Agonist anti-trkc antibodies and methods using same

• US 20090202526A1
• Filed: 12/23/2004
• Published: 08/13/2009
• Est. Priority Date: 12/23/2003
• Status: Active Grant

• Current Assignee: NXP B.V. (NXP Semiconductors NV)
• Original Assignee: Rinat Neuroscience Corp. (Pfizer Inc.)
• Inventors: Pons, Jaume
• Granted Patent: US 7,968,690 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The invention concerns agonist anti-trkC antibodies, polypeptides, and polynucleotides encoding the same. The invention further concerns use of such antibodies, polypeptides and/or polynucleotides in the treatment and/or prevention of neuropathies, such as sensory neuropathies, including taxol-induced sensory neuropathy, cisplatin-induced sensory neuropathy, and pyridoxine-induced sensory neuropathy.

Claims

1. An agonist anti-trkC antibody comprising a heavy chain CDRs comprising:

(a) a CDR1 of the formula GYTFTSYXaaXaaH (SEQ ID NO;

     16), wherein Xaa at position 8 is R or W, and Xaa at position 9 is I, L, R, or M;

(b) a CDR2 of the formula EIYPSNXaaRTNYNEKFXaaS (SEQ ID NO;

17), wherein Xaa at position 7 is A, T, S, or G; and

Xaa at position 16 is K or E; and

(c) a CDR3 of the formula KYYYGNXaaXaaRSWYFDV (SEQ ID NO;

     18), wherein Xaa at position 7 is T or S;

wherein Xaa at position 8 is R, Q, K, S, or Y;

wherein the agonist anti-trkC antibody is not an antibody comprising a heavy chain CDRs comprising a CDR1 region of SEQ ID NO;

22, a CDR2 region of SEQ ID NO;

23, and a CDR3 region of SEQ ID NO;

24.

2. The agonist anti-trkC antibody of claim 1, wherein the agonist anti-trkC antibody further comprises a light chain variable region.

4. The agonist anti-trkC antibody of claim 1, wherein the agonist anti-trkC antibody further comprises a heavy chain variable region.

6. The agonist anti-trkC antibody of any of claims 1-5, wherein the agonist anti-trkC antibody binds human trkC.

7. The agonist anti-trkC antibody of claim 6, wherein the agonist anti-trkC antibody binds to human trkC with a K_D less than about 5 nM.

8. The agonist anti-trkC antibody of claim 6, wherein the agonist anti-trkC antibody further binds rodent trkC.

9. The agonist anti-trkC antibody of any of claims 1-5, wherein the agonist anti-trkC antibody is a monoclonal antibody.

10. The agonist anti-trkC antibody of any of claims 1-5, wherein the agonist anti-trkC antibody is a humanized antibody.

11. The agonist anti-trkC antibody of any of claims 1-5, wherein the agonist anti-trkC antibody comprises a heavy chain variable region comprising:

(a) a CDR1 region of SEQ ID NO;

4;

(b) a CDR2 region of SEQ ID NO;

5; and

(c) a CDR3 region of SEQ ID NO;

6.

12. The agonist anti-trkC antibody of claim 11, wherein the heavy chain variable region consists of the sequence of SEQ ID NO:

1.

13. The agonist anti-trkC antibody of any of claims 1-5, wherein the agonist anti-trkC antibody comprises a light chain variable region comprising:

(a) a CDR1 region of SEQ ID NO;

7;

(b) a CDR2 region of SEQ ID NO;

8; and

(c) a CDR3 region of SEQ ID NO;

9.

14. The agonist anti-trkC antibody of claim 13, wherein the light chain variable region consists of the sequence of SEQ ID NO:

2.

15. The agonist anti-trkC antibody of any of claims 1-5, wherein the agonist anti-trkC antibody comprises

(a) a heavy chain variable region comprising:

(i) a CDR1 region of SEQ ID NO;

4;

(ii) a CDR2 region of SEQ ID NO;

5; and

(iii) a CDR3 region of SEQ ID NO;

6; and

(b) a light chain variable region comprising;

(i) a CDR1 region of SEQ ID NO;

7;

(b) a CDR2 region of SEQ ID NO;

8; and

(c) a CDR3 region of SEQ ID NO;

9.

16. The agonist anti-trkC antibody of claim 15, wherein the heavy chain variable region consists of SEQ ID NO:

1, and the light chain variable region consists of the sequence of SEQ ID NO;

2.

17. The agonist anti-trkC antibody of claim 15, wherein the heavy chain consists of the sequence of SEQ ID NO:

28, and the light chain variable region consists of the sequence of SEQ ID NO;

29.

18. A nucleic acid encoding an agonist anti-trkC antibody of any of claims 1-17.

19. The nucleic acid of claim 18, wherein the nucleic acid comprises the sequence of SEQ ID NO:

12 encoding the heavy chain variable region of the agonist anti-trkC antibody, and the sequence of SEQ ID NO;

10 encoding the light chain variable region of the agonist anti-trkC antibody.

20. The nucleic acid of claim 19, wherein the nucleic acid comprises the sequence of SEQ ID NO:

13 encoding the heavy chain of the agonist anti-trkC antibody, and the sequence of SEQ ID NO;

11 encoding the light chain variable region of the agonist anti-trkC antibody.

