Human gm-csf antigen binding proteins

Abstract

Antigen binding proteins that bind to human GM-CSF protein are provided. Nucleic acids encoding the antigen binding protein, vectors, and cells encoding the same are also provided. The antigen binding proteins can inhibit binding of GM-CSF to GM-CSFR, inhibit GM-CSF-induced proliferation and signaling of myeloid lineage cell lines and inhibit GM-CSF-induced activation of human monocytes.

What is claimed is: 
     
         1 . An isolated antigen binding protein that binds GM-CSF, comprising:
 A) one or more heavy chain complementary determining regions (CDRHs) selected from the group consisting of:   (i) a CDRH1 selected from the group consisting of SEQ ID NO: 10, 22, 70 94 and 142;   (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 11, 23, 28, 35, 47, 59, 71, 95, 106, 119 and 143;   (iii) a CDRH3 selected from the group consisting of SEQ ID NO: 12, 24, 36, 48, 60, 72, 83, 96, 108, 120, 132, and 144; and   (iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 4 amino acids;   B) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of:   (i) a CDRL1 selected from the group consisting of SEQ ID NO: 4, 16, 30, 40, 52, 64, 88, 100, 107, 112, 118, 124, 125 and 136;   (ii) a CDRL2 selected from the group consisting of SEQ ID NO: 5, 17, 29, 34, 41, 65, 77, 101, 113, 130, 131 and 137;   (iii) a CDRL3 selected from the group consisting of SEQ ID NO: 6, 18, 42, 46, 66, 78, 84, 89, 90, 102, 114, 126, and 138; and   (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 4 amino acids; or   C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B).   
     
     
         2 . The isolated antigen-binding protein of  claim 1  that comprises at least one CDRH of A) and at least one CDRL of B). 
     
     
         3 . The isolated antigen-binding protein of  claim 1  that comprises at least two CDRH of A) and at least two CDRL of B). 
     
     
         4 . The isolated antigen-binding protein of  claim 1  that comprises said CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3. 
     
     
         5 . The isolated antigen binding protein of  claim 1 , wherein
 said CDRH of A) is selected from the group consisting of:
 (i) a CDRH1 selected from the group consisting of SEQ ID NO: 10, 22, 70 94 and 142; 
 (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 11, 23, 28, 35, 47, 59, 71, 95, 106, 119 and 143; 
 (iii) a CDRH3 selected from the group consisting of SEQ ID NO: 12, 24, 36, 48, 60, 72, 83, 96, 108, 120, 132, and 144; and 
 (iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids; said CDRL of B) is selected from the group consisting of: 
 (i) a CDRL1 selected from the group consisting of SEQ ID NO: 4, 16, 30, 40, 52, 64, 88, 100, 107, 112, 118, 124, 125 and 136; 
 (ii) a CDRL2 selected from the group consisting of SEQ ID NO: 5, 17, 29, 34, 41, 65, 77, 101, 113, 130, 131 and 137; 
 (iii) a CDRL3 selected from the group consisting of SEQ ID NO: 6, 18, 42, 46, 66, 78, 84, 89, 90, 102, 114, 126, and 138; and 
 (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids; or 
 C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B). 
   
     
     
         6 . The isolated antigen binding protein of  claim 1  comprising
 A) a CDRH selected from the group consisting of 
 (i) a CDRH1 selected from the group consisting of SEQ ID NO: 10, 22, 70 94 and 142; 
 (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 11, 23, 28, 35, 47, 59, 71, 95, 106, 119 and 143; 
 (iii) a CDRH3 selected from the group consisting of SEQ ID NO: 12, 24, 36, 48, 60, 72, 83, 96, 108, 120, 132, and 144; 
 B) a CDRL selected from the group consisting of 
 (i) a CDRL1 selected from the group consisting of SEQ ID NO: 4, 16, 30, 40, 52, 64, 88, 100, 107, 112, 118, 124, 125 and 136; 
 (ii) a CDRL2 selected from the group consisting of SEQ ID NO: 5, 17, 29, 34, 41, 65, 77, 101, 113, 130, 131 and 137; 
 (iii) a CDRL3 selected from the group consisting of SEQ ID NO: 6, 18, 42, 46, 66, 78, 84, 89, 90, 102, 114, 126, and 138; or 
 C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B). 
 
