Anti-βKlotho antibody and its use

Abstract

The present invention relates to a novel anti-βKlotho antibody and its use.The anti-βKlotho antibody can be used for the treatment of diseases mediated by βKlotho or mediated by βKlotho-FGFR1c-FGF21, particularly metabolic disorders, such as type 1 diabetes, type 2 diabetes, dyslipidemia, nonalcoholic fatty liver disease (NASH), nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to Chinese Patent Application No. 202111683753.3, filed on December 30, 2021, the entire contents of which are incorporated herein by reference for all purposes.

[0002] The present invention relates generally to the field of biopharmaceuticals, and specifically to a novel anti-βKlotho antibody or antigen-binding fragment thereof, a pharmaceutical composition comprising said antibody or antigen-binding fragment thereof, and medical uses of said antibody or antigen-binding fragment thereof. [Background technology]

[0003] Fibroblast factor 21 (FGF21) is a member of the FGF19 subfamily of the fibroblast factor (FGF) family, which plays an important role in regulating sugar, lipid and energy metabolism. In addition to FGF21, the FGF19 subfamily includes two other members, FGF19 and FGF23. Unlike classical fibroblast factors that need to bind to heparin to function, the three proteins of the FGF19 subfamily do not bind to heparin, are secreted into the blood and function physiologically in other tissues or organs of the body. Therefore, the three proteins, such as FGF21, are also called endocrine fibroblast factors. FGF21 is mainly expressed in the liver, and also in small amounts in tissues such as the pancreas and brain. It acts on tissue organs such as adipose tissue and the central nervous system, improving insulin sensitivity, increasing glucose removal in the blood, inhibiting the breakdown of hepatic sugar, improving energy consumption, increasing the ketogenic activity of the liver, and reducing triglyceride levels in the blood. In addition to FGF21, FGF19 is mainly expressed by the small intestine and acts mainly on hepatocytes, where it is involved in regulating the synthesis and secretion of bile acids, while FGF23 is a phosphaturic hormone that plays an important role in regulating phosphate balance in humans.

[0004] Three FGF19 subfamily proteins, including FGF21, exert their physiological functions by activating FGF receptors (FGFRs). They cannot activate FGF receptors alone and need to exert their physiological functions with the help of another co-receptor, which is the Klotho protein. Klotho proteins are classified into two groups, αKlotho and βKlotho, which are required for FGF19, FGF21 and FGF23 to bind with high affinity to their cognate FGF receptors. Here, αKlotho mediates FGF receptor activation by FGF23, while βKlotho mediates receptor activation by FGF19 and FGF21. βKlotho is a single-pass type 1 membrane protein with an extracellular domain consisting of two internal repeats that are homologous to members of family 1 glycosidases but lack glucosidase catalytic activity. βKlotho expression was detected in tissues such as liver, pancreas, adipose and central nervous system. According to research, β-klotho deficiency (KLB - / - ) showed that CYP7A1 and CY8B1 mRNA levels were elevated in mice, leading to increased bile acid synthesis and secretion.

[0005] FGF21 binds to FGF receptors to form a ternary complex with βKlotho, and this structure promotes the dimerization of FGF receptors, forming a hexameric complex to activate FGF receptors, and the activated FGF receptors further activate downstream signaling pathways such as MAPK (Erk1 / 2) and AKT1 to exert their biological functions. FGF21 can activate FGF receptors on adipocytes, thereby promoting the expression of GLUT-1 by adipocytes, thereby increasing glucose absorption by adipocytes, and at the same time upregulating the expression of UCP-1 and promoting the brown-like transformation of adipocytes, and further inducing the expression and secretion of adiponectin or other adipocyte factors that have insulin-sensitizing effects. Adipocyte factors such as adiponectin can further act on other tissues or organs (e.g., the liver) and further improve whole-body metabolism. In recent years, some studies have shown that FGF21 also acts on the central nervous system, in addition to indirectly regulating sugar, lipid, and energy metabolism, it also affects the desire to consume alcohol and sugar in humans or mice. Transgenic mice overexpressing FGF21 exhibit a series of metabolically related phenotypes, including slow growth rate, low blood glucose and triglyceride levels, resistance to type 2 diabetes with age, pancreatic islet hyperplasia and obesity. In rat or non-human primate models, animals exhibit changes such as normal restoration of blood glucose (level of blood glucose), reduced blood triglyceride and cholesterol levels, increased glucose tolerance and insulin sensitivity after injection of FGF21 fusion protein. At the same time, FGF21 increases the animal's activity level, metabolic rate and energy expenditure, and further reduces the animal's body weight and body fat. In a mouse model of non-alcoholic steatohepatitis, modified FGF21 protein improves the degree of hepatic steatosis, reduces liver damage and reduces molecular markers of inflammation in the liver. These studies indicate that FGF21 may be useful in treating metabolic-related diseases such as non-alcoholic steatohepatitis, type 2 diabetes, obesity and dyslipidemia.

[0006] Among FGF receptors, only FGFR1c, 2c, 3c and 4 can bind to Klotho, whereas FGFR1b, 2b and 3b cannot. In vitro experiments have shown that FGF21 activates FGFR1c, 2c and 3c receptors with the help of βKlotho. In vivo experiments have shown that the metabolic regulation action of FGF21 is mainly mediated by FGFR1c and βKlotho receptors, and knocking out FGFR1c or βKlotho significantly weakens the metabolic improvement action brought about by FGF21. Therefore, it is speculated that molecules that can mimic the action of FGF21 and activate FGFR1c and βKlotho receptors (e.g., activating βKlotho antibodies) may also be useful in the treatment of metabolic-related diseases such as non-alcoholic steatohepatitis.

[0007] At present, there are not many studies on antibodies targeting βKlotho. The ones that are progressing relatively quickly are Genentech's BFKB8488A (anti-FGFR1 / KLB bispecific antibody) in Phase II clinical trials, NGM Biopharmaceuticals' NGM313 (monoclonal stimulatory antibody) is also in Phase II clinical trials (all clinical trial indications are non-alcoholic steatohepatitis), and other companies' products, such as Amgen, Regeneron and Novartis, are all in the preclinical stage. All of the above drugs are in the early clinical stage, and the therapeutic effect is uncertain, so the market is calling for the use of antibody drugs against the above targets in various treatments. Summary of the Invention

[0008] According to a first aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3), and the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.2; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0009] (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.20 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.20; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO.26 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.26; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.27 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.27; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0010] (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.2; the sequence of HCDR3 is a sequence shown in SEQ ID NO.31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.31; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is the sequence shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 6; or (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0011] (7) The sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; and the sequence of LCDR2 is a sequence shown in SEQ the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (8) The sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; and the sequence of LCDR2 is a sequence shown in SEQ the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0012] (9) The sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.20 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.20; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; and the sequence of LCDR2 is a sequence shown in SEQ the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (10) The sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.31; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.42 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.42; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; Here, the sequences of the HCDRs and LCDRs are provided as defined by Kabat for an anti-βKlotho antibody or antigen-binding portion thereof.

[0013] According to a second aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof comprising a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3), and the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.8; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.10; the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO.16 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.16; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0014] (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 22 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 22; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 23; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO.28 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.28; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0015] (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.8; the sequence of HCDR3 is a sequence shown in SEQ ID NO.32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.32; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO.35 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.35; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0016] (7) the sequence of HCDR1 is a sequence shown in SEQ ID NO.39 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.39; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (8) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0017] (9) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 46 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 46; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 23; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (10) The sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.32; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; Herein, there is provided an anti-βKlotho antibody or antigen-binding portion thereof, wherein the HCDR and LCDR sequences are defined by IMGT.

[0018] According to a third aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region has an amino acid sequence set forth in SEQ ID NO. 12, 18, 24, 29, 33, 36, 41, 43, 47 or 49, or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to an amino acid sequence set forth in SEQ ID NO. 12, 18, 24, 29, 33, 36, 41, 43, 47 or 49; and / or the light chain variable region has an amino acid sequence set forth in SEQ ID NO. 13, 19, 25, 30, 37, 44 or 48, or an amino acid sequence which has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to an amino acid sequence set forth in SEQ ID NO. 13, 19, 25, 30, 37, 44 or 48; An anti-βKlotho antibody or an antigen-binding portion thereof is provided.

[0019] According to a fourth aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1, the sequence of HCDR2 is a sequence shown in SEQ ID NO.2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.2, and the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3, or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; or

[0020] (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.20 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.20; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO.26 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.26; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; or

[0021] (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.2; the sequence of HCDR3 is a sequence shown in SEQ ID NO.31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.31; or (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; or

[0022] (7) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.31; Here, the HCDR sequences are provided for an anti-βKlotho antibody or antigen-binding portion thereof as defined by Kabat.

[0023] According to a fifth aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof comprising a light chain variable region, the light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); (1) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.5 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.5; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.6; or (2) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.15 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.15; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.6; or

[0024] (3) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.21 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.21; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.6; or (4) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.27 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.27; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.6; or (5) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.34 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.34; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0025] (6) the sequence of LCDR1 is a sequence as shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence as shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence as shown in SEQ ID NO.42 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence as shown in SEQ ID NO.42; the sequence of LCDR3 is a sequence as shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence as shown in SEQ ID NO.6; or (7) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.45 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.45; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; Here, the LCDR sequences are provided for anti-βKlotho antibodies or antigen-binding portions thereof as defined by Kabat.

[0026] According to a sixth aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7, the sequence of HCDR2 is a sequence shown in SEQ ID NO.8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.8, and the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9, or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 16 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 16; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 17; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; or

[0027] (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 22 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 22; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 23; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO.28 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.28; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; or

[0028] (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.8; the sequence of HCDR3 is a sequence shown in SEQ ID NO.32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.32; or (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO.35 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.35; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; or (7) the sequence of HCDR1 is a sequence shown in SEQ ID NO.39 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.39; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; or (8) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; or

[0029] (9) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 46 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 46; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 23; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; or (10) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.32; Here, an anti-βKlotho antibody or antigen-binding portion thereof is provided, wherein the HCDR sequences are defined by IMGT.

[0030] According to a seventh aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof, comprising a light chain variable region, the light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); the sequence of LCDR1 is a sequence as shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO.10; the sequence of LCDR2 is a sequence as shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence as shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO.6; Herein, an anti-βKlotho antibody or an antigen-binding portion thereof is provided, wherein the LCDR sequence is defined by IMGT.

[0031] According to an eighth aspect, the present invention provides an isolated nucleic acid molecule encoding the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects. According to a ninth aspect, the present invention provides a vector comprising the nucleic acid molecule according to the eighth aspect. According to a tenth aspect, the present invention provides a host cell containing a nucleic acid molecule according to the eighth aspect or a vector according to the ninth aspect.

