RU2845857C2 - βKLOTO ANTIBODY AND USE THEREOF - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: disclosed are antibodies to βKlotho and their antigen-binding sites, pharmaceutical compositions containing them, as well as the use of said antibodies and pharmaceutical compositions. Also disclosed are nucleic acid molecules coding said antibodies or their antigen-binding sites, and containing said nucleic acids, expression vectors and host cells for producing antibodies or their antigen-binding sites.

EFFECT: antibodies to βKlotho can be used in the treatment of diseases mediated by βKlotho or βKlotho-FGFR1c-FGF21, in particular, diseases with metabolic disorders, such as type 1 diabetes, type 2 diabetes, dyslipidemia, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cardiovascular disease, metabolic syndrome or obesity.

27 cl, 12 dwg, 6 tbl, 7 ex

Description

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from Chinese Patent Application No. 202111683753.3, filed on December 30, 2021, the contents of which are incorporated by reference in their entirety for all purposes.

AREA OF TECHNOLOGY

This application relates generally to the field of biopharmaceuticals and, in particular, to novel antibodies to β-Klotho or antigen-binding fragments thereof, pharmaceutical compositions containing the antibodies or antigen-binding fragments thereof, and medical and pharmaceutical uses of the antibodies or antigen-binding fragments thereof.

PRIOR ART

Fibroblast growth factor 21 (FGF21), a member of the FGF19 subfamily of fibroblast growth factors, plays an important role in the regulation of glucose, lipid, and energy metabolism. In addition to FGF21, the FGF19 subfamily has two other members, FGF19 and FGF23. Unlike classical fibroblasts, which require heparin binding to perform their function, the three proteins of the FGF19 subfamily do not bind heparin and can be secreted into the blood to perform physiological function in other tissues or organs of the body. Thus, the three proteins, including FGF21, are also referred to as endocrine fibroblast growth factors. FGF21 is predominantly expressed in the liver, but also in small amounts in the pancreas and brain. It can act on adipose tissue, central nervous system and other tissues and organs, improving insulin sensitivity, increasing blood glucose clearance, inhibiting liver glycogenolysis, increasing energy consumption, enhancing liver ketogenesis, reducing blood triglyceride levels and so on. In addition to FGF21, FGF19 is mainly expressed in the small intestine and mainly acts on hepatocytes, and plays a role in regulating the synthesis and secretion of bile acids in hepatocytes. FGF23 is a phosphaturic hormone that plays a vital role in regulating human phosphate balance.

Three proteins of the FGF19 subfamily, including FGF21, exert their physiological functions by activating the FGF receptor (FGFR). They are unable to activate the FGF receptor on their own, but require the help of co-receptors, i.e., Klotho proteins, to perform their physiological functions. Klotho proteins are divided into αKlotho and βKlotho, which are required for high-affinity binding of FGF19, FGF21, and FGF23 to their homologous FGF receptors. αKlotho mediates FGF receptor activation by FGF23, whereas βKlotho mediates receptor activation by FGF19 and FGF21. βKlotho is a monotopic type I membrane protein with an extracellular domain consisting of two internal repeats homologous to members of the glycosidase family 1 but lacking glucosidase catalytic activity. β-klotho expression was detected in the liver, pancreas, fat, and central nervous system. Studies have shown that CYP7A1 and CY8B1 mRNA levels were elevated in β-klotho-deficient (KLB ^-/- ) mice, and bile acid synthesis and secretion were increased.

FGF21 binds with FGF receptor and β-Klotho to form a ternary complex, which promotes the dimerization of FGF receptor, and then forms a six-membered complex to activate FGF receptor. The activated FGF receptor will further activate the downstream MAPK(Erk1/2) and AKT1 signaling pathways to exert their biological functions. FGF21 activates FGF receptor on adipocytes, promoting GLUT-1 expression in adipocytes and increasing glucose uptake by adipocytes. In addition, FGF21 can increase the expression of UCP-1 and promote adipocyte transformation into brown-like cells. FGF21 can also induce the expression and secretion of adiponectin or other adipocytokines, which enhance insulin sensitivity. Adiponectin and other adipokines act on other tissues or organs (e.g., liver) to improve systemic metabolism. Recent studies have also shown that FGF21 can act on the central nervous system and, in addition to indirectly regulating carbohydrate, lipid, and energy metabolism, it also affects alcohol and sugar craving in humans or mice. Transgenic mice overexpressing FGF21 exhibited a wide range of metabolism-related phenotypes, including slow growth, low blood glucose and triglyceride levels, resistance to aging-associated type 2 diabetes, islet hyperplasia, and obesity. In rat or non-human primate models, injection of the FGF21 fusion protein in animals showed restored glucose levels, reduced blood triglyceride and cholesterol levels, increased glucose tolerance, and increased insulin sensitivity. In addition, FGF21 increased activity, metabolic rate, and energy expenditure in animals, thereby reducing body weight and body fat. In a mouse model of non-alcoholic steatohepatitis, the modified FGF21 protein alleviated the degree of hepatic steatosis, reduced liver injury, and decreased molecular markers of inflammation in the liver. These studies suggest that FGF21 has potential for use in the treatment of metabolic diseases such as non-alcoholic steatohepatitis, type 2 diabetes, obesity, and dyslipidemia.

Among the FGF receptors, only FGFR1c, 2c, 3c and 4 can bind to Klotho, whereas FGFR1b, 2b and 3b are unable to bind to Klotho. In vitro experiments show that FGF21 can activate FGFR1c, 2c and 3c receptors via β-Klotho. In vivo experiments show that the effects of FGF21 on metabolism are mainly mediated by FGFR1c and β-Klotho receptors. Thus, it is suggested that molecules that mimic the action of FGF21 and activate FGFR1c and β-Klotho receptors (such as activating antibodies to β-Klotho) may also have potential for the treatment of metabolic diseases such as non-alcoholic steatohepatitis.

There are several ongoing studies of antibodies targeting β-Klotho. Among these, relatively rapidly advancing ones include Genentech’s BFKB8488A (an FGFR1/KLB bispecific antibody), which is in a Phase II clinical trial; and NGM 313 (an agonist monoclonal antibody), which is also being studied in a Phase II clinical trial with non-alcoholic steatohepatitis as an entry requirement. Products from other companies, such as Amgen, Regeneron, and Novartis, are being studied in the preclinical phase. Given that these drugs are in early preclinical stages and their efficacy has not yet been established, there is a need for a variety of antibody drugs targeting the above targets.

SUMMARY OF THE INVENTION

In a first aspect of the present application there is provided an anti-β-Klotho antibody or 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), and wherein:

(1) the HCDR1 sequence is the sequence set forth in SEQ ID NO:l or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO:l, the HCDR2 sequence is the sequence set forth in SEQ ID NO:2 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO:2, the HCDR3 sequence is the sequence set forth in SEQ ID NO:3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO:3, the LCDR1 sequence is the sequence set forth in SEQ ID NO:4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 5 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 5, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(2) the HCDR1 sequence is the sequence set forth in SEQ ID NO:l or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO:l, the HCDR2 sequence is the sequence set forth in SEQ ID NO:14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO:14, the HCDR3 sequence is the sequence set forth in SEQ ID NO:3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO:3, the LCDR1 sequence is the sequence set forth in SEQ ID NO:4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 15 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 15, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 20 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 20, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 21 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 21, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 26 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 26, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 14, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 27 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 27, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 2 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 2, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 31, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 5 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 5, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 14, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 34 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 34, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 27 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 27, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(8) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 42 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 42, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(9) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 20 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 20, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 45 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 45, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(10) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 31, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 42 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 42, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6;

where the HCDR and LCDR sequences are defined as defined by Kabat.

In a second aspect of the present application there is provided an anti-β-Klotho antibody or 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), and wherein:

(1) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 8 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 8, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(2) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 16 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 16, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 22 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 22, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 23, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 28 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 28, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 8 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 8, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 32, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 35 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 35, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 39 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 39, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(8) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(9) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 46 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 46, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 23, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(10) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 32, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6;

where the HCDR and LCDR sequences are defined as defined by IMGT.

In a third aspect of the present application there is provided an antibody to β-Klotho or an antigen-binding portion thereof comprising a heavy chain variable region and a light chain variable region, wherein:

the heavy chain variable region has an amino acid sequence as set forth in SEQ ID NO: 12, 18, 24, 29, 33, 36, 41, 43, 47 or 49, or has 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 as 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 as set forth in SEQ ID NO: 13, 19, 25, 30, 37, 44 or 48, or has an amino acid sequence that has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the amino acid sequence as set forth in SEQ ID NO: 13, 19, 25, 30, 37, 44 or 48.

In a fourth aspect of the present application there is provided an anti-βKlotho antibody or antigen-binding portion thereof comprising a heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3), wherein:

(1) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 2 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 2, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(2) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 14, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 20 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 20, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 26 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 26, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 14, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 2 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 2, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 31; or

(6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 31;

where HCDR sequences are defined as defined by Kabat.

In a fifth aspect of the present application there is provided an anti-βKlotho antibody or antigen-binding portion thereof comprising a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2) and a light chain CDR3 (LCDR3), wherein:

(1) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 5 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 5, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(2) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 15 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 15, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(3) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 21 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 21, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(4) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 27 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 27, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(5) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 34 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 34, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(6) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 42 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 42, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(7) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 45 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 45, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6;

where LCDR sequences are defined as defined by Kabat.

In a sixth aspect of the present application there is provided an anti-β-Klotho antibody or antigen-binding portion thereof comprising a heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3), wherein:

(1) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 8 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 8, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(2) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 16 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 16, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 22 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 22, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 23, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 28 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 28, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 8 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 8, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 32; or

(6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 35 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 35, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 39 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 39, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(8) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(9) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 46 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 46, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 23, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(10) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 32;

where HCDR sequences are defined as defined by IMGT.

In a seventh aspect of the present application there is provided an anti-β-Klotho antibody or antigen-binding portion thereof comprising a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2) and a light chain CDR3 (LCDR3), wherein:

the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6;

where LCDR sequences are defined as defined by IMGT.

In an eighth aspect of the present application there is provided an isolated nucleic acid molecule encoding an anti-βKlotho antibody or antigen-binding portion thereof according to aspects five to seven.

In a ninth aspect of the present application there is provided a vector comprising a nucleic acid molecule according to the eighth aspect.

In a tenth aspect of the present application there is provided a host cell comprising a nucleic acid molecule according to the eighth aspect or a vector according to the ninth aspect.

In an eleventh aspect of the present application there is provided an antibody-drug conjugate comprising an anti-β-Klotho antibody or antigen-binding portion thereof according to aspects one to seven, conjugated to a therapeutic substance.

In a twelfth aspect of the present application there is provided a pharmaceutical composition comprising an anti-β-Klotho antibody or antigen-binding portion thereof according to aspects one to seven or an antibody-drug conjugate according to the eleventh aspect and a pharmaceutically acceptable carrier.