21. A vector comprising the nucleic acid of claim 18.

22. A host cell comprising the nucleic acid of claim 18.

23. A pharmaceutical composition comprising (a) an effective amount of the agonist anti-trkC antibody of any of claims 1-17 and (b) a pharmaceutical acceptable excipient.

24. A kit comprising the agonist anti-trkC antibody of any of claims 1-17.

25. A method of making an agonist anti-trkC antibody, said method comprising expressing a polynucleotide encoding the agonist anti-trkC antibody of any of claims 1-17 in a host cell.

3. An agonist anti-trkC antibody comprising a light chain CDRs comprising:

(a) a CDR1 of the formula RASESXaaDXaaYGISFXaaXaa (SEQ ID NO;

19), wherein Xaa at position 6 is I or V;

Xaa at position 8 is N or S;

Xaa at position 14 is L or M;

Xaa at position 15 is A, T, or N;

(b) a CDR2 of the formula AASNXaaGS (SEQ ID NO;

20), wherein Xaa at position 5 is R, L, or Q; and

(c) a CDR3 of the formula QQSKXaaVPRT (SEQ ID NO;

21), wherein Xaa at position 5 is T, A, S, or E;

wherein the agonist anti-trkC antibody is not an antibody comprising a light chain CDRs comprising a CDR1 region of SEQ ID NO;

25, a CDR2 region of SEQ ID NO;

26, and a CDR3 region of SEQ ID NO;

27.

5. An agonist anti-trkC antibody comprising:

(a) a heavy chain CDRs comprising;

(i) a CDR1 of the formula GYTFTSYXaaXaaH (SEQ ID NO;

     16), wherein Xaa at position 8 is R or W, and Xaa at position 9 is I, L, R, or M;

(ii) a CDR2 of the formula EIYPSNXaaRTNYNEKFXaaS (SEQ ID NO;

17), wherein Xaa at position 7 is A, T, S, or G; and

Xaa at position 16 is K or E; and

(iii) a CDR3 of the formula KYYYGNXaaXaaRSWYFDV (SEQ ID NO;

     18), wherein Xaa at position 7 is T or S;

wherein Xaa at position 8 is R, Q, K, S, or Y; and

(b) a light chain CDRs comprising;

(i) a CDR1 of the formula RASESXaaDXaaYGISFXaaXaa (SEQ ID NO;

19), wherein Xaa at position 6 is I or V;

Xaa at position 8 is N or S;

Xaa at position 14 is L or M;

Xaa at position 15 is A, T, or N;

(ii) a CDR2 of the formula AASNXaaGS (SEQ ID NO;

20), wherein Xaa at position 5 is R, L, or Q; and

(iii) a CDR 3 of the formula QQSKXaaVPRT (SEQ ID NO;

21), wherein Xaa at position 5 is T, A, S, or E;

wherein the agonist anti-trkC antibody is not an antibody comprising (a) a heavy chain CDRs comprising a CDR1 region of SEQ ID NO;

22, a CDR2 region of SEQ ID NO;

23, and a CDR3 region of SEQ ID NO;

24; and

(b) a light chain CDRs comprising a CDR1 region of SEQ ID NO;

25, a CDR2 region of SEQ ID NO;

26, and a CDR3 region of SEQ ID NO;

27.

26. A polypeptide that binds to trkc, comprising:

(a) a CDR1 of the formula GYTFTSYXaaXaaH (SEQ ID NO;

     16), wherein Xaa at position 8 is R or W, and Xaa at position 9 is I, L, R, or M;

(b) a CDR2 of the formula EIYPSNXaaRTNYNEKFXaaS (SEQ ID NO;

     17), wherein Xaa at position 7 is A, T, S, or G; and

Xaa at position 16 is K or E; and

(c) a CDR3 of the formula KYYYGNXaaXaaRSWYFDV (SEQ ID NO;

     18), wherein Xaa at position 7 is T or S;

wherein Xaa at position 8 is R, Q, K, S, or Y;

wherein the polypeptide is not a polypeptide comprising CDRs comprising a CDR1 region of SEQ ID NO;

22, a CDR2 region of SEQ ID NO;

23, and a CDR3 region of SEQ ID NO;

24.

27. A polypeptide that binds to trkC, comprising:

(a) a CDR1 of the formula RASESXaaDXaaYGISFXaaXaa (SEQ ID NO;

19), wherein Xaa at position 6 is I or V;

Xaa at position 8 is N or S;

Xaa at position 14 is L or M;

Xaa at position 15 is A, T, or N;

(b) a CDR2 of the formula AASNXaaGS (SEQ ID NO;

20), wherein Xaa at position 5 is R, L, or Q; and

(c) a CDR3 of the formula QQSKXaaVPRT (SEQ ID NO;

21), wherein Xaa at position 5 is T, A, S, or E;

wherein the polypeptide is not a polypeptide comprising CDRs comprising a CDR1 region of SEQ ID NO;

25, a CDR2 region of SEQ ID NO;

26, and a CDR3 region of SEQ ID NO;

27.