Anti-VEGF antibodies

• US 7,375,193 B2
• Filed: 09/29/2006
• Issued: 05/20/2008
• Est. Priority Date: 04/07/1997
• Status: Expired due to Fees

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Baca, Manuel, Lowman, Henry B., Presta, Leonard G., Wells, James A., Chen, Yvonne Man-Yee
• Primary Examiner(s): Blanchard; David J.
• Assistant Examiner(s): Tungaturthi; Parithosh K.
• Application Number:
  US11/537,015
• Publication Number:
  US 20070248610A1
• Time in Patent Office: 599 Days
• Field of Search: 530/387.1, 530/387.3, 530/388.85, 424/130.1, 435/320.1, 536/23.53
• US Class Current: 530/387.1
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/22 against growth factors ; against 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 2317/55 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 2317/567 Framework region [FR]
• 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

Humanized and variant anti-VEGF antibodies and various uses therefor are disclosed. The anti-VEGF antibodies have strong binding affinities for VEGF; inhibit VEGF-induced proliferation of endothelial cells in vitro; and inhibit tumor growth in vivo.

Claims

1. An aqueous formulation useful for inhibiting VEGF-induced angiogenesis in a subject, comprising as the active compound a humanized anti-VEGF antibody in a buffer, wherein the anti-VEGF antibody comprises a heavy chain variable domain comprising the following heavy chain complementarity determining region (CDR) amino acid sequences:

CDRH1 (GYTFTNYGMN;

SEQ ID NO;

     1), CDRH2 (WINTYTGEPTYAADFKR;

SEQ ID NO;

     2) and CDRH3 (YPHYYGSSHWYFDV;

SEQ ID NO;

     3) and a light chain variable domain comprising the following light chain CDR amino acid sequences;

CDRL1 (SASQDISNYLN;

SEQ ID NO;

     4), CDRL2 (FTSSLHS;

SEQ ID NO;

     5) and CDRL3 (QQYSTVPWT;

SEQ ID NO;

     6).

2. The aqueous formulation of claim 1, wherein the buffer is phosphate.

3. The aqueous formulation of claim 2, further comprising a sugar and a non-ionic surfactant.

4. The aqueous formulation of claim 3, wherein the sugar is trehalose and the non-ionic surfactant is polysorbate.

5. The aqueous formulation of claim 1, wherein said anti-VEGF antibody comprises a heavy chain variable domain sequence of SEQ ID NO:

7 and a light chain variable domain sequence of SEQ ID NO;

8.

6. The aqueous formulation of claim 5, wherein the buffer is phosphate.

7. The aqueous formulation of claim 6, further comprising a sugar and a non-ionic surfactant.

8. The aqueous formulation of claim 7, wherein the sugar is trehalose and the non-ionic surfactant is polysorbate.

9. A pharmaceutical formulation comprising an anti-VEGF antibody, wherein the anti-VEGF antibody comprises a heavy chain variable domain comprising the following heavy chain CDR amino acid sequences:

CDRH1 (GYTFTNYGMN;

SEQ ID NO;

     1), CDRH2 (WINTYTGEPTYAADFKR;

SEQ iD NO;

     2) and CDRH3 (YPHYYGSSHWYFDV;

SEQ ID NO;

     3) and a light chain variable domain comprising the following light chain CDR amino acid sequences;

CDRL1 (SASQDISNYLN;

SEQ ID NO;

     4), CDRL2 (FTSSLHS;

SEQ ID NO;

     5) and CDRL3 (QQYSTVPWT;

SEQ ID NO;

     6).

10. The pharmaceutical formulation of claim 9, wherein the pharmaceutical formulation comprises at least one of the following ingredients:

a buffer, a sugar and a non-ionic surfactant.

11. The pharmaceutical formulation of claim 10, wherein the buffer is phosphate.

12. The pharmaceutical formulation of claim 10, wherein the sugar is trehalose.

13. The pharmaceutical formulation of claim 10, wherein the non-ionic surfactant is polysorbate.

14. The pharmaceutical formulation of claim 10, wherein the pharmaceutical formulation comprises a buffer, a sugar and a non-ionic surfactant.

15. The pharmaceutical formulation of claim 14, wherein the buffer is phosphate, the sugar is trehalose and the non-ionic surfactant is polysorbate.

16. The pharmaceutical formulation of claim 9, wherein said anti-VEGF antibody comprises a heavy chain variable domain sequence of SEQ ID NO:

7 and a light chain variable domain sequence of SEQ ID NO;

8.

17. The pharmaceutical formulation of claim 16, wherein the pharmaceutical formulation comprises at least one of the following ingredients:

a buffer, a sugar and a non-ionic surfactant.

18. The pharmaceutical formulation of claim 17, wherein the buffer is phosphate.

19. The pharmaceutical formulation of claim 17, wherein the sugar is trehalose.

20. The pharmaceutical formulation of claim 17, wherein the non-ionic surfactant is polysorbate.

21. The pharmaceutical formulation of claim 17, wherein the pharmaceutical formulation comprises a buffer, a sugar and a non-ionic surfactant.

22. The pharmaceutical formulation of claim 21, wherein the buffer is phosphate, the sugar is trehalose and the non-ionic surfactant is polysorbate.