Antibody neutralizers of human granulocyte macrophage colony stimulating factor
The present invention relates to a human monoclonal antibody or fragment thereof which specifically binds to and neutralizes primate GM-CSF.
1. A human monoclonal antibody or fragment thereof which specifically binds to and neutralizes primate GM-CSF, comprising in its light chain variable region a CDR1 comprising an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 comprising an amino acid sequence as set out in SEQ ID) NO: 17 and a CDR3comprising an amino acid sequence as set out in SEQ ID NO: 18; and comprising in its heavy chain variable region a CDR1 comprising an amino acid sequence as set out in SEQ ID NO: 14, a CDR2 comprising an amino acid sequence as set out in SEQ ID NO: 15 and a CDR3 comprising an amino acid sequence as set out in any of SEQ ID NOs: 1-13 or 56.
2. The human monoclonal antibody or fragment thereof according to claim 1 having an equilibrium disassociation constant K D of between about 4 ×10 −9 M and about 0.04 ×10 −9 M.
3. The human monoclonal antibody or fragment thereof according to claim 1 comprising in its light chain variable region a CDR1 comprising an amino acid sequence as set out in SEQ TD NO: 16, a CDR2 having an amino acid sequence as set out in SEQ ID NO: 17, and a CDR3 having an amino acid sequence as set out in SEQ ID) NO: 18, and comprising in its heavy chain variable region a CDR1 comprising an amino acid sequence as set out in SEQ ID NO: 14 a CDR2 comprising an amino acid sequence as set out in SEQ ID NO: 15 and a CDR3 comprising an amino acid sequence as set out in SEQ ID NO: 2.
4. The human monoclonal antibody or fragment thereof according to claim 1 wherein the primate GM-CSF is a human GM-CSF.
5. The human monoclonal antibody or fragment thereof according to claim 1 wherein the primate is a non-human primate.
6. The human monoclonal antibody fragment according to claim 1 wherein said fragment is an scFv, an Fv, a diabody, a tandem diabody, a Fab, a Fab′ or a F(ab) 2 .
7. The human monoclonal antibody according to claim 1 , wherein the antibody is IgG.
8. The u an monoclonal antibody according to claim 7 , wherein the IgG is an IgG1 or IgG4.
9. A polynucleotide molecule encoding the human monoclonal antibody or fragment according to claim 1 .
10. A pharmaceutical composition comprising a human monoclonal antibody or fragment thereof according to claim 1 or the polynucleotide molecule according to claim 9 .
11. The human monoclonal antibody or fragment thereof according to claim 1 , comprising in its light chain variable region an amino acid sequence as set out in any of SEQ ID NOs: 19, 54 or 55.
12. The human monoclonal antibody or fragment thereof according to claim 1 , comprising in its heavy chain variable region an amino acid sequence as set out in any of SEQ ID NOs: 20-33, 52 or 53.
13. The human monoclonal antibody according to claim 1 , comprising a light chain amino acid sequence as set out in SEQ ID NO: 34 and a heavy chain amino acid sequence as set out in any of SEQ ID NOs: 35-48.
14. The human monoclonal antibody according to claim 13 , comprising a light chain amino acid sequence as set out in SEQ ID NO: 34 and a heavy chain amino acid sequence as set out in SEQ ID NO: 35.
15. The human monoclonal antibody or fragment thereof according to claim 1 , comprising in its light chain variable region an amino acid sequence as set out in SEQ ID NO: 19 and comprising in its heavy chain variable region an amino acid sequence as set out in SEQ ID NO: 21 or 52.
16. An immunoglobulin G antibody which binds to human GM-CSF, comprising in its light chain variable region a CDR1 comprising an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 comprising an amino acid sequence as set out in SEQ ID NO: 17and a CDR3 comprising an amino acid sequence as set out in SEQ ID NO: 18; and
comprising in its heavy chain variable region a CDR 1 comprising an amino acid sequence as set out in SEQ ID NO: 14, a CDR2 comprising an amino acid sequence as set out in SEQ ID NO: 15 and a CDR3 comprising an amino acid sequence as set out in SEQ ID NO: 2.
17. The antibody of claim 16 which binds to human GM-CSF with an equilibrium disassociation constant KD of between about 4 ×10 −9 M and about 0.04 ×10 −9 M.
18. The antibody of claim 16 which neutralizes human GM-CSF as determined in a TF-1 growth inhibition assay.
19. The antibody of claim 18 having n IC 50 value of approximately 3 ×10 −10 M as determined in a TF-1 growth inhibition assay.
20. The antibody of claim 17 or 18 , comprising in its light chain variable region the amino acid sequence as set out in SEQ ID NO: 19 and comprising in its heavy chain variable region the amino acid sequence as set out in SEQ ID NO: 21.