[0032] According to an eleventh aspect, the present invention provides an antibody-drug conjugate comprising an anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the embodiments of the first to seventh aspects, which is bound to a therapeutic agent. According to a twelfth aspect, the present invention provides a pharmaceutical composition comprising an anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects, or an antibody-drug conjugate according to the eleventh aspect, and a pharma- ceutical acceptable carrier.

[0033] According to a thirteenth aspect, the present invention relates to a use of an anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects, a nucleic acid molecule according to the eighth aspect, a vector according to the ninth aspect, a host cell according to the tenth aspect, or an antibody-drug conjugate according to the eleventh aspect, in the manufacture of a medicament for treating a disease mediated by βKlotho or mediated by βKlotho-FGFR1c-FGF21, wherein the disease is, for example, a metabolic disorder, such as type 1 diabetes, type 2 diabetes, dyslipidemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity.

[0034] According to a fourteenth aspect, the present invention provides a method for treating a disease in an individual mediated by βKlotho or mediated by βKlotho-FGFR1c-FGF21, comprising administering to the individual a therapeutically effective amount of an anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects, an antibody-drug conjugate according to the eleventh aspect, or a pharmaceutical composition according to the twelfth aspect, wherein the disease is, for example, a metabolic disorder, such as type 1 diabetes, type 2 diabetes, dyslipidemia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity.

[0035] According to a fifteenth aspect, the present invention provides a conjugate comprising the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects and a detectable marker. According to a sixteenth aspect, the present invention provides a fusion protein comprising the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects. [Brief description of the drawings]

[0036] [Figure 1] FIG. 1 shows the concentration profile of human or crab-eating monkey FGFR1c / βKlotho receptor upon activation with antibody CB-8-42, control antibody and FGF19 by reporter gene assay. [Diagram 2] FIG. 1 shows the results of monitoring the body weight of crab-eating monkeys treated with vehicle or antibody CB-8-42. [Diagram 3] FIG. 1 shows monitoring of relative body weight changes in crab-eating monkeys treated with vehicle or antibody CB-8-42. [Figure 4] FIG. 1 shows the results of monitoring the BMI of crab-eating monkeys treated with vehicle or antibody CB-8-42.

[0037] [Diagram 5] FIG. 1 shows the results of monitoring food intake in crab-eating monkeys treated with vehicle or antibody CB-8-42. [Figure 6] FIG. 1 shows the change in liver fat content in crab-eating monkeys before and after treatment with vehicle or antibody CB-8-42. [Figure 7] FIG. 1 shows the change in fasting blood glucose in crab-eating monkeys before and after treatment with vehicle or antibody CB-8-42. [Figure 8] FIG. 1 shows the change in serum insulin levels in crab-eating monkeys before and after treatment with vehicle or antibody CB-8-42.

[0038] [Figure 9] FIG. 1 shows the change in serum triglyceride levels in crab-eating monkeys before and after treatment with vehicle or antibody CB-8-42. [Figure 10] FIG. 1 shows the change in serum total cholesterol levels in crab-eating monkeys before and after treatment with vehicle or antibody CB-8-42. [Figure 11] FIG. 1 shows the changes in serum low density lipoprotein levels in crab-eating monkeys before and after treatment with vehicle or antibody CB-8-42. [Figure 12] FIG. 1 shows the changes in serum high density lipoprotein levels in crab-eating monkeys before and after treatment with vehicle or antibody CB-8-42. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] Detailed Description of the Invention [Definition] Unless otherwise specified, all scientific and technical terms used herein have the same meaning as those skilled in the art understand.For definitions and terms in the art, those skilled in the art can refer to Current Protocols in Molecular Biology (Ausubel), among others.Abbreviations of amino acid residues are the standard three-letter and / or one-letter codes used in the art, which refer to one of the 20 common L-amino acids.

[0040] Notwithstanding the numerical ranges and parameter approximations set forth in the broad scope of the invention, the numerical values ​​set forth in the specific examples are described as precisely as possible. However, any numerical value inherently contains a certain degree of error due to the standard deviation present in each measurement. In addition, all ranges disclosed herein should be understood to cover all subranges contained within the range. For example, the range "1-10" described should be considered to include any and all subranges between a minimum value of 1 and a maximum value of 10 (including the endpoints), i.e., all subranges starting from a minimum value of 1 or more, e.g., 1-6.1, and all subranges ending from a maximum value of 10 or less, e.g., 5.5-10. In addition, any reference referred to as "incorporated herein" should be understood to be incorporated in its entirety.

[0041] As used herein, the term "subject" or "individual" refers to a mammal, such as a human, but may also be other animals, such as wild, domestic, or laboratory animals (e.g., orangutans, monkeys, rats, mice, rabbits, guinea pigs, tarantulas, ground squirrels, etc.). As used herein, the term "antigen" refers to a predetermined target to which an antibody can selectively bind. Examples of antigens include, but are not limited to, polypeptides, sugars, nucleic acids, lipids, haptens, or other natural or synthetic compounds.

[0042] In a broad sense, an "antibody" can refer to an immunoglobulin molecule capable of specifically binding to a target via at least one antigen recognition site located in the variable region of the immunoglobulin molecule, and thus encompasses a complete antibody / full-length antibody, a single antibody chain, or any antigen-binding fragment of an antibody (also called an "antigen-binding portion"). When "antibody" and "antigen-binding fragment / portion" appear in the same context, "antibody" can be understood as being complete to "antigen-binding fragment / portion", and both commonly correspond to the broad antibody concept.

[0043] The term "βklotho" or "βklotho polypeptide" and similar terms as used herein include any polypeptide ("polypeptide" and "protein" are used interchangeably herein) from any vertebrate, including mammals such as primates (e.g., humans, cynos), dogs, and rodents (e.g., mice and rats), or any naturally occurring βklotho, and in some embodiments, includes related βklotho polypeptides, including SNP variants thereof, unless otherwise specified. βklotho contains two domains, βklotho1 (KLB1) and βklothoo2 (KLB2). Each βklotho domain contains a glycosyl hydrolase 1 region. For example, the KLB1 domain of human βklotho includes amino acid residues 1 to 508, and the glycosyl hydrolase 1 region includes amino acid residues 77 to 508, and the KLB2 domain of human βklotho includes amino acid residues 509 to 1044, and the glycosyl hydrolase 1 region includes amino acid residues 517 to 967. The amino acid sequence of human βklotho (NCBI Reference Sequence: NM_175737.4) is as follows:

[0044]

[0045] βklotho polypeptides further include allelic variants (e.g., SNP variants), splicing variants, fragments, derivatives, substitution, deletion and insertion variants, fusion polypeptides and interspecies homologues sufficient to maintain βklotho activity and / or generate an anti-βklotho immune response. Those skilled in the art should recognize that the anti-βklotho antibodies provided herein may bind to βklotho polypeptides, βklotho polypeptide fragments, βklotho antigens and / or βklotho epitopes. The epitopes may be part of a larger βklotho antigen, a larger βklotho polypeptide fragment, or even a larger βklotho polypeptide. βklotho can exist in native or denatured form. The βklotho polypeptides described herein can be isolated from a variety of sources, such as human tissue sources or other sources, or can be prepared by recombinant or synthetic methods. βklotho polypeptides can include polypeptides having the same amino acid sequence as the corresponding naturally occurring βklotho polypeptide. βklotho polypeptides include truncated or secreted forms of βklotho polypeptides (e.g., extracellular domain sequences), mutant forms of the polypeptides (e.g., alternative splice forms), and allelic variants. Orthologs of βklotho polypeptides are also well known in the art.

[0046] The term "fibroblast growth factor" refers to a family of growth factors that includes 22 members of the human FGF family. The FGF19 subfamily of fibroblast growth factors consists of human FGF21, FGF23 and FGF19, and mouse FGF15. The role of FGF family members is the result of heparin-dependent binding to one or more members of the FGF receptor tyrosine kinase (FGFR) family, which includes four members, each with a tyrosine kinase domain, namely FGFR1, FGFR2, FGFR3 and FGFR4, and two splice variants of each of FGFR1, FGFR2 and FGFR3. These splice variants occurring in exon 3 of FGFR1, FGFR2 and FGFR3 are designated "b" and "c" variants (e.g., FGFR1b, FGFR2b, FGFR3c, FGFR1c, FGFR2c and FGFR3c, which are also referred to as FGFR1(III)b, FGFR2(III)b, FGFR3(III)b, FGFR1(III)c, FGFR2(III)c and FGFR3(III)c, respectively).

[0047] The term "anti-βKlotho antibody" or "antibody that binds to βKlotho" includes an antibody that can bind to βKlotho with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent when targeting βKlotho. Preferably, the anti-βKlotho antibody binds to unrelated non-βKlotho proteins at a level of less than about 10% of the antibody's binding to βKlotho protein, as measured, for example, by fluorescence-activated cell sorting (FACS) analysis or immunoassay, for example, radioimmunoassay (RIA). As described above, an antibody that "specifically binds" to βKlotho or an antibody that is "specific" to βKlotho. In some embodiments, the dissociation constant (Kd) of the antibody described herein that binds to βklotho is 500nM, 100nM, 10nM, 9nM, 8nM, 7nM, 6nM, 5nM, 4nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM, or 0.1nM or less. In some embodiments, the anti-βklotho antibody binds to an epitope of βklotho that is conserved between βklotho from different species (e.g., between human and crab-eating monkey βklotho).

[0048] The term "agonist antibody" refers to an antibody that elicits a response, e.g., an antibody that mimics at least one functional activity of a target polypeptide (e.g., FGF19 or FGF21). Agonist antibodies include antibodies that are ligand mimetics, e.g., a ligand binds to a cell surface receptor, the binding of which induces cell signaling or activity through an intracellular cell signaling pathway, and an antibody induces similar cell signaling or activation.

[0049] A "full-length antibody (intact antibody)" refers to a protein that includes at least two heavy chains (H) and two light chains (L) linked together via disulfide bonds. Each heavy chain includes a heavy chain variable region (abbreviated as VH) and a heavy chain constant region. The heavy chain constant region includes three domains: CH1, CH2, and CH3. Each light chain includes a light chain variable region (abbreviated as VL) and a light chain constant region. The light chain constant region includes a domain CL. The VH and VL regions may be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with more conservative regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. These variable regions of the heavy and light chains include binding domains that interact with antigens. The constant region of an antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and the first component (Clq) of the classical complement system. A full-length antibody (intact antibody) can be any type of antibody, such as IgD, IgE, IgG, IgA, or IgM (or a subclass of the above), but an antibody need not belong to any particular class. Immunoglobulins can be assigned to different classes based on the antibody amino acid sequence of the constant domain of the heavy chain. There are usually five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and some of these classes can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different immunoglobulin classes are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are known. The antibody of the present invention also includes a chimeric antibody or a humanized antibody. Those skilled in the art know that the complementarity determining region (CDR, usually CDR1, CDR2 and CDR3) is the region that has the greatest influence on the affinity and specificity of the antibody in the variable region.The CDR amino acid sequence of VH or VL is defined by many common definition methods, such as the IMGT definition, the Chothia definition, and the Kabat definition. For a given antibody variable region amino acid sequence, the CDR amino acid sequence in the VH and VL amino acid sequence can usually be determined by various definition methods. In an embodiment of the present invention, the CDR amino acid sequence is defined using Kabat or IMGT. For a given antibody variable region amino acid sequence, the CDR amino acid sequence of the variable region amino acid sequence can be analyzed by various methods.

