Human Oncostatin M Antibodies and Methods of Use

Abstract

Antibodies and compositions capable of neutralizing oncostatin M biological functions are useful in treating diseases and disorders associated with oncostatin M, such as osteoarthritis and idiopathic pulmonary fibrosis.

1 . An isolated antibody that specifically binds to human OSM protein and modulates the interaction between human OSM protein and human gp130 protein, comprising a heavy chain complementarity determining region 3 (H-CDR3) selected from the amino acid sequence of SEQ ID NOS: 20 and 21. 
     
     
         2 . The antibody of  claim 1 , further comprising a heavy chain framework 1 sequence, H-CDR1 sequence, framework 2 sequence, H-CDR2 sequence, and framework 3 sequence having the amino acid sequence of SEQ ID NO: 48. 
     
     
         3 . The antibody of  claim 2 , wherein the heavy chain residue S31 contacts the OSM protein having the amino acid sequence of SEQ ID NO: 11 at position Q20 and heavy chain residues T30 and Y52 contact the OSM protein having the amino acid sequence of SEQ ID NO: 11 at position G120. 
     
     
         4 . The antibody of  claim 2 , wherein residues of the human variable light chain framework are derived from a human Vkappa germline gene. 
     
     
         5 . The antibody of  claim 4 , wherein the Vkappa germline gene is an IGKV4 germline gene sequence. 
     
     
         6 . The antibody of  claim 2 , further comprising a light chain variable region comprising SEQ ID NO: 8, wherein X 1  is Y, S, or A; X 2  is K, E, or N; X 3  is Y, W or F; and X 4  is W. 
     
     
         7 . The antibody of  claim 6 , wherein the L-CDR3 sequence comprises an amino acid sequence of SEQ ID NO: 29. 
     
     
         8 . The antibody of  claim 7 , wherein the L-CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 27, 28, 45, and 46. 
     
     
         9 . The antibody of  claim 6 , wherein the L-CDR1 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 23-25 and 30-41. 
     
     
         10 . The antibody of  claim 9 , wherein the L-CDR2 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 26 and 42-44. 
     
     
         11 . An isolated antibody that specifically binds to human OSM protein and modulates the interaction between human OSM and human gp130 protein, comprising a light chain variable region amino acid sequence selected from the group consisting of SEQ ID NOS: 49-53 and/or a heavy chain variable region amino acid sequence selected from the group consisting of SEQ ID NOS: 54 and 55. 
     
     
         12 . The isolated antibody of  claim 11 , wherein the antibody comprises a light chain variable region amino acid sequence of SEQ ID NO: 53 and a heavy chain variable region amino acid sequence SEQ ID NO: 54. 
     
     
         13 . The isolated antibody of  claim 11 , wherein an antibody paratope contacts epitope residues of human OSM protein having the amino acid sequence of SEQ ID NO: 11 at positions Q16, Q20, and G120. 
     
     
         14 . An isolated antibody comprising a light chain variable region amino acid sequence of SEQ ID NO: 51 and a heavy chain variable region amino acid sequence SEQ ID NO: 55. 
     
     
         15 . The isolated antibody of  claim 14 , further comprising a human heavy chain constant region selected from the group consisting of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. 
     
     
         16 . The isolated antibody of  claim 15 , wherein the constant region comprises a human IgG isotype. 
     
     
         17 . The isolated antibody of  claim 16 , wherein the isotype is IgG1. 
     
     
         18 . The isolated antibody of  claim 17 , wherein the constant region is mutated to render the antibody non-lytic. 
     
     
         19 . The isolated antibody of  claim 16 , wherein the constant region is mutated to enhance the affinity of the antibody to the neonatal receptor (FcRn) as compared to an antibody with the wild-type IgG1 constant domain sequence. 
     
     
         20 . The isolated antibody of  claim 19 , wherein the constant region is mutated at positions 428 and 434, wherein the numbering is according to the Kabat EU numbering. 
     
     
         21 . The isolated antibody of  claim 20 , wherein the mutations are M428L and N434S, wherein the numbering is according to the Kabat EU numbering. 
     
