Monoclonal antibodies directed to the HER2 receptor

• US 5,677,171 A
• Filed: 08/05/1994
• Issued: 10/14/1997
• Est. Priority Date: 01/12/1988
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Fendly, Brian M., Ullrich, Axel, Shepard, H. Michael, Hudziak, Robert M.
• Primary Examiner(s): Feisee, Lila
• Assistant Examiner(s): Bansal, Geetha P.
• Application Number:
  US08/286,303
• Time in Patent Office: 1,166 Days
• Field of Search: 530/387.7, 530/388.8, 530/388.85, 530/381.1, 435/7.23, 435/240.27, 435/172.2, 435/70.21
• US Class Current: 435/7.23
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/191 Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• CPC Class Codes: A61K 38/2006 IL-1
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 47/6843 the antibody targeting a material from animals or humans
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/3015 Breast
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Abstract

Monoclonal antibodies which bind to the extracellular domain of the HER2 receptor and inhibit growth of SK-BR-3 breast tumor cells, which overexpress HER2, are disclosed. The monoclonal antibodies can be used for in vitro assays for detecting a tumor characterized by amplified expression of HER2.

Claims

1. A monoclonal antibody which specifically binds to the extracellular domain of the HER2 receptor and inhibits growth of SK-BR-3 breast tumor cells in cell culture by greater than 20%, at an antibody concentration on of 0.5-30 μ

g/ml, wherein said SK-BR-3 cells are cultured in culture medium comprising 10% fetal bovine serum and said growth inhibition is determined six days after exposure of said SK-BR-3 cells to said antibody.

2. A monoclonal antibody as in claim 1 wherein said antibody inhibits growth of said SK-BR-3 breast tumor cells in cell culture by greater than 50%, at an antibody concentration of 0.5-3.0 μ

g/ml, wherein said growth inhibition is determined six days after exposure of said SK-BR-3 cells to said antibody.

3. The monoclonal antibody as in claim 1 which comprises murine antigen binding region residues and human antibody residues.

4. A monoclonal antibody which specifically binds to the extracellular domain of the HER2 receptor, sensitizes tumor cells to TNF-α

, and inhibits growth of SK-BR-3 breast tumor cells in cell culture by greater than 20% at an antibody concentration on of 0.5-3.0 μ

g/ml, wherein said growth inhibition is determined six days after exposure of said SK-BR-3 cells to said antibody.

5. A monoclonal antibody which specifically binds to the extracellular domain of the HER2 receptor, sensitizes tumor cells to cisplatin, and inhibits growth of SK-BR-3 breast tumor cells in cell culture by greater than 20%, at an antibody concentration of 0.5-3.0 μ

g/ml, wherein said growth inhibition is determined six days after exposure of said SK-BR-3 cells to said antibody.

6. A monoclonal antibody which specifically binds to the extracellular domain of the HER2 receptor, sensitizes tumor cells to doxorubicin, and inhibits growth of SK-BR-3 breast tumor cells in cell culture by greater than 20% at an antibody concentration, of 0.5 -3.0 μ

g/ml, wherein said growth inhibition is determined six days after exposure of said SK-BR-3 cells to said antibody.

7. A monoclonal antibody which binds to the HER2 receptor epitope to which monoclonal antibody 4D5 (ATCC CRL 10463) binds.

8. A monoclonal antibody which has the identifying biological characteristics of monoclonal antibody 4D5 (ATCC CRL 10463).

9. A monoclonal antibody as in claim 8 which comprises antigen binding region residues from monoclonal antibody 4D5 and human antibody residues.

10. A monoclonal antibody which specifically binds to the extracellular domain of the HER2 receptor and sensitizes tumor cells to TNF-α

.

11. A monoclonal antibody as in claim 10 wherein the tumor cells are SK-BR-3 cells.

12. A monoclonal antibody as in claim 10 which is a murine monoclonal antibody.

13. A monoclonal antibody as in claim 10 which comprises murine antigen binding region residues and human antibody residues.

14. A monoclonal antibody as in claim 13 which inhibits growth of tumor cells in a patient treated with a therapeutically effective amount of said antibody.

15. A monoclonal antibody as in claim 10 which downregulates the HER2 receptor.

16. A monoclonal antibody as in claim 10 wherein said antibody activates human complement.

17. A monoclonal antibody as in claim 10, wherein said antibody mediates human antibody dependent cellular cytotoxicity.

18. An immunotoxin which is a conjugate of a cytotoxic moiety and the antibody of claim 10.

19. An immunotoxin as in claim 18 wherein the cytotoxic moiety is a cytotoxic drug or an enzymatically active toxin.

20. An immunotoxin as in claim 18 wherein the cytotoxic moiety is a radioactive isotope.

21. An immunotoxin as in claim 18 wherein the cytotoxic moiety is ricin A chain.

22. A hybridoma producing the monoclonal antibody of claim 10.

23. A hybridoma as in claim 22 which is ATCC CRL 10463.

24. An assay for detecting a tumor comprising the steps of:

exposing a cell to said antibody of claim 10, and

determining the extent of binding of said antibody to said cell.

25. An assay as in claim 24 wherein said antibody is 4D5 (ATCC CRL 10463).

26. An assay as in claim 24 wherein the assay is an ELISA assay.

27. A monoclonal antibody as in claim 10 wherein said antibody binds to the HER2 receptor epitope to which monoclonal antibody 4D5 (ATCC CRL 10463) binds.

28. A monoclonal antibody as in claim 10 which is detectably labeled.

29. A monoclonal antibody as in claim 28 wherein the label is a radiolabel, enzyme label or fluorochrome label.

30. A monoclonal antibody as in claim 10 which inhibits growth of tumor cells in a patient treated with a therapeutically effective amount of said antibody.

31. A monoclonal antibody as in claim 30 wherein the tumor cells are breast, renal, gastric or salivary gland tumor cells.

32. A monoclonal antibody as in claim 30 wherein the tumor cells are breast tumor cells.

33. A liposome comprising said antibody of claim 10.

34. A composition comprising said antibody of claim 10 and a pharmaceutically acceptable vehicle.

35. A monoclonal antibody as in claim 10 which downregulates HER2 receptor levels on SK-BR-3 cells.

36. A monoclonal antibody which specifically binds to the extracellular domain of the HER2 receptor and sensitizes tumor cells to cisplatin or doxorubicin.

37. A monoclonal antibody as in claim 36 wherein the tumor cells are human breast tumor cells.

38. A monoclonal antibody as in claim 36 which sensitizes tumor cells to cisplatin.

39. A monoclonal antibody as in claim 36 which sensitizes tumor cells to doxorubicin.