In a thirteenth aspect of the present application there is provided the use of an anti-βKlotho antibody or antigen-binding portion thereof according to aspects one to seven, 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 the treatment of a disease mediated by βKlotho or βKlotho-FGFR1c-FGF21, 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.

In a fourteenth aspect of the present application, there is provided a method of treating a subject for a disease mediated by βKlotho or βKlotho-FGFR1c-FGF21, comprising administering to the subject a therapeutically effective amount of an antibody to βKlotho or an antigen-binding portion thereof according to aspects one to seven, an antibody-drug conjugate according to the eleventh aspect, or a pharmaceutical composition according to the twelfth aspect. For example, the disease is 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.

In a fifteenth aspect of the present application there is provided a conjugate comprising an antibody to β-Klotho or an antigen-binding portion thereof according to aspects one to seven, and a detectable label.

In a sixteenth aspect of the present application, there is provided a fusion protein comprising an antibody to β-Klotho or an antigen-binding portion thereof according to aspects one to seven.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

Figure 1 shows concentration-dependent activation curves of human or cynomolgus monkey FGFR1c/βKlotho receptor by CB-8-42 antibody, control antibody, and FGF19 as determined by a reporter gene assay.

Fig. 2 shows the results of monitoring the body weight of cynomolgus macaques treated with vehicle or CB-8-42 antibody.

Fig. 3 shows the results of monitoring the relative change in body weight of cynomolgus macaques treated with vehicle or CB-8-42 antibody.

Fig. 4 shows the results of monitoring the body mass index (BMI) of cynomolgus macaques treated with vehicle or CB-8-42 antibody.

Fig. 5 shows the results of monitoring food consumption of cynomolgus macaques treated with vehicle or CB-8-42 antibody.

Fig. 6 shows changes in liver fat content of cynomolgus macaques before and after exposure to vehicle or CB-8-42 antibody.

Fig. 7 shows changes in fasting blood glucose in cynomolgus macaques before and after exposure to vehicle or CB-8-42 antibody.

Fig. 8 shows changes in serum insulin levels in cynomolgus macaques before and after exposure to vehicle or CB-8-42 antibody.

Fig. 9 shows the changes in serum triglyceride levels of cynomolgus monkeys before and after exposure to vehicle or CB-8-42 antibody.

Fig. 10 shows changes in total cholesterol levels in the serum of cynomolgus monkeys before and after exposure to vehicle or CB-8-42 antibody.

Fig. 11 shows changes in serum LDL levels in cynomolgus monkeys before and after exposure to vehicle or CB-8-42 antibody.

Fig. 12 shows changes in serum high-density lipoprotein levels in cynomolgus monkeys before and after exposure to vehicle or CB-8-42 antibody.

INFORMATION CONFIRMING THE POSSIBILITY OF IMPLEMENTING THE INVENTION

DEFINITIONS

Unless otherwise specified, all scientific and technical terms used in this document have the same meaning as commonly understood by those skilled in the art. Definitions and terminology used in the art can be found in particular in the document Current Protocols in Molecular Biology (Ausubel). The abbreviations for amino acid residues are standard 3-letter and/or 1-letter codes used in the art to designate one of the 20 basic L-amino acids.

While the numerical ranges and approximations of the parameters are shown in this application in broad ranges, the numerical values shown in specific embodiments are described as precisely as possible. However, any numerical values in principle contain some errors due to the presence of standard deviations in their respective measurements. In addition, all ranges set forth herein should be understood as covering all possible ranges contained therein. For example, the range "from 1 to 10" should be considered to cover all possible subranges from the minimum value of 1 to the maximum value of 10, inclusive, that is, all subranges starting from a minimum value of 1 or more, such as from 1 to 6.1, and subranges ending with a maximum value of 10 or less, such as from 5.5 to 10. In addition, any reference indicated as "incorporated in this specification" should be understood as being included in its entirety.

As used herein, the term "subject" or "individual" refers to a mammal, such as a human, as well as other animals, such as wild animals, domestic animals, or experimental animals (e.g., gorillas, monkeys, rats, mice, rabbits, guinea pigs, marmots, or chipmunks).

As used herein, the term "antigen" is 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 compounds of natural or artificial origin.

"Antibody" in the broad sense refers 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 an intact antibody/full-length antibody, a single chain of an antibody, or any antigen-binding fragment of an antibody (also referred to as an "antigen-binding region"). When "antibody" and "antigen-binding fragment/antigen-binding region" appear in the same context, "antibody" can be understood as a collection of "antigen-binding fragments/antigen-binding regions" and together they correspond to the concept of "antibody" in the broad sense.

As used herein, the term "β-klotho" or "β-klotho polypeptide" or the like includes polypeptides that are derived from any vertebrate ("polypeptide" and "protein" are used interchangeably herein) or any naturally occurring β-klotho. Vertebrates include mammals such as primates (e.g., humans, cynomolgus monkeys), dogs, and rodents (e.g., mice and rats), unless otherwise noted. Some embodiments encompass related β-klotho polypeptides, such as SNP (single nucleotide polymorphism) variants, β-klotho comprises two domains, such as β-klotho 1 (KLB1) and β-klotho 2 (KLB2). Each β-klotho domain comprises a glycosyl hydrolase region. For example, the KLB1 domain of human β-klotho contains amino acid residues 1-508, and glycoside hydrolase region 1 contains amino acid residues 77-508. The KLB2 domain of human β-klotho contains amino acid residues 509-1044, and glycoside hydrolase region 1 contains amino acid residues 517-967. The amino acid sequence of human β-klotho (NCBI reference sequence: NM 175737.4) is as follows:

β-klotho polypeptides include allelic variants such as SNP variants, splice variants, fragments, derivatives, substitution, deletion, and insertion variants, fusion polypeptides, and interspecies homologues that retain β-klotho activity and/or are sufficient to elicit an immune response against β-klotho. Those skilled in the art will appreciate that the β-klotho antibodies provided herein can bind to β-klotho polypeptides, β-klotho polypeptide fragments, β-klotho antigens, and/or β-klotho epitopes. An epitope can be part of a larger β-klotho antigen, which can be part of a larger β-klotho polypeptide fragment, which in turn can be part of a larger β-klotho polypeptide. β-klotho can exist in its natural or denatured form. The β-klotho polypeptides described herein may be isolated from a variety of sources, such as human tissue species or other sources, or produced by recombinant or synthetic means. The β-klotho polypeptides may comprise a polypeptide having the same amino acid sequence as a corresponding naturally occurring β-klotho polypeptide. β-klotho polypeptides include truncated or secreted forms of the β-klotho polypeptide (such as the extracellular domain sequence), variant forms of the polypeptide (such as various splice forms), and allelic variants. Orthologs of β-klotho polypeptides are also well known in the art.

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 murine FGF15. The role of FGF family members is a consequence of heparin-dependent binding to one or more members of the FGF receptor tyrosine kinase family. FGFR contains four members, each with a tyrosine kinase domain, namely FGFR1, FGFR2, FGFR3, and FGFR4, and two splice variants each of FGFR1, FGFR2, and FGFR3. These splice variants occurring in exon 3 of FGFR1, FGFR2, and FGFR3 are designated as “b” and “c” variants, such as FGFR1b, FGFR2b, FGFR3c, FGFR1c, FGFR2c, and FGFR3c, which are also designated FGFR1(III)b, FGFR2(III)b, FGFR3(III)b, FGFR1(III)c, FGFR2(III)c, and FGFR3(III)c, respectively.

The term "anti-β-klotho antibody" or "antibody that binds to β-klotho" includes an antibody that is capable of binding to β-klotho with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent targeting β-klotho. Preferably, the extent of binding of the anti-β-klotho antibody to irrelevant non-β-klotho proteins is less than about 10% of the extent of binding of the antibody to β-klotho, such as as determined by fluorescence activated cell sorting (FACS) or immunoassays such as radioimmunoassay (RIA). Antibodies that "specifically bind" or "have specificity" for β-klotho are described above. In some embodiments, the dissociation constant of an antibody described herein that binds to β-klotho is less than or equal to 500 nM, 100 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM. In some embodiments, the anti-β-klotho antibody binds to epitopes that are conserved between β-klothos from different species, such as human β-klotho and cynomolgus monkey β-klotho.

The term "agonist antibody" is an antibody that triggers a response, such as an antibody that mimics at least one functional activity of a target polypeptide, such as FGF19 or FGF21. Agonist antibodies include antibodies that are mimetics of a ligand, such that when the ligand binds to a cell surface receptor, the binding triggers signaling or cell activity through an intracellular signaling pathway, and when the antibody triggers similar signaling or cell activation.

An "intact/full-length antibody" refers to a protein that contains at least two heavy (H) chains and two light (L) chains linked together by disulfide bonds. Each heavy chain contains a heavy chain variable region (VH) and a heavy chain constant region (CH) containing three domains, CHI, CH2, and CH3. Each light chain contains a light chain variable region (VL) and a light chain constant region containing one CL domain. The VH and VL regions can be further subdivided into multiple regions of high variability, termed complementarity determining regions (CDRs). Between the CDRs are more conserved regions, termed framework regions (FRs). Each VH or VL region consists of three CDRs and four FRs arranged in the following order from amino-terminus to carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. These variable regions of the heavy and light chains contain the binding domains that interact with antigens. The constant region of an antibody can mediate the binding of immunoglobulins to tissues or factors in the host, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. A full-length/intact antibody can be any type of antibody, such as IgD, IgE, IgG, IgA, or IgM antibodies (or subclasses of the above), but is not limited to any particular type. Depending on the amino acid sequences of the constant domains of the heavy chains of antibodies, immunoglobulins can be classified into different classes. Generally, immunoglobulins have five major classes, i.e., IgA, IgD, IgE, IgG, and IgM. Several of these classes may be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant domains of the heavy chain corresponding to the different classes of immunoglobulins are designated α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional structures of the different classes of immunoglobulins are well known. The antibodies of this application also encompass chimeric or humanized antibodies. It is well known to those skilled in the art that the complementarity determining regions (CDRs, typically including CDR1, CDR2, and CDR3) are the subregions within the variable regions that most influence the affinity and specificity of the antibody. The CDR sequences in VH or VL can be determined by a variety of well-known methods, including IMGT, Chothia determination and Kabat determination. In embodiments of the present invention, the amino acid sequences of the CDRs are determined according to the Kabat or IMGT definition. With respect to the amino acid sequence of the variable region of a given antibody, the amino acid sequences of the CDRs in the variable region of the amino acid sequence can be analyzed in various ways.

The term "murine antibody" refers to an antibody produced by fusing B cells from immunized mice with myeloma cells, selecting hybridized fusion mouse cells capable of both indefinite proliferation and antibody secretion, and screening, recovery, and purification of the resulting antibody. Murine antibody is generally immunogenic and therefore requires subsequent humanization.

The term "humanized antibody" refers to an antibody produced by grafting CDR sequences derived from another mammalian species, such as a mouse species, onto human framework sequences. To maintain binding affinity, some residues of the framework segments (called FRs) may be modified. The humanized antibodies or fragments thereof of this application can be produced by methods known to those skilled in the art.

