WSX receptor agonist antibodies

Abstract

The WSX receptor and antibodies which bind thereto (including agonist and neutralizing antibodies) are disclosed, including various uses therefor. Uses for WSX ligands (e.g., anti-WSX receptor agonist antibodies or OB protein) in hematopoiesis are also disclosed.

1 . An agonist antibody which specifically binds to a receptor having a WSX motif, wherein said receptor comprises an extracellular domain, wherein the extracellular domain comprises the extracellular domain sequence within SEQ ID NO: 2.  
     
     
         2 . The antibody of  claim 1  which specifically binds to a human receptor having a WSX motif.  
     
     
         3 . The antibody of  claim 2  which specifically binds to a human receptor variant 13.2.  
     
     
         4 . The antibody of  claim 1  which binds a receptor with a WSX motif with a Kd of no more than about 1×10 −8 M.  
     
     
         5 . The antibody of  claim 4  which binds a receptor with a WSX motif with a Kd of no more than about 1×10 −9 M.  
     
     
         6 . The antibody of  claim 2  which also binds to murine receptor with a WSX motif.  
     
     
         7 . The antibody of  claim 1  which has an IC50 in a KIRA ELISA of about 0.5 micrograms/ml or less.  
     
     
         8 . The antibody of  claim 7  which has an IC50 in a KIRA ELISA of about 0.2 micrograms/ml or less.  
     
     
         9 . The antibody of  claim 8  which has an IC50 in a KIRA ELISA of about 0.1 micrograms/ml or less.  
     
     
         10 . The antibody of  claim 1  which has biological characteristics of antibody 2D7 (ATCC Accession Number HB-12249).  
     
     
         11 . The antibody of  claim 10  which binds to the epitope on a receptor, with a WSX motif, bound by antibody 2D7.  
     
     
         12 . The antibody of  claim 10  which has complementarity determining region (CDR) residues from antibody 2D7.  
     
     
         13 . The antibody of  claim 1  which has the biological characteristics of antibody 1G4 (ATCC Accession Number HB-12243).  
     
     
         14 . The antibody of  claim 13  which binds to the epitope on a receptor, with a WSX motif, bound by antibody 1 G4.  
     
     
         15 . The antibody of  claim 13  which has complementarity determining region (CDR) residues from antibody 1 G4.  
     
     
         16 . The antibody of  claim 1  which has the biological characteristics of antibody 1E11 (ATCC Accession Number HB-12248).  
     
     
         17 . The antibody of  claim 16  which binds to the epitope on WSX receptor bound by antibody 1E11.  
     
     
         18 . The antibody of  claim 16  which has complementarity determining region (CDR) residues from antibody 1E11.  
     
     
         19 . The antibody of  claim 1  which has the biological characteristics of antibody 1C11 (ATCC Accession Number HB-12250).  
     
     
         20 . The antibody of  claim 19  which binds to the epitope on WSX receptor bound by antibody 1C11.  
     
     
         21 . The antibody of  claim 19  which has complementarity determining region (CDR) residues from antibody 1C11.  
     
     
         22 . The antibody of  claim 1  comprising hypervariable region residues of clone 3 antibody (SEQ ID NO:48).  
     
     
         23 . The antibody of  claim 1  comprising hypervariable region residues of clone 4 antibody (SEQ ID NO:49).  
     
     
         24 . The antibody of  claim 1  comprising hypervariable region residues of clone 17 antibody (SEQ ID NO:50).  
     
     
         25 . The antibody of  claim 1  which is a monoclonal antibody.  
     
     
         26 . The antibody of  claim 1  which is a hum an antibody.  
     
     
         27 . The antibody of  claim 1  which is a humanized antibody.  
     
     
         28 . The antibody of  claim 1  which is a n antibody fragment.  
     
     
         29 . The antibody fragment of  claim 28  which is an F(ab′) 2 .  
     
     
         30 . A composition comprising the antibody of  claim 1  and a physiologically acceptable carrier.  
     
     
         31 . The composition of  claim 30  which is sterile.  
     
     
         32 . The composition of  claim 31  which is lyophilized.  
     
     
         33 . The composition of  claim 30  further comprising a cytokine.  
     
     
         34 . A method for activating a WSX receptor comprising exposing the WSX receptor to an amount of the antibody of  claim 1  which is effective for activating the WSX receptor.  
     
     
         35 . A method for enhancing proliferation or differentiation of a cell comprising the WSX receptor comprising exposing the cell to an amount of the antibody of  claim 1  which is effective for enhancing proliferation or differentiation of the cell.  
     
