; according to the body fat analysis, the candidate antibody reversed the weight loss of both fat and muscle compared with the isotype control group.

[0632] Table 20-1: Mass and proportion of fat and muscle in mice of different groups

[0633] Table 20-2: Statistical analysis of p-values ​​of fat and muscle mass and proportion in mice of different groups

[0634] [Corrected according to Rule 91, April 2025] Further, to analyze the neutralization effect of the test drug on the target GDF15, the levels of free and total (free + bound) GDF15 in the serum of all tumor-bearing groups (excluding the NTA group) at the experimental endpoint were measured. The results are shown in Figures 31A and 31B. The serum free GDF15 results showed that doses of 3 mg / kg and 10 mg / kg were sufficient to neutralize the free GDF15 in all mice in the corresponding experimental groups, meaning the free GDF15 concentration decreased to the level of the isotype control group (<1 ng / mL). The total GDF15 concentration showed that the total GDF15 concentration in the treatment groups (positive control group, candidate antibody group) was around 2-3 μg / mL, with no statistically significant difference between the treatment groups (statistical analysis was performed using one-way ANOVA, P < 0.05 was considered statistically significant).

[0635] 9. Validation of the activity of candidate antibodies in tumor immunology

[0636] [Corrected according to Rule 91, 02.04.2025] To verify the activity of the candidate antibody in tumor immunity, this test case used C57BL / 6-hPDL1 humanized mice to inoculate MC38-hPDL1-hGDF15 cells and its parent cell line MC38-hPDL1 to model tumor cells. Eight mice were used in each group. Anti-PDL1 drugs (Tecentriq, or T-drug) were administered alone or in combination with GDF15 antibody. Tumor volume changes and survival rates were observed (T-drug 5 mg / kg, GDF15 antibody prepared in Example 3 20 mg / kg, 8 animals per group). The positive control group consisted of GDF15 antibody replaced with a positive antibody. The selected positive antibodies (i.e., control antibodies) were GDAb2 (see step 1 of Test Example 1 for the specific amino acid sequence) and GDAb5 (Visugromab, see step 4 of Test Example 3 for the specific amino acid sequence). The results are shown in Tables 21 and 22, and Figures 32A, 32B, 32C, 32D, and 32E. The results indicated that the candidate antibody G2-H8-H1L1-hIgG1 (gsm) combined with drug T (G4), and G2-H5-H4.2L4-hIgG1 combined with drug T (G5) showed a better anti-tumor trend than drug T alone (G2), GDAb2 (G6), and GDAb5 combined with drug T (G7). (The last sentence appears to be incomplete and possibly refers to a measurement or measurement.) 3 As a humanitarian endpoint, the survival rate of each group of animals was observed. Among them, the combination of G2-H8-H1L1-hIgG1(gsm) molecules showed a better anti-tumor trend compared with T drug alone.

[0637] G1: hIgG1 (20mg / kg) + hIgG1 (5mg / kg);

[0638] G2: hIgG1 (20mg / kg) + Tecentriq (5mg / kg);

[0639] G3: G2-H1-hz2-hIgG1(20mg / kg)+Tecentriq(5mg / kg);

[0640] G4: G2-H8-H1L1-hIgG1(gsm)(20mg / kg)+Tecentriq(5mg / kg);

[0641] G5: G2-H5-H4.2L4-hIgG1(20mg / kg)+Tecentriq(5mg / kg);

[0642] G6: GDAb2(20mg / kg)+Tecentriq(5mg / kg);

[0643] G7: GDAb5(20mg / kg)+Tecentriq(5mg / kg);

[0644] G8: hIgG1 (5mg / kg);

[0645] G9: Tecentriq (5mg / kg).

[0646] (In this test case, the constant region of the antibody heavy chain in groups G3-G5 all used hIgG1, and G2-H1-hz2-hIgG1 is the same as G2-H1-hz2-hIgG1 (LALAKA,-K). The same applies to groups G4 and G5.)

