IP Library › Granted Patent US 8,426,562
Granted Patent B2
US 8,426,562 · App. 12/846,440 · Granted Apr 23, 2013

Methods and compositions for modulating tumor cell activity

Inventors: Maureen D. O'Connor-McCourt (Beaconsfield, CA); Christiane Cantin (Pierrefonds, CA); Anne E. G. Lenferink (Lorraine, CA)
Assignee: National Research Council of Canada
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 8,426,562
App. No.
12/846,440
Granted
Apr 23, 2013
Kind
B2
Abstract

Antibodies which target clusterin, a protein involved in the epithelial-to-mesenchymal transition of carcinoma cells, are identified and characterized. The antibodies may be used to modulate tumor cell activity through binding the clusterin.

Claims (76)

1. A method for modulating activity of carcinoma cells in a subject having a carcinoma by inhibiting epithelial-to-mesenchymal transitions in the carcinoma cells, the method comprising administering to the subject an antibody which specifically binds a site in the amino acid sequence VEVSRKNPKFMETVAEKALQEYR (SEQ ID NO.: 5) of human clusterin.

2. The method of claim 1 , wherein the antibody is a monoclonal antibody and has

a) a light chain variable region comprising three complementarity-determining regions of SEQ ID NO.:8 or SEQ ID NO.:9 and a heavy chain variable region comprising a CDR1 consensus as set forth in SEQ ID NO.:6, a CDR2 consensus as set forth in SEQ ID NO.:7 and a CDR3 having an amino acid sequence as set forth in SEQ ID NO.:165;

b) a light chain variable region comprising three complementarity-determining regions of SEQ ID NO.:10 and a heavy chain variable region comprising a CDR1 consensus as set forth in SEQ ID NO.:6, a CDR2 consensus as set forth in SEQ ID NO.:7 and a CDR3 having an amino acid sequence as set forth in SEQ ID NO.:166; or

c) a light chain variable region comprising three complementarity-determining regions of SEQ ID NO.:11 and a heavy chain variable region comprising a CDR1 consensus as set forth in SEQ ID NO.:6, a CDR2 consensus as set forth in SEQ ID NO.:7 and a CDR3 having an amino acid sequence as set forth in SEQ ID NO.:167.

3. The method of claim 1 , wherein the antibody comprises a heavy chain variable region as set forth in SEQ ID NO.:24.

4. The method of claim 1 , wherein the antibody comprises three complementary determining regions set forth in SEQ ID NO.:24.

5. The method of claim 4 , wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:24 are GYSFTGYN (SEQ ID NO.:89), IDPYNGDT (SEQ ID NO.:123) and ARGAYGSSYAY (SEQ ID NO.:169).

6. The method of claim 1 , wherein the antibody is monoclonal.

7. The method of claim 1 , wherein the antibody is polyclonal.

8. The method of claim 1 , wherein the subject has breast carcinoma.

9. The method of claim 1 , wherein the subject has prostate carcinoma.

10. The method of claim 8 , wherein the administration reduces metastasis to the lung.

11. The method of claim 9 , wherein the administration reduces metastasis to the lung.

12. A method for reducing metastasis of carcinoma cells or late-stage tumor progression of carcinoma by inhibiting epithelial to mesenchymal transition of carcinoma cells, the method comprising administering an antibody to a subject having carcinoma, wherein the antibody specifically binds a site in the amino acid sequence VEVSRKNPKFMETVAEKALQEYR (SEQ ID NO.: 5) of human clusterin.

13. The method of claim 12 , wherein the antibody binds to secreted clusterin.

14. The method of claim 12 , wherein the antibody is a monoclonal antibody that comprises:

a) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:8 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:20;

b) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:9 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:20;

c) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:10 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:21;

d) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:11 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:22;

e) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:12 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:23 or

f) three complementarity-determining regions of a light chain variable region and three complementary-determining regions of a heavy chain variable region as set forth in SEQ ID NO.:24.

15. The method of claim 14 , wherein the monoclonal antibody comprises:

a) a light chain variable region as set forth in SEQ ID NO.: 8 and a heavy chain variable region as set forth in SEQ ID NO.:20;

b) a light chain variable region as set forth in SEQ ID NO.: 9 and a heavy chain variable region as set forth in SEQ ID NO.:20;

c) a light chain variable region as set forth in SEQ ID NO.: 10 and a heavy chain variable region as set forth in SEQ ID NO.:21;

d) a light chain variable region as set forth in SEQ ID NO.: 11 and a heavy chain variable region as set forth in SEQ ID NO.: 22;

e) a light chain variable region as set forth in SEQ ID NO.: 12 and a heavy chain variable region as set forth in SEQ ID NO.:23, or

f) a light chain variable region and a heavy chain variable region as set forth in SEQ ID NO.:24.