     
     
         7 . The isolated antigen binding protein of  claim 6 , wherein said antigen binding protein comprises
 A) a CDRH1 of SEQ ID NO: 10, 22, 70 and 142 a CDRH2 of SEQ ID NO: 11, 23, 35, 47, 59, 71, 95 and 143, and a CDRH3 of SEQ ID NO: 12, 24, 36, 48, 60, 72, 96, 108, 120, 132, and 144, and   B) a CDRL1 of SEQ ID NO: 4, 16, 40, 52, 64, 88, 100, 112, 124, and 136, a CDRL2 of SEQ ID NO: 5, 17, 29, 41, 65, 77, 89, 101, 113 and 137, and a CDRL3 of SEQ ID NO: 6, 18, 42, 66, 78, 126, and 138.   
     
     
         8 . The isolated antigen binding protein of  claim 1 , wherein said antigen binding protein comprises a heavy chain variable region (VH) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 9, 21, 33, 45, 57, 69, 81, 93, 105, 117, 129, and 141, and/or a light chain variable region (VL) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, and 135. 
     
     
         9 . The isolated antigen binding protein of  claim 8 , wherein the VH has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 9, 21, 33, 45, 57, 69, 81, 93, 105, 117, 129, and 141, and/or the VL has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, and 135. 
     
     
         10 . The isolated antigen binding protein of  claim 8 , wherein the VH is selected from the group consisting of SEQ ID NO: 9, 21, 33, 45, 57, 69, 81, 93, 105, 117, 129, and 141, and/or the VL is selected from the group consisting of SEQ ID NO: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, and 135. 
     
     
         11 . An isolated antigen binding protein that binds GM-CSF, wherein said antigen binding protein comprises:
 A) one or more heavy chain CDRs (CDRHs) selected from the group consisting of:   (i) a CDRH1 selected from the group consisting of SEQ ID NO: 10, 22, 70 94 and 142;   (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 11, 23, 28, 35, 47, 59, 71, 95, 106, 119 and 143;   (iii) a CDRH3 selected from the group consisting of SEQ ID NO: 12, 24, 36, 48, 60, 72, 83, 96, 108, 120, 132, and 144;   B) one or more light chain CDRs (CDRLs) selected from the group consisting of:   (i) a CDRL1 selected from the group consisting of SEQ ID NO: 4, 16, 30, 40, 52, 64, 88, 100, 107, 112, 118, 124, 125 and 136;   (ii) a CDRL2 selected from the group consisting of SEQ ID NO: 5, 17, 29, 34, 41, 65, 77, 101, 113, 130, 131 and 137;   (iii) a CDRL3 selected from the group consisting of SEQ ID NO: 6, 18, 42, 46, 66, 78, 84, 89, 90, 102, 114, 126, and 138; or   C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B).   
     
     
         12 . The isolated antigen binding protein of  claim 11 , wherein said antigen binding protein comprises:
 A) one or more CDRHs selected from the group consisting of:   (i) a CDRH1 selected from the group consisting of SEQ ID NO: 10, 22, 70 94 and 142;   (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 11, 23, 28, 35, 47, 59, 71, 95, 106, 119 and 143;   (iii) a CDRH3 selected from the group consisting of SEQ ID NO: 12, 24, 36, 48, 60, 72, 83, 96, 108, 120, 132, and 144;   B) one or more CDRLs selected from the group consisting of:   (i) a CDRL1 selected from the group consisting of SEQ ID NO: 4, 16, 30, 40, 52, 64, 88, 100, 107, 112, 118, 124, 125 and 136;   (ii) a CDRL2 selected from the group consisting of SEQ ID NO: 5, 17, 29, 34, 41, 65, 77, 101, 113, 130, 131 and 137;   (iii) a CDRL3 selected from the group consisting of SEQ ID NO: 6, 18, 42, 46, 66, 78, 84, 89, 90, 102, 114, 126, and 138; or   C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B).   
     