The term "chimeric antibody" refers to an antibody in which the variable region sequence is derived from one species and the constant region sequence is derived from another species, such as an antibody in which the variable region sequence is derived from a murine antibody and the constant region sequence is derived from a human antibody. The chimeric antibodies or fragments thereof of this application can be produced using gene recombination techniques. For example, a chimeric antibody can be produced by cloning recombinant DNA comprising a promoter and a sequence encoding a variable region of a monoclonal antibody of this application that is not human, in particular murine, and a sequence encoding a constant region of a human antibody. The chimeric antibodies of this application encoded by such recombinant genes will, for example, be chimeric mouse-human, and their specificity is determined by variable regions derived from mouse DNA, and their isoforms are determined by constant regions derived from human DNA.

The term "partially humanized antibody" refers to an antibody that comprises a constant region from a human and a variable region (including CDRs) from a non-human antibody, such as a murine antibody.

The term "semi-humanized antibody" is one type of humanized antibody and refers to an antibody in which one chain of the antibody contains a mouse variable region and the other chain of the antibody contains a humanized variable region, i.e., a half-humanized antibody.

The term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies. Thus, the individual antibodies that make up the population are identical except for naturally occurring mutations that may be present in a small number of individuals.

In this specification, the term "antigen-binding fragment" or "antigen-binding portion" are used interchangeably and in particular refer to antibody fragments such as Fv, Fab, F(ab') ₂ or Fab' or any fragment which is capable of increasing the half-life by chemical modification or by incorporation into liposomes such as the addition of poly(alkylene)glycols such as polyethyleneglycol ("PEGylated") (designated as PEGylated fragments of Fv-PEG, scFv-PEG, Fab-PEG, F(ab') ₂ -PEG or Fab'-PEG) ("PEG" means polyethyleneglycol), wherein the fragments have β-klotho-binding activities. Preferably, the functional fragment consists of or comprises a portion of the sequence of the variable region of the heavy chain or the variable region of the light chain of the antibody from which it is derived. The portion of the sequence is sufficient to retain the same binding specificity and sufficient affinity as the antibody from which it is derived. Such a functional fragment will comprise at least 5 amino acids, preferably 10, 15, 25, 50 and 100 contiguous amino acids of the sequence of the antibody from which it is derived. Examples of antigen-binding fragments include (1) Fab fragments, which may be monovalent fragments having VL-CL chains and VH-CH1 chains; (2) F(ab') ₂ fragments, which may be divalent fragments having two Fab' fragments joined by disulfide bridges in the hinge region (i.e., Fab'dimers); and (3) Fv fragments having VL and VH domains from a single arm of an antibody, without limitation.

The term "single-chain variable fragment (scFv)" refers to a single polypeptide chain formed by a VH domain and a VL domain connected via a peptide linker. (scFv) ₂ contains two VH domains connected by a peptide linker and two VL domains that are joined to two VH domains via disulfide bridges.

The term "Fc fragment", "Fc domain", "Fc moiety" or the like refers to a portion of the constant region of the heavy chain of an antibody, including the hinge region, the CH2 region and the CH3 region of the constant region. The Fc region of an anti-β-klotho antibody may be engineered or modified, including modifications related to effector functions, to reduce or eliminate antibody-dependent cytotoxicity and/or complement-dependent cytotoxicity, which may be achieved by introducing one or more amino acid substitutions/mutations in the Fc region of the antibody.

The term "specific binding" refers to a non-random binding reaction between two molecules, such as the binding of an antibody to an epitope of an antigen.

The term "multi-antibody" also referred to as "multispecific antibody" is a molecule that has binding specificity for at least two different antigens, where a molecule that binds to only two antigens is also referred to as a dual antibody (i.e., a bispecific antibody, BsAb).

The term "bispecific antibody" refers to an antibody that has the ability to bind to two antigenic epitopes. The two epitopes may be on different antigens or on the same antigen. Bispecific antibodies may have a variety of structural configurations. For example, a bispecific antibody may consist of two Fc regions and two binding moieties fused to them, respectively (similar to a native antibody except that the two arms bind to different antigenic targets or epitopes). The antigen-binding moiety may be in the form of a single-chain variable fragment (scfv) or a Fab fragment.

In general, recommendations for the production of a monoclonal antibody or a functional fragment thereof, in particular a mouse monoclonal antibody or a functional fragment thereof, can be found in the procedures 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 procedures for the production of a monoclonal antibody from hybridoma cells described by Kohler and Milstein (Nature, 256:495-497, 1975).

The term "conservative variation" or "conservative amino acid substitutions" refers to a substitution that does not substantially affect or reduce the affinity of a protein, such as the affinity of an antibody for β-klotho. For example, a human antibody that specifically binds to β-klotho may include up to about 1, up to about 2, up to about 5, up to about 10, or up to about 15 conservative substitutions and specifically binds to a β-klotho polypeptide. The term "conservative variation" also includes the use of a substituted amino acid in place of an unsubstituted parent amino acid, so long as the antibody specifically binds to β-klotho. Non-conservative substitutions are those that reduce the activity or binding of β-klotho.

The term "isolated" biological components (e.g., nucleic acids, proteins (including antibodies), or organelles) have been substantially separated or purified from other biological components (i.e., other chromosomal and accessory chromosomal DNA and RNA, proteins, and organelles) of the environment in which the components naturally occur (e.g., cells). Nucleic acids and proteins that have been "isolated" include those that have been purified by standard purification techniques. The term also includes nucleic acids and proteins produced by recombinant expression in host cells, as well as chemically synthesized nucleic acids.

The term "derived sequence" refers to a sequence that has at least 80% identity (preferably 85%, 90%, 95%, 98% or 99%) to a sequence of interest and has the same or similar function as the sequence of interest.

As used herein, a "pharmaceutical composition" refers to a combination of at least one drug and, optionally, a pharmaceutically acceptable carrier or adjuvant that are combined together to achieve a specific purpose. In some embodiments, a pharmaceutical composition includes a combination that is separated in time and/or space, so long as it is capable of acting together to achieve the objectives of the invention. For example, the ingredients contained in a pharmaceutical composition (e.g., antibodies, nucleic acid molecules, combinations of nucleic acid molecules, and/or conjugates described herein) can be administered to a subject together or separately. When the components contained in a pharmaceutical composition are administered to a subject separately, the components can be administered to the subject simultaneously or sequentially. Preferably, the pharmaceutically acceptable carrier is water, a buffered aqueous solution, an isotonic saline solution such as PBS (phosphate buffer), glucose, mannitol, dextrose, lactose, starch, magnesium stearate, cellulose, magnesium carbonate, 0.3% glycerol, hyaluronic acid, ethanol or polyalkylene glycols such as polypropylene glycol, or triglycerides. The type of pharmaceutically acceptable carrier depends, inter alia, on whether the composition of the invention is formulated for oral, nasal, intradermal, subcutaneous, intramuscular or intravenous administration. The compositions of the invention may contain wetting agents, emulsifying agents or buffering agents as auxiliary substances. The pharmaceutical compositions or pharmaceutical formulations described in this application can be administered by any suitable route, such as orally, nasal, intradermally, subcutaneously, intramuscularly or intravenously.

As used herein, a "therapeutically effective amount" or "effective amount" refers to a dose sufficient to demonstrate benefit to the subject to which it is administered. The actual dose administered, the rate, and the frequency of administration will depend on the condition and severity of the disease of the subject being treated. The physician's prescription (e.g., the dose prescribed) is ultimately the responsibility of and dependent on the physician or other physicians, and will generally take into account the disease being treated, the condition of the individual patient, the site of administration, the route of administration, and other factors known to the physician.

The EC ₅₀ value generally refers to the concentration of a drug, antibody or toxin that produces a biological effect corresponding to 50% of the maximal after a specified exposure time. Pharmaceutically, in addition to being used to characterize the ability to activate agonists in in vitro experiments, it can also be used to indicate the plasma concentration required to achieve a biological effect equal to half the maximal in vivo. In some literature, EC ₅₀ is also used to characterize the potency of a compound at the cellular level, including agonism and antagonism. EC ₅₀ values can be determined by methods such as ELISA (enzyme-linked immunosorbent assay).

In this specification, the term "fusion protein" in a general context is a protein consisting of at least two domains, with the individual domains not naturally associated with each other and encoded by separate genes, wherein the individual genes are associated with each other and are transcribed and translated as a unit, resulting in a single protein. In the technical context of this application, a "fusion protein" comprising an antibody or an antigen-binding portion thereof refers to a product obtained by fusing an antibody or an antigen-binding portion thereof with another biologically active protein using genetic engineering techniques, and such antibody-fused proteins have both the antigen-binding ability of the antibody and the unique biological characteristics of the biologically active protein fused to the antibody.

The term "identity/homology/identity" in the context of an amino acid sequence or nucleic acid sequence is defined as the percentage of identical residues in a variant of the amino acid sequence or nucleic acid sequence that, after alignment and, if necessary, the introduction of gaps, achieves the maximum percentage of homology. Methods and computer programs for alignment are well known in the art.

In a first aspect of the present application there is provided an antibody to β-Klotho 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), and wherein:

(1) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 2 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 2, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 5 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 5, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(2) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 14, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 15 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 15, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 20 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 20, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 21 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 21, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 26 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 26, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 14, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 27 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 27, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 2 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 2, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 31, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 5 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 5, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 14, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 34 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 34, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 27 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 27, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(8) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 42 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 42, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(9) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 20 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 20, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 45 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 45, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(10) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 31, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 42 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 42, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6;

where the HCDR and LCDR sequences are defined as defined by Kabat.

In a second aspect of the present application there is provided an antibody to β-Klotho or an antigen-binding portion thereof, comprising a heavy chain variable region and a light 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), and the light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2) and a light chain CDR3 (LCDR3), and wherein:

(1) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 8 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 8, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80%, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(2) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 16 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 16, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 22 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 22, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 23, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 28 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 28, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 8 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 8, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 32, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 35 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 35, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 39 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 39, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(8) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(9) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 46 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 46, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 23, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6; or

(10) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 32, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80% identity, 85%, 90%, 95% or 99% with the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95% or 99% identity with the sequence set forth in SEQ ID NO: 6;

where the HCDR and LCDR sequences are defined as defined by IMGT.

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

In some embodiments of the first and second aspects, the light chain variable region has an amino acid sequence as set forth in SEQ ID NO: 13, 19, 25, 30, 37, 44 or 48, or has 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 as set forth in SEQ ID NO: 13, 19, 25, 30, 37, 44 or 48.

In some incarnations of the first and second aspects

(1) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 12 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 13; or

(2) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 18 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 19; or

(3) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 24 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 25; or

(4) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 29 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 30; or

(5) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 33 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 13; or

(6) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 36 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 37; or

(7) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 41 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 30; or

(8) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 43 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 44; or

(9) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 47 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 48; or

(10) the sequence of the variable region of the heavy chain is the sequence set forth in SEQ ID NO: 49, and the sequence of the variable region of the light chain is the sequence set forth in SEQ ID NO: 44.