[0647] Table 21: Statistical Analysis of Survival Curves for Groups G1-G7

[0648] Table 22: Statistical Analysis of Survival Curves in Groups G8-G9

[0649] Experiments showed that, 33 days after administration, the tumors in animals inoculated with MC38-hPDL1 were all controlled with drug T, and the tumor volume was all within 100 mm. 3 However, in animals vaccinated with MC38-hPDL1-hGDF15, all tumors progressed after treatment with drug T, with an average tumor volume of 800 mm. 3 The two studies showed a statistically significant difference (P<0.05), thus demonstrating that overexpression of hGDF15 does indeed induce tumor tolerance to PD-1.

[0650] Using the anti-GDF15 antibody prepared in Example 3 of this invention in combination with drug T can induce tumor volume reduction and regression in animals to varying degrees. At 33 days post-administration (the last time point when all animals in all groups survived), the TGI (tumor inhibition rate) of the drug T alone group (G2 group) was 57%. In the GDAb2 and drug T combined group (G6 group), 2 out of 8 animals showed complete regression, while the rest continued to progress, with a TGI of 45%. In the G2-H5-H4.2L4-hIgG1 and drug T combined group (G5 group), 4 animals showed regression and reduction, with tumor volume controlled at 200 mmHg. 3 Below, the TGI was 74%; in the group using the combination of G2-H8-H1L1-hIgG1 (gsm) and T drug (G4 group), 5 animals showed shrinkage and regression, with tumor volume all below 200 mm. 3 The TGI was 77% in the group using G2-H1-hz2-hIgG1 and T-drug in combination (G3 group); the progression of the animals in this group was similar to that of the T-drug monotherapy group, with a TGI of 57%; in the group using GDAb5 and T-drug in combination (G7 group), one animal showed tumor shrinkage, with a TGI of 53%. Tumor volume and TGI results are shown in Figures 32-33. Therefore, the results indicate that the candidate antibodies G2-H8-H1L1-hIgG1 (gsm) and G2-H5-H4.2L4-hIgG1 showed a better anti-tumor trend than GDAb2.

[0651] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0652] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. An antibody or its antigen-binding fragment, characterized in that, Include: Selected from at least one of the following CDR sequences or amino acid sequences that have at least 66% identity with them: Heavy chain variable region CDR sequences: SEQ ID NO:1~34 and SEQ ID NO:74~76; Light chain variable region CDR sequences: SEQ ID NO:36~73 and SEQ ID NO:77~82.

2. The antibody or its antigen-binding fragment according to claim 1, characterized in that, The antibodies include: The heavy chain variable region CDR1 is selected from any one of the amino acids in SEQ ID NO:1, SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:12, SEQ ID NO:15, SEQ ID NO:23 and SEQ ID NO:32; The heavy chain variable region CDR2 is represented by an amino acid selected from any one of SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:10, SEQ ID NO:13, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:33, SEQ ID NO:74, SEQ ID NO:75 and SEQ ID NO:76; The heavy chain variable region CDR3 is selected from any one of SEQ ID NO:3, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:11, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:

34. The light chain variable region CDR1 is selected from any one of SEQ ID NO:36, SEQ ID NO:39, SEQ ID NO:43, SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO:52, SEQ ID NO:55, SEQ ID NO:58, SEQ ID NO:63, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:77, SEQ ID NO:78 and SEQ ID NO:79; The light chain variable region CDR2 is selected from any one of the amino acids in SEQ ID NO:37, SEQ ID NO:40, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:56, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:64, and SEQ ID NO:71; or The light chain variable region CDR3 is selected from any one of SEQ ID NO:38, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:51, SEQ ID NO:54, SEQ ID NO:57, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:72, SEQ ID NO:80, SEQ ID NO:81 and SEQ ID NO:

82.

3. The antibody or its antigen-binding fragment according to claim 1 or 2, characterized in that, The antibodies include: The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:1, 2, and 3, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:9, 75, and 11, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:7, 5, and 8, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:9, 10, and 11, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:12, 13, and 14, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:15, 16, and 14, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:15, 19, and 20, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:4, 21, and 22, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:23, 24, and 25, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:12, 26, and 27, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:7, 28, and 29, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:7, 5, and 30, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:7, 5, and 31, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:32, 33, and 34, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:9, 74, and 11, respectively; or The heavy chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:9, 76, and 11, respectively; Optionally, the antibody comprises: The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:73, 53, and 54, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:36, 37, and 38, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:43, 44, and 45, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:39, 40, and 41, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:39, 40, and 42, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:46, 47, and 48, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:49, 50, and 51, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:52, 53, and 54, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:49, 47, and 51, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:55, 56, and 57, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:58, 59, and 60, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:49, 61, and 62, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:63, 64, and 65, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:66, 40, and 67, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:68, 40, and 69, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:70, 71, and 72, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:77, 53, and 54, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:78, 53, and 54, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:79, 53, and 54, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:39, 40, and 80, respectively; or The light chain variable region CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:39, 40, and 81, respectively; or The light chain variable regions CDR1, CDR2, and CDR3 sequences are shown in the amino acid sequences of SEQ ID NO:39, 40, and 82, respectively.

4. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, characterized in that, The antibodies include: The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:73, 53, and 54, respectively; The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 2, and 3, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:36, 37, and 38, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 75, and 11, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:43, 44, and 45, respectively; The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 41, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:7, 5, and 8, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 42, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 10, and 11, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:43, 44, and 45, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:12, 13, and 14, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:46, 47, and 48, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:15, 16, and 14, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:49, 50, and 51, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:52, 53, and 54, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:15, 19, and 20, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:49, 47, and 51, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:4, 21, and 22, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:55, 56, and 57, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:23, 24, and 25, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:58, 59, and 60, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:12, 26, and 27, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:49, 61, and 62, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:7, 28, and 29, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:63, 64, and 65, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:7, 5, and 30, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:66, 40, and 67, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:7, 5, and 31, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:68, 40, and 69, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:32, 33, and 34, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:70, 71, and 72, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 74, and 11, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:43, 44, and 45, respectively; or or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:9, 76, and 11, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:43, 44, and 45, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:77, 53, and 54, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:78, 53, and 54, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:1, 17, and 18, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:79, 53, and 54, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 80, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 81, respectively; or The heavy chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:4, 5, and 6, respectively, and the light chain variable regions CDR1, CDR2, and CDR3 sequences shown in the amino acid sequences of SEQ ID NO:39, 40, and 82, respectively; or Optionally, the antibody or its antigen-binding fragment specifically recognizes GDF15.

5. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, characterized in that, The antibody further comprises: At least one of the heavy chain framework region sequence and the light chain framework region sequence; Wherein, at least a portion of at least one of the heavy chain framework region sequence and the light chain framework region sequence is derived from at least one of murine antibodies, human antibodies, primate antibodies or mutants thereof; Optionally, at least a portion of the heavy chain framework region sequence and the light chain framework region sequence are derived from a human antibody or a mutant thereof.

6. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, characterized in that, The antibody has a heavy chain variable region of the amino acid sequence shown in any one of SEQ ID NO:83-100, SEQ ID NO:124-127, SEQ ID NO:132-135, SEQ ID NO:140-141 and SEQ ID NO:144-145; Optionally, the antibody has a light chain variable region of the amino acid sequence shown in any one of SEQ ID NO:102-122, SEQ ID NO:128-131, SEQ ID NO:136-139, SEQ ID NO:142-143 and SEQ ID NO:146-147.

7. The antibody or its antigen-binding fragment according to claim 6, characterized in that, The antibody has The heavy chain variable region of the amino acid sequence shown in SEQ ID NO:144 and the light chain variable region of the amino acid sequence shown in SEQ ID NO:146; Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:124 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

129. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:135 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

139. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:83 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

102. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:84 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

103. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:85 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

104. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:86 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

105. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:87 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

106. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:88 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

107. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:89 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

108. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:90 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

109. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:91 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

110. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:92 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

111. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:93 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

112. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:94 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

113. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:95 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

114. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:96 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

115. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:97 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

116. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:98 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

105. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:99 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

105. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:100 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

105. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:89 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

117. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:89 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

118. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:89 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

119. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:84 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

120. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:84 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

121. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:84 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

122. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:124 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

128. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:124 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

130. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:124 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

131. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:125 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

128. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:125 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

129. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:125 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

130. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:125 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

131. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:126 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

128. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:126 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

129. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:126 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

130. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:126 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

131. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:127 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

128. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:127 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

129. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:127 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

130. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:127 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

131. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:132 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

136. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:133 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

136. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:134 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

136. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:135 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

136. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:132 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

137. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:133 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

137. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:134 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

137. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:135 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

137. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:132 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

138. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:133 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

138. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:134 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

138. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:135 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

138. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:132 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

139. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:133 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

139. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:134 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

139. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:140 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

142. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:141 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:142; Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:140 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

143. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:141 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

143. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:144 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

147. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:145 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

146. Optionally, the antibody has a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:145 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:

147.

