Treatment with anti-alpha2 integrin antibodies

• US 8,298,531 B2
• Filed: 11/06/2009
• Issued: 10/30/2012
• Est. Priority Date: 11/06/2008
• Status: Active Grant

• Current Assignee: Ichnos Sciences SA
• Original Assignee: Glenmark Pharmaceuticals SA (Glenmark Pharmaceuticals Limited)
• Inventors: Mottl, Harald
• Primary Examiner(s): Gussow, Anne M.
• Application Number:
  US12/614,178
• Publication Number:
  US 20100158904A1
• Time in Patent Office: 1,089 Days
• Field of Search: None
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• 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 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/38 : of the suprarenal hormones
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/2839 : against the integrin superfamily
• CPC Class Codes: C07K 16/2842 : against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• 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

Abstract

The invention relates to treatment of cancer. More specifically the invention relates to methods of treating cancer selected from the group consisting of squamous cell cancer, lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer, as well as B-cell lymphoma including low grade/follicular non-Hodgkin'"'"'s lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom'"'"'s Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema such as that associated with brain tumors, Meigs'"'"' syndrome, melanoma, mesothelioma, multiple myeloma, fibrosarcoma, osteosarcoma and epidermoid carcinoma, by administering antibodies directed to α2β1 integrin.

Claims

1. A method of treating cancer selected from the group consisting of non-small cell lung cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, kidney cancer, prostate cancer, mesothelioma, fibrosarcoma, osteosarcoma, epidermoid carcinoma, metastatic colorectal, metastatic prostate and metastatic breast cancer, comprising administering to a subject a therapeutically effective amount of a humanized anti-α

2 integrin antibody comprising;

(i) a heavy chain variable region comprising the amino acid sequence of (a) HCDR1 (GFSLTNYGIH, SEQ ID NO;

1), HCDR2 (VIWARGFTNYNSALMS, SEQ ID NO;

2) and HCDR3 (ANDGVYYAMDY, SEQ ID NO;

3), or (b) SEQ ID NO;

40; and

(ii) a light chain variable region comprising the amino acid sequence of (a) an LCDR1 selected from SANSSVNYIH (SEQ ID NO;

4) or SAQSSVNYIH (SEQ ID NO;

112), (b) LCDR2 (DTSKLAS;

SEQ ID NO;

5) and (c) LCDR3 (QQWTTNPLT, SEQ ID NO;

6).

2. The method of claim 1, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

185.

3. The method of claim 2, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

185 in which position 30 is Thr and/or position 31 is Asn.

4. The method of claim 2, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

185 in which (a) position 71 is Lys, (b) position 73 is Asn, (c) position 78 is Val, or (d) any combination of (a)-(c).

5. The method of claim 1, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs:

70-79 and SEQ ID NOs;

109-111.

6. The method of claim 1, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs:

70-75, SEQ ID NOs;

77-79 and SEQ ID NOs;

109-111.

7. The method of claim 1, wherein the heavy chain variable region further comprises a FW4 region comprising the amino acid sequence WGQGTLVTVSS (SEQ ID NO:

13).

8. The method of claim 1, wherein the heavy chain variable region comprises the amino acid sequence of HCDR1 (SEQ ID NO:

1), HCDR2 (SEQ ID NO;

2) and HCDR3 (SEQ ID NO;

3).

9. The method of claim 1, wherein the humanized anti-α

2 integrin antibody comprises a heavy chain comprising SEQ ID NO;

187.

10. The method of claim 1, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:

186.

11. The method of claim 10, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:

186 in which the asparagine (N) at amino acid position 26 is replaced by glutamine (Q).

12. The method of claim 10, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:

186 in which (a) position 2 is Phe, (b) position 45 is Lys, (c) position 48 is Tyr, or (d) any combination of (a)-(c).

13. The method of claim 1, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO:

41, SEQ ID NOs;

80-92 and SEQ ID NO;

108.

14. The method of claim 1, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs:

90-92.

15. The method of claim 1, wherein the light chain variable region further comprises a FW4 region comprising the amino acids sequence FGQGTKVEIK of SEQ ID NO:

38.

