Human Anti-NGF Neutralizing Antibodies As Selective NGF Pathway Inhibitors

Abstract

This invention provides antibodies that interact with or bind to human nerve growth factor (NGF) and neutralize the function of NGF thereby. The invention also provides pharmaceutical compositions of said antibodies and methods for neutralizing NGF function, and particularly for treating NGF-related disorders (e.g., chronic pain) by administering a pharmaceutically effective amount of anti-NGF antibodies. Methods of detecting the amount of NGF in a sample using anti-NGF antibodies are also provided.

1 . An isolated antibody or an antigen-binding fragment thereof that binds specifically to nerve growth factor (NGF), wherein the antibody or fragment comprises a heavy chain variable region and a light chain variable region,
 wherein the heavy chain variable region comprises a CDR1 selected from SEQ ID NO: 22, SEQ ID NO: 92, SEQ ID NO: 98, SEQ ID NO: 104, SEQ ID NO: 110, or SEQ ID NO: 116; a CDR2 selected from SEQ ID NO: 18, SEQ ID NO: 93, SEQ ID NO: 99, SEQ ID NO: 105, SEQ ID NO: 111, or SEQ ID NO: 117; and a CDR3 selected from SEQ ID NO: 14, SEQ ID NO: 94, SEQ ID NO: 100, SEQ ID NO: 106, SEQ ID NO: 112, or SEQ ID NO: 118; and   wherein the light chain variable region comprises a CDR1 selected from SEQ ID NO: 24, SEQ ID NO: 95, SEQ ID NO: 107, SEQ ID NO: 113, SEQ ID NO: 119, SEQ ID NO: 122, SEQ ID NO: 125, SEQ ID NO: 128, or SEQ ID NO: 132; a CDR2 selected from SEQ ID NO: 20, SEQ ID NO: 96, SEQ ID NO: 108, SEQ ID NO: 114, SEQ ID NO: 120, SEQ ID NO: 123, SEQ ID NO: 126, SEQ ID NO: 129, or SEQ ID NO: 133; and a CDR3 selected from SEQ ID NO: 16, SEQ ID NO: 97, SEQ ID NO: 109, SEQ ID NO: 115, SEQ ID NO: 121, SEQ ID NO: 124, SEQ ID NO: 127, SEQ ID NO: 130, or SEQ ID NO: 134.   
     
     
         2 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the heavy chain variable region comprises a sequence selected from SEQ ID NO: 10, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, or SEQ ID NO: 87. 
     
     
         3 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the light chain variable region comprises a sequence selected from SEQ ID NO: 12, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NOs: 88-91, or SEQ ID NO: 131. 
     
     
         4 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody comprises a light chain comprising a sequence of SEQ ID NO: 44 and a heavy chain comprising a sequence selected from SEQ ID NOs: 40-43. 
     
     
         5 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or fragment thereof is a human antibody or fragment thereof. 
     
     
         6 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or fragment thereof neutralizes human NGF bioactivity in a standard in vitro assay with an IC 50  of about 1×10 −8  M or less. 
     
     
         7 . A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         8 . A nucleic acid molecule that encodes the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         9 . A host cell comprising the nucleic acid molecule of  claim 8 . 
     
     
         10 . A recombinant antibody that specifically binds to human NGF comprising a heavy chain variable region and a light chain variable region, wherein the antibody is isolated from a host cell that expresses a heavy chain variable region nucleic acid comprising the sequence of SEQ ID NO: 9 and a light chain variable region nucleic acid comprising the sequence of SEQ ID NO: 11. 
     
     
         11 . The recombinant antibody of  claim 10 , wherein the host cell secretes the antibody and the antibody is isolated from the culture medium of the host cell. 
     
     
         12 . The recombinant antibody of  claim 10 , wherein the host cell is a Chinese Hamster Ovary cell. 
     
     
         13 . A pharmaceutical composition comprising a therapeutically effective amount of the recombinant antibody of  claim 10  and a pharmaceutically acceptable carrier. 
     
     
         14 . A method for treating pain associated with increased expression of NGF or sensitivity to NGF in a patient in need thereof comprising administering to the patient the pharmaceutical composition of  claim 13 . 
     
     
         15 . The method of  claim 14 , wherein the pharmaceutical composition is administered to the patient parenterally. 
     
     
         16 . The method of  claim 14 , wherein the pharmaceutical composition is administered to the patient by subcutaneous or intravenous injection. 
     
     
         17 . The method of  claim 14 , wherein the pain is osteoarthritis pain. 
     
     
         18 . The method of  claim 17 , wherein the osteoarthritis pain is osteoarthritis knee pain. 
     
     
         19 . The method of  claim 14 , wherein the pharmaceutical composition comprises about 3 mg to about 30 mg of the recombinant antibody.