     
         13 . The isolated antigen binding protein of  claim 1 , wherein said antigen binding protein is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antibody fragment thereof. 
     
     
         14 . The isolated antigen binding protein of  claim 13 , wherein said antibody fragment is a Fab fragment, a Fab′ fragment, a F(ab′) 2  fragment, a Fv fragment, a diabody, or a single chain antibody molecule. 
     
     
         15 . The isolated antigen binding protein of  claim 13 , wherein said antigen binding protein is a human antibody. 
     
     
         16 . The isolated antigen binding protein of  claim 13 , wherein said antigen binding protein is a monoclonal antibody. 
     
     
         17 . The isolated antigen binding protein of  claim 1  wherein said antigen binding protein is of the IgG1-, IgG2- IgG3- or IgG4-type. 
     
     
         18 . The isolated antigen binding protein of  claim 17 , wherein said antigen binding protein is of the IgG1- or IgG2-type. 
     
     
         19 . The isolated antigen binding protein of any of  claims 1 , wherein said antigen binding protein is coupled to a labeling group. 
     
     
         20 . The isolated antigen binding protein of  claim 1 , wherein said antigen binding protein inhibits binding of GM-CSF to the extracellular portion of human GM-CSF. 
     
     
         21 . A nucleic acid molecule encoding the antigen binding protein according to  claim 1 . 
     
     
         22 . The nucleic acid molecule according to  claim 21 , wherein said nucleic acid molecule is operably linked to a control sequence. 
     
     
         23 . A vector comprising a nucleic acid molecule according to  claim 21 . 
     
     
         24 . A vector comprising a nucleic acid molecule according to  claim 22 . 
     
     
         25 . A host cell comprising the nucleic acid molecule according to  claim 22 . 
     
     
         26 . A host cell comprising the vector according to  claim 24 . 
     
     
         27 . A method of making the antigen binding protein according to  claim 1 , comprising the step of preparing said antigen binding protein from a host cell that secretes said antigen binding protein. 
     
     
         28 . A pharmaceutical composition comprising at least one antigen binding protein according to  claim 1 , and pharmaceutically acceptable excipient. 
     
     
         29 . The pharmaceutical composition of  claim 28 , further comprises an additional active agent. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein said additional active agent is selected from the group consisting of a radioisotope, radionuclide, a toxin, or a therapeutic and a chemotherapeutic group. 
     
     
         31 . A method for treating or preventing a condition associated with GM-CSF in a patient, comprising administering to a patient in thereof an effective amount of at least one isolated antigen binding protein according to  claim 1 . 
     
     
         32 . A method of  claim 31 , wherein the condition is selected from the group consisting of rheumatic disorders, autoimmune disorders, hematological disorders, oncological disorders, inflammatory disorders, degenerative conditions of the nervous system, gastrointestinal, gastrourinary disorders and endocrine disorders. 
     
     
         33 . A method of  claim 31 , wherein the condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, asthma, psoriasis, atopic dermatitis and sarcoidosis. 
     
     
         34 . A method of  claim 31 , wherein the isolated antigen-binding protein is administered alone or as a combination therapy. 
     
     
         35 . A method of inhibiting binding of GM-CSF to the extracellular portion of GM-CSFR in a patient comprising administering an effective amount of at least one antigen binding protein according to  claim 1 . 
     
     
         36 . A method of inhibiting GM-CSF activity in a patient comprising administering an effective amount of at least one antigen binding protein according to  claim 1 . 
     
     
         37 . A method of  claim 36 , wherein the GM-CSF activity is selected from the group consisting of differentiation, survival, proliferation and activation of myeloid lineage cells.