In a third aspect of the present application there is provided an antibody to β-Klotho or an antigen-binding portion thereof comprising a heavy chain variable region and a light chain variable region, wherein:

the heavy chain variable region has an amino acid sequence as set forth in SEQ ID NO: 12, 18, 24, 29, 33, 36, 41, 43, 47 or 49, or has 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 as 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 as set forth in SEQ ID NO: 13, 19, 25, 30, 37, 44 or 48, or has an amino acid sequence that has at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to the amino acid sequence as set forth in SEQ ID NO: 13, 19, 25, 30, 37, 44 or 48.

In a fourth aspect of the present application there is provided an antibody to β-Klotho or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3), wherein:

(1) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 2 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 2, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(2) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 14, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 20 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 20, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 26 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 26, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 14, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 2 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 2, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 31; or

(6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 3; or

(7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 38, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 31;

where HCDR sequences are defined as defined by Kabat.

In a fifth aspect of the present application there is provided an antibody to β-Klotho or an antigen-binding portion thereof, comprising a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2) and a light chain CDR3 (LCDR3), wherein:

(1) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 5 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 5, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(2) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 15 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 15, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(3) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 21 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 21, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(4) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 27 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 27, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(5) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 34 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 34, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(6) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 42 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 42, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6; or

(7) the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 45 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 45, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6;

where LCDR sequences are defined as defined by Kabat.

In a sixth aspect of the present application there is provided an anti-β-Klotho antibody or antigen-binding portion thereof comprising a heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3), wherein:

(1) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence as set forth in SEQ ID NO: 8 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 8, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(2) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 16 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 16, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 22 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 22, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 23, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 28 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 28, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 8 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 8, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 32; or

(6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 35 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 35, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 17, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 39 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 39, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(8) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(9) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 46 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 46, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 23, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 9; or

(10) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 40, and the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 32;

where HCDR sequences are defined as defined by IMGT.

In a seventh aspect of the present application there is provided an antibody to β-Klotho or an antigen-binding portion thereof, comprising a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2) and a light chain CDR3 (LCDR3), wherein:

the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6 or has at least 80%, 85%, 90%, 95%, or 99% identity to the sequence set forth in SEQ ID NO: 6;

where LCDR sequences are defined as defined by IMGT.

In some embodiments of the fifth to seventh aspects, the anti-β-Klotho antibody or antigen-binding portion thereof binds to human β-Klotho. In some embodiments, the anti-β-Klotho antibody or antigen-binding portion thereof specifically binds to human β-Klotho.

In some embodiments of the first to seventh aspects, the anti-β-Klotho antibody is an intact antibody, a single chain variable fragment (scFv), a bispecific antibody, or a multispecific antibody.

In some embodiments of the first to seventh aspects, the antigen-binding portion of the β-Klotho antibody is Fab, Fab', Fv, or F(ab') ₂ .

In some embodiments of the first through seventh aspects, the anti-β-Klotho antibody is a murine antibody, a chimeric antibody, a humanized antibody, or a fully human antibody.

In some embodiments of the first through seventh aspects, the anti-β-Klotho antibody is a monoclonal antibody.

In some embodiments of the first to seventh aspects, the anti-β-Klotho antibody is of the IgM, IgD, IgA, IgA, or IgE type. In some embodiments, the anti-β-Klotho antibody is an IgG antibody. In some more specific embodiments, the anti-β-Klotho antibody is an IgGl antibody.

In some embodiments of the first through seventh aspects, the anti-β-Klotho antibody is of the IgG1, IgG2, or IgG4 isotype.

In some embodiments of the first to seventh aspects, the anti-β-Klotho antibody is of the chimeric IgG1/IgG4, IgG2/IgG4, or IgG1/IgG2 type.

In some embodiments of the first through seventh aspects, the anti-β-Klotho antibody comprises a kappa isoform or a lambda isoform of a light chain constant region.

In some embodiments of the first to seventh aspects, the anti-β-Klotho antibody comprises a human IgG1 heavy chain constant region and a human kappa light chain constant region.

In some embodiments of the first through seventh aspects, the anti-β-Klotho antibody or antigen-binding portion thereof is for use in drug therapy.

In some embodiments of the first to seventh aspects, the anti-β-Klotho antibody or antigen-binding portion thereof has ADCC (antibody-dependent cytotoxicity) or CDC (complement-dependent cytotoxicity) activity.

In some embodiments of the first through seventh aspects, the anti-β-Klotho antibody comprises a wild-type Fc region.

In some embodiments of the first to seventh aspects, the anti-β-Klotho antibody or antigen-binding portion thereof is modified to have enhanced ADCC or CDC activity.

In some embodiments of the first to seventh aspects, the anti-β-Klotho antibody or antigen-binding portion thereof is modified such that it has reduced ADCC or CDC activity.

With respect to the βKlotho target and in vivo use of the antibody contemplated in this application, an antibody with reduced or even eliminated ADCC or CDC activity may be preferred, since excessively strong FC influence may interfere with or even weaken the efficacy of the antibody. Methods for reducing or eliminating Fc influence are known in the art, such as 1) modification of amino acid residues by mutation (preferably weakening binding to the corresponding receptors), 2) modifications by glycosylation, and 3) βC4 modification of the antibody.

In some embodiments of the first to seventh aspects, the anti-β-Klotho antibody has a heavy chain variable region as set forth in SEQ ID NO: 49, a light chain variable region as set forth in SEQ ID NO: 44, a heavy chain constant region as set forth in SEQ ID NO: 50, and a light chain constant region as set forth in SEQ ID NO: 51.

In an eighth aspect of the present application, there is provided an isolated nucleic acid molecule encoding an anti-β-Klotho antibody or an antigen-binding portion thereof according to aspects one to seven. In some embodiments, there is provided a combination of isolated polynucleotides comprising a polynucleotide encoding a light chain of an antibody of the present application or an antigen-binding portion thereof and a polynucleotide encoding a heavy chain of an antibody of the present application or an antigen-binding portion thereof. In some embodiments, the polynucleotide is operably linked to a regulatory sequence that can be recognized by host cells transformed with the vector.

In a ninth aspect of the present application, there is provided a vector (eg, an expression vector) comprising a nucleic acid molecule or a combination of polynucleotides according to the eighth aspect.

In some embodiments, the expression vector of this application comprises a nucleic acid molecule or a combination of polynucleotides described herein, operably linked to a regulatory sequence that allows expression of the polypeptide encoded by the polynucleotides in a host cell or cell-free expression system. The choice of expression vector depends on the choice of host cells, and can be selected to have the desired expression and regulatory characteristics in the selected host cells.

An "expression vector" is a vector containing one or more expression control sequences. An "expression control sequence" is a DNA sequence that controls and regulates the transcription and/or translation of another DNA sequence.

The nucleic acid in the vector may be operably linked to one or more expression control sequences. As used herein, the term "operably linked" means inserted into a genetic construct such that the expression control sequence effectively controls expression of the target coding sequence. 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 typically within 100 nucleotides upstream of a transcription initiation site (usually near the RNA polymerase II start site). In order for a coding sequence to be under the control of a promoter, the translation initiation site of the reading frame of the polypeptide to be translated must be located within 1 to 50 nucleotides downstream of the promoter. Enhancers provide specificity of expression in terms of timing, position, and level. Unlike promoters, enhancers can function at various distances from the transcription site. Enhancers can also be located downstream of the transcription initiation site. When RNA polymerase is able to transcribe a coding sequence into mRNA, which can then be translated into the protein encoded by the coding sequence, the coding sequence is "operably linked" to the expression regulatory sequence in the cell and is "under the control" of the expression regulatory sequence.

Suitable vectors include plasmids and viral vectors derived from, for example, phages, baculoviruses, tobacco mosaic viruses, herpes viruses, cytomegaloviruses, retroviruses, vaccinia viruses, adenoviruses, and adeno-associated viruses, but are not limited to. A variety of vectors and expression systems are commercially available from companies such as Novagen (Madison, WI), Clontech (Palo Alto, CA), Stratagene (LaJolla, CA), and Lrvitrogen Life Technologies (Carlsbad, CA).

The expression vector may contain a marker sequence. The marker sequence is typically expressed as a fusion with the encoded polypeptide. Such markers may be inserted at any position within the polypeptide, including the carboxy- or amino-terminus. Examples of useful markers include Fc fragments, polyhistidine, green fluorescent protein (GFP), glutathione S-transferase (GST), c-myc, hemagglutinin, Flag™ markers (Kodak, NewHaven, CT), maltose E binding protein, and protein A. In some embodiments, a nucleic acid molecule encoding a β-Klotho fusion polypeptide is in a vector comprising a nucleic acid encoding one or more domains of an Ig heavy chain constant region, such as, but not limited to, an amino acid sequence (Fc fragment) corresponding to the hinge region, CH2 region, and CH3 region of the Cγ1 chain of a human immunoglobulin.

In a tenth aspect of the present application, there is provided a host cell comprising 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 cell, a eukaryotic cell or a phage. The prokaryotic host cell may be Escherichia coli, Bacillus subtilis, Streptomyces or Proteus mirabilis. The eukaryotic host cell may be a fungus such as Pichia pastoris, Saccharomyces cerevisiae, Schizosaccharomyces cerevisiae or Trichoderma, an insect cell such as a caterpillar or a plant cell such as tobacco, or a mammalian cell such as a BHK cell (Syrian baby hamster kidney cell), a CHO cell (Chinese hamster ovary cell), a COS cell (African green monkey cell) or a myeloma cell. In some embodiments, the host cells described herein are preferably mammalian cells, more preferably BHK cells, CHO cells, NSO cells or COS cells.

In an eleventh aspect of the present application there is provided an antibody-drug conjugate, also referred to as an ADC, comprising an anti-β-Klotho antibody or antigen-binding portion thereof according to any embodiment of the first to seventh aspects, conjugated to a therapeutic substance.

In a twelfth aspect of the present application there is provided a pharmaceutical composition comprising an anti-β-Klotho antibody or antigen-binding portion thereof according to aspects one to seven or an antibody-drug conjugate according to the eleventh aspect and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is for treating a disease mediated by βKlotho or βKlotho-FGFR1c-FGF21, such as a disease requiring treatment that stimulates or enhances the effect of FGF19 and/or FGF21 in vivo. In some particular embodiments, the disease is 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.

In some embodiments, the pharmaceutical composition may further comprise one or more lubricating agents (such as talc, magnesium stearate, and mineral oil), wetting agents, emulsifying agents, suspending agents, preservatives (such as benzoic acid, sorbic acid, and calcium propionate), sweetening agents, and/or flavoring agents. In some embodiments, the pharmaceutical compositions may be formulated as tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, suppositories, or capsules.

In some embodiments, the pharmaceutical compositions of this application can be delivered by any pharmaceutically acceptable route of administration, including, but not limited to, oral administration, parenteral administration, nasal administration, rectal administration, intraperitoneal administration, intravascular injection, subcutaneous administration, transdermal administration, and inhalation administration.