8. An antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, characterized in that, The antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:144, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

146. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:124, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

129. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:135, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

139. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:83, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

102. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:84, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

103. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:85, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

104. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:86, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

105. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:87, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

106. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:88, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

107. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:89, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

108. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:90, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

109. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:91, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

110. Optionally, the antibody comprises three heavy chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:92 and a light chain variable region of the amino acid sequence shown in SEQ ID NO:

111. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:93, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

112. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:94, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

113. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:95, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

114. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:96, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

115. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:97, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

116. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:98, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

105. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:99, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

105. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:100, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

105. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:89, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

117. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:89, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

118. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:89, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

119. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:84, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

120. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:84, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

121. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:84, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

122. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:124, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

128. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:124, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

130. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:124, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

131. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:125, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

128. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:125, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

129. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:125, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

130. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:125, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

131. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:126, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

128. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:126, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

129. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:126, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

130. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:126, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

131. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:127, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

128. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:127, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

129. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:127, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

130. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:127, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

131. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:132, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

136. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:133, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

136. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:134, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

136. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:135, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

136. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:132, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

137. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:133, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

137. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:134, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

137. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:135, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

137. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:132, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

138. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:133, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

138. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:134, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

138. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:135, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

138. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:132, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

139. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:133, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

139. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:134, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

139. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:140, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

142. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:141, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

142. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:140, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

143. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:141, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

143. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:144, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

147. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:145, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

146. Optionally, the antibody comprises three light chain variable regions (CDRs) in the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:145, and three light chain variable regions (CDRs) in the light chain variable region of the amino acid sequence shown in SEQ ID NO:

147. The aforementioned CDR sequence also contains an amino acid sequence that is at least 66% identical to it. The aforementioned CDR was determined according to the Kabat, IMGT, Chothia, and North numbering system.

9. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, characterized in that, The antibody contains at least one of a heavy chain constant region and a light chain constant region, and at least a portion of at least one of the heavy chain constant region and the light chain constant region is derived from at least one of a murine antibody, a human antibody, a primate antibody or a mutant thereof. Optionally, both the light chain constant region and the heavy chain constant region are derived from human IgG antibodies or their mutants; Optionally, the heavy chain constant region is a human IgG mutant; Optionally, the heavy chain constant region, compared to the heavy chain constant region of the human wild-type IgG1 antibody, has at least one of the following site mutations: L234A, L235A, G237A, and K447 are missing; Optionally, the heavy chain constant region has an amino acid sequence as shown in SEQ ID NO:148 or SEQ ID NO:228; Optionally, the light chain constant region has the amino acid sequence shown in SEQ ID NO:

149.

10. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, characterized in that, The antibody has a heavy chain as shown in any one of the amino acid sequences of SEQ ID NO: 150-164, 166-182, 229 or a light chain as shown in any one of the amino acid sequences of SEQ ID NO: 183-197, 199-217. Optionally, the antibody comprises: The heavy chain as shown in the amino acid sequence of SEQ ID NO:181 and the light chain as shown in the amino acid sequence of SEQ ID NO:216; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:229 and the light chain as shown in the amino acid sequence of SEQ ID NO:216; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:171 and the light chain as shown in the amino acid sequence of SEQ ID NO:207; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:178 and the light chain as shown in the amino acid sequence of SEQ ID NO:213; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 150 and the light chain as shown in the amino acid sequence of SEQ ID NO: 183; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 151 and the light chain as shown in the amino acid sequence of SEQ ID NO: 184; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:152 and the light chain as shown in the amino acid sequence of SEQ ID NO:185; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 153 and the light chain as shown in the amino acid sequence of SEQ ID NO: 186; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:154 and the light chain as shown in the amino acid sequence of SEQ ID NO:187; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 155 and the light chain as shown in the amino acid sequence of SEQ ID NO: 188; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 156 and the light chain as shown in the amino acid sequence of SEQ ID NO: 189; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 157 and the light chain as shown in the amino acid sequence of SEQ ID NO: 190; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 158 and the light chain as shown in the amino acid sequence of SEQ ID NO: 191; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 159 and the light chain as shown in the amino acid sequence of SEQ ID NO: 192; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 160 and the light chain as shown in the amino acid sequence of SEQ ID NO: 193; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 161 and the light chain as shown in the amino acid sequence of SEQ ID NO: 194; or The heavy chain as shown in the amino acid sequence SEQ ID NO:162 and the light chain as shown in the amino acid sequence SEQ ID NO:195; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 163 and the light chain as shown in the amino acid sequence of SEQ ID NO: 196; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 166 and the light chain as shown in the amino acid sequence of SEQ ID NO: 199; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 167 and the light chain as shown in the amino acid sequence of SEQ ID NO: 199; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 168 and the light chain as shown in the amino acid sequence of SEQ ID NO: 199; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:169 and the light chain as shown in the amino acid sequence of SEQ ID NO:200; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:169 and the light chain as shown in the amino acid sequence of SEQ ID NO:201; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:169 and the light chain as shown in the amino acid sequence of SEQ ID NO:202; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:170 and the light chain as shown in the amino acid sequence of SEQ ID NO:203; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:170 and the light chain as shown in the amino acid sequence of SEQ ID NO:204; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:170 and the light chain as shown in the amino acid sequence of SEQ ID NO:205; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:171 and the light chain as shown in the amino acid sequence of SEQ ID NO:206; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:171 and the light chain as shown in the amino acid sequence of SEQ ID NO:208; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:171 and the light chain as shown in the amino acid sequence of SEQ ID NO:209; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:172 and the light chain as shown in the amino acid sequence of SEQ ID NO:206; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:172 and the light chain as shown in the amino acid sequence of SEQ ID NO:207; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:172 and the light chain as shown in the amino acid sequence of SEQ ID NO:208; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:172 and the light chain as shown in the amino acid sequence of SEQ ID NO:209; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:173 and the light chain as shown in the amino acid sequence of SEQ ID NO:206; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:173 and the light chain as shown in the amino acid sequence of SEQ ID NO:207; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:173 and the light chain as shown in the amino acid sequence of SEQ ID NO:208; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:173 and the light chain as shown in the amino acid sequence of SEQ ID NO:209; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:174 and the light chain as shown in the amino acid sequence of SEQ ID NO:206; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:174 and the light chain as shown in the amino acid sequence of SEQ ID NO:207; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:174 and the light chain as shown in the amino acid sequence of SEQ ID NO:208; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:174 and the light chain as shown in the amino acid sequence of SEQ ID NO:209; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:175 and the light chain as shown in the amino acid sequence of SEQ ID NO:210; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 175 and the light chain as shown in the amino acid sequence of SEQ ID NO: 211; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:175 and the light chain as shown in the amino acid sequence of SEQ ID NO:212; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:175 and the light chain as shown in the amino acid sequence of SEQ ID NO:213; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:176 and the light chain as shown in the amino acid sequence of SEQ ID NO:210; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 176 and the light chain as shown in the amino acid sequence of SEQ ID NO: 211; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:176 and the light chain as shown in the amino acid sequence of SEQ ID NO:212; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 176 and the light chain as shown in the amino acid sequence of SEQ ID NO: 213; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:177 and the light chain as shown in the amino acid sequence of SEQ ID NO:210; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:177 and the light chain as shown in the amino acid sequence of SEQ ID NO:211; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:177 and the light chain as shown in the amino acid sequence of SEQ ID NO:212; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:177 and the light chain as shown in the amino acid sequence of SEQ ID NO:213; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:178 and the light chain as shown in the amino acid sequence of SEQ ID NO:210; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 178 and the light chain as shown in the amino acid sequence of SEQ ID NO: 211; or The heavy chain as shown in the amino acid sequence of SEQ ID NO: 178 and the light chain as shown in the amino acid sequence of SEQ ID NO: 212; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:179 and the light chain as shown in the amino acid sequence of SEQ ID NO:214; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:179 and the light chain as shown in the amino acid sequence of SEQ ID NO:215; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:180 and the light chain as shown in the amino acid sequence of SEQ ID NO:214; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:180 and the light chain as shown in the amino acid sequence of SEQ ID NO:215; or The heavy chain as shown in the amino acid sequence of SEQ ID NO:181 and the light chain as shown in the amino acid sequence of SEQ ID NO:217; or The heavy chain as shown in the amino acid sequence SEQ ID NO:182 and the light chain as shown in the amino acid sequence SEQ ID NO:216; or The heavy chain is shown in the amino acid sequence SEQ ID NO:182 and the light chain is shown in the amino acid sequence SEQ ID NO:

217.

11. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, characterized in that, The antibody includes at least one selected from monoclonal antibodies, polyclonal antibodies, multimeric antibodies, and CDR transplantation antibodies; Optionally, the antibody includes at least one selected from single-chain antibodies, Fab antibodies, Fv antibodies, single-chain antibodies, single-domain antibodies, and the smallest recognition unit; Optionally, the antigen-binding fragment includes at least one of the following: Fab fragment, (Fab)2 fragment, scFv-Fc fusion protein, scFv-Fv fusion protein, Fv fragment, and minimum recognition unit.

12. A nucleic acid molecule, characterized in that, The nucleic acid molecule encodes the antibody or its antigen-binding fragment as described in any one of claims 1 to 11.

13. The nucleic acid molecule according to claim 12, characterized in that, The nucleic acid molecule in question is DNA.

14. An expression carrier, characterized in that, Carrying the nucleic acid molecule as described in claim 12 or 13.

15. The expression vector according to claim 14, characterized in that, The expression vector is a eukaryotic expression vector or a prokaryotic expression vector, preferably a plasmid expression vector.

16. A recombinant cell, characterized in that, The recombinant cell carries the nucleic acid molecule as described in claim 12 or 13; or, Express the antibody or antigen-binding fragment thereof as described in any one of claims 1 to 11.

17. The recombinant cell according to claim 16, characterized in that, The recombinant cells are obtained by introducing the expression vector of claim 14 or 15 into host cells; Optionally, the recombinant cells are eukaryotic cells; Preferably, the recombinant cells are mammalian cells.

18. A pharmaceutical composition, characterized in that, contain: The antibody or antigen-binding fragment thereof as described in any one of claims 1 to 11; The nucleic acid molecule according to claim 12 or 13; The expression vector as described in claim 14 or 15; or The recombinant cells according to claim 16 or 17; Optionally, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

19. A combination drug or pillbox, characterized in that, include: The antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 18, shall be the first active ingredient; as well as Anti-PDL1 drugs serve as the second active ingredient; Optionally, the anti-PDL1 drug is an anti-PDL1 antibody.

20. Use of the antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, the nucleic acid molecule according to claim 12 or 13, the expression vector according to claim 14 or 15, the recombinant cell according to claim 16 or 17, the pharmaceutical composition according to claim 18, or the combination drug or kit according to claim 19, wherein the use includes: Used for the prevention and / or treatment of cancer and cachexia; Used to prepare drugs for the prevention and / or treatment of cancer and cachexia.

21. A reagent kit, characterized in that, include: The antibody according to any one of claims 1 to 11, the nucleic acid molecule according to claim 12 or 13, the expression vector according to claim 14 or 15, or the recombinant cell according to claim 16 or 17.

22. Use of the antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, the nucleic acid molecule according to claim 12 or 13, the expression vector according to claim 14 or 15, or the recombinant cell according to claim 16 or 17, wherein the use includes: Used to detect GDF15; A kit for the detection of GDF15.

23. A method for preventing and / or treating cancer and cachexia, characterized in that, include: Administer to a subject a pharmaceutically acceptable amount of an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 11, a nucleic acid molecule as described in claim 12 or 13, an expression vector as described in claim 14 or 15, a recombinant cell as described in claim 16 or 17, a pharmaceutical composition as described in claim 18, or a combination drug or kit as described in claim 19.

24. A method for detecting GDF15, characterized in that, include: The sample to be tested is tested using the antibody or antigen-binding fragment thereof as described in any one of claims 1 to 11, or the kit as described in claim 21; Optionally, the antibody or its antigen-binding fragment forms an immune complex with GDF15 in the sample to be tested; The presence of the immune complex is detected, and the presence of the immune complex is used to determine whether the sample to be tested contains GDF15.

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