     
         22 . An antigen binding fragment of the antibody of  claim 14 . 
     
     
         23 . The antigen binding fragment of  claim 22 , wherein said fragment is selected from the group consisting of a Fab, Fab′, Fd, F(ab) 2 , and ScFv. 
     
     
         24 . A pharmaceutical composition comprising the isolated antibody of  claim 14  and a pharmaceutically acceptable excipient or carrier. 
     
     
         25 . A method of treating a human patient afflicted with a disease or disorder responsive to modulation of the interaction between human OSM protein and human gp130 protein, said method comprising the step of administering to said patient a therapeutically effective amount of the composition of  claim 24 . 
     
     
         26 . The method of  claim 25 , wherein the disease or disorder is an arthropathy selected form the group consisting of osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, neuropathic arthropathy, reactive arthritis, and rotator cuff tear arthropathy. 
     
     
         27 . A method of treating a human patient afflicted with a disease or disorder characterized by the release of pro-inflammatory cytokines and chemokines by macrophages and monocytes, comprising the step of administering to said patient a therapeutically effective amount of the composition of  claim 24 . 
     
     
         28 . A method according to  claim 25 , wherein the disease or disorder is selected from the group consisting of rheumatoid arthritis, juvenile onset arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, chronic plaque disease, lupus erythematosus, inflammatory lung disease, idiopathic pulmonary fibrosis, sepsis, pre-eclampsia, COPD, asthma, and multiple sclerosis. 
     
     
         29 . A method of treating a human patient according to  claim 25 , wherein the patient is afflicted with a fibrotic disease selected from the group consisting of atherosclerosis, diabetic nephropathy, pulmonary fibrosis, idiopathic pulmonary fibrosis, systemic sclerosis, and cirrhosis. 
     
     
         30 . An isolated polynucleotide encoding the heavy chain and/or light chain of the isolated antibody of  claim 14 . 
     
     
         31 . A stably transformed or transfected recombinant host cell comprising the isolated polynucleotide of  claim 30 . 
     
     
         32 . The stably transformed or transfected recombinant host cell of  claim 31 , comprising a vector comprising a polynucleotide encoding the light chain variable amino acid sequence of SEQ ID NO: 53 and a second polynucleotide encoding the heavy chain variable amino acid sequence of SEQ ID NO: 54. 
     
     
         33 . The stably transformed or transfected recombinant host cell of  claim 31 , comprising a vector comprising a polynucleotide encoding the light chain variable amino acid sequence of SEQ ID NO: 51 and a second polynucleotide encoding the heavy chain variable amino acid sequence of SEQ ID NO: 55. 
     
     
         34 . The host cell of  claim 33 , wherein said cell is mammalian. 
     
     
         35 . The host cell of  claim 34 , wherein said cell is CHO. 
     
     
         36 . A process for the manufacture of an antibody, comprising the steps of culturing a host cell of  claim 34  and recovering the antibody from the cell. 
     
     
         37 . A kit comprising a sterile preparation of the isolated antibody of  claim 14  and instructions for the administration of the antibody to a subject in need thereof. 
     
     
         38 . An isolated antibody that specifically binds to human OSM protein, comprising:
 a. a light chain complementarity determining region 1 (L-CDR1) amino acid sequence selected from the group consisting of SEQ ID NOS: 23-25, and 30-41;   b. a light chain complementarity determining region 2 (L-CDR2) amino acid sequence selected from the group consisting of SEQ ID NOS: 26, 42-44; and   c. a light chain complementarity determining region 3 (L-CDR3) amino acid sequence selected from the group consisting of SEQ ID NOS: 10, 27-29, 45, 47.   
     
     
         39 . An isolated antibody that specifically binds to OSM, comprising:
 a. a heavy chain complementarity determining region 1 (H-CDR1) amino acid sequence selected from the group consisting of SEQ ID NOS: 14 and 15;   b. a heavy chain complementarity determining region 2 (H-CDR2) amino acid sequence selected from the group consisting of SEQ ID NOS: 16-18; and   c. a heavy chain complementarity determining region 3 (H-CDR3) amino acid sequence selected from the group consisting of SEQ ID NOS: 19-22.   
     