In some embodiments, a pharmaceutical composition for therapeutic use may be formulated for storage as a lyophilized formulation or in the form of an aqueous solution by mixing substances having the desired purity with pharmaceutically acceptable carriers or excipients, where applicable.

In a thirteenth aspect of the present application there is provided the use of an anti-βKlotho antibody or antigen-binding portion thereof according to aspects one to seven, 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 the treatment of a disease mediated by βKlotho or βKlotho-FGFR1c-FGF21, such as a disease requiring treatment that stimulates or enhances the effect of FGF19 and/or FGF21 in vivo. In some particular embodiments, the disease is 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.

In a fourteenth aspect of the present application, there is provided a method of treating a βKlotho or βKlotho-FGFR1c-FGF21 mediated disease in a subject (such as a disease requiring treatment that stimulates or enhances the effects of FGF19 and/or FGF21 in vivo), comprising administering to the subject a therapeutically effective amount of an anti-βKlotho antibody or antigen-binding portion thereof according to aspects one to seven, an antibody-drug conjugate according to aspect eleven, or a pharmaceutical composition according to aspect twelfth. In some particular embodiments, the disease is a metabolic disorder, including type 1 diabetes, type 2 diabetes, dyslipidemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, obesity, or any disease, disorder, or condition, without limitation, that typically requires treatment that stimulates or enhances the effects of FGF19 and/or FGF21 in vivo. In some embodiments of the method for treating or preventing a disease, disorder, or condition, the method comprises exposing cells to an antibody to β-klotho in vitro.

In some embodiments of aspects twelve to fourteen, the anti-β-Klotho antibody or antigen-binding portion thereof may be used in therapy alone or in combination with other compositions. For example, the anti-β-Klotho antibody may be administered together with at least one additional therapeutic agent and/or adjuvant. In some embodiments, the additional compounds are therapeutic antibodies other than anti-β-klotho antibodies, including drugs for the treatment of diabetes mellitus, dyslipidemia, NASH, NAFLD, cardiovascular disease, metabolic syndrome, or obesity, such as biguanidines, sulfonylureas, thiazolidinediones, glucagon-like peptide-1 (GLP-1) analogs, peroxisome proliferator-activated receptor (PPAR) gamma agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, bromocriptine formulations, bile acid chelators, insulin, alpha glucosidase inhibitors, sodium glucose cotransporter 2 (SGLT-2) inhibitors, appetite suppressants and weight loss drugs, anti-inflammatory drugs such as aspirin and ibuprofen, and so on, without limitation.

In a fifteenth aspect of the present application, there is provided a conjugate comprising an antibody to β-Klotho or an antigen-binding portion thereof according to aspects one to seven and a detectable label. The detectable label may, for example, be a detectable fluorescent label, a chemiluminescent label or an isotopic label.

In a sixteenth aspect of the present application, there is provided a fusion protein comprising an antibody to β-Klotho or an antigen-binding portion thereof according to aspects one to seven. Examples of antibody fusion proteins include Fab fusion proteins, Fc fusion proteins and single-chain variable fragment (scFv) fusion proteins, which are named depending on the site to which the effector protein (e.g., cytokine) is fused.

In some embodiments of the fifteenth to sixteenth aspects, the conjugate may be formed by synthesizing an anti-β-klotho antibody of this application that is covalently linked to one or more non-antibody active agents via a linker. In some embodiments, the antibody of this application is conjugated or recombinantly fused to a diagnostic, detecting or therapeutic agent or any other molecule. Conjugated or recombinantly fused antibodies may be used, for example, to monitor or predict the onset, occurrence, progression and/or severity of a β-klotho-mediated disease as part of a clinical trial to determine the efficacy of a particular therapy. Such diagnostics and detection may be accomplished, for example, by conjugating the antibody to a detectable marker. Detectable markers include, but are not limited to, enzymes, prosthetic groups, fluorescent markers, chemiluminescent markers, and isotopic markers. In some embodiments, an antibody of this application may be conjugated or fused to a therapeutic moiety or drug moiety (which may also be an antibody-drug conjugate of the eleventh aspect) that modifies a particular biological response. The therapeutic or pharmaceutical moiety is not limited to typical chemotherapeutic agents. For example, the drug moiety may be a protein, peptide, polypeptide, or small molecule toxin having a desired biological activity.

It should be understood that the following detailed description is intended only to enable those skilled in the art to better understand this application and is not intended to limit it in any way. Those skilled in the art may make various modifications and changes to the embodiments described.

DESCRIPTION OF EXAMPLES OF IMPLEMENTING THE INVENTION

Particular embodiments of this application will be described in detail below in connection with the Examples, however, those skilled in the art will understand that the examples given below only illustrate the inventions of this application and should not be considered as limiting the scope of this application.

EXAMPLE 1: Antibody detection based on phage display

To obtain antibodies that specifically bind to human β-Klotho, the inventors carried out work with phage display based on a phage library of a single-chain natural human antibody.

First, the extracellular segment of human β-Klotho protein (R&D systems, 5889-KB-050) was biotinylated for liquid-phase panning. Then, ProX screening of specific antibodies was performed using a phage display library of single-chain natural human antibody (Shanghai Ruizhi Chemical Research Co., Ltd.). In each round of panning, the library was first incubated with streptavidin-coupled Dynabeads to remove non-specific Dynabead conjugates. The library was then panned using biotinylated extracellular segment of human β-Klotho proteins to enrich the phage library for antibodies specific for human β-Klotho. Non-specific antibodies were removed from the phage library by multiple washes, and the phage library antibodies that specifically bind to human β-Klotho were isolated by elution with trypsin or a known anti-β-Klotho antibody (Tab hIgG1 antibody, 5H23 from CN patent 201580016315.8 (NGM)). The eluted phage were infected with Escherichia coli TGI using helper phage M13K07 (New England BioLabs.Inc.) to obtain a library for the next round of panning. Typically, each round of panning includes negative selection, positive selection, washing, elution, and amplification. After each round of panning, if the majority of output clones are non-duplicate single clones, panning was continued for up to 3 rounds based on the sequencing results. Otherwise, if the proportion of repeated sequences is high, panning is terminated at this round. The phage products from each round are saved for subsequent use.

Monoclones were selected from the panned library and grown overnight in 2YT medium containing 100 μg/ml ampicillin and 2% glucose. Overnight monoclonal cultures were transferred to 2YT medium containing 100 μg/ml ampicillin. Induced scFv expression was performed at a final IPTG concentration of 1 mM and at 30°C for 16 h. The supernatant after centrifugation of the bacterial suspension was taken and positive clones were screened using the following method.

ELISA-based binding assay: 100 μl of 1 μg/ml streptavidin was added to a 96-well plate and immobilized on the plate surface overnight at 4°C. After blocking at room temperature, 50 μl of 0.5 μg/ml biotinylated human β-Klotho extracellular segment were added for incubation at room temperature. After washing, 60 μl of blocking solution were added for incubation at room temperature. After incubation with 40 μl of scFv supernatant at room temperature, 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 antibody conjugated with HRP and antibody specific to hIgG-Fc conjugated with HRP were added and incubated at room temperature. After washing, 100 μl of 3,3',5,5'-tetramethylbenzidine (TMB) substrate solution were added and the plate was incubated at room temperature in the dark for 15 minutes. 100 μl of 1 M HCl were added to stop the reaction and the optical density was read at 450 nm.

ELISA-based competition assay: 100 µl of 1 µg/ml streptavidin were added to a 96-well plate and immobilized on the plate surface overnight at 4°C. After blocking at room temperature, 50 µl of 0.5 µg/ml biotinylated extracellular human β-Klotho protein were added for incubation at room temperature. After washing, 60 µl of Tab hIgG1 3 µg/ml were added for incubation at room temperature (blocking solution was added to the control wells with Tab hIgG1 and hIgG1 isotype antibody). Then 40 µl of scFv supernatant were added for incubation at room temperature and Tab hIgG1 antibodies and hIgG1 isotype control were added to the control wells at a final concentration of 1 µg/ml. After washing, anti-Myc antibody conjugated with HRP and antibody specific to hIgG-Fc conjugated with HRP were added for incubation at room temperature. After washing, 100 μl of TMB were added for incubation at room temperature in the dark for 15 minutes. 100 μl of 1 M HCl were added to stop the reaction and the optical density was read at 450 nm.

According to the analysis of the results, if the antibody clone satisfied the condition of _OD450 >0.4 in the ELISA binding assay and the ratio of OD450 (binding in ELISA)/OD450 (competition ELISA)≥2, the antibody clone was considered to be able to specifically bind to human βKlotho, and its antigen-binding epitope was similar to or identical to that of Tab hIgG1 antibody. If the antibody clone satisfied the condition of _OD450 >0.4 in the ELISA binding assay and the ratio of OD450 (binding in ELISA)/OD450 (competition ELISA)<2, the antibody clone was considered to bind to an epitope different from that of Tab hIgG1 antibody. Antibody clones having binding epitopes similar or identical to those of the Tab hIgG1 antibody and having binding epitopes partially different from those of the Tab hIgG1 antibody were selected for sequencing. Finally, twenty-two variable region sequences of antibodies binding to human β-Klotho were obtained, designated 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, respectively. Full-length antibodies containing the above-mentioned variable regions of the antibody were then prepared using the constant region of human IgG1 heavy chain and the constant region of human lambda or kappa light chain.

EXAMPLE 2. Screening for antibodies capable of activating human or monkey FGFR1c/βKlotho receptors using a reporter gene assay

The ability of the full-length antibodies described in Example 1 to activate the human FGFR1c/βKlotho receptor was determined in a reporter gene assay. This method is applied to a stable transgenic cell line. After the human FGFR1c/βKlotho receptor is activated by FGF19 or antibody, it recruits a downstream signaling pathway that results in the phosphorylation of ERK. Phosphorylation of ERK further results in the phosphorylation of Gal4-Elk1 and binding to the USA promoter region of DNA. Transcription of the luciferase reporter gene is then triggered, allowing the activation of the FGFR1c/βKlotho receptor by FGF19 or antibody to be determined by measuring luciferase levels.

The following method was used to construct a stable transgenic cell line with a reporter gene. First, two plasmids carrying the Gal4-Elk1 and 5xUAS-Luc reporters were transferred into rat L6 cells and, after antibiotic selection, stable cell lines expressing the target molecules were obtained. Then, the cells were transfected with plasmids encoding the human FGFR1c and βKlotho genes or the cynomolgus monkey FGFR1c and βKlotho genes, and, after several rounds of antibiotic selection, stable transgenic FGFR1c/ptoioTo/Gal4-Elkl/Luc cell lines were obtained.

Activation of human FGFR1c/βKlotho receptor by antibody was determined using the following method. 40 μl of antibody or FGF19 solution at three times the final concentration were added to a 96-well plate. Stable transgenic cells were then added at the appropriate density in a volume of 80 μl or mixed with the antibody. The mixture was then incubated overnight in an incubator at 37°C, 5% _CO2 and saturated humidity. The next day, luciferase levels in the cells were determined using the One-Glo kit (Promega).