16. The method of claim 14 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:8 are SSVSY (SEQ ID NO.:61), DTS and FQGSGYPFT (SEQ ID NO.:141) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:20 are GYSFTGYN (SEQ ID NO.:85), IDPYYGTP (SEQ ID NO.:119) and ALNSLLRLNAMDY (SEQ ID NO.:165).

17. The method of claim 14 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:9 are QDINKY (SEQ ID NO.:62), YTS and LQYDNLLRT (SEQ ID NO.:142) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:20 are GYSFTGYN (SEQ ID NO.:85), IDPYYGTP (SEQ ID NO.:119) and ALNSLLRLNAMDY (SEQ ID NO.:165).

18. The method of claim 14 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:10 are QSVNSSNYSY (SEQ ID NO.:63), YAS, QHSWEIPWT (SEQ ID NO.:143) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:21 are GYTFTDYS (SEQ ID NO.:86), INTETGEP (SEQ ID NO.:120) and ARTGSSGYFDC (SEQ ID NO.:166).

19. The method of claim 14 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:11 are QSLLYSSNQKNY (SEQ ID NO.:64), WAS, QQYYIYPRT (SEQ ID NO.:144) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:22 are GYTFTNYG (SEQ ID NO.:87), INTYTGEP (SEQ ID NO.:121) and ARDGFLYFFDY (SEQ ID NO.:167).

20. The method of claim 14 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:12 are QSLLNSRTRKNY (SEQ ID NO.:65), WAS, KQSYNLWT (SEQ ID NO.:145) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:23 are GFNIKDIY (SEQ ID NO.:88), IDPAYGNT (SEQ ID NO.:122) and ARRYDTAMDY (SEQ ID NO.:168).

21. The method of claim 12 , wherein the antibody is monoclonal.

22. The method of claim 12 , wherein the antibody is polyclonal.

23. The method of claim 12 , wherein the subject has breast carcinoma.

24. The method of claim 12 , wherein the subject has prostate carcinoma.

25. The method of claim 23 , wherein the administration reduces metastasis to the lung.

26. The method of claim 24 , wherein the administration reduces metastasis to the lung.

27. A method for treating metastatic carcinoma, the method comprising administering an antibody to a subject having metastatic carcinoma, wherein the antibody specifically binds a site in the amino acid sequence VEVSRKNPKFMETVAEKALQEYR (SEQ ID NO.: 5) of human clusterin.

28. The method of claim 27 , wherein the antibody binds to secreted clusterin.

29. The method of claim 27 , wherein the antibody is a monoclonal antibody that comprises:

a) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:8 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:20;

b) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:9 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:20;

c) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:10 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:21;

d) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:11 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:22;

e) three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:12 and three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:23, or

f) three complementarity-determining regions of a light chain variable region and three complementary-determining regions of a heavy chain variable region as set forth in SEQ ID NO.:24.

30. The method of claim 29 , wherein the monoclonal antibody comprises:

a) a light chain variable region as set forth in SEQ ID NO.: 8 and a heavy chain variable region as set forth in SEQ ID NO.:20;

b) a light chain variable region as set forth in SEQ ID NO.: 9 and a heavy chain variable region as set forth in SEQ ID NO.:20;

c) a light chain variable region as set forth in SEQ ID NO.: 10 and a heavy chain variable region as set forth in SEQ ID NO.:21;

d) a light chain variable region as set forth in SEQ ID NO.: 11 and a heavy chain variable region as set forth in SEQ ID NO.:22;

e) a light chain variable region as set forth in SEQ ID NO.: 12 and a heavy chain variable region as set forth in SEQ ID NO.:23, or

f) a light chain variable region and a heavy chain variable region as set forth in SEQ ID NO.:24.

31. The method of claim 29 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:8 are SSVSY (SEQ ID NO.:61), DTS and FQGSGYPFT (SEQ ID NO.:141) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:20 are GYSFTGYN (SEQ ID NO.:85), IDPYYGTP (SEQ ID NO.:119) and ALNSLLRLNAMDY (SEQ ID NO.:165).

32. The method of claim 29 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:9 are QDINKY (SEQ ID NO.:62), YTS and LQYDNLLRT (SEQ ID NO.:142) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:20 are GYSFTGYN (SEQ ID NO.:85), IDPYYGTP (SEQ ID NO.:119) and ALNSLLRLNAMDY (SEQ ID NO.:165).

33. The method of claim 29 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:10 are QSVNSSNYSY (SEQ ID NO.:63), YAS, QHSWEIPWT (SEQ ID NO.:143) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:21 are GYTFTDYS (SEQ ID NO.:86), INTETGEP (SEQ ID NO.:120) and ARTGSSGYFDC (SEQ ID NO.:166).

