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 human antibody that binds specifically to NGF, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence that has at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10, and wherein the light chain variable region comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 12. 
     
     
         2 - 6 . (canceled) 
     
     
         7 . The antibody of  claim 1  which comprises:
 a. a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 10, and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 12; 
 b. a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 14, and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 16; 
 c. a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 18, and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 16; or 
 d. a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 22, and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 16. 
 
     
     
         8 - 12 . (canceled) 
     
     
         13 . The antibody of  claim 1 , comprising:
 a. human heavy chain framework regions, a human heavy chain CDR1 region comprising the sequence of SEQ ID NO: 22, a human heavy chain CDR2 region comprising the sequence of SEQ ID NO: 18, and a human heavy chain CDR3 region comprising the sequence of SEQ ID NO:14; and   b. human light chain framework regions, a human light chain CDR1 region comprising the sequence of SEQ ID NO: 24, a human light chain CDR2 region comprising the sequence of SEQ ID NO: 20, and a human light chain CDR3 region comprising the sequence of SEQ ID NO:16.   
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The antibody of  claim 13 , wherein the antibody dissociates from a human NGF polypeptide with a K D  of about 1×10 −9  or less and neutralizes human NGF bioactivity in a standard in vitro assay with an IC 50  of about 1×10 −8 M or less. 
     
     
         17 - 23 . (canceled) 
     
     
         24 . The antibody of  claim 1 , wherein the antibody is a fully human antibody. 
     
     
         25 . The antibody of  claim 1 , wherein the antibody inhibits NGF signaling. 
     
     
         26 . A method of treating a condition caused by increased expression of NGF or increased sensitivity to NGF in a patient, comprising administering to a patient a pharmaceutically effective amount of the antibody of  claim 25 . 
     
     
         27 . The method of  claim 26 , wherein the condition is acute pain, dental pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immune deficiency syndrome (“AIDS”), toxins, chemotherapy, general headache, migraine, cluster headache, mixed-vascular or non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, fibromyalgia, inflammatory bowel disorders, irritable bowel syndrome, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia or allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, colitis, gastric ulceration, duodenal ulcers, vasomotor or allergic rhinitis, or bronchial disorders, dysmenorrhoea, dyspepsia, gastroesophageal reflux, pancreatitis, or visceralgia. 
     
     
         28 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody of  claim 25 . 
     
     
         29 . (canceled) 
     
     
         30 . A method for detecting NGF in a biological sample comprising:
 a. contacting the sample with the antibody of  claim 1 , under conditions that allow for binding of the antibody to NGF; and   b. measuring the level of bound antibody in the sample.   
     
     
         31 . An isolated human antibody that specifically binds nerve growth factor, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising an amino acid sequence as set forth in 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, and wherein the light chain comprises a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 12, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, or SEQ ID NO: 131. 
     
     
         32 - 48 . (canceled) 
     
     
         49 . The antibody of  claim 31 , wherein the antibody inhibits NGF signaling. 
     
     
         50 . A method of treating a condition caused by increased expression of NGF or increased sensitivity to NGF in a patient, comprising administering to a patient a pharmaceutically effective amount of the antibody of  claim 49 . 
     
     
         51 . The method of  claim 50 , wherein the condition is acute pain, dental pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immune deficiency syndrome (“AIDS”), toxins, chemotherapy, general headache, migraine, cluster headache, mixed-vascular or non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, fibromyalgia, inflammatory bowel disorders, irritable bowel syndrome, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia or allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, colitis, gastric ulceration, duodenal ulcers, vasomotor or allergic rhinitis, or bronchial disorders, dysmenorrhoea, dyspepsia, gastroesophageal reflux, pancreatitis, or visceralgia. 
     
     
         52 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody of  claim 49 . 
     
     
         53 . (canceled) 
     
     
         54 . A method for detecting NGF in a biological sample comprising:
 a. contacting the sample with the antibody of  claim 31 , under conditions that allow for binding of the antibody to NGF; and   b. measuring the level of bound antibody in the sample.   
     
     
         55 . A nucleic acid molecule that encodes the antibody of  claim 31 . 
     
     
         56 . A host cell comprising the nucleic acid of  claim 55 . 
     
     
         57 . An isolated cell line that produces the antibody of  claim 31 . 
     
     
         58 - 67 . (canceled) 
     
     
         68 . An isolated nucleic acid molecule comprising a nucleotide sequence that encodes an amino acid as set forth in any of SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42 SEQ ID NO: 43, SEQ ID NO: 44, or any of SEQ ID NOS: 79-134. 
     
     
         69 - 83 . (canceled)