The measurement results regarding the activation of human or monkey FGFR1c/βKlotho receptor by antibodies are shown in the following table.

As shown in the results in Table 1, some of the human β-Klotho antibodies obtained in this application through the phage display library screening technology had an activating effect on human and/or cynomolgus monkey β-Klotho/FGFR1c.

EXAMPLE 3. Determination of antibody binding to human βKlotho, human αKlotho and mouse βKlotho by ELISA

In this Example, the binding of certain antibodies from Example 1 to human βKlotho, human αKlotho, and mouse βKlotho was determined using an ELISA assay as described below. A solution of the extracellular segment of the human βKlotho protein (R&D systems), human αKlotho (R&D systems), and mouse βKlotho (R&D systems) at a certain concentration was added to a 96-well plate with immobilized nickel ions (Pierce), and the plate was incubated overnight at room temperature. The next day, the plate was blocked with PBS/1% BSA, and then antibodies were added to the wells at various concentrations. After incubating the plate for 1.5 hours at room temperature, HRP-labeled anti-human IgG Fab secondary antibody was added to the wells and the plate was incubated for 30 minutes at room temperature. After adding the substrate and allowing the reaction to proceed for 15 minutes at room temperature, a stop solution was added. The OD ₄₅₀ values were read. The exemplary antibody binding data to human βKlotho, human αKlotho, and mouse βKlotho in the ELISA assay are as follows.

As shown in Table 2, the antibodies CB-1, CB-6, CB-8, CB-10, CB-16, CB-23 and CB-28 to human β-Klotho of this application can specifically bind to human β-Klotho. CB-1, CB-6, CB-8 and CB-10 do not bind to human α-Klotho and are highly selective for human β-Klotho protein. In addition, some antibodies of this application, such as CB-10, can bind to mouse β-Klotho.

EXAMPLE 4. Determination of antibody affinity using the Biacore assay

The binding affinity of CB-1, CB-6, CB-8, and CB-10 antibodies was determined using the Biacore affinity assay. Their binding affinity to human β-Klotho was assessed by determining the equilibrium dissociation constants (KD) of purified antibodies. Specifically, an anti-His tag antibody was immobilized on a CM5 chip using a histidine-tagged capture agent in a flow cell. The extracellular segment of human β-Klotho proteins (~80RU) was captured in the flow cells. Purified antibodies (in 0.005% Tween in 2% HEPES buffer) were then injected at a flow rate of 30 L/min and the binding kinetics were assessed at 25°C. The results are shown below.

As shown by the data in Table 3, the anti-human β-Klotho antibodies of this application, such as CB-1, CB-6, CB-8 and CB-10, have strong binding affinity for human β-Klotho.

EXAMPLE 5. Modification accompanied by affinity maturation of antibodies

Affinity maturation modifications were performed on the human β-Klotho antibodies of this application using a phage display method. The CB-8 antibody is used as an example to describe the affinity maturation method below.

The variable region gene sequence of the CB-8 antibody was inserted into a phage-plasmid vector, and the following four rich mutant libraries were constructed using the phage-plasmid vector as a template: 1) a rich mutant library containing combinations of single point mutations having a random mutated amino acid in each of the light chain CDR1, light chain CDR3, and heavy chain CDR3; 2) a rich mutant library containing combinations of single point mutations having a random mutated amino acid in each of the light chain CDR2, heavy chain CDR1, and heavy chain CDR2; 3) a rich mutant library containing combinations of two point mutations having random mutations of two adjacent amino acids in the light chain CDR3; and 4) a rich mutant library containing combinations of two point mutations having random mutations of two adjacent amino acids in the heavy chain CDR3. Plasmids in four rich mutant libraries were inserted into phage libraries that met capacity requirements, and the diversity of the phage libraries was determined by sequencing.

The extracellular segment of human β-Klotho protein (Kactus Biosystems) was used for panning of phages from libraries. The extracellular segment of human β-Klotho protein was immobilized on the surface of an immunoassay tube, which was then blocked with a blocking solution of 5% milk in PBS. Phage at an appropriate concentration were added to the immunoassay tube and incubated for 2 hours at room temperature. The immunoassay tube was washed several times with PBST and then three times with PBS. Finally, phages bound to the extracellular segment of human β-Klotho protein were eluted with 0.25% trypsin and collected. The collected phages were used to infect E. coli SS320, thereby amplifying the phages. The amplified phages were collected and panned again using the method described above. A total of three rounds of panning were performed.

After panning, monoclonal clones were selected from the libraries for amplification, and positive clones that bound to human β-Klotho protein were detected by ELISA. These positive clones were then sequenced. The method for detecting phage binding to human β-Klotho protein by ELISA is described below. Human β-Klotho protein was immobilized on the surface of a 96-well plate, and then the plate was blocked with a blocking solution of 5% milk in PBS. Phage supernatants were added for incubation at room temperature for one hour. The plate was washed with PBST and then incubated with HRP-labeled anti-M13 antibody for one hour. After several washes, TMB substrate solution was added for incubation at room temperature for 5-10 minutes. Finally, 2 M _H2SO4 was added to _stop the reaction and the optical density was read at 450 nm.

The titers of positive clones were determined, and then the binding of the phages to different titers of human β-Klotho protein was determined using ELISA. The affinity of the positive antibodies was ranked according to the approximated binding curve. Based on the ranking results, the variable region sequences of the top 8 in terms of antibody binding affinity were selected. The sequences are presented in the table below.

The variable region sequences of eight CB-8 derived antibodies and the original CB-8 sequence were used to generate full-length antibodies using the human IgG1 heavy chain constant region and the human kappa light chain constant region. The sequences of the CDRs and variable regions in this application are as follows:

The antibodies described above were affinity tested using Gator (Gator bio). Briefly, the antibody was first immobilized using a protein A probe (Gator bio). After baseline monitoring for 60 seconds, antibody-antigen binding to the above-described extracellular segment of human β-Klotho protein at different concentrations (400 nM-50 nM) was determined. Dissociation was then determined in buffer K (Gator bio). Meanwhile, the function of the antibody to activate the human or cynomolgus monkey FGFR1c/β-Klotho receptor was determined using the reporter gene assay described in Example 2. The results are shown in Table 5.

As shown in Table 5, after modification accompanied by affinity maturation, the binding affinities of all modified antibodies to human βKlotho, human βKlotho/FGFR1c, and cynomolgus monkey βKlotho/FGFR1c were significantly improved compared with the CB-8 antibody before modification.

EXAMPLE 6. Modification of a possible post-translational modification site

In this application, the CDRs were further analyzed in detail in antibodies after modification accompanied by affinity maturation. Below, the antibody CB-8-24 is used as an example to describe the method of modifying a possible post-translational modification site.

Sequence analysis revealed that a possible NQ deamination site was present in CDR2 of the heavy chain of CB-8-24, while the corresponding site in CB-8-40 was SG, which avoids potential deamination problems. As an example, a sequence of a new antibody CB-8-42 was designed based on the sequences of CB-8-24 and CB-8-40. The sequence of the human IgG1 heavy chain constant region (E233A/L235A) and the sequence of the human kappa chain constant region were used to generate a full-length antibody containing the VH and VL of CB-8-42.

The function of the full-length CB-8-42 antibody to activate human or monkey FGFR1c/βKlotho receptor was determined using the reporter gene assay as described in Example 2. The results (see Table 6) showed that the activating effect of CB-8-42 on FGFR1c/βKlotho receptor was significantly stronger than that of the control antibody. In particular, the maximal cellular response of CB-8-42 was higher than that of the control antibody. The results are shown in Fig. 1. Meanwhile, the activating function of the antibodies to FGFR2c/βKlotho, FGFR3c/βKlotho or FGFR4/βKlotho was determined using the same method. The results showed that CB-8-42 could not activate FGFR2c/βKlotho, FGFR3c/βKlotho or FGFR4/βKlotho receptor, demonstrating its superior specificity for human FGFR1c/βKlotho.

Taking into account the above results, the anti-human β-Klotho antibodies of the present application, in particular CB-8-42, show better performance than the control antibody (5H23, the sequence of which is taken from the 5H23 antibody described in patent CN 201580016315.8 (NGM)) in such parameters as binding ability or binding specificity, or the ability to activate the receptor. For example, as shown in Fig. 1 and Table 6, the ability of CB-8-42 to activate human FGFR1c/β-Klotho is almost twice that of the control antibody, and its maximum relative activity is significantly better than that of the control antibody (Fig. 1).

EXAMPLE 7. In vivo pharmacodynamic study in animals

In this Example, the efficacy of the anti-human β-Klotho antibody was assessed in vivo in an in vivo efficacy assessment animal model (using the cynomolgus macaque as an example).

In this application, the potential metabolism-improving effect of an antibody to human β-Klotho (using CB-8-42 as an example) was investigated in a cynomolgus macaque obesity model. The in vivo efficacy of the antibody of this application was assessed by monitoring changes in food intake, body weight, BMI, and biochemical parameters (fasting blood glucose, insulin, triglycerides, cholesterol, low-density lipoprotein, high-density lipoprotein, liver fat content, etc.) in cynomolgus macaques following antibody injection.

In the present study, ten obese male cynomolgus macaques (>11 years old, weighing >8.5 kg, and having liver fat content ≥8% by MRI) were recruited. According to body weight and liver fat content, the animals were randomly divided into vehicle group (n=5) and antibody group (n=5), and acclimatized for 2 weeks. During this period, clinical observations and food intake statistics were collected daily, and body weight measurements and BMI calculations were performed weekly. Meanwhile, basic blood biochemical parameters including fasting blood glucose, insulin, triglycerides, cholesterol, low-density lipoprotein, and high-density lipoprotein were determined before administration. Following a 2-week acclimation period, animals received subcutaneous injections of vehicle (20 mM histidine buffer, 4.5% sorbitol, pH 5.7) or anti-β-Klotho antibody (CB-8-42, 10 mg/kg) on days 1, 29, and 57. Clinical observations and food intake statistics were collected daily throughout the study, and body weights were measured weekly. Blood samples were collected from animals after an overnight fast at three weeks (day 22), seven weeks (day 50), and eleven weeks (day 78) after the first dose, and serum glucose, insulin, triglycerides, cholesterol, low-density lipoprotein, and high-density lipoprotein levels were determined. Liver fat content was determined by MRI at six and 12 weeks after the first dose.

Body weight

As shown in Figs. 2-4, there was no significant change in the body weight of the animals receiving the vehicle. In contrast, the body weight of the animals receiving the CB-8-42 antibody to human β-Klotho gradually decreased. By the eleventh week after administration, the body weight of the animals receiving CB-8-42 decreased by an average of 20%. Accordingly, there was no significant change in the BMI of the animals receiving the vehicle, while the BMI of the animals receiving the CB-8-42 antibody to human β-Klotho decreased by an average of 20%.