16. The method of claim 1, wherein the light chain variable region comprises the amino acid sequence of LCDR1 (SEQ ID NO:

4), LCDR2 (SEQ ID NO;

5) and LCDR3 (SEQ ID NO;

6).

17. The method of claim 1, wherein the light chain variable region comprises the amino acid sequence of LCDR1 (SEQ ID NO:

112), LCDR2 (SEQ ID NO;

5) and LCDR3 (SEQ ID NO;

6).

18. The method of claim 1, wherein the humanized anti-α

2 integrin antibody comprises a light chain comprising SEQ ID NO;

188.

19. The method of claim 1, wherein the humanized anti-α

2 integrin antibody comprises;

(i) a heavy chain variable region comprising the amino acid sequence of HCDR1 (GFSLTNYGIH, SEQ ID NO;

1), HCDR2 (VIWARGFTNYNSALMS, SEQ ID NO;

2) and HCDR3 (ANDGVYYAMDY, SEQ ID NO;

3); and

(ii) a light chain variable region comprising the amino acid sequence of LCDR1 (SAQSSVNYIH, SEQ ID NO;

112), LCDR2 (DTSKLAS;

SEQ ID NO;

5) and LCDR3 (QQWTTNPLT, SEQ ID NO;

6).

20. The method of claim 1, wherein (a) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

185, (b) the light chain variable region comprises the amino acid sequence of SEQ ID NO;

186, or (c) both (a) and (b).

21. The method of claim 1, wherein (a) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

185 in which position 30 is Thr and/or position 31 is Asn;

(b) the light chain variable region comprises the amino acid sequence of SEQ ID NO;

186 in which the asparagine (N) at amino acid position 26 is replaced by glutamine (Q);

or (c) both (a) and (b).

22. The method of claim 1, wherein (i) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

185 in which (a) position 71 is Lys, (b) position 73 is Asn, (c) position 78 is Val, or (d) any combination of (a)-(c);

(ii) the light chain variable region comprises the amino acid sequence of SEQ ID NO;

186 in which (a) position 2 is Phe, (b) position 45 is Lys, (c) position 48 is Tyr, or (d) any combination of (a)-(c);

or (iii) both (i) and (ii).

23. The method of claim 1, wherein (a) the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs:

70-79 and SEQ ID NOs;

109-111;

(b) the light chain variable region comprises an amino acid sequence selected from SEQ ID NO;

41, SEQ ID NOs;

80-92 and SEQ ID NO;

108;

or (c) both (a) and (b).

24. The method of claim 1, wherein (a) the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs:

70-75, SEQ ID NOs;

77-79 and SEQ ID NOs;

109-111;

(b) the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs;

90-92;

or (c) both (a) and (b).

25. The method of claim 1, wherein the humanized anti-α

2 integrin antibody comprises a heavy chain comprising SEQ ID NO;

187 and a light chain comprising SEQ ID NO;

188.

26. The method of claim 1, wherein the humanized anti-α

2 integrin antibody comprises a heavy chain comprising SEQ ID NO;

174 or SEQ ID NO;

176 and a light chain comprising SEQ ID NO;

178.

27. The method of claim 1, wherein the humanized anti-α

2 integrin antibody recognizes the I domain of human α

2 integrin.

28. The method of claim 27, wherein the α

2β

1 integrin ligand is selected from collagen, laminin, Echovirus-1, decorin, E-cadherin, matrix metalloproteinase I (MMP-I), endorepellin, collectin and C1q complement protein.

29. The method of claim 1, wherein the humanized anti-α

2 integrin antibody binds α

2β

1 integrin.

30. The method of claim 1, wherein the humanized anti-α

2 integrin antibody inhibits binding of α

2 or α

2β

1 integrin to an α

2β

1 integrin ligand.