[0050] The term "mouse antibody" refers to an antibody obtained by fusing B cells and myeloma cells from an immunized mouse, screening the mouse hybrid cells that can grow indefinitely and secrete antibodies, and then screening, producing and purifying them; mouse antibodies are generally immunogenic and therefore must be humanized afterwards.

[0051] The term "humanized antibody" refers to an antibody obtained by grafting CDR sequences from other mammalian species, such as mouse, onto human framework sequences. Some residues in the framework (referred to as FR) section can be modified to maintain binding affinity. The humanized antibody or fragment thereof according to the present invention can be produced by techniques well known to those skilled in the art.

[0052] The term "chimeric antibody" refers to an antibody whose variable region sequence is derived from one species and whose constant region sequence is derived from another species, for example, whose variable region sequence is derived from a mouse antibody and whose constant region sequence is derived from a human antibody. The chimeric antibody or fragment thereof according to the present invention can be produced using recombinant gene technology. For example, said chimeric antibody can be produced by cloning a recombinant DNA comprising a promoter, a sequence encoding the variable region of a non-human (particularly mouse) monoclonal antibody according to the present invention, and a sequence encoding the constant region of a human antibody. The chimeric antibody according to the present invention encoded by such a recombinant gene is, for example, a mouse-human chimera, whose specificity is determined by the variable region derived from the mouse DNA and whose allotype is determined by the constant region derived from the human DNA.

[0053] The term "partially humanized antibody" refers to an antibody that comprises a constant region of human origin and a variable region (including the CDRs) of non-human (such as mouse) origin. The term "semi-humanized antibody" refers to a type of humanized antibody, one of whose antibody chains contains a mouse variable region and the other antibody chain contains a humanized variable region, i.e., a semi-humanized antibody. The term "monoclonal antibody" refers to an antibody obtained from a substantially homogenous population of antibodies, in which the individual antibodies comprising the population are identical except for the possible presence of naturally occurring mutations in a few individuals.

[0054] As used herein, the terms "antigen-binding fragment" or "antigen-binding portion" or "antigen-binding region" are used interchangeably and refer to a portion of an antibody that contains amino acid residues that interact with an antigen and confer specificity and affinity to the binding agent for the antigen, in particular antibody fragments such as Fv, Fab, F(ab')2 or Fab', or any fragment that may be chemically modified or incorporated into liposomes to extend its half-life, such as the addition of poly(alkylene) glycol ("polyethylene glycol", PEGylation) (PEGylated fragments of Fv-PEG, scFv-PEG, Fab-PEG, F(ab')2-PEG or Fab'-PEG) ("PEG": polyethylene glycol), and the fragments have βKlotho binding activity. Preferably, the functional fragment consists of or comprises a subsequence of the heavy or light variable chain of the antibody from which it is derived, which subsequence is sufficient to retain the same binding specificity and sufficient affinity as the antibody from which it is derived, and the functional fragment comprises at least 5 amino acids, preferably 10, 15, 25, 50 and 100 consecutive amino acids of the antibody sequence from which it is derived. Examples of antigen-binding fragments include, but are not limited to, (1) a Fab fragment, which may be a monovalent fragment having a VL-CL chain and a VH-CH1 chain, (2) a F(ab')2 fragment, which may be a bivalent fragment having two Fab' fragments linked by a disulfide bridge in the hinge region (i.e., a Fab' dimer), and (3) an Fv fragment of the VL and VH domains having a single arm of an antibody.

[0055] The term "single chain antibody (scFv)" refers to a single polypeptide chain in which a VH domain and a VL domain are linked via a peptide linker. (scFv)2 contains two VH domains linked via a peptide linker and two VL domains linked to the two VH domains via disulfide bridges.

[0056] The terms "Fc fragment", "Fc region", "Fc domain", "Fc portion", or similar terms refer to a portion of the antibody heavy chain constant region, including the hinge region, CH2 fragment and CH3 fragment of the constant region. The Fc region of the anti-βKlotho antibody can be engineered or modified, including modifications related to effector function, for example, to reduce or eliminate antibody-dependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC), which can be achieved by introducing one or more amino acid substitutions / mutations into the Fc region of the antibody.

[0057] As used herein, the term "specific binding" refers to a non-random binding reaction between two molecules, for example, the binding of an antibody to an antigen epitope. The term "polyantibody", also called a "multispecific antibody", is a molecule that has binding specificities for at least two different antigens; such molecules that bind only two antigens are also called dual antibodies (i.e., bispecific antibodies, BsAbs).

[0058] The term "bispecific antibody" refers to an antibody that has the ability to simultaneously bind to two different antigen epitopes. The two antigen epitopes may be on different antigens or on the same antigen. Bispecific antibodies may have multiple structural configurations. For example, bispecific antibodies may be composed of two Fc fragments and two antigen binding moieties fused thereto (similar to natural antibodies, except that the two arms bind to different antigen targets or epitopes), and the antigen binding moieties may be in the form of single chain antibodies (scfv) or in the form of Fab fragments.

[0059] Generally, for the preparation of monoclonal antibodies or functional fragments thereof, in particular of mouse-derived monoclonal antibodies or functional fragments thereof, reference can be made in particular to the techniques described in the manual "Antibodies" (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor NY, pp. 726, 1988) or the technique of production from hybridoma cells by Kohler and Milstein (Nature, 256: 495-497, 1975).

[0060] The term "conservative variant" or "conservative amino acid substitution" refers to a substitution that does not substantially affect or reduce the affinity of a protein, for example, the affinity of an antibody to βKlotho. For example, a human antibody that specifically binds to βKlotho may contain about 1 or less, about 2 or less, about 5 or less, about 10 or less, or about 15 or less conservative substitutions and specifically bind to βKlotho polypeptide. The term "conservative variant" also includes the use of substituted amino acids in place of unsubstituted parent amino acids, as long as the antibody specifically binds to βKlotho. Non-conservative substitutions reduce activity or bind to βKlotho.

[0061] The term "isolated" biological component (e.g., a nucleic acid, protein (including an antibody), or organelle) refers to one that has been substantially separated or purified from other biological components (i.e., other chromosomal and additional chromosomal DNA and RNA, proteins and organelles) in the naturally occurring environment (e.g., a cell) of that component. Nucleic acids and proteins that have already been "isolated" include those that have been purified by standard purification methods. The term also includes nucleic acids and proteins produced by recombinant expression in a host cell, as well as chemically synthesized nucleic acids.

[0062] The term "derived sequence" refers to a sequence that has at least 80% (preferably 85%, 90%, 95%, 98%, or 99%) sequence identity to the sequence to which it is related and has the same or a similar function.

[0063] The term "pharmaceutical composition" as used herein refers to a combination of at least one drug and a pharma- ceutical acceptable carrier or auxiliary substance that are combined together to achieve a particular purpose. In some embodiments, the pharmaceutical composition includes combinations that are separated in time and / or space, so long as they can act together to achieve the purpose of the invention. For example, the components included in the pharmaceutical composition (e.g., the antibody, nucleic acid molecule, combination of nucleic acid molecules, and / or conjugates according to the invention) may be administered to an individual all at once or separately. When the components included in the pharmaceutical composition are administered to an individual separately, the components may be administered to the individual simultaneously or sequentially. Preferably, the pharmaceutical carrier is water, a buffered aqueous solution, an isotonic salt solution such as PBS (phosphate buffer), glucose, mannitol, dextrorotatory glucose, lactose, starch, magnesium stearate, cellulose, magnesium carbonate, 0.3% glycerin, hyaluronic acid, ethanol, polyalkylene glycols such as polypropylene glycols and triglycerides, and the like. The type of pharmaceutical carrier used will depend, inter alia, on whether the composition of the present invention is formulated for oral, nasal, intradermal, subcutaneous, intramuscular or intravenous administration. The composition of the present invention may contain wetting agents, emulsifiers or buffer substances as additives. The pharmaceutical composition or pharmaceutical formulation of the present invention may be administered by any suitable route, such as oral, nasal, intradermal, subcutaneous, intramuscular or intravenous administration.

[0064] The term "therapeutically effective amount" or "effective amount" as used herein refers to a dose sufficient to show its benefit to the individual to whom it is administered. The actual amount administered, the rate and time course of administration depend on the condition and severity of the individual to be treated. The prescription for treatment (e.g., the determination of dosage, etc.) is ultimately the responsibility of specialists and other physicians, and is generally determined by considering the disease to be treated, the individual condition of the patient, the delivery site, the method of administration, and other factors known to physicians.

[0065] EC 50 The EC value primarily refers to the concentration of a corresponding drug, antibody, or toxin that can reach 50% of its maximum biological effect after a specific exposure time. In pharmacology, it is used to characterize the activation ability of an agonist in in vitro experiments, as well as to indicate the blood concentration required to reach half of the maximum biological effect in vivo. In some literature, the EC 50 It is also used to characterize the potency (including agonism and antagonism) of compounds at a cellular level, and EC 50 The levels can be measured by methods such as ELISA.

[0066] The term "fusion protein" as used herein, in a general context, refers to a protein that consists of at least two domains that are not naturally associated, but are encoded by separate genes that are linked and transcribed and translated as a whole to produce a single protein. In the technical background of the present invention, a "fusion protein" that includes an antibody or antigen-binding portion refers to a product that is obtained by fusing an antibody or antigen-binding portion with another biologically active protein using genetic engineering techniques, and such an antibody fusion protein combines the antigen-binding ability of an antibody with the unique biological properties of the biologically active protein fused to the antibody.

[0067] The term "identity / homology / matching" of an amino acid or nucleic acid sequence is defined as the percentage of identical residues in the amino acid or nucleotide sequence variants after sequence alignment and capping, if necessary, to reach a maximum percentage of identity. Methods and computer programs for alignment are known to those skilled in the art.

[0068] According to a first aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3), and the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.2; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0069] (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.20 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.20; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO.26 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.26; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.27 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.27; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0070] (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.2; the sequence of HCDR3 is a sequence shown in SEQ ID NO.31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.31; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0071] (7) The sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; and the sequence of LCDR2 is a sequence shown in SEQ the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (8) The sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; and the sequence of LCDR2 is a sequence shown in SEQ the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0072] (9) The sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.20 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.20; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; and the sequence of LCDR2 is a sequence shown in SEQ the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (10) The sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.31; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.42 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.42; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; Here, the sequences of the HCDRs and LCDRs are provided as defined by Kabat for an anti-βKlotho antibody or antigen-binding portion thereof.