Food consumption

As shown in Fig. 5, the food intake of the vehicle-treated animals remained essentially stable throughout the experiment, and the food intake was approximately 140 g/day. The food intake of the animals treated with the CB-8-42 antibody to human β-Klotho was significantly reduced after exposure. During the acclimation phase, the average food intake was approximately 112 g/day, and during the antibody exposure phase, the food intake decreased to approximately 78 g/day, a reduction of approximately 30%.

Liver fat content

As shown in Fig. 6, the liver fat content of the vehicle-treated animals gradually increased and there was a statistically significant difference in the liver fat content twelve weeks after exposure compared to before administration (p<0.05). After exposure to the anti-human β-Klotho antibody CB-8-42, the average liver fat content of the animals decreased from 12.1% before administration to 7.5% six weeks after the first dose and remained at 8.1% twelve weeks after exposure. Before administration, the liver fat content of the antibody-treated group was comparable to that of the vehicle-treated group, both were 12.1%. Twelve weeks after receiving the anti-human β-Klotho antibody, the liver fat content of the antibody-treated group was significantly lower than that of the vehicle-treated group (8.1% versus 21.6%, p<0.01).

Fasting blood glucose levels

As shown in Fig. 7, fasting blood glucose in animals receiving vehicle increased slowly during the course of the experiment, whereas fasting blood glucose in animals treated with CB-8-42 antibody to human β-Klotho decreased significantly.

Serum insulin level

As shown in Fig. 8, the serum insulin level of animals receiving the vehicle increased significantly during the experiment, whereas after exposure to the CB-8-42 antibody to human β-Klotho, the serum insulin level of animals decreased significantly.

Serum triglyceride level

As shown in Fig. 9, the serum triglyceride level of animals receiving the vehicle increased significantly during the experiment, whereas after exposure to the CB-8-42 antibody to human β-Klotho, the serum triglyceride level of animals remained stable.

Total serum cholesterol level

As shown in Fig. 10, the total cholesterol level in the serum of animals receiving the vehicle remained stable during the experiment, whereas after exposure to the CB-8-42 antibody to human β-Klotho, the total cholesterol level in the serum of animals decreased significantly.

Serum low-density lipoprotein level

As shown in Fig. 11, the serum LDL level of animals treated with vehicle remained generally stable during the experiment, whereas the serum LDL level of animals treated with CB-8-42 antibody to human β-Klotho was significantly reduced.

Serum high-density lipoprotein level

As shown in Fig. 12, the serum HDL level of animals treated with vehicle and CB-8-42 antibody to human β-Klotho remained stable during the experiment.

According to the above results, the administration of the anti-β-Klotho antibody of the present application can significantly improve the metabolic rate of cynomolgus macaques compared with the vehicle-treated group. The changes in food intake, body weight, BMI, and various biochemical indices such as fasting blood glucose, insulin, triglycerides, cholesterol, low-density lipoprotein, high-density lipoprotein, liver fat content, etc. in cynomolgus macaques demonstrated great promise and possible clinical efficacy of the anti-human β-Klotho antibody of the present application in treating or alleviating diabetes, dyslipidemia, non-alcoholic steatohepatitis (NASH), non-alcoholic steatohepatitis (NAFLD), cardiovascular disease, metabolic syndrome, or obesity. Overall, the results of the in vivo pharmacodynamic animal experiments demonstrate that the human β-Klotho antibody of this application had a significant effect in alleviating the above-described diseases in the cynomolgus macaque obesity model and had good safety in vivo.

The use of embodiments or introductory words before an example (e.g., "such as") in this document is intended only to better illustrate the inventions in this application and does not limit the scope of the inventions unless otherwise required. The language in the description should not be construed as an indication that any element not mentioned in the claims is mandatory for the embodiment of the inventions in this application.

All publications and patent applications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application were individually and specifically indicated to be incorporated by reference. Furthermore, any theory, mechanism, evidence or discovery described herein is intended to further facilitate the understanding of this application and is not intended to limit this application to such theory, mechanism, evidence or discovery in any way. Although this application has been shown and described in detail in the drawings and foregoing description, this application is to be considered illustrative and not limiting.

--->

<?xml version="1.0" encoding="UTF-8"?>

<!DOCTYPE ST26SequenceListing PUBLIC "-//WIPO//DTD Sequence Listing

1.3//EN" "ST26SequenceListing_V1_3.dtd">

<ST26SequenceListing originalFreeTextLanguageCode="en"

nonEnglishFreeTextLanguageCode="ru" dtdVersion="V1_3"

fileName="P24507RU-st26-RU.xml" softwareName="WIPO Sequence"

softwareVersion="2.2.0" productionDate="2024-08-28">

<ApplicationIdentification>

<IPOfficeCode>CN</IPOfficeCode>

<ApplicationNumberText>PCT/CN2022/143127</ApplicationNumberText>

<FilingDate>2022-12-29</FilingDate>

</ApplicationIdentification>

<ApplicantFileReference>P24507RU</ApplicantFileReference>

<EarliestPriorityApplicationIdentification>

<IPOfficeCode>CN</IPOfficeCode>

<ApplicationNumberText>202111683753.3</ApplicationNumberText>

<FilingDate>2021-12-30</FilingDate>

</EarliestPriorityApplicationIdentification>

<ApplicantName languageCode="en">SHANGHAI JMC-BIO TECHNOLOGY

CO., LTD. </ApplicantName>

<ApplicantNameLatin>SHANGHAI JMT-BIO TECHNOLOGY CO.,

LTD.</ApplicantNameLatin>

<InventionTitle languageCode="en">Antibody to β-Klotho and its

application</InventionTitle>

<SequenceTotalQuantity>52</SequenceTotalQuantity>

<SequenceData sequenceIDNumber="1">

<INSDSeq>

<INSDSeq_length>5</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..5</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q52">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>SYGIS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="2">

<INSDSeq>

<INSDSeq_length>17</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..17</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q53">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>WISAYNGNTNYAQKLQG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="3">

<INSDSeq>

<INSDSeq_length>9</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..9</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q54">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>LYGSGSLYY</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="4">

<INSDSeq>

<INSDSeq_length>11</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..11</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q55">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>QASQDIRNYIN</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="5">

<INSDSeq>

<INSDSeq_length>7</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..7</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q56">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>AASSLQS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="6">

<INSDSeq>

<INSDSeq_length>10</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..10</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q57">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>QQSYSTPQWT</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="7">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q58">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>GYTFTSYG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="8">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q59">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>ISAYNGNT</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="9">

<INSDSeq>

<INSDSeq_length>11</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..11</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q60">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>ATLYGSGSLYY</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="10">

<INSDSeq>

<INSDSeq_length>6</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..6</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q61">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>QDIRNY</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="11">

<INSDSeq>

<INSDSeq_length/>

<INSDSeq_moltype/>

<INSDSeq_division/>

<INSDSeq_sequence>000</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="12">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q63">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMG

WISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLYGSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="13">

<INSDSeq>

<INSDSeq_length>108</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..108</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q64">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>DIVMTQSPSSLSAPVGDRVTITCQASQDIRNYINWFQQKPGKAPKLLIY

AASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQWTFGQGTKVEIK</INSDSeq_s

sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="14">

<INSDSeq>

<INSDSeq_length>17</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..17</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q65">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>WISAYNGRTNYAQKLQG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="15">

<INSDSeq>

<INSDSeq_length>7</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..7</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q66">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>AASRLQS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="16">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q67">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>GYRFTSYG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="17">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q68">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>ISAYNGRT</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="18">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q69">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYRFTSYGISWVRQAPGQGLEWMG

WISAYNGRTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLYGSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="19">

<INSDSeq>

<INSDSeq_length>108</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..108</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q70">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>DIVMTQSPSSLSAPVGDRVTITCQASQDIRNYINWFQQKPGKAPKLLIY

AASRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQWTFGQGTKVEIK</INSDSeq_s

sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="20">

<INSDSeq>

<INSDSeq_length>17</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..17</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q71">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>WISAYTGNTNYAQKLQG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="21">

<INSDSeq>

<INSDSeq_length>7</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..7</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q72">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>AASSRQS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="22">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q73">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>GYTFRSYG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="23">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q74">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>ISAYTGNT</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="24">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q75">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYTFRSYGISWVRQAPGQGLEWMG

WISAYTGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLYGSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="25">

<INSDSeq>

<INSDSeq_length>108</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..108</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q76">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>DIVMTQSPSSLSAPVGDRVTITCQASQDIRNYINWFQQKPGKAPKLLIY

AASSRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQWTFGQGTKVEIK</INSDSeq_s

sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="26">

<INSDSeq>

<INSDSeq_length>5</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..5</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q77">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>SGGIS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="27">

<INSDSeq>

<INSDSeq_length>7</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..7</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q78">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>AASFLQS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="28">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q79">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>GYTFTSGG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="29">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q80">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYTFTSGGISWVRQAPGQGLEWMG

WISAYNGRTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLYGSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="30">

<INSDSeq>

<INSDSeq_length>108</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..108</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q81">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>DIVMTQSPSSLSAPVGDRVTITCQASQDIRNYINWFQQKPGKAPKLLIY

AASFLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQWTFGQGTKVEIK</INSDSeq_s

sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="31">

<INSDSeq>

<INSDSeq_length>9</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..9</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q82">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>LLPSGSLYY</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="32">

<INSDSeq>

<INSDSeq_length>11</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..11</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q83">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>ATLLPSGSLYY</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="33">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q84">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMG

WISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLLPSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="34">

<INSDSeq>

<INSDSeq_length>7</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..7</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q85">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>AASGLQS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="35">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q86">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>GYTFKSYG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="36">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q87">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYTFKSYGISWVRQAPGQGLEWMG

WISAYNGRTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLYGSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="37">

<INSDSeq>

<INSDSeq_length>108</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..108</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q88">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>DIVMTQSPSSLSAPVGDRVTITCQASQDIRNYINWFQQKPGKAPKLLIY

AASGLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQWTFGQGTKVEIK</INSDSeq_s

sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="38">

<INSDSeq>

<INSDSeq_length>17</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..17</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q89">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>WISAYSGNTNYAQKLQG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="39">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q90">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>GYAFTSYG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="40">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q91">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>ISAYSGNT</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="41">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q92">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYAFTSYGISWVRQAPGQGLEWMG

WISAYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLYGSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="42">

<INSDSeq>

<INSDSeq_length>7</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..7</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q93">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>AASYLQS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="43">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q94">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMG

WISAYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLYGSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="44">

<INSDSeq>

<INSDSeq_length>108</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..108</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q95">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>DIVMTQSPSSLSAPVGDRVTITCQASQDIRNYINWFQQKPGKAPKLLIY

AASYLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQWTFGQGTKVEIK</INSDSeq_s

sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="45">

<INSDSeq>

<INSDSeq_length>7</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..7</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q96">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>AASHLQS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="46">

<INSDSeq>

<INSDSeq_length>8</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..8</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q97">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>GYLFTSYG</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="47">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q98">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYLFTSYGISWVRQAPGQGLEWMG

WISAYTGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLYGSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="48">

