Anti-α;β;antibodies and uses thereof

• US 8,992,924 B2
• Filed: 05/17/2011
• Issued: 03/31/2015
• Est. Priority Date: 07/08/2005
• Status: Active Grant

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen Idec MA Inc. (Biogen, Inc.)
• Inventors: Violette, Shelia M., Koopman, Louise A., Simon, Kenneth J., Weinreb, Paul H., Saldanha, Jose W., Lugovskoy, Alexey A., van Vlijmen, Herman W. T.
• Primary Examiner(s): Shukla, Ram R
• Assistant Examiner(s): HOLLERAN, ANNE L
• Application Number:
  US13/109,168
• Publication Number:
  US 20110305629A1
• Time in Patent Office: 1,414 Days
• Field of Search: 424/130.1, 424/133.1, 424/135.1, 424/138.1, 424/139.1, 424/143.1, 424/152.1, 424/156.1, 424/172.1, 424/174.1, 424/800, 424/801
• US Class Current: 424/143.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2839 : against the integrin superfamily
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/77 : Internalization into the cell
• CPC Class Codes: G01N 2333/70546 : Integrin superfamily, e.g. VLAs, leuCAM, GPIIb/GPIIIa, LPAM
• CPC Class Codes: G01N 2800/085 : Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
• CPC Class Codes: G01N 2800/12 : Pulmonary diseases
• CPC Class Codes: G01N 2800/20 : Dermatological disorders
• CPC Class Codes: G01N 2800/347 : Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
• CPC Class Codes: G01N 33/57407 : Specifically defined cancers
• CPC Class Codes: G01N 33/57492 : involving compounds localized on the membrane of tumor or cancer cells
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere
• CPC Class Codes: Y10S 424/80 : Antibody or fragment thereof whose amino acid sequence is disclosed in whole or in part
• CPC Class Codes: Y10S 424/801 : involving antibody or fragment thereof produced by recombinant dna technology

Abstract

The present invention is in the fields of cell biology, immunology and oncology. The invention provides humanized antibodies that recognize α_vβ₆ integrins, which antibodies comprise a variable region of nonhuman origin and at least a portion of an immunoglobulin of human origin. The invention also provides methods for preparation of such antibodies, pharmaceutical compositions comprising them, and methods of treating, diagnosing and/or preventing various diseases and disorders by administering the humanized anti-α_vβ₆ antibodies of the invention. The invention also relates to the identification of differential expression of the integrin α_vβ₆ on the surfaces of tumor cells and tissues, the use of this differential expression in determining the metastatic potential of tumor cells, and methods of diagnosis and treatment/prevention of tumor metastasis and for elimination of residual metastatic tumor cells using ligands, particularly antibodies, that bind to integrin α_vβ₆.

Claims

1. A method of treating a human subject having a disease mediated by α

vβ

6, comprising administering to the subject a humanized antibody or an antigen binding fragment thereof that specifically binds to α

vβ

6, thereby alleviating or postponing the onset of the disease, wherein the antibody or the antigen binding fragment thereof comprises;

(a) a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO;

144, SEQ ID NO;

145, or SEQ ID NO;

146 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO;

139, SEQ ID NO;

140, SEQ ID NO;

141, SEQ ID NO;

142, or SEQ ID NO;

143;

(b) a heavy chain variable domain comprising a variant of the amino acid sequence set forth in SEQ ID NO;

1 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO;

2, wherein the variant of SEQ ID NO;

1 comprises one or both of Q3M and N73S amino acid substitutions in SEQ ID NO;

1;

(c) a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO;

1 and a light chain variable domain comprising a variant of the amino acid sequence set forth in SEQ ID NO;

2, wherein the variant of SEQ ID NO;

2 comprises one or more amino acid substitutions selected from the group consisting of L48W, I59V, A61V and Y88F in SEQ ID NO;

2;

or

(d) a heavy chain variable domain comprising a variant of the amino acid sequence set forth in SEQ ID NO;

1 and a light chain variable domain comprising a variant of the amino acid sequence set forth in SEQ ID NO;

2, wherein the variant of SEQ ID NO;

1 comprises one or both of Q3M and N73S amino acid substitutions in SEQ ID NO;

1 and the variant of SEQ ID NO;

2 comprises one or more of the amino acid substitutions selected from the group consisting of L48W, I59V, A61V and Y88F in SEQ ID NO;

2,

wherein the disease mediated by α

vβ

6 is fibrosis, Alport'"'"'s Syndrome, acute lung injury, or acute kidney injury.