[0073] According to a second aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof comprising a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3), and the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.8; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.10; the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO.16 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.16; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0074] (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 22 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 22; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 23; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO.28 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.28; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0075] (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.8; the sequence of HCDR3 is a sequence shown in SEQ ID NO.32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.32; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO.35 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.35; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0076] (7) the sequence of HCDR1 is a sequence shown in SEQ ID NO.39 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.39; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (8) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or

[0077] (9) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 46 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 46; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 23; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (10) The sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.32; and the sequence of LCDR1 is a sequence shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; Herein, there is provided an anti-βKlotho antibody or antigen-binding portion thereof, wherein the HCDR and LCDR sequences are defined by IMGT.

[0078] In some embodiments of the first and second aspects, the heavy chain variable region has an amino acid sequence set forth in SEQ ID NO.12, 18, 24, 29, 33, 36, 41, 43, 47 or 49, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to the amino acid sequence set forth in SEQ ID NO.12, 18, 24, 29, 33, 36, 41, 43, 47 or 49.

[0079] In some embodiments of the first and second aspects, the light chain variable region has an amino acid sequence set forth in SEQ ID NO.13, 19, 25, 30, 37, 44 or 48, or an amino acid sequence that has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to an amino acid sequence set forth in SEQ ID NO.13, 19, 25, 30, 37, 44 or 48.

[0080] In some embodiments of the first and second aspects, (1) the heavy chain variable region sequence is the sequence shown in SEQ ID NO.12 and the light chain variable region sequence is the sequence shown in SEQ ID NO.13; or (2) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 18 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 19; or (3) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 24 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 25; or (4) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 29 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 30; or

[0081] (5) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 33 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 13; or (6) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 36 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 37; or (7) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 41 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 30; or

[0082] (8) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 43 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 44; or (9) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 47 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 48; or (10) The heavy chain variable region sequence is the sequence shown in SEQ ID NO. 49, and the light chain variable region sequence is the sequence shown in SEQ ID NO. 44.

[0083] According to a third aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region has an amino acid sequence set forth in SEQ ID NO. 12, 18, 24, 29, 33, 36, 41, 43, 47 or 49, or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to an amino acid sequence set forth in SEQ ID NO. 12, 18, 24, 29, 33, 36, 41, 43, 47 or 49; and / or the light chain variable region has an amino acid sequence set forth in SEQ ID NO. 13, 19, 25, 30, 37, 44 or 48, or an amino acid sequence which has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to an amino acid sequence set forth in SEQ ID NO. 13, 19, 25, 30, 37, 44 or 48; An anti-βKlotho antibody or an antigen-binding portion thereof is provided.

[0084] According to a fourth aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1, the sequence of HCDR2 is a sequence shown in SEQ ID NO.2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.2, and the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3, or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; or

[0085] (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.20 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.20; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO.26 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.26; the sequence of HCDR2 is a sequence shown in SEQ ID NO.14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.14; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; or

[0086] (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.2; the sequence of HCDR3 is a sequence shown in SEQ ID NO.31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.31; or (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3; or

[0087] (7) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1; the sequence of HCDR2 is a sequence shown in SEQ ID NO.38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.38; the sequence of HCDR3 is a sequence shown in SEQ ID NO.31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.31; Here, the HCDR sequences are provided for an anti-βKlotho antibody or antigen-binding portion thereof as defined by Kabat.

[0088] According to a fifth aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof comprising a light chain variable region, the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); (1) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.5 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.5; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.6; or (2) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.15 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.15; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.6; or

[0089] (3) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.21 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.21; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.6; or (4) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.27 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.27; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence shown in SEQ ID NO.6; or

[0090] (5) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.34 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.34; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; or (6) the sequence of LCDR1 is a sequence as shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence as shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence as shown in SEQ ID NO.42 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence as shown in SEQ ID NO.42; the sequence of LCDR3 is a sequence as shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the sequence as shown in SEQ ID NO.6; or

[0091] (7) the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.4; the sequence of LCDR2 is a sequence shown in SEQ ID NO.45 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.45; the sequence of LCDR3 is a sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6; Here, the LCDR sequences are provided for anti-βKlotho antibodies or antigen-binding portions thereof as defined by Kabat.

[0092] According to a sixth aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7, the sequence of HCDR2 is a sequence shown in SEQ ID NO.8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.8, and the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9, or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 16 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 16; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 17; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; or

[0093] (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 22 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 22; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 23; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO.28 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.28; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; or

[0094] (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.8; the sequence of HCDR3 is a sequence shown in SEQ ID NO.32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.32; or (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO.35 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.35; the sequence of HCDR2 is a sequence shown in SEQ ID NO.17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.17; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; or

[0095] (7) the sequence of HCDR1 is a sequence shown in SEQ ID NO.39 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.39; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; or (8) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.9; or

[0096] (9) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 46 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 46; the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 23; the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; or (10) the sequence of HCDR1 is a sequence shown in SEQ ID NO.7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.7; the sequence of HCDR2 is a sequence shown in SEQ ID NO.40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.40; the sequence of HCDR3 is a sequence shown in SEQ ID NO.32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.32; Here, an anti-βKlotho antibody or antigen-binding portion thereof is provided, wherein the HCDR sequences are defined by IMGT.

[0097] According to a seventh aspect, the present invention provides an anti-βKlotho antibody or an antigen-binding portion thereof comprising a light chain variable region, the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); the sequence of LCDR1 is a sequence as shown in SEQ ID NO.10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO.10; the sequence of LCDR2 is a sequence as shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO.11; the sequence of LCDR3 is a sequence as shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO.6; Herein, an anti-βKlotho antibody or an antigen-binding portion thereof is provided, wherein the LCDR sequence is defined by IMGT.

[0098] In some embodiments of the first to seventh aspects, the anti-βKlotho antibody or antigen-binding portion thereof binds to human βKlotho. In some specific embodiments, the anti-βKlotho antibody or antigen-binding portion thereof specifically binds to human βKlotho. In some embodiments of the first to seventh aspects, the anti-βKlotho antibody is a complete antibody, a single chain antibody (scFv), a bispecific antibody, or a multispecific antibody. In some embodiments of the first to seventh aspects, the antigen-binding portion of the anti-βKlotho antibody is Fab, Fab', Fv, or F(ab')2.

[0099] In some embodiments of the first to seventh aspects, the anti-βKlotho antibody is a mouse antibody, a chimeric antibody, a humanized antibody, or a fully human antibody. In some embodiments of the first to seventh aspects, the anti-βKlotho antibody is a monoclonal antibody. In some embodiments of the first to seventh aspects, the anti-Klotho antibody is an IgM, IgD, IgG, IgA or IgE type antibody. In some specific embodiments, the anti-Klotho antibody is an IgG antibody. In some more specific embodiments, the anti-Klotho antibody is an IgG1 antibody.

[0100] In some embodiments of the first to seventh aspects, the anti-βKlotho antibody is of the IgG1, IgG2, or IgG4 isotype. In some embodiments of the first to seventh aspects, the anti-βKlotho antibody is of the IgG1 / IgG4, IgG2 / IgG4 or IgG1 / IgG2 chimeric type. In some embodiments of the first to seventh aspects, the anti-βKlotho antibody comprises a light chain constant region of the κ or λ subtype.

[0101] In some embodiments of the first to seventh aspects, the anti-βKlotho antibody comprises a human IgG1 heavy chain constant region and a human κ light chain constant region. In some embodiments of the first to seventh aspects, the anti-βKlotho antibody or antigen-binding portion thereof is used in medical treatment. In some embodiments of the first to seventh aspects, the anti-βKlotho antibody or antigen-binding portion thereof has ADCC activity or CDC activity.

[0102] In some embodiments of the first to seventh aspects, the anti-βKlotho antibody comprises a wild-type Fc region. In some embodiments of the first to seventh aspects, the anti-βKlotho antibody or antigen-binding portion thereof has enhanced ADCC activity or CDC activity due to engineering modification. In some embodiments of the first to seventh aspects, the anti-βKlotho antibody or antigen-binding portion thereof has reduced ADCC activity or CDC activity due to engineering modification.

[0103] For the in vivo application of the target βKlotho and antibody of the present invention, an antibody with reduced or even eliminated ADCC or CDC activity may be advantageous, because too strong Fc effect may affect or even weaken the efficacy of the antibody. Means for reducing or removing Fc effect are known in the art, and include, for example, 1) antibody modification of amino acid residues (mainly weakening binding to related receptors), 2) glycosylation modification, 3) IgG4 type antibody modification, etc. In some embodiments of the first to seventh aspects, the anti-βKlotho antibody has a heavy chain variable region represented by SEQ ID NO.49, a light chain variable region represented by SEQ ID NO.44, a heavy chain constant region represented by SEQ ID NO.50, and a light chain constant region represented by SEQ ID NO.51.

[0104] According to an eighth aspect, the present invention provides an isolated nucleic acid molecule encoding the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects. In some embodiments of the first to fifth aspects, the antibody or antigen-binding portion thereof according to the invention may be a chimeric antibody or a humanized antibody, including a semi-humanized antibody, a partially humanized antibody or a fully human antibody. In some embodiments, the polynucleotide is operably linked to a regulatory sequence, which is recognizable in a host cell transformed with the vector.

[0105] According to a ninth aspect, the present invention provides a vector (eg an expression vector) comprising a combination of nucleic acid molecules or polynucleotides according to the eighth aspect. In some embodiments, an expression vector according to the invention comprises a nucleic acid molecule according to the invention or a combination of polynucleotides according to the invention, said polynucleotides being operatively linked to regulatory sequences that allow the polypeptides encoded thereby to be expressed in a host cell or a cell-free expression system. The choice of expression vector will depend on the choice of host cell and may be selected to have the desired expression and regulatory characteristics in the chosen host cell.

[0106] An "expression vector" is a vector that contains one or more expression control sequences; an "expression control sequence" is a DNA sequence that controls and regulates the transcription and / or translation of other DNA sequences. The nucleic acid in the vector may be operably linked to one or more expression control sequences. As used herein, "operably linked" refers to an expression control sequence incorporated into a genetic construct such that it effectively controls the expression of a coding sequence of interest. Examples of expression control sequences include promoters, enhancers, and transcription termination regions. A promoter is an expression control sequence consisting of a region of a DNA molecule that is 100 nucleotides upstream of the transcription start point (usually near the start site of RNA polymerase II). To place a coding sequence under the control of a promoter, the translation start site of a polypeptide translation reading frame must be located between 1 and about 50 nucleotides downstream of the promoter. Enhancers provide expression specificity in terms of time, position, and level. Unlike promoters, enhancers can function at different distances from the transcription site. Enhancers may be located downstream of the transcription start site. A coding sequence is "operably linked" to and "under the control" of an expression control sequence in a cell if RNA polymerase can transcribe the coding sequence into mRNA, which can then be translated into the protein encoded by the coding sequence.

