Anti-NGF antibodies and methods using same

• US 20040237124A1
• Filed: 12/24/2003
• Published: 11/25/2004
• Est. Priority Date: 12/24/2002
• Status: Active Grant

• Current Assignee: Rinat Neuroscience Corp. (Pfizer Inc.)
• Original Assignee: Rinat Neuroscience Corp. (Pfizer Inc.)
• Inventors: Rosenthal, Arnon, Pons, Jaume
• Granted Patent: US 7,449,616 B2
• Time in Patent Office: Days
• US Class Current: 800/6
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The invention concerns anti-NGF antibodies (such as anti-NGF antagonist antibodies), and polynucleotides encoding the same. The invention further concerns use of such antibodies and/or polynucleotides in the treatment and/or prevention of pain, including post-surgical pain, rheumatoid arthritis pain, and osteoarthritis pain.

Claims

1. An anti-nerve growth factor (NGF) antibody wherein said antibody:

(a) binds NGF with a K_D of less than about 2 nM;

(b) inhibits human NGF-dependent survival of mouse E13.5 trigeminal neurons with an IC50 of about 100 pM or less, wherein the IC50 is measured in the presence of about 15 pM human NGF; and

(c) inhibits human NGF-dependent survival of mouse E13.5 trigeminal neurons with an IC50 of about 10 pM or less, wherein the IC50 is measured in the presence of about 1.5 pM of NGF.

2. The antibody of claim 1, wherein the antibody is humanized.

3. The antibody of claim 1, wherein the antibody is affinity matured.

4. The antibody of claim 1, wherein the antibody is a monoclonal antibody.

5. The antibody of claim 1, wherein the antibody is isolated.

31. A pharmaceutical composition comprising (a) the antibody of any of claims 1, 6, 8, 10, 17, 19, 21, and 27, and (b) a pharmaceutically acceptable excipient.

32. A kit comprising the antibody of any of claims 1, 6, 8, 10, 17, 19, 21, and 27.

33. A method of making the antibody of claim 1, said method comprising expressing a polynucleotide encoding the antibody of claim 1 in a host cell.

6. An antibody comprising a heavy chain variable region comprising:

(a) a CDR1 region of SEQ ID NO;

9, wherein I34 is S, L, V A, or I; and

N35 is substituted with N, T or S;

(b) a CDR2 region of SEQ ID NO;

10, wherein M50 is I, G, Q, S, or L;

A62 is A, or S;

and L63 is L or V; and

(c) a CDR3 region of SEQ ID NO;

11, wherein Y100 is Y, L, or R;

wherein Y101 is Y or W;

wherein G103 is G, A, or S;

wherein T104 is T or S;

wherein S105 is S, A, or T;

wherein Y106 is Y, R, T, or M;

wherein Y107 is Y or F;

wherein F108 is F or W;

wherein D109 is D, N, or G; and

wherein Y110 is Y, K, S, R or T;

wherein the antibody binds NGF.

7. The antibody of claim 6, wherein the antibody further comprises a light chain variable region.

8. An antibody comprising a light chain variable region comprising:

(a) a CDR1 region of SEQ ID NO;

12, wherein S26 is S or F;

D28 is D, S, A, or Y; and

H32 is H, N, or Q;

(b) a CDR2 region of SEQ ID NO;

13, wherein I51 is I, T, V or A; and

S56 is S or T; and

(c) a CDR3 region of SEQ ID NO;

14, wherein K92 is K, H, R, or S; and

wherein Y96 is Y or R;

wherein the antibody binds NGF.

9. The antibody of claim 8, wherein the antibody further comprises a heavy chain variable region.

10. An antibody comprising (a) a heavy chain variable region comprising:

(i) a CDR1 region of SEQ ID NO;

9, wherein I34 is substituted with S, L, V A, or I; and

N35 is substituted with N, T or S;

(ii) a CDR2 region of SEQ ID NO;

10, wherein M50 is I, G, Q, S, or L;

A62 is A, or S; and

L63 is L or V; and

(iii) a CDR3 region of SEQ ID NO;

11, wherein Y100 is Y, L, or R;

wherein Y101 is Y or W;

wherein G103 is G, A, or S;

wherein T104 is T or S;

wherein S105 is S, A, or T;

wherein Y106 is Y, R, T, or M;

wherein Y107 is Y or F;

wherein F108 is F or W;

wherein D109 is D, N, or G;

wherein Y110 is Y, K, S, R or T; and

(b) a light chain variable region comprising;

(i) a CDR1 region of SEQ ID NO;

12, wherein S26 is S or F;

D28 is D, S, A, or Y; and

H32 is H, N, or Q;

(ii) a CDR2 region of SEQ ID NO;

13, wherein 151 is I, T, V or A; and

S56 is S or T; and

(iii) a CDR3 region of SEQ ID NO;

14, wherein S91 is S or E;

K92 is K, H, R, or S; and

wherein Y96 is Y or R;

wherein the antibody binds NGF.

11. The antibody of any of claims 6-10, wherein the antibody binds human NGF.

12. The antibody of claim 11, wherein the antibody further binds rodent NGF.

13. The antibody of any of claims 6-10, wherein the antibody is a monoclonal antibody.

14. The antibody of any of claims 6-10, wherein the antibody is a humanized antibody.

15. The antibody of any of claims 6-10, wherein the antibody binds NGF with a K_D of about 2 nM or less.

16. The antibody of claim 15, wherein the K_D is about 100 pM or less.

17. An antibody comprising a heavy chain variable region comprising:

(a) a CDR1 region shown in SEQ ID NO;

3;

(b) a CDR2 region shown in SEQ ID NO;

4; and

(c) a CDR3 region shown in SEQ ID NO;

5;

wherein the antibody binds NGF.

18. The antibody of claim 17, wherein the antibody further comprises a light chain variable region.

28. The antibody of any of claims 17, 19, or 21, wherein the antibody is humanized.

29. The antibody of any of claims 17, 19, or 21, wherein the antibody is affinity matured.

30. The antibody of any of claims 17, 19, or 21, wherein the antibody is a monoclonal antibody.

19. An antibody comprising a light chain variable region comprising:

(a) a CDR1 region shown in SEQ ID NO;

6;

(b) a CDR2 region shown in SEQ ID NO;

7; and

(c) a CDR3 region shown in SEQ ID NO;

8;

wherein the antibody binds NGF.

20. The antibody of claim 19, wherein the antibody further comprises a heavy chain variable region.

21. The antibody of claim 19, wherein the antibody further comprises a heavy chain variable region comprising:

(a) a CDR1 region shown in SEQ ID NO;

3;

(b) a CDR2 region shown in SEQ ID NO;

4; and

(c) a CDR3 region shown in SEQ ID NO;

5.

22. The antibody of claim 21, wherein the heavy chain variable region consists of the sequence shown in SEQ ID NO:

1.

23. The antibody of claim 21, wherein the light chain variable region consists of the sequence shown in SEQ ID NO:

2.

24. The antibody of claim 22, wherein the heavy chain variable region consists of the sequence shown in SEQ ID NO:

2.

25. The antibody of claim 21, wherein the heavy chain consists of the amino acid sequence shown in SEQ ID NO:

16.

26. The antibody of claim 21, wherein the light chain consists of the amino acid sequence shown in SEQ ID NO:

17.

27. The antibody of claim 25, wherein the light chain consists of the amino acid sequence shown in SEQ ID NO:

17.