31. The method of claim 1, wherein the humanized anti-α

2 integrin antibody binds an epitope of α

2 integrin, the epitope comprising;

(a) a Lys residue corresponding to position 192 of the α

2 integrin amino acid sequence set forth in SEQ ID NO;

8 or position 40 of the α

2 integrin I domain amino acid sequence set forth in SEQ ID NO;

11;

(b) an Asn residue corresponding to position 225 of the α

2 integrin amino acid sequence set forth in SEQ ID NO;

8 or position 73 of the α

2 integrin I domain amino acid sequence set forth in SEQ ID NO;

11;

(c) a Gln residue corresponding to position 241 of the α

2 integrin amino acid sequence set forth in SEQ ID NO;

8 or position 89 of the α

2 integrin I domain amino acid sequence set forth in SEQ ID NO;

11;

(d) a Tyr residue corresponding to position 245 of the α

2 integrin amino acid sequence set forth in SEQ ID NO;

8 or position 93 of the α

2 integrin I domain amino acid sequence set forth in SEQ ID NO;

11;

(e) an Arg residue corresponding to position 317 of the α

2 integrin amino acid sequence set forth in SEQ ID NO;

8 or position 165 of the α

2 integrin I domain amino acid sequence set forth in SEQ ID NO;

11;

(f) an Asn residue corresponding to position 318 of the α

2 integrin amino acid sequence set forth in SEQ ID NO;

8 or position 166 of the α

2 integrin I domain amino acid sequence set forth in SEQ ID NO;

11;

or

(g) any combination of (a) to (f).

32. The method of claim 1, wherein the humanized anti-α

2 integrin antibody is a full length antibody.

33. The method of claim 1, wherein the humanized anti-α

2 integrin antibody is an antigen binding fragment.

34. The method of claim 1, wherein the cancer is selected from the group consisting of pancreatic cancer, breast cancer, colon cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, metastatic colorectal, and metastatic breast cancer.

35. The method of claim 1, wherein the cancer is selected from the group consisting of pancreatic cancer, breast cancer, colon cancer, colorectal cancer, non-small cell lung cancer, and fibrosarcoma.

36. The method of claim 1, wherein the cancer is pancreatic cancer, breast cancer or metastatic breast cancer.

37. The method of claim 26, wherein the co-administered one or more cancer medications comprise another antibody, chemo-therapeutic agent, cytotoxic agent, anti-angiogenic agent, immunosuppressive agent, prodrug, cytokine, cytokine antagonist, cytotoxic radiotherapy, corticosteroid, anti-emetic cancer vaccine, analgesic, anti-vascular agent, or growth-inhibitory agent.

38. The method of claim 1, wherein the antibody or the composition is administered by intravenous infusion or intravenous bolus.

39. The method of claim 1, wherein the therapeutically effective amount ranges from about 0.1 to about 100 mg/kg.

40. The method of claim 1, wherein the antibody or the composition is administered once every two weeks.

41. The method of claim 1, wherein the method is not associated with (a) platelet activation, (b) platelet aggregation, (c) a decrease in circulating platelet count, (d) bleeding complications, or (e) any combination of (a) to (d).

42. The method of claim 1, wherein the antibody or the composition is co-administered with one or more cancer medications.

43. A method of treating cancer selected from the group consisting of non-small cell lung cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, kidney cancer, prostate cancer, mesothelioma, fibrosarcoma, osteosarcoma, epidermoid carcinoma, metastatic colorectal, metastatic prostate and metastatic breast cancer, comprising administering to a subject a composition comprising a therapeutically effective amount of a humanized anti-α

2 integrin antibody comprising;

(i) a heavy chain variable region comprising the amino acid sequence of (a) HCDR1 (GFSLTNYGIH, SEQ ID NO;

1), HCDR2 (VIWARGFTNYNSALMS, SEQ ID NO;

2) and HCDR3 (ANDGVYYAMDY, SEQ ID NO;

3), or (b) SEQ ID NO;

40; and

(ii) a light chain variable region comprising the amino acid sequence of (a) an LCDR1 selected from SANSSVNYIH (SEQ ID NO;

4) or SAQSSVNYIH (SEQ ID NO;

112), (b) LCDR2 (DTSKLAS;

SEQ ID NO;

5) and (c) LCDR3 (QQWTTNPLT, SEQ ID NO;

6) and a pharmaceutically acceptable carrier.