[0107] Suitable expression vectors include, but are not limited to, plasmids and viral vectors derived from, for example, phage, baculovirus, tobacco mosaic virus, herpes virus, cytomegalovirus, retrovirus, vaccinia virus, adenovirus and adeno-associated virus. Many vectors and expression systems are commercially available from companies such as Novagen (Madison, WI), Clontech (Palo Alto, CA), Stratagene (LaJolla, CA) and Invitrogen Life Technologies (Carlsbad, CA).

[0108] The expression vector may contain a tag sequence. The tag sequence is usually expressed as a fusion with the encoded polypeptide. Such tags may be inserted at any position within the polypeptide, including the carboxyl or amino terminus. Examples of useful tags include, but are not limited to, Fc fragment, polyhistidine, green fluorescent protein (GFP), glutathione S-transferase (GST), c-myc, hemagglutinin, FlagTM tag (Kodak, New Haven, CT), maltose E binding protein, and protein A. In some embodiments, the nucleic acid molecule encoding the βKlotho fusion polypeptide is present in a vector that contains a nucleic acid encoding one or more domains of the Ig heavy chain constant region, the domains corresponding to, for example, the amino acid sequences of the hinge region, CH2 region, and CH3 region of the human immunoglobulin Cγ1 chain (Fc fragment).

[0109] According to a tenth aspect, the present invention provides a host cell containing a nucleic acid molecule according to the eighth aspect or a vector according to the ninth aspect. In some embodiments, the host cell may be a prokaryotic host cell, a eukaryotic host cell or a phage. The prokaryotic host cell may be Escherichia coli, Bacillus subtilis, Streptomyces or Proteus mirabilis. The eukaryotic host cell may be, for example, Pichia pastoris, Saccharomyces cerevisiae, Schizosaccharomyces pombe, fungi such as Trichoderma, insect cells such as Fallopia or plant cells such as tobacco, or mammalian cells such as BHK cells, CHO cells, COS cells, myeloma cells, etc. In some embodiments, the host cell is preferably a mammalian cell, more preferably a BHK cell, a CHO cell, an NSO cell or a COS cell.

[0110] According to an eleventh aspect, the present invention provides an antibody-drug conjugate (also called an antibody-drug conjugate) comprising an anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the embodiments of the first to seventh aspects, which is bound to a therapeutic agent.

[0111] According to a twelfth aspect, the present invention provides a pharmaceutical composition comprising an anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects, or an antibody-drug conjugate according to the eleventh aspect, and a pharma- ceutical acceptable carrier. In some embodiments, the pharmaceutical composition is used to treat diseases mediated by βKlotho or βKlotho-FGFR1c-FGF21 (e.g., diseases that require mimicking or enhancing the in vivo action of FGF19 and / or FGF21). In some embodiments, the disease is a metabolic disorder, including but not limited to type 1 diabetes, type 2 diabetes, dyslipidemia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity.

[0112] In some embodiments, the pharmaceutical composition may further comprise one or more of a lubricant (e.g., talc, magnesium stearate, mineral oil, etc.), a wetting agent, an emulsifying agent, a suspending agent, a benzoic acid, a preservative (e.g., sorbic acid, calcium propionate, etc.), a sweetener enhancer, and / or a flavoring agent, etc. In some embodiments, the pharmaceutical composition of the present invention may be prepared in the form of a tablet, pill, powder, lozenge, elixir, suspension, emulsion, solution, syrup, suppository, capsule, etc.

[0113] In some embodiments, the pharmaceutical compositions of the present invention may be delivered using any physiologically acceptable method of administration, including, but not limited to, oral administration, parenteral administration, nasal administration, rectal administration, intraperitoneal administration, intravascular injection, subcutaneous administration, transdermal administration, inhalation administration, and the like. In some embodiments, pharmaceutical compositions for therapeutic purposes can be prepared and stored in the form of lyophilized formulations or aqueous solutions by mixing reagents having the desired purity and, optionally, pharma- ceutically acceptable carriers, excipients, etc.

[0114] According to a thirteenth aspect, the present invention provides use of an anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects, a nucleic acid molecule according to the eighth aspect, a vector according to the ninth aspect, a host cell according to the tenth aspect, or an antibody-drug conjugate according to the eleventh aspect, in the manufacture of a medicament for treating a disease mediated by βKlotho or mediated by βKlotho-FGFR1c-FGF21 (e.g., a disease requiring mimicking or enhancing the in vivo action of FGF19 and / or FGF21). In some embodiments, the disease is a metabolic disease, including but not limited to type 1 diabetes, type 2 diabetes, dyslipidemia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity.

[0115] According to a fourteenth aspect, the present invention provides a method for treating a disease mediated by βKlotho or mediated by βKlotho-FGFR1c-FGF21 in an individual (e.g., a disease in which the in vivo action of FGF19 and / or FGF21 needs to be mimicked or enhanced), comprising administering to the individual a therapeutically effective amount of an anti-βKlotho antibody or antigen-binding portion thereof according to the first to seventh aspects, an antibody-drug conjugate according to the eleventh aspect, or a pharmaceutical composition according to the twelfth aspect. In some embodiments, the disease is a metabolic disorder, including, but not limited to, type 1 diabetes, type 2 diabetes, dyslipidemia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, obesity, or broadly any disease, disorder, or condition in which the in vivo action of FGF19 and / or FGF21 needs to be mimicked or enhanced. In some embodiments of the method of treating or preventing a disease, disorder, or condition, the method comprises exposing a cell to an anti-βKlotho antibody in vitro.

[0116] In some embodiments of the twelfth to fourteenth aspects, the anti-βKlotho antibody or antigen-binding portion thereof according to the present invention can be used alone or in combination with other compositions in therapy. For example, the anti-βKlotho antibody can be administered with at least one additional therapeutic agent and / or adjuvant. In some embodiments, the additional compound is a therapeutic antibody other than the anti-βKlotho antibody, which includes, but is not limited to, a drug for the treatment of diabetes, dyslipidemia, NASH, NAFLD, cardiovascular disease, metabolic syndrome, or obesity, such as biguanides, sulfonylureas, thiazolidinediones, GLP-1 analogs, PPARγ agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, bromocriptine preparations, bile acid sequestrants, insulin, α-glucosidase inhibitors, SGLT-2 inhibitors, appetite suppressants, and weight loss drugs, anti-inflammatory drugs (e.g., aspirin, ibuprofen), etc.

[0117] According to a fifteenth aspect, the present invention provides a conjugate comprising the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects and a detectable marker. The detectable marker is, for example, a detectable fluorescent marker, a chemiluminescent marker, an isotopic marker, or the like.

[0118] According to a sixteenth aspect, the present invention provides a fusion protein comprising the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of the first to seventh aspects. Examples of the antibody fusion protein include Fab fusion proteins, Fc fusion proteins, and single-chain antibody (scFv) fusion proteins, which are named according to the site to which an effector protein (e.g., a cellular factor) is fused.

[0119] In some embodiments of the fifteenth or sixteenth aspect, the conjugate can be formed by synthesizing the anti-βKlotho antibody of the present invention covalently linked to a linker and one or more non-antibody agents. In some embodiments, the antibody of the present invention is conjugated or recombinantly fused to a diagnostic, detection or therapeutic agent, or any other molecule. The conjugated or recombinantly fused antibody can be used, for example, to monitor or predict the onset, development, progression and / or severity of βKlotho-mediated disease as part of a clinical trial method, for example, to determine the effectiveness of a particular treatment. Such diagnosis and detection can be achieved, for example, by binding the antibody to a detectable marker. Detectable markers include, but are not limited to, enzymes, prosthetic groups, fluorescent markers, chemiluminescent markers, isotopic markers, and the like. In some embodiments, the antibody of the present invention can be conjugated or recombinantly fused to a therapeutic or drug moiety that modifies a particular biological response (here also may be an antibody-drug conjugate as described in the eleventh aspect). The therapeutic or drug moiety is not limited to a typical chemotherapeutic agent. For example, the drug moiety may be a protein, peptide, polypeptide, small molecule toxin, etc. possessing a desired biological activity.

[0120] It should be understood that the above detailed description is intended only to allow those skilled in the art to more clearly understand the present invention, but is not intended to limit any aspect. Those skilled in the art may make various modifications and changes to the above embodiments. EXAMPLES

[0121] It should be noted that the above detailed description is merely intended to enable those skilled in the art to more clearly understand the contents of the present invention, and is not intended to limit the present invention in any manner. Those skilled in the art may make various changes and modifications to the embodiments. EXAMPLES

[0122] Phage display-based antibody discovery To obtain an antibody that specifically binds to human βKlotho, the present inventors carried out a phage display work based on a natural single-chain antibody phage library of human origin.

[0123] First, human βKlotho extracellular domain protein (R&D systems, 5889-KB-050) was biotinylated and used for liquid-phase panning. Then, a human-derived natural single-chain antibody phage display bank (Shanghai Ruizhi Chemical Research Co., Ltd.) was used to screen for ProX-specific antibodies. For each round of panning, the library was first incubated with Dynabeads streptavidin magnetic beads to remove non-specific binders from the Dynabeads magnetic beads. Then, the library was panned with biotinylated human βKlotho extracellular domain protein to enrich for human βKlotho-specific phage antibodies. Non-specific phage antibodies were removed by multiple washes, and phage antibodies that specifically bind to human βKlotho were recovered by elution with trypsin or a known βKlotho antibody (Tab hIgG1 antibody: its sequence is derived from 5H23 described in NGM patent CN201580016315.8). The eluted phages were infected into E. coli TG1 to generate libraries for the next round with the help of helper phage M13KO7 (New Engiand BioLabs. Inc.). Usually, each round of panning includes negative selection, positive selection, washing, elution, and amplification. After each round of panning, based on the results of sequencing, if most of the output clones are non-overlapping single clones, panning continues for up to three rounds. Otherwise, if the proportion of repetitive sequences is high, panning ends at this round. The output phages from each round are kept for subsequent use.

[0124] Monoclonals were selected from the panned library and grown overnight in 2YT medium containing 100 μg / mL ampicillin and 2% glucose. The overnight cultured monoclonals were transferred to 2YT medium containing 100 μg / mL ampicillin. Expression of scFv was induced by culturing at 30°C for 16 hours with a final concentration of 1 mM IPTG. The bacterial solution was centrifuged to collect the supernatant, and positive clones were screened as follows.

[0125] Binding ELISA: 100 μL of 1 μg / mL streptavidin was added to a 96-well plate and coated overnight at 4°C. After blocking at room temperature, 50 μL of 0.5 μg / mL biotinylated human βKlotho extracellular domain protein was added and incubated at room temperature. After washing, 60 μL of blocking solution was added and incubated at room temperature. Then, 40 μL of scFv supernatant was added and incubated at room temperature, and Tab hIgG1 antibody and hIgG1 isotype control were added to the control wells at a final concentration of 1 μg / mL, respectively. After washing, anti-Myc-HRP and anti-hIgG-Fc-specific-HRP were added and incubated at room temperature, and after washing, 100 μL of 3,3',5,5'-tetramethylbenzidine (TMB) substrate solution was added and incubated at room temperature for 15 minutes in the dark, and 100 μL of 1M HCl was added to stop the reaction, and the absorbance at 450 nm was read.