     
         36 . An isolated nucleic acid molecule encoding the antibody of  claim 1 .  
     
     
         37 . A vector comprising the nucleic acid molecule of  claim 36 .  
     
     
         38 . A host cell comprising the nucleic acid molecule of  claim 36 .  
     
     
         39 . A method of producing an agonist antibody which specifically binds to the WSX receptor comprising culturing the host cell of  claim 38  and recovering the antibody from the cell culture.  
     
     
         40 . A method for identifying an antibody which decreases body weight or fat-depot weight or food intake in an obese animal, comprising the steps of: 
 (a) producing agonist antibodies which specifically bind to the extracellular domain of a receptor having a WSX motif comprising the extracellular domain sequence within SEQ ID NO: 2; and    (b) selecting an agonist antibody produced in step (a) which has the ability to decrease body weight or fat-depot weight or food intake in an obese animal.    
     
     
         41 . The method of  claim 40  wherein said obese animal is an ob/ob mouse.  
     
     
         42 . The method of  claim 40  wherein said antibodies produced in step (a) specifically bind to and activates human receptor variant 13.2 (SEQ ID NO: 2).  
     
     
         43 . The method of  claim 40  wherein said antibodies produced in step (a) bind to the extracellular domain of said receptor having a WSX motif with a Kd of no more than about 1×10 −8  M.  
     
     
         44 . The method of  claim 43  wherein said Kd is no more than about 1×10 −9  M.  
     
     
         45 . The method of  claim 42  wherein said antibodies also bind to a murine receptor having a WSX motif.  
     
     
         46 . The method of  claim 40  wherein said antibodies produced in step (a) have an IC50 in a KIRA ELISA of about 0.5 μg/ml or less.  
     
     
         47 . The method of  claim 46  wherein said antibodies have an IC50 in a KIRA ELISA of about 0.2 μg/ml or less.  
     
     
         48 . The method of  claim 47  wherein said antibodies have an IC50 in a KIRA ELISA of about 0.2 μg/ml or less.  
     
     
         49 . The method of  claim 40  wherein said antibodies produced in step (a) have biological characteristics of an antibody selected from the group consisting of antibodies 2D7 (ATCC Accession Number HB-12249), 1 G4 (ATCC Accession Number HB-12243),1E11 (ATCC Accession Number HB-12248) and 1C11 (ATCC Accession Number HB-12250).  
     
     
         50 . The method of  claim 40  wherein said antibodies bind to the epitope bound by an antibody selected from the group consisting of 2D7 (ATCC Accession Number HB-12249),1G4 (ATCC Accession Number HB-12243),1E11 (ATCC Accession Number HB-12248) and 1C11 (ATCC Accession Number HB-12250).  
     
     
         51 . The method of  claim 40  wherein said antibodies have complementarity determining region (CDR) residues from an antibody selected from the group consisting of 2D7 (ATCC Accession Number HB-12249), 1 G4 (ATCC Accession Number HB-12243), 1E11 (ATCC Accession Number HB-12248) and 1C11 (ATCC Accession Number HB-12250).  
     
     
         52 . The method of  claim 40  wherein at least one of said antibodies produced in step (a) comprises hypervariable region residues of clone 3 antibody (SEQ ID NO: 48).  
     
     
         53 . The method of  claim 40  wherein at least one of said antibodies produced in step (a) comprises hypervariable region residues of clone 4 antibody (SEQ ID NO: 49).  
     
     
         54 . The method of  claim 40  wherein at least one of said antibodies produced in step (a) comprises hypervariable region residues of clone 17 antibody (SEQ ID NO: 50).  
     
     
         55 . The method of  claim 40  wherein said antibodies produced in step (a) are monoclonal antibodies.  
     
     
         56 . The method of  claim 40  wherein at least one of said antibodies produced in step (a) is a human antibody.  
     
     
         57 . The method of  claim 40  wherein at least one of said antibodies produced in step (a) is a humanized antibody.  
     
     
         58 . The method of  claim 40  wherein at least one of said antibodies produced in step (a) is an antibody fragment.  
     
     
         59 . The method of  claim 58  wherein said antibody fragment is an F(ab′) 2 .  
     
     
         60 . The method of  claim 40  further comprising the step of converting the antibody identified in step (c) into a composition by admixing it with a physiologically acceptable carrier.  
     
     
         61 . The method of  claim 60  wherein said composition is sterile.  
     
     
         62 . The method of  claim 61  wherein said composition is lyophilized.  
     
     
         63 . The method of  claim 60  wherein said composition further comprises a cytokine.