Methods of treating FGF21-associated disorders
The present invention relates to monoclonal antibodies and antigen-binding fragments thereof that bind to human β-klotho, and pharmaceutical compositions and methods of treatment comprising the same.
1. An isolated antibody or antigen-binding fragment thereof that specifically binds to the β-klotho sequence (SEQ ID NO: 262), and said antibody or antigen-binding fragment thereof comprises one of:
(i) a heavy chain variable region comprising three heavy chain CDRs, wherein the three heavy chain CDRs comprise SEQ ID NOS: 23, 24, and 25, and a light chain variable region comprising three light chain CDRs, wherein the three light chain CDRs comprise SEQ ID NOS: 33, 34, and 35;
(ii) a heavy chain variable region comprising three heavy chain CDRs, wherein the three heavy chain CDRs comprise SEQ ID NOS: 26, 27, and 28, and a light chain variable region comprising three light chain CDRs, wherein the three light chain CDRs comprise SEQ ID NOS: 36, 37, and 38;
(iii) a heavy chain variable region comprising three heavy chain CDRs, wherein the three heavy chain CDRs comprise SEQ ID NOS: 268, 24, and 25, and a light chain variable region comprising three light chain CDRs, wherein the three light chain CDRs comprise SEQ ID NOS: 33, 34, and 35; and
(iv) a heavy chain variable region comprising three heavy chain CDRs, wherein the three heavy chain CDRs comprise SEQ ID NOS: 269, 270, and 271, and a light chain variable region comprising three light chain CDRs, wherein the three light chain CDRs comprise SEQ ID NOS: 272, 273, and 35.
2. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain sequence (VH) comprising the amino acid sequence of SEQ ID NO: 29 or an amino acid sequence with at least 80%, 90%, 95%, or 97% identity thereof; and a variable light chain sequence (VL) comprising the amino acid sequence of SEQ ID NO: 39 or an amino acid sequence with at least 80%, 90%, 95%, or 97% identity thereof.
3. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain sequence (VH) comprising the amino acid sequence of SEQ ID NO: 29 and a variable light chain sequence (VL) comprising the amino acid sequence of SEQ ID NO: 39.
4. A method of reducing body weight comprising administering to a human subject in need thereof a pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 3 in an amount effective to reduce body weight of the human subject.
5. A method of reducing appetite or food intake comprising administering to a human subject in need thereof a pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 3 in an amount effective to reduce appetite or food intake in the human subject.
6. A method of reducing plasma triglyceride (TG) concentrations or plasma total cholesterol (TC) concentrations in a human subject, comprising administering to the human subject in need thereof a pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 3 in an amount effective to reduce the TG concentrations or the TC concentrations in the human subject.
7. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 or SEQ ID NO: 71 and a light chain comprising the amino acid sequence of SEQ ID NO: 41.
8. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.