[0126] Competitive ELISA: 100 μL of 1 μg / mL streptavidin was added to a 96-well plate and coated overnight at 4°C. After blocking at room temperature, 50 μL of 0.5 μg / mL biotinylated human βKlotho extracellular domain protein was added and incubated at room temperature. After washing, 60 μL of 3 μg / mL Tab hIgG1 was added and incubated at room temperature (Tab hIgG1 and hIgG1 isotype antibody control wells were blocking solution). Then, 40 μL of scFv supernatant was added, and Tab hIgG1 and hIgG1 isotype antibodies were added to the control wells at a final concentration of 1 μg / mL, respectively, and incubated at room temperature. After washing, anti-Myc-HRP and anti-hIgG-Fc-specific-HRP were added and incubated at room temperature, and after washing, 100 μL of TMB was added and incubated at room temperature for 15 minutes in the dark, and 100 μL of 1M HCl was added to stop the reaction, and the absorbance at 450 nm was read.

[0127] In analyzing the results, the OD in the binding ELISA 450 >0.4 and OD 450 (combined ELISA) / OD 450 If the condition of OD ≥ 2 (competitive ELISA) is satisfied, the antibody clone is considered to be capable of specifically binding to human βKlotho and has an antigen-binding epitope similar or identical to that of the Tab hIgG1 antibody. In addition, if the condition of OD ≥ 2 is satisfied, the antibody clone is considered to be capable of specifically binding to human βKlotho and has an antigen-binding epitope similar or identical to that of the Tab hIgG1 antibody. 450 >0.4 and OD 450 (combined ELISA) / OD 450If the condition of (competitive ELISA) ratio <2 is satisfied, it is considered to be an antibody clone that binds to an epitope different from that of Tab hIgG1 antibody. Antibody clones similar or identical to the Tab hIgG1 antibody binding epitope and clones with different partial epitopes were selected and sequenced, and finally 22 variable region sequences of human βKlotho binding antibodies were obtained, which were named CB-1, CB-2, CB-4, CB-5, CB-6, CB-8, CB-9, CB-10, CB-11, CB-14, CB-16, CB-17, CB-18, CB-19, CB-21, CB-22, CB-23, CB-24, CB-25, CB-26, CB-27, and CB-28. Then, using the human heavy chain IgG1 constant region and the human light chain λ or κ constant region, full-length antibodies containing the above antibody variable regions were prepared. EXAMPLES

[0128] Screening for antibodies that activate human or monkey FGFR1c / βKlotho receptors by reporter assay Based on the reporter gene assay, whether the full-length antibody described in Example 1 can activate human FGFR1c / βKlotho receptor was measured. In this method, the principle that human FGFR1c / βKlotho receptor is activated by FGF19 or antibody in stable transgenic cell line, then promotes the transmission of downstream signaling pathway, causes ERK phosphorylation, and further causes Gal4-Elk1 phosphorylation, binds to the USA promoter region on DNA, and then initiates the transcription of luciferase reporter gene was utilized, and the activation effect of FGF19 or antibody on FGFR1c / βKlotho receptor was measured by measuring luciferase level.

[0129] The following method was used to construct a stable transfected cell line with a reporter gene. First, two reporter plasmids, Gal4-Elk1 and 5xUAS-Luc, were introduced into rat L6 cells, and after screening with antibiotics, a cell line stably expressing the target molecule was obtained. Then, a plasmid encoding human FGFR1c and βKlotho genes or crab-eating monkey FGFR1c and βKlotho genes was further transfected, and after several rounds of antibiotic pressure screening, an FGFR1c / βKlotho / Gal4-Elk1 / Luc stable transfected cell line was obtained.

[0130] The function of the antibody on activating human FGFR1c / βKlotho receptor was measured using the following method. 40 μL of a solution containing 3 times the final concentration of antibody or FGF19 was added to a 96-well plate, and then 80 μL of the above stable transformed cells with appropriate density was added to mix with the antibody, and incubated overnight in an incubator at 37°C, 5% CO2 air and saturated humidity. The next day, the luciferase level in the cells was detected using the One-Glo (Promega) kit. The data measuring antibody activation of human or monkey FGFR1c / βKlotho receptor function are shown in the table below.

[0131] [Table 1]

[0132] As shown in the results in Table 1, some of the anti-human βKlotho antibodies obtained by the phage display technology screening according to the present invention have an activating effect on human and / or crab-eating monkey βKlotho / FGFR1c. EXAMPLES

[0133] Detection of antibody binding to human βKlotho, human αKlotho and mouse βKlotho by ELISA In this example, the ELISA method was used to detect the binding of some of the antibodies in Example 1 with human βKlotho, human αKlotho, and mouse βKlotho. During the detection, a specific concentration of extracellular domain protein solution of human βKlotho (R&D Systems), human αKlotho (R&D Systems), or mouse βKlotho (R&D Systems) was added to a nickel-coated 96-well plate (Pierce) and incubated at room temperature overnight. The next day, after blocking the plate with PBS / 1% BSA, different concentrations of antibodies were added to the reaction wells and incubated at room temperature for 1.5 hours, and then HRP-labeled anti-human anti-human IgG Fab secondary antibody was added to the reaction wells and further incubated at room temperature for 30 minutes. After adding the substrate and reacting at room temperature for 15 minutes, a stop solution was added to measure the OD 450 The values ​​were read. For the ELISA assay, exemplary data regarding the binding of human βKlotho, human αKlotho, and mouse βKlotho to the antibodies are as follows:

[0134] [Table 2]

[0135] As shown in the data in Table 2, the anti-human βKlotho antibodies CB-1, CB-6, CB-8, CB-10, CB-16, CB-23, and CB-28 of the present invention can all specifically bind to human βKlotho, while CB-1, CB-6, CB-8, and CB-10 do not bind to human αKlotho and have high selective specificity for human-derived βKlotho protein. Furthermore, the partial antibody of the present invention (e.g., CB-10) can also bind to mouse βKlotho. EXAMPLES

[0136] Antibody Biacore affinity measurements The binding affinity of four antibodies, CB-1, CB-6, CB-8, and CB-10, was measured based on the Biacore affinity assay. The binding strength of the purified antibodies to human βKlotho was evaluated by measuring the equilibrium dissociation constant (KD) of the antibodies. Specifically, anti-His tag antibodies were immobilized on the flow cell of a CM5 chip using a His capture agent. Human βKlotho extracellular domain protein (~80 RU) was captured on the flow cell. The purified antibodies (in HEPES buffer containing 0.005% Tween 20) were then injected at a flow rate of 30 L / min, and the binding kinetics (binding kinetics) at 25°C were evaluated. The results are as follows.

[0137] [Table 3]

[0138] As shown by the data in Table 3, the anti-human βKlotho antibodies according to the present invention, for example, CB-1, CB-6, CB-8, and CB-10, have strong binding affinity to human βKlotho. EXAMPLES

[0139] Modification of antibody affinity maturation Using the phage display method, affinity maturation modification of the anti-human βKlotho antibody of the present invention was carried out. The affinity maturation method is explained below using CB-8 as an example. The gene sequences of the variable regions of the CB-8 antibody were constructed in phage plasmid vectors, and the vectors were used as templates to construct the following four saturation mutation libraries. 1) a saturation mutation library of single point mutation combinations containing one randomly mutated amino acid in each of the light chain CDR1, light chain CDR3, and heavy chain CDR3; 2) a saturation mutation library of single point mutation combinations containing one randomly mutated amino acid in each of the light chain CDR2, heavy chain CDR1, and heavy chain CDR2; 3) a saturation mutation library of two-point mutation combinations of random mutations of two adjacent amino acids in the light chain CDR3; 4) A saturation mutation library of a combination of two randomly mutated amino acids adjacent to each other in the heavy chain CDR3. The plasmids of these four saturation mutation libraries were constructed as phage libraries that met the library capacity requirements, and the diversity of the phage libraries was determined by sequencing.

[0140] The phages from the above library were panned using human βKlotho extracellular domain protein (Kactus Biosystems Co., Ltd.). The human βKlotho extracellular domain protein was coated on an immunotube, and then blocked with 5% milk-PBS blocking solution. A certain concentration of phages was added to the immunotube and incubated at room temperature for 2 hours. The immunotube was washed multiple times with PBST, and then washed three more times with PBS. Finally, the phages bound to the human βKlotho extracellular domain protein were eluted with 0.25% trypsin and collected. The collected phages were infected into E. coli SS320, and the phages were amplified. The amplified phages were collected and panned again as described above. A total of three rounds of panning were performed.

[0141] Monoclonals were selected and amplified from the panned library, and positive clones that bind to human βKlotho protein were screened using ELISA, and the sequences of the positive clones were determined. The method for measuring the binding of phages to human βKlotho protein by ELISA was as follows. Human βKlotho protein was coated on a 96-well plate, and then blocked with 5% milk PBS blocking solution. After adding the phage supernatant, it was incubated at room temperature for 1 hour, and the plate was washed with PBST, and then HRP-labeled anti-M13 antibody was added and incubated for 1 hour. After multiple washes, TMB substrate solution was added and incubated at room temperature for 5 to 10 minutes, and finally 2M H2SO4 was added to stop the reaction, and the absorbance at 450 nm was read. The titer of the positive clones was measured, and then ELISA was used to detect the binding of different titers of phages to human βKlotho protein. The affinity of the positive antibodies was ranked according to the fitted binding curve. Based on the ranking results, the top 8 antibody variable region sequences of each antibody binding ability were selected (sequences are shown in the table below).

[0142] Eight CB-8 antibody-derived antibody variable region sequences and the original CB-8 sequence were prepared as full-length antibodies using human heavy chain IgG1 constant regions and human light chain kappa constant regions. The CDR and variable region sequences of the relevant sequences according to the invention are as follows: [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0143] The above antibodies were subjected to affinity measurement using Gator (Gator bio). Briefly, the antibodies were first captured using a Protein A-coated probe (Gator bio), and the baseline was monitored for 60 seconds. After that, the binding between the antibodies and the antigen was measured at different concentrations (400 nM to 50 nM) of the above human βKlotho extracellular domain protein, and then dissociation was detected in K buffer (Gator bio). At the same time, the function of the antibodies to activate the FGFR1c / βKlotho receptor in humans or crab-eating monkeys was detected by the reporter gene assay described in Example 2. The results are shown in Table 5.