2. The method of claim 1, wherein the disease is fibrosis.

3. The method of claim 2, wherein the fibrosis is scleroderma, scarring, liver fibrosis, kidney fibrosis, gut fibrosis, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, biliary duct injury-induced fibrosis, head and neck fibrosis, burn induced fibrosis, surgical fibrosis, spinal cord fibrosis, or lung fibrosis.

4. The method of claim 2, wherein the fibrosis is lung fibrosis.

5. The method of claim 4, wherein the lung fibrosis is idiopathic pulmonary fibrosis.

6. The method of claim 2, wherein the fibrosis is liver fibrosis.

7. The method of claim 2, wherein the fibrosis is scleroderma.

8. The method of claim 2, wherein the fibrosis is scarring.

9. The method of claim 2, wherein the fibrosis is kidney fibrosis.

10. The method of claim 2, wherein the fibrosis is gut fibrosis.

11. The method of claim 2, wherein the fibrosis is radiation-induced fibrosis.

12. The method of claim 2, wherein the fibrosis is bleomycin-induced fibrosis.

13. The method of claim 2, wherein the fibrosis is asbestos-induced fibrosis.

14. The method of claim 2, wherein the fibrosis is biliary duct injury-induced fibrosis.

15. The method of claim 2, wherein the fibrosis is head and neck fibrosis.

16. The method of claim 2, wherein the fibrosis is burn induced fibrosis.

17. The method of claim 2, wherein the fibrosis is surgical fibrosis.

18. The method of claim 2, wherein the fibrosis is spinal cord fibrosis.

19. The method of claim 1, wherein the disease is Alport'"'"'s Syndrome.

20. The method of claim 1, wherein the humanized antibody or the antigen binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:

145 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO;

140.

21. The method of claim 1, wherein the disease is acute lung injury.

22. The method of claim 1, wherein the disease is acute kidney injury.

23. A method of treating a human subject having a disease mediated by α

vβ

6, comprising administering to the subject an antibody or an antigen binding fragment thereof that specifically binds to α

vβ

6, wherein the antibody or the antigen binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO;

146 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO;

143, wherein the disease mediated by α

vβ

6 is fibrosis, Alport'"'"'s Syndrome, acute lung injury, or acute kidney injury.

24. The method of claim 23, wherein the disease is fibrosis.

25. The method of claim 24, wherein the fibrosis is scleroderma, scarring, liver fibrosis, kidney fibrosis, gut fibrosis, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, biliary duct injury-induced fibrosis, head and neck fibrosis, burn induced fibrosis, surgical fibrosis, spinal cord fibrosis, or lung fibrosis.

26. The method of claim 24, wherein the fibrosis is lung fibrosis.

27. The method of claim 26, wherein the lung fibrosis is idiopathic pulmonary fibrosis.

28. The method of claim 24, wherein the fibrosis is liver fibrosis.

29. The method of claim 24, wherein the fibrosis is scleroderma.

30. The method of claim 24, wherein the fibrosis is scarring.

31. The method of claim 24, wherein the fibrosis is kidney fibrosis.

32. The method of claim 24, wherein the fibrosis is gut fibrosis.

33. The method of claim 24, wherein the fibrosis is radiation-induced fibrosis.

34. The method of claim 24, wherein the fibrosis is bleomycin-induced fibrosis.

35. The method of claim 24, wherein the fibrosis is asbestos-induced fibrosis.

36. The method of claim 24, wherein the fibrosis is biliary duct injury-induced fibrosis.

37. The method of claim 24, wherein the fibrosis is head and neck fibrosis.

38. The method of claim 24, wherein the fibrosis is burn induced fibrosis.

39. The method of claim 24, wherein the fibrosis is surgical fibrosis.

40. The method of claim 24, wherein the fibrosis is spinal cord fibrosis.

41. The method of claim 23, wherein the disease is acute lung injury.

42. The method of claim 23, wherein the disease is acute kidney injury.

43. The method of claim 23, wherein the disease is Alport'"'"'s Syndrome.