     
         40 . An isolated antibody that specifically binds to OSM, comprising the H-CDR1, H-CDR2 and HCDR3 of  claim 39  and:
 a. a light chain complementarity determining region 1 (L-CDR1) amino acid sequence selected from the group consisting of SEQ ID NOS: 23-25, and 30-41; 
 b. a light chain complementarity determining region 2 (L-CDR2) amino acid sequence selected from the group consisting of SEQ ID NOS: 26, 42-44; and 
 c. a light chain complementarity determining region 3 (L-CDR3) amino acid sequence selected from the group consisting of SEQ ID NOS: 10, 27-29, 45, 47. 
 
     
     
         41 . An isolated antibody that specifically binds to OSM, comprising:
 an H-CDR1 having an amino acid sequence of SEQ ID NO: 14;   an H-CDR2 having an amino acid sequence of SEQ ID NO: 17;   an H-CDR3 having an amino acid sequence of SEQ ID NO: 21;   an L-CDR1 having an amino acid sequence of SEQ ID NO: 38;   an L-CDR2 having an amino acid sequence of SEQ ID NO: 43; and   an L-CDR3 having an amino acid sequence of SEQ ID NO: 46.   
     
     
         42 . The isolated antibody of  claim 41 , further comprising a human heavy chain constant region selected from the group consisting of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. 
     
     
         43 . The isolated antibody of  claim 42 , wherein the constant region comprises a human IgG isotype. 
     
     
         44 . The isolated antibody of  claim 43 , wherein the isotype is IgG1. 
     
     
         45 . The isolated antibody of  claim 44 , wherein the constant region is mutated to render the antibody non-lytic. 
     
     
         46 . The isolated antibody of  claim 43 , wherein the constant region is mutated to enhance the affinity of the antibody to the neonatal receptor (FcRn) as compared to an antibody with the wild-type IgG1 constant domain sequence. 
     
     
         47 . The isolated antibody of  claim 46 , wherein the constant region is mutated at positions 428 and 434, wherein the numbering is according to the Kabat EU numbering. 
     
     
         48 . The isolated antibody of  claim 47 , wherein the mutations are M428L and N434S, wherein the numbering is according to the Kabat EU numbering. 
     
     
         49 . An antigen binding fragment of the antibody of  claim 41 . 
     
     
         50 . The antigen binding fragment of  claim 49 , wherein said fragment is selected from the group consisting of a Fab, Fab′, Fd, F(ab) 2 , and ScFv. 
     
     
         51 . A pharmaceutical composition comprising the isolated antibody of  claim 41  and a pharmaceutically acceptable excipient or carrier. 
     
     
         52 . An isolated polynucleotide encoding the heavy chain and/or light chain of the isolated antibody of  claim 41 . 
     
     
         53 . A stably transformed or transfected recombinant host cell comprising the isolated polynucleotide of  claim 52 . 
     
     
         54 . The stably transformed or transfected recombinant host cell of  claim 53 , comprising a vector comprising a polynucleotide encoding an L-CDR1 having an amino acid sequence of SEQ ID NO: 38, an L-CDR2 having an amino acid sequence of SEQ ID NO: 43, and an L-CDR3 having an amino acid sequence of SEQ ID NO: 46; and a second polynucleotide encoding an H-CDR1 having an amino acid sequence of SEQ ID NO: 14, an H-CDR2 having an amino acid sequence of SEQ ID NO: 17, and an H-CDR3 having an amino acid sequence of SEQ ID NO: 21 
     
     
         55 . The host cell of  claim 54 , wherein said cell is mammalian. 
     
     
         56 . The host cell of  claim 55 , wherein said cell is CHO. 
     
     
         57 . A process for the manufacture of an antibody, comprising the steps of culturing a host cell of  claim 55  and recovering the antibody from the cell. 
     
     
         58 . Any invention described herein.