[0144] [Table 5]

[0145] As shown in Table 5, the affinity maturation modification resulted in significantly improved binding affinities for all modified antibodies to human βKlotho, human βKlotho / FGFR1c, and crab-eating monkey βKlotho / FGFR1c compared to the unmodified antibody CB-8. EXAMPLES

[0146] Modification of potential PTM sites In the present invention, detailed analysis of the CDR sequences of affinity-matured antibodies is carried out, and the following introduces a method for modifying potential PTM sites using CB-8-24 as an example.

[0147] CDR sequence analysis showed that CB-8-24 has a potential deamidation site NG in the heavy chain CDR2, but the same site in the corresponding CB-8-40 is SG, which may avoid the potential deamidation problem. For example, a new antibody sequence, CB-8-42, was designed after considering the sequences of CB-8-24 and CB-8-40. A full-length antibody containing the VH and VL of CB-8-42 was prepared using human IgG1 (E233A / L235A) heavy chain constant region sequence and human kappa constant region sequence. [Table 6]

[0148] The constant region sequences are as follows: Heavy chain constant region sequence (HC): ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPALAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO.50

[0149] Light chain constant region sequence (LC): RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO.51

[0150] The reporter gene assay described in Example 2 was used to detect the function of CB-8-42 full-length antibody to activate human or monkey FGFR1c / βKlotho receptor (see Table 6). The effect of CB-8-42 to activate FGFR1c / βKlotho receptor was significantly stronger than that of the control antibody, and in particular, the maximum response of cells to CB-8-42 was higher than that of the control antibody (results shown in Figure 1). At the same time, using the same method, the function of the antibody to activate FGFR2c / βKlotho, FGFR3c / βKlotho, and FGFR4 / βKlotho was detected. As a result, CB-8-42 was unable to activate FGFR2c / βKlotho, FGFR3c / βKlotho, and FGFR4 / βKlotho receptors, and showed excellent specificity for human FGFR1c / βKlohto, and the results are shown in Table 6.

[0151] [Table 7]

[0152] Taking the above results together, the anti-human βKlotho antibody of the present invention (particularly CB-8-42) is superior to the control antibody (5H23, whose sequence is derived from the antibody 5H23 described in NGM Patent CN201580016315.8) in binding ability, binding specificity, or ability to activate the receptor. For example, as shown in Figure 1 and Table 6, the ability of CB-8-42 to activate human FGFR1c / βKlotho is nearly twice that of the control antibody, and the maximum relative activity is significantly superior to that of the control antibody (Figure 1). EXAMPLES

[0153] In vivo drug efficacy studies in animals In this example, the in vivo efficacy of an anti-human βKlotho antibody was evaluated in an animal (eg, crab-eating monkey) in vivo efficacy evaluation model. The present invention examines the potential metabolic improvement effect of anti-human βKlotho antibody (e.g., CB-8-42) in an obese crab-eating monkey model, and considers the in vivo efficacy of the antibody of the present invention by monitoring changes in biochemical indicators such as food intake, body weight, BMI, fasting blood glucose, insulin, triglyceride, cholesterol, low-density lipoprotein, high-density lipoprotein, and liver fat content of the crab-eating monkey after antibody injection.

[0154] In the actual study, 10 animals aged 11 years or older and weighing 8.5 kg or more were selected to detect male obese crab-eating monkeys with MRI liver fat content ≥ 8%, and randomly assigned to a vehicle group (n = 5) and an antibody group (n = 5) based on body weight and liver fat content, and entered a 2-week adaptation period, during which clinical observations and food intake statistics were performed daily, body weight measurements and BMI calculations were performed once a week, and basic blood biochemistry indicators such as fasting blood glucose, insulin, triglycerides, cholesterol, low-density lipoprotein, and high-density lipoprotein before administration were detected at the same time. On the 1st, 29th, and 57th days after the end of the 2-week adaptation period, the animals were administered vehicle (20 mM histidine buffer, 4.5% sorbitol, pH 5.7) or anti-βKlotho antibody (CB-8-42, 10 mg / kg) by subcutaneous injection, respectively. During the test period, clinical observations and food intake statistics were performed daily, and body weight measurements were performed once a week. Three weeks (day 22), seven weeks (day 50), and eleven weeks (day 78) after the first feeding, blood was drawn from the animals after an overnight fast to measure serum levels of glucose, insulin, triglycerides, cholesterol, low-density lipoprotein, and high-density lipoprotein. Six and 12 weeks after the first feeding, the animals' liver fat content was measured using MRI techniques.

[0155] Body weight experiment results As shown in Figures 2 to 4, no significant change was observed in the body weight of the animals in the solvent-treated group, but the body weight of the animals in the anti-human βKlotho antibody CB-8-42-administered group gradually decreased, and by the 11th week after administration, the body weight of the animals in the CB-8-42-administered group had decreased by an average of 20%. Correspondingly, no significant change was observed in the BMI of the animals in the solvent-treated group, but the BMI of the animals in the anti-human βKlotho antibody CB-8-42-administered group had decreased by an average of 20%.

[0156] Food intake experiment results As shown in Figure 5, the food intake of the animals in the vehicle-treated group remained essentially stable throughout the experimental period, at approximately 140 g / day. Animals treated with the anti-human βKlotho antibody CB-8-42 showed a significant decrease in food intake after treatment. During the adaptation period, the animals had an average food intake of approximately 112 g / day, and during the antibody treatment period, the average food intake dropped to an average of 78 g / day, a decrease of approximately 30%.

[0157] Liver fat content test results As shown in FIG. 6, the liver fat content of the animals in the vehicle-treated group gradually increased, and the liver fat content after 12 weeks of treatment was statistically different from that before treatment (p<0.05). After treatment with anti-human βKlotho antibody CB-8-42, the average liver fat content of the animals decreased from 12.1% before treatment to 7.5% 6 weeks after the first treatment, and after 12 weeks, the average liver fat content was maintained at 8.1%. The liver fat content of the animals in the antibody group before treatment was equivalent to that of the vehicle group, both of which were 12.1%. After 12 weeks of treatment with anti-human βKlotho antibody CB-8-42 antibody, the liver fat content of the animals in the antibody group according to the present invention was significantly lower than that of the vehicle group (8.1% vs. 21.6%, p<0.01).

[0158] Fasting blood glucose content test results As shown in FIG. 7, the fasting blood glucose of the animals in the vehicle-treated group gradually increased during the experiment, but after treatment with the anti-human βKlotho antibody CB-8-42, the fasting blood glucose of the animals was significantly lower than that before treatment.

[0159] Serum insulin level laboratory results As shown in FIG. 8, the serum insulin levels of the animals in the vehicle-treated group increased significantly during the experimental period, but after administration of the anti-human βKlotho antibody CB-8-42, the serum insulin levels of the animals decreased significantly.

[0160] Serum triglyceride level laboratory results As shown in FIG. 9, the serum triglyceride levels of the animals in the vehicle-treated group increased significantly over the course of the experiment, whereas the serum triglyceride levels of the animals after treatment with the anti-human βKlotho antibody CB-8-42 remained stable.

[0161] Serum total cholesterol level laboratory results As shown in FIG. 10, the serum total cholesterol levels of the animals in the vehicle-treated group remained stable throughout the experimental period, whereas after administration of the anti-human βKlotho antibody CB-8-42, the serum total cholesterol levels of the animals were significantly reduced compared to those before administration.

[0162] Serum low-density lipoprotein levels laboratory results As shown in FIG. 11, the serum low-density lipoprotein levels of the animals in the solvent-treated group remained substantially stable throughout the experimental period, whereas after administration of the anti-human βKlotho antibody CB-8-42, the serum low-density lipoprotein levels of the animals were significantly reduced compared to before administration.

[0163] Serum high density lipoprotein level laboratory results As shown in FIG. 12, serum high density lipoprotein levels in the vehicle-treated and anti-human βKlotho antibody CB-8-42-treated animals remained stable over the course of the experiment.

[0164] As can be seen from the above experimental results, the use of the anti-βKlotho antibody of the present invention can significantly improve the metabolic level of crab-eating monkeys compared with the solvent group, and the changes in various biochemical indicators such as feeding, body weight, BMI, fasting blood glucose, insulin, triglycerides, cholesterol, low density lipoprotein, high density lipoprotein, and liver fat content of crab-eating monkeys show the great potential and potential clinical therapeutic effect of the anti-human βKlotho antibody of the present invention in the treatment or alleviation of diabetes, dyslipidemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity. Overall, the results of the in vivo efficacy experiment showed that the anti-human βKlotho antibody of the present invention has a significant effect of improving the above-mentioned diseases in the obese crab-eating monkey model, and has good in vivo safety.

[0165] The use of any embodiment or exemplary language provided herein (e.g., "for example," "such as," "such as," etc.) is intended to provide a better understanding of the invention and does not limit the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as required to the practice of the invention.

[0166] All publications and patent applications cited in this specification are incorporated herein by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Furthermore, any theory, mechanism, demonstration, or discovery described herein is intended to further enhance the understanding of the present invention, and is not intended to limit the present invention in any manner to such theory, mechanism, demonstration, or discovery. Although the present invention has been illustrated and described in detail in the accompanying drawings and the foregoing description, it should be considered as illustrative rather than limiting on the present invention.

Claims

1. An anti-βKlotho antibody or antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3); the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO.1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.1, the sequence of HCDR2 is a sequence shown in SEQ ID NO.2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.2, the sequence of HCDR3 is a sequence shown in SEQ ID NO.3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.3, and the sequence of LCDR1 is a sequence shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.5 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.5, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 14, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 3, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO. 15 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 15, the sequence of LCDR3 is the sequence shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 6, or (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 20 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 20, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 3, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.21 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.21, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 26 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 26, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 14, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 3, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.27 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.27, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 2, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 31, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.5 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.5, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (6) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 14 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 14, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 3, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO. 34 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 34, the sequence of LCDR3 is the sequence shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 6, or (7) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 38, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 3, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.27 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.27, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (8) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 38, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 3, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO. 42 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 42, the sequence of LCDR3 is the sequence shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 6, or (9) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 20 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 20, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 3, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is a sequence shown in SEQ ID NO. 45 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 45, the sequence of LCDR3 is a sequence shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 6, or (10) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 38, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 31, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO. 42 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 42; the sequence of LCDR3 is the sequence shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 6; wherein the sequences of HCDR and LCDR are as defined by Kabat: An anti-βKlotho antibody or an antigen-binding portion thereof.

2. An anti-βKlotho antibody or antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3); the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 7, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 8, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 16 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 16, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 17, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 22 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 22, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 23, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 9, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 28 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 28, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 17 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 17, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 7, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 8, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 32, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (6) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 35 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 35, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 17 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 17, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 9, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (7) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 39 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 39, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 40, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (8) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 7, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 40, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (9) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 46 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 46, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 23, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO.11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.11, the sequence of LCDR3 is the sequence shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO.6, or (10) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 7, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 40, the sequence of HCDR3 is a sequence shown in SEQ ID NO. 32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 32, and the sequence of LCDR1 is a sequence shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. the sequence of LCDR2 is the sequence shown in SEQ ID NO. 11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 11; the sequence of LCDR3 is the sequence shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 6; wherein the sequences of HCDR and LCDR are defined by IMGT: An anti-βKlotho antibody or an antigen-binding portion thereof.