34. The method of claim 29 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:11 are QSLLYSSNQKNY (SEQ ID NO.:64), WAS, QQYYIYPRT (SEQ ID NO.:144) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:22 are GYTFTNYG (SEQ ID NO.:87), INTYTGEP (SEQ ID NO.:121) and ARDGFLYFFDY (SEQ ID NO.:167).

35. The method of claim 29 , wherein the three complementarity-determining regions of a light chain variable region set forth in SEQ ID NO.:12 are QSLLNSRTRKNY (SEQ ID NO.:65), WAS, KQSYNLWT (SEQ ID NO.:145) and wherein the three complementarity-determining regions of a heavy chain variable region set forth in SEQ ID NO.:23 are GFNIKDIY (SEQ ID NO.:88), IDPAYGNT (SEQ ID NO.:122) and ARRYDTAMDY (SEQ ID NO.:168).

36. The method of claim 27 , wherein the antibody is monoclonal.

37. The method of claim 27 , wherein the antibody is polyclonal.

38. The method of claim 27 , wherein the subject has metastatic breast carcinoma.

39. The method of claim 27 , wherein the subject has metastatic prostate carcinoma.

40. The method of claim 38 , wherein the administration reduces metastasis to the lung.

41. The method of claim 39 , wherein the administration reduces metastasis to the lung.

42. The method as claimed in claim 12 , wherein the antibody is a monoclonal antibody and has

a) a light chain variable region comprising three complementarity-determining regions of SEQ ID NO.:8 or SEQ ID NO.:9 and a heavy chain variable region comprising a CDR1 consensus as set forth in SEQ ID NO.:6, a CDR2 consensus as set forth in SEQ ID NO.:7 and a CDR3 having an amino acid sequence as set forth in SEQ ID NO.:165;

b) a light chain variable region comprising three complementarity-determining regions of SEQ ID NO.:10 and a heavy chain variable region comprising a CDR1 consensus as set forth in SEQ ID NO.:6, a CDR2 consensus as set forth in SEQ ID NO.:7 and a CDR3 having an amino acid sequence as set forth in SEQ ID NO.:166; or

c) a light chain variable region comprising three complementarity-determining regions of SEQ ID NO.:11 and a heavy chain variable region comprising a CDR1 consensus as set forth in SEQ ID NO.:6, a CDR2 consensus as set forth in SEQ ID NO.:7 and a CDR3 having an amino acid sequence as set forth in SEQ ID NO.:167.

43. The method as claimed in claim 27 , wherein the antibody is a monoclonal antibody and has;

a) a light chain variable region comprising three complementarity-determining regions of SEQ ID NO.:8 or SEQ ID NO.:9 and a heavy chain variable region comprising a CDR1 consensus as set forth in SEQ ID NO.:6, a CDR2 consensus as set forth in SEQ ID NO.:7 and a CDR3 having an amino acid sequence as set forth in SEQ ID NO.:165;

b) a light chain variable region comprising three complementarity-determining regions of SEQ ID NO.:10 and a heavy chain variable region comprising a CDR1 consensus as set forth in SEQ ID NO.:6, a CDR2 consensus as set forth in SEQ ID NO.:7 and a CDR3 having an amino acid sequence as set forth in SEQ ID NO.:166; or

c) a light chain variable region comprising three complementarity-determining regions of SEQ ID NO.:11 and a heavy chain variable region comprising a CDR1 consensus as set forth in SEQ ID NO.:6, a CDR2 consensus as set forth in SEQ ID NO.:7 and a CDR3 having an amino acid sequence as set forth in SEQ ID NO.:167.

Assignments (4)
RELEASE OF SECURITY INTEREST Recorded Nov 20, 2023
From: JOINT-STOCK COMPANY GENERIUM
To: ALETHIA BIOTHERAPEUTICS INC.
Reel/Frame 065622/0749 →
LICENSE Recorded Mar 25, 2015
From: NATIONAL RESEARCH COUNCIL OF CANADA
To: ALETHIA BIOTHERAPEUTICS INC.
Reel/Frame 035251/0608 →
DEED OF HYPOTHEC ON SPECIFIC UNIVERSALITIES OF MOVABLE PROPERTY Recorded Jan 10, 2014
From: ALETHIA BIOTHERAPEUTICS INC./ALETHIA BIOTHERAPEUTIQUES INC.
To: IBC GENERIUM LLC
Reel/Frame 031968/0937 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 23, 2012
From: O'CONNOR-MCCOURT, MAUREEN D.; CANTIN, CHRISTIANE; LENFERINK, ANNE E.G.
To: NATIONAL RESEARCH COUNCIL OF CANADA
Reel/Frame 027573/0626 →
Continuity (3)
Division 11991459
Provisional Application 60716086 · Sep 13, 2005
Related Publication 20110033471A1 · Feb 10, 2011