Antigen-binding proteins that activate the leptin receptor

Abstract

The present invention provides antibodies and antigen-binding fragments of antibodies that bind to leptin receptor (LEPR), and methods of using the same. According to certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR and activate LEPR signaling. In other embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind to LEPR and enhance sensitization of LEPR to an antigen. In certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR in the presence and absence of leptin. In certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that induce signaling in cells expressing LEPR mutants that otherwise exhibit defective or impaired signaling in the presence of leptin. The antibodies and antigen-binding fragments of the present invention are useful for the treatment of lipodystrophies and other diseases and disorders associated with or caused by leptin deficiency or leptin resistance.

What is claimed is: 
     
         1 - 14 .(canceled) 
     
     
         15 . A method for treating a disease or condition associated with or caused by a signaling-defective or signaling-impaired leptin receptor (LEPR) mutation in a subject in need thereof, the method comprising administering, to the subject, a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an antibody or antigen-binding fragment thereof that binds LEPR and activates LEPR signaling which comprises a light chain variable region that comprises the LCDRs of a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10; and a heavy chain variable region that comprises the HCDRs of a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, 26 or 34. 
     
     
         16 . The method of  claim 15 , wherein the signaling-defective or signaling impaired LEPR mutation is LEPR-A409E or LEPR-P316T. 
     
     
         17 . The method of  claim 15 , wherein the disease or condition associated with or caused by a signaling-defective or signaling-impaired LEPR mutation is early-onset obesity. 
     
     
         18 - 24 . (canceled) 
     
     
         25 . The method of  claim 15  wherein the antibody or antigen-binding fragment comprises a heavy chain variable region that comprises
 a HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 28, 
 a HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 30, and 
 a HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 32; and 
 a light chain variable region that comprises 
 a LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 12, 
 a LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 14, and 
 a LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16. 
 
     
     
         26 . The method of  claim 15  wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10; and
 a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO:  26 . 
 
     
     
         27 . The method of  claim 26  wherein the antibody or antigen-binding fragment thereof is an antibody. 
     
     
         28 . The method of  claim 27  wherein
 the heavy chain variable region is linked to a human heavy chain constant domain; and 
 the light chain variable region is linked to a human light chain constant domain. 
 
     
     
         29 . The method of  claim 28  wherein the disease or condition is lipodystrophy. 
     
     
         30 . The method of  claim 29  wherein the antibody is administered subcutaneously. 
     
     
         31 . The method of  claim 28  wherein the disease or condition is obesity. 
     
     
         32 . The method of  claim 31  wherein the antibody is administered subcutaneously. 
     
     
         33 . The method of  claim 28  wherein the disease or condition is congenital generalized lipodystrophy. 
     
     
         34 . The method of  claim 28  wherein the disease or condition is acquired generalized lipodystrophy. 
     
     
         35 . The method of  claim 28  wherein the disease or condition is familial partial lipodystrophy. 
     
     
         36 . The method of  claim 28  wherein the disease or condition is acquired partial lipodystrophy. 
     
     
         37 . The method of  claim 28  wherein the disease or condition is abdominal lipodystrophy. 
     
     
         38 . The method of  claim 28  wherein the disease or condition is lipoatrophia annularis. 
     
     
         39 . The method of  claim 28  wherein the disease or condition is localized lipodystrophy. 
     
     
         40 . The method of  claim 28  wherein the disease or condition is HIV-associated lipodystrophy. 
     
     
         41 . A method for treating a disease or condition associated with or caused by a signaling-defective or signaling-impaired leptin receptor (LEPR) mutation in a subject in need thereof, the method comprising administering, to the subject, a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an antibody or antigen-binding fragment thereof that binds LEPR and activates LEPR signaling and competes for binding to LEPR with an antibody that comprises a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10; and a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 26. 
     
     
         42 . A method for treating a disease or condition associated with or caused by a signaling-defective or signaling-impaired leptin receptor (LEPR) mutation in a subject in need thereof, the method comprising administering, to the subject, a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an antibody or antigen-binding fragment thereof that binds LEPR at the same epitope as an antibody that comprises a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10; and a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 26 and activates LEPR signaling.