3. The heavy chain variable region has an amino acid sequence set forth in SEQ ID NO. 12, 18, 24, 29, 33, 36, 41, 43, 47, or 49, or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to the amino acid sequence set forth in SEQ ID NO. 12, 18, 24, 29, 33, 36, 41, 43, 47, or 49; An anti-βKlotho antibody or an antigen-binding portion thereof according to claim 1 or 2.

4. The light chain variable region has an amino acid sequence set forth in SEQ ID NO. 13, 19, 25, 30, 37, 44, or 48, or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to the amino acid sequence set forth in SEQ ID NO. 13, 19, 25, 30, 37, 44, or 48; The anti-βKlotho antibody or an antigen-binding portion thereof according to any one of claims 1 to 3.

5. (1) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 12 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 13; or (2) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 18 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 19; or (3) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 24 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 25; or (4) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 29 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 30; or (5) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 33 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 13; or (6) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 36 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 37; or (7) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 41 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 30; or (8) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 43 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 44; or (9) the heavy chain variable region sequence is the sequence shown in SEQ ID NO. 47 and the light chain variable region sequence is the sequence shown in SEQ ID NO. 48; or (10) The heavy chain variable region sequence is the sequence shown in SEQ ID NO. 49, and the light chain variable region sequence is the sequence shown in SEQ ID NO. 44; The anti-βKlotho antibody or an antigen-binding portion thereof according to any one of claims 1 to 4.

6. An anti-βKlotho antibody or antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region has an amino acid sequence set forth in SEQ ID NO. 12, 18, 24, 29, 33, 36, 41, 43, 47, or 49, or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to an amino acid sequence set forth in SEQ ID NO. 12, 18, 24, 29, 33, 36, 41, 43, 47, or 49; and / or The light chain variable region has an amino acid sequence set forth in SEQ ID NO. 13, 19, 25, 30, 37, 44, or 48, or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to the amino acid sequence set forth in SEQ ID NO. 13, 19, 25, 30, 37, 44, or 48; An anti-βKlotho antibody or an antigen-binding portion thereof.

7. An anti-βKlotho antibody or an antigen-binding portion thereof, comprising a heavy chain variable region, the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 2 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 2, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 3; (2) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 14 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 14, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 3; (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 20 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 20, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 3; (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 26 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 26, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 14 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 14, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 3; (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 2 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 2, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 31 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 31; (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 38, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 3 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 3; (7) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 1 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 1, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 38 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 38, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 31 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 31; wherein the HCDR sequence is as defined by Kabat: An anti-βKlotho antibody or an antigen-binding portion thereof.

8. An anti-βKlotho antibody or an antigen-binding portion thereof, comprising a light chain variable region, the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); (1) the sequence of LCDR1 is a sequence as shown in SEQ ID NO.4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO.4, the sequence of LCDR2 is a sequence as shown in SEQ ID NO.5 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO.5, and the sequence of LCDR3 is a sequence as shown in SEQ ID NO.6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO.6; (2) the sequence of LCDR1 is a sequence as set forth in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as set forth in SEQ ID NO. 4, the sequence of LCDR2 is a sequence as set forth in SEQ ID NO. 15 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as set forth in SEQ ID NO. 15, and the sequence of LCDR3 is a sequence as set forth in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as set forth in SEQ ID NO. 6; (3) the sequence of LCDR1 is a sequence as set forth in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as set forth in SEQ ID NO. 4, the sequence of LCDR2 is a sequence as set forth in SEQ ID NO. 21 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as set forth in SEQ ID NO. 21, and the sequence of LCDR3 is a sequence as set forth in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as set forth in SEQ ID NO. 6; (4) the sequence of LCDR1 is a sequence as shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 4, the sequence of LCDR2 is a sequence as shown in SEQ ID NO. 27 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 27, and the sequence of LCDR3 is a sequence as shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 6; (5) the sequence of LCDR1 is a sequence as shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as shown in SEQ ID NO. 4, the sequence of LCDR2 is a sequence as shown in SEQ ID NO. 34 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as shown in SEQ ID NO. 34, and the sequence of LCDR3 is a sequence as shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as shown in SEQ ID NO. 6; (6) the sequence of LCDR1 is a sequence as shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 4, the sequence of LCDR2 is a sequence as shown in SEQ ID NO. 42 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 42, and the sequence of LCDR3 is a sequence as shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 6; (7) The sequence of LCDR1 is a sequence shown in SEQ ID NO. 4 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 4, the sequence of LCDR2 is a sequence shown in SEQ ID NO. 45 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 45, and the sequence of LCDR3 is a sequence shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 6; wherein the LCDR sequence is as defined by Kabat: An anti-βKlotho antibody or an antigen-binding portion thereof.

9. An anti-βKlotho antibody or an antigen-binding portion thereof, comprising a heavy chain variable region, the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3); (1) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 7, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 8 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 8, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 9; (2) the sequence of HCDR1 is a sequence as shown in SEQ ID NO. 16 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as shown in SEQ ID NO. 16, the sequence of HCDR2 is a sequence as shown in SEQ ID NO. 17 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as shown in SEQ ID NO. 17, and the sequence of HCDR3 is a sequence as shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence as shown in SEQ ID NO. 9; (3) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 22 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 22, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 23, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 9; (4) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 28 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 28, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 17 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 17, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 9; (5) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 7 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 7, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 8 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 8, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 32 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 32; or (6) the sequence of HCDR1 is a sequence shown in SEQ ID NO. 35 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 35, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 17 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 17, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 9; (7) the sequence of HCDR1 is a sequence as shown in SEQ ID NO. 39 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 39, the sequence of HCDR2 is a sequence as shown in SEQ ID NO. 40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 40, and the sequence of HCDR3 is a sequence as shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 9, or (8) the sequence of HCDR1 is a sequence as shown in SEQ ID NO. 7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 7, the sequence of HCDR2 is a sequence as shown in SEQ ID NO. 40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 40, and the sequence of HCDR3 is a sequence as shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 9; (9) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 46 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 46, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 23 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 23, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 9 or has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the sequence shown in SEQ ID NO. 9, or (10) The sequence of HCDR1 is a sequence shown in SEQ ID NO. 7 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 7, the sequence of HCDR2 is a sequence shown in SEQ ID NO. 40 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 40, and the sequence of HCDR3 is a sequence shown in SEQ ID NO. 32 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence shown in SEQ ID NO. 32; wherein the HCDR sequence is defined by IMGT: An anti-βKlotho antibody or an antigen-binding portion thereof.

10. An anti-βKlotho antibody or an antigen-binding portion thereof, comprising a light chain variable region, the light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); The sequence of LCDR1 is a sequence as shown in SEQ ID NO. 10 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 10, the sequence of LCDR2 is a sequence as shown in SEQ ID NO. 11 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 11, and the sequence of LCDR3 is a sequence as shown in SEQ ID NO. 6 or has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the sequence as shown in SEQ ID NO. 6; wherein the LCDR sequence is defined by IMGT: An anti-βKlotho antibody or an antigen-binding portion thereof.

11. and / or the anti-βKlotho antibody or antigen-binding portion thereof binds to human βKlotho, preferably specifically binds to human βKlotho; and / or The anti-βKlotho antibody is a complete antibody, a single chain antibody (scFv), a bispecific antibody or a multispecific antibody; and / or The antigen-binding portion of the anti-βKlotho antibody may be Fab, Fab', Fv or F(ab'). ２ and / or The anti-βKlotho antibody is a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody, and / or The anti-βKlotho antibody is a monoclonal antibody, and / or said anti-βKlotho antibody is of the IgG1, IgG2 or IgG4 isotype; and / or the anti-βKlotho antibody is an IgG1 / IgG4, IgG2 / IgG4 or IgG1 / IgG2 chimeric antibody; The anti-βKlotho antibody comprises a light chain constant region of the κ or λ subtype; and / or The anti-βKlotho antibody comprises a human IgG1 heavy chain constant region and a human κ light chain constant region; and / or The anti-βKlotho antibody comprises a wild-type or engineered Fc region, the engineered Fc region causing the antibody to have attenuated ADCC and / or CDC effects. An antibody or antigen-binding portion thereof according to any one of claims 1 to 10.

12. The antibody has a heavy chain variable region represented by SEQ ID NO. 49, a light chain variable region represented by SEQ ID NO. 44, a heavy chain constant region represented by SEQ ID NO. 50, and a light chain constant region represented by SEQ ID NO.

51. An antibody or antigen-binding portion thereof according to any one of claims 1 to 11.

13. An antibody or antigen-binding portion thereof according to any one of claims 1 to 12 for use in medical therapy.

14. An isolated nucleic acid molecule encoding the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of claims 1 to 13.

15. A vector comprising the nucleic acid molecule of claim 14.

16. A host cell comprising the nucleic acid molecule of claim 14 or the vector of claim 15.

17. An antibody-drug conjugate comprising the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of claims 1 to 13 conjugated to a therapeutic agent.

18. A pharmaceutical composition comprising an anti-βKlotho antibody or an antigen-binding portion thereof according to any one of claims 1 to 13, or an antibody-drug conjugate according to claim 17, and a pharma- ceutical acceptable carrier.

19. The pharmaceutical composition is for treating a disease mediated by βKlotho or mediated by βKlotho-FGFR1c-FGF21; 19. The pharmaceutical composition of claim 18, wherein the disease is, for example, a metabolic disease, such as type 1 diabetes, type 2 diabetes, dyslipidemia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity.

20. Use of an anti-βKlotho antibody or an antigen-binding portion thereof according to any one of claims 1 to 13, a nucleic acid molecule according to claim 14, a vector according to claim 15, a host cell according to claim 16, or an antibody-drug conjugate according to claim 17 in the manufacture of a medicament for treating a disease mediated by βKlotho or mediated by βKlotho-FGFR1c-FGF21, comprising: The disease is, for example, a metabolic disease, such as type 1 diabetes, type 2 diabetes, dyslipidemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity.

21. 1. A method of treating a disease mediated by βKlotho or βKlotho-FGFR1c-FGF21 in an individual, comprising: Administering to said individual a therapeutically effective amount of an anti-βKlotho antibody or antigen-binding portion thereof according to any one of claims 1 to 13, an antibody-drug conjugate according to claim 17, or a pharmaceutical composition according to claim 18; The method, wherein the disease is, for example, a metabolic disease, such as type 1 diabetes, type 2 diabetes, dyslipidemia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity.

22. A conjugate comprising the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of claims 1 to 13 and a detectable marker.

23. A fusion protein comprising the anti-βKlotho antibody or an antigen-binding portion thereof according to any one of claims 1 to 13.

Images