<INSDSeq>

<INSDSeq_length>108</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..108</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q99">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>DIVMTQSPSSLSAPVGDRVTITCQASQDIRNYINWFQQKPGKAPKLLIY

AASHLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQWTFGQGTKVEIK</INSDSeq_s

sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="49">

<INSDSeq>

<INSDSeq_length>118</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..118</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q100">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMG

WISAYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCATLLPSGSLYYWGQGTLVTVSS<

/INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="50">

<INSDSeq>

<INSDSeq_length>330</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..330</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q101">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG

VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPALAG

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL

TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

K</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="51">

<INSDSeq>

<INSDSeq_length>107</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..107</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q102">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>synthetic construct</INSDQualifier_value>

<NonEnglishQualifier_value>synthetic

construction</NonEnglishQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS

GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC</INSDSeq_se

quence>

</INSDSeq>

</SequenceData>

<SequenceData sequenceIDNumber="52">

<INSDSeq>

<INSDSeq_length>1044</INSDSeq_length>

<INSDSeq_moltype>AA</INSDSeq_moltype>

<INSDSeq_division>PAT</INSDSeq_division>

<INSDSeq_feature-table>

<INSDFeature>

<INSDFeature_key>source</INSDFeature_key>

<INSDFeature_location>1..1044</INSDFeature_location>

<INSDFeature_quals>

<INSDQualifier>

<INSDQualifier_name>mol_type</INSDQualifier_name>

<INSDQualifier_value>protein</INSDQualifier_value>

</INSDQualifier>

<INSDQualifier id="q104">

<INSDQualifier_name>organism</INSDQualifier_name>

<INSDQualifier_value>Homo sapiens</INSDQualifier_value>

</INSDQualifier>

</INSDFeature_quals>

</INSDFeature>

</INSDSeq_feature-table>

<INSDSeq_sequence>MKPGCAAGSPGNEWIFFSTDEITTRYRNTMSNGGLQRSVILSALILLRA

VTGFSGDGRAIWSKNPNFTPVNESQLFLYDTFPKNFFWGIGTGALQVEGSWKKDGKGPSIWDHFIHTHLK

NVSSTNGSSDSYIFLEKDLSALDFIGVSFYQFSISWPRLFPDGIVTVANAKGLQYYSTLLDALVLRNIEP

IVTLYHWDLPLALQEKYGGWKNDTIIDIFNDYATYCFQMFGDRVKYWITIHNPYLVAWHGYGTGMHAPGE

KGNLAAVYTVGHNLIKAHSKVWHNYNTHFRPHQKGWLSITLGSHWIEPNRSENTMDIFKCQQSMVSVLGW

FANPIHGDGDYPEGMRKKLFSVLPIFSEAEKHEMRGTADFFAFSFGPNNFKPLNTMAKMGQNVSLNLREA

LNWIKLEYNNPRILIAENGWFTDSRVKTEDTTAIYMMKNFLSQVLQAIRLDEIRVFGYTAWSLLDGFEWQ

DAYTIRRGLFYVDFNSKQKERKPKSSAHYYKQIIRENGFSLKESTPDVQGQFPCDFSWGVTESVLKPESV

ASSPQFSDPHLYVWNATGNRLLHRVEGVRLKTRPAQCTDFVNIKKQLEMLARMKVTHYRFALDWASVLPT

GNLSAVNRQALRYYRCVVSEGLKLGISAMVTLYYPTHAHLGLPEPLLHADGWLNPSTAEAFQAYAGLCFQ

ELGDLVKLWITINEPNRLSDIYNRSGNDTYGAAHNLLVAHALAWRLYDRQFRPSQRGAVSLSLHADWAEP

ANPYADSHWRAAERFLQFEIAWFAEPLFKTGDYPAAMREYIASKHRRGLSSSALPRLTEAERRLLKGTVD

FCALNHFTTRFVMHEQLAGSRYDSDRDIQFLQDITRLSSPTRLAVIPWGVRKLLRWVRRNYGDMDIYITA

SGIDDQALEDDRLRKYYLGKYLQEVLKAYLIDKVRIKGYYAFKLAEEKSKPRFGFFFTSDFKAKSSIQFYN

KVISSRGFPFENSSSRCSQTQENTECTVCLFLVQKKPLIFLGCCFFSTLVLLLSIAIFQRQKRRKFWKAK

NLQHIPLKKGKRVVS</INSDSeq_sequence>

</INSDSeq>

</SequenceData>

</ST26SequenceListing>

<---

Claims (69)

1. An anti-β-Klotho antibody or 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), and wherein: (a1) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 42, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (a2) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 2, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 5, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (a3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 15, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (a4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 20, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 21, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (a5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 26, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 27, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (a6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 2, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 31, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 5, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (a7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 14, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 34, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (a8) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 27, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (a9) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 38, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 42, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (a10) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 1, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 20, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 3, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 4, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 45, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; where the HCDR and LCDR sequences in (a1)-(a10) are defined as defined by Kabat; or (b1) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; (b2) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 8, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (b3) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 16, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (b4) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 22, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (b5) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 28, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (b6) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 8, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 32, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (b7) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 35, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 17, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (b8) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 39, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (b9) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 7, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 40, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; or (b10) the HCDR1 sequence is the sequence set forth in SEQ ID NO: 46, the HCDR2 sequence is the sequence set forth in SEQ ID NO: 23, the HCDR3 sequence is the sequence set forth in SEQ ID NO: 9, the LCDR1 sequence is the sequence set forth in SEQ ID NO: 10, the LCDR2 sequence is the sequence set forth in SEQ ID NO: 11, and the LCDR3 sequence is the sequence set forth in SEQ ID NO: 6; where the HCDR and LCDR sequences in (b1)-(b10) are defined according to the IMGT definition. 2. The β-Klotho antibody or antigen-binding portion thereof according to claim 1, wherein the heavy chain variable region has an amino acid sequence as set forth in SEQ ID NO: 49, 12, 18, 24, 29, 33, 36, 41, 43 or 47, or has an amino acid sequence that has an identity of at least 80%, at least 85%, at least 90%, at least 95% or at least 99% with the amino acid sequence as set forth in SEQ ID NO: 49, 12, 18, 24, 29, 33, 36, 41, 43 or 47. 3. The β-Klotho antibody or antigen-binding portion thereof according to claim 1 or 2, wherein the light chain variable region has an amino acid sequence as set forth in SEQ ID NO: 44, 13, 19, 25, 30, 37 or 48, or has an amino acid sequence having an identity of at least 80%, at least 85%, at least 90%, at least 95% or at least 99% with the amino acid sequence as set forth in SEQ ID NO: 44, 13, 19, 25, 30, 37 or 48. 4. An antibody to β-Klotho or an antigen-binding portion thereof according to any one of claims 1-3, wherein (1) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 49 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 44; or (2) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 12 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 13; or (3) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 18 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 19; or (4) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 24 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 25; or (5) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 29 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 30; or (6) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 33 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 13; or (7) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 36 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 37; or (8) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 41 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 30; or (9) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 43 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 44; or (10) the sequence of the variable region of the heavy chain is the sequence set forth in SEQ ID NO: 47, and the sequence of the variable region of the light chain is the sequence set forth in SEQ ID NO: 48. 5. An antibody to β-Klotho or an antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein: (1) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 49 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 44; or (2) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 12 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 13; or (3) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 18 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 19; or (4) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 24 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 25; or (5) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 29 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 30; or (6) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 33 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 13; or (7) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 36 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 37; or (8) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 41 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 30; or (9) the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 43 and the light chain variable region sequence is the sequence set forth in SEQ ID NO: 44; or (10) the sequence of the variable region of the heavy chain is the sequence set forth in SEQ ID NO: 47, and the sequence of the variable region of the light chain is the sequence set forth in SEQ ID NO: 48. 6. The antibody or antigen-binding portion thereof according to any one of claims 1 to 5, wherein the anti-β-Klotho antibody or antigen-binding portion thereof binds to human β-Klotho. 7. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antibody to β-Klotho is an intact antibody or a single-chain variable fragment (scFv). 8. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antigen-binding portion of the antibody to β-Klotho is Fab, Fab', Fv or F(ab') ₂ . 9. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antibody to β-Klotho is a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody. 10. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antibody to β-Klotho is a monoclonal antibody. 11. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antibody to β-Klotho has an IgG1, IgG2 or IgG4 isotype. 12. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antibody to β-Klotho is a chimeric type of IgG1/IgG4, IgG2/IgG4 or IgG1/IgG2. 13. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antibody to β-Klotho comprises a light chain constant region of the kappa subtype or the lambda subtype. 14. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antibody to β-Klotho comprises a constant region of a human IgG1 heavy chain and a constant region of a human kappa light chain. 15. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antibody to β-Klotho comprises a wild-type Fc region or comprises a modified Fc region such that the antibody has reduced ADCC (antibody-dependent cytotoxicity) and/or CDC (complement-dependent cytotoxicity) activities. 16. The antibody or antigen-binding portion thereof according to claim 6, wherein the anti-β-Klotho antibody or antigen-binding portion thereof specifically binds to human β-Klotho. 17. The antibody or antigen-binding portion thereof according to any one of claims 1-5, wherein the antibody has a heavy chain variable region as set forth in SEQ ID NO: 49, a light chain variable region as set forth in SEQ ID NO: 44, a heavy chain constant region as set forth in SEQ ID NO: 50, and a light chain constant region as set forth in SEQ ID NO: 51. 18. An isolated nucleic acid molecule encoding an antibody to β-Klotho or an antigen-binding portion thereof according to any one of claims 1-17. 19. An expression vector comprising a nucleic acid molecule according to claim 18, wherein the expression vector is intended for producing an antibody to β-Klotho or its antigen-binding region according to any one of claims 1-17. 20. A host cell comprising a nucleic acid molecule according to claim 18 or an expression vector according to claim 19, wherein the host cell is intended for producing an antibody to βKlotho or its antigen-binding region according to any one of claims 1-17. 21. A pharmaceutical composition comprising an antibody to β-Klotho or an antigen-binding portion thereof according to any one of claims 1-17 and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is intended for the treatment of a disease mediated by β-Klotho or β-Klotho-FGFR1c-FGF21. 22. Use of an antibody to β-Klotho or an antigen-binding portion thereof according to any one of claims 1-17 in the manufacture of a medicament for the treatment of a disease mediated by β-Klotho or β-Klotho-FGFR1c-FGF21. 23. The use according to claim 22, wherein the disease is a metabolic disorder. 24. Use according to claim 23, wherein the disease is type 1 diabetes, type 2 diabetes, dyslipidemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome or obesity. 25. A method for treating a disease mediated by βKlotho or βKlotho-FGFR1c-FGF21 in a subject, comprising administering to the subject a therapeutically effective amount of an antibody to βKlotho or an antigen-binding portion thereof according to any one of claims 1-17 or a pharmaceutical composition according to claim 21. 26. The method according to claim 25, wherein the disease is a metabolic disorder. 27. The method of claim 26, wherein the disease is type 1 diabetes, type 2 diabetes, dyslipidemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, or obesity.