Compositions and methods of treating tumors

• US 7,625,558 B2
• Filed: 03/19/2002
• Issued: 12/01/2009
• Est. Priority Date: 03/04/1998
• Status: Expired due to Term

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Greene, Mark I., O'Rourke, Donald M., Murali, Ramachandran, Park, Byeong-Woo
• Primary Examiner(s): Yaen, Christopher H
• Application Number:
  US10/100,952
• Publication Number:
  US 20020165193A1
• Time in Patent Office: 2,814 Days
• Field of Search: 424/130.1, 424/136.1, 424/138.1, 424/139.1, 424/141.1, 424/143.1, 424/174.1
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/572 cytotoxic response
• 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 38/1709 from mammals
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• 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 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Abstract

Methods of treating an individual who has an erbB protein mediated tumor is disclosed. Methods of preventing erbB protein mediated tumors in an individual are disclosed. The methods comprise adminstering to the individual a nucleic acid molecule that encodes a protein that dimerizes with an erbB protein and that is deficient in tyrosine kinase activity. Composition that comprise such nucleic acid molecules including pharmaceutical compositions are disclosed.

Claims

1. A method of treating an individual who has an erbB protein mediated tumor which method comprises steps of:

(a) administering to said individual an antibody which inhibits formation of erbB protein dimers that produce elevated tyrosine kinase activity in a tumor cell, said inhibition having a cytostatic effect on the tumor cell; and

(b) thereafter exposing said individual to a therapeutically effective amount of anti-cancer radiation.

2. The method of claim 1 wherein said erbB-protein mediated tumor is a p185-mediated tumor and/or an EGFR-mediated tumor.

3. The method of claim 1 wherein said antibody interacts with an erbB protein in a tumor cell to alter the erbB protein sufficient to result in a decreased propensity of it to dimerize with another erbB protein.

4. The method of claim 1 wherein said antibody competitively interacts with an erbB protein in a tumor cell to competitively inhibit dimer formation with another erB protein and prevents elevated tyrosine kinase activity.

15. The method according to claim 1 wherein the antibody inhibits formation of a p185 homodimer.

16. The method according to claim 1 wherein the antibody inhibits formation of an EGFR homodimer.

17. The method according to claim 1 wherein the antibody inhibits formation of a heterodimer of p185 and EGFR.

21. The method according to claim 1, wherein the antibody inhibits ligand independent formation of erbB protein dimers.

33. The method according to any one of claims 1 to 32, wherein said radiation is gamma radiation.

34. The method according to any one of claims 1 to 33, wherein said erbB protein mediated tumor is a p185 mediated tumor.

35. The method according to any one of claims 1 to 33, wherein said erbB protein mediated tumor is an EGFR mediated tumor.

36. The method according to any one of claims 1 to 35, wherein dimerization is inhibited by a physical alteration of the erbB protein monomer so that it is less thermodynamically disposed to form a dimer.

37. The method according to claim 36, wherein the physical alteration comprises a steric alteration of the erbB monomer.

38. The method according to claim 36 wherein the physical alternation comprises a conformational alteration of the erbB monomer.

39. The method according to claim 36, wherein the physical alteration comprises an electrostatic alteration of the erbB monomer.

40. The method according to any one of claims 1 to 39, wherein said tumor is an adenocarcinoma.

41. The method according to any one of claims 1 to 39, wherein said tumor is a human breast carcinoma.

5. A method of treating an individual who has a tumor, wherein said tumor is characterized by tumor cells that have multimeric receptor ensembles which provide tyrosine kinase activity associated with a transformed phenotype, wherein said multimeric receptor ensembles comprise

(i) erbB homodimers that are mutant EGFR homodimers or p185 homodimers;

or

(ii) erbB heterodimers that are p185/EGFR heterodimers, p185/mutant EGFR heterodimers, p185/erbB3 heterodimers, p185/erbB4 heterodimers or EGFR/mutant EGFR heterodimers; and

which method comprises steps of;

(a) administering to the individual, an antibody that disrupts the kinase activity associated with the multimeric receptor ensemble, said disruption having a cytostatic effect on the tumor cell; and

(b) thereafter exposing the individual to a therapeutic amount of gamma radiation.

18. The method according to claim 5 wherein the antibody inhibits formation of a p185 homodimer.

19. The method according to claim 5 wherein the antibody inhibits formation of an EGFR homodimer.

20. The method according to claim 5 wherein the antibody inhibits formation of a heterodimer of p185 and EGFR.

22. The method according to claim 5, wherein the antibody disrupts ligand independent kinase activity associated with the multimeric receptor ensemble.

6. A method of treating an individual who has a tumor, wherein said tumor is characterized by tumor cells that comprise EGFR, said method comprising the steps of:

(a) administering to the individual, an antibody that disrupts kinase activity mediated by EGFR, said disruption having a cytostatic effect on the tumor cells; and

(b) thereafter exposing the individual to a therapeutic amount of gamma radiation.

23. The method according to claim 6, wherein the antibody disrupts ligand independent kinase activaty mediated by EGFR.

7. A method for inhibiting proliferation of a tumor cell, said tumor cell being from an erbB mediated tumor,

which method comprises steps of:

(a) contacting the cell with an antibody that inhibits formation of an erbB protein dimer, which erbB protein dimer produces tyrosine kinase activity in the tumor cell and wherein inhibiting the formation of said erbB protein dimer has a cytostatic effect on the tumor cell; and

(b) thereafter exposing the tumor cell to an effective amount of anti-cancer radiation.

8. The method according to claim 7 wherein the antibody inhibits formation of a p185 homodimer.

9. The method according to claim 7 wherein the antibody inhibits formation of an EGFR homodimer.

10. The method according to claim 7 wherein the antibody inhibits formation of a heterodimer of p185 and EGFR.

24. The method according to claim 7, wherein the antibody inhibits ligand independent formation of the erbB protein dimer.

11. A method for inhibiting proliferation of a tumor cell, said tumor cell being from an erbB mediated tumor,

which method comprises steps of:

(a) contacting the cell with an antibody that disrupts erbB kinase activity said disruption having a cytostatic effect on the tumor cell; and

(b) thereafter exposing the tumor cell to an effective amount of anti-cancer radiation.

12. The method according to claim 11 wherein the antibody inhibits kinase activity mediated by an EGFR homodimer.

13. The method according to claim 11 wherein the antibody inhibits kinase activity mediated by a p185 homodimer.

14. The method according to claim 11 wherein the antibody inhibits kinase activity mediated by a heterodimer of p185 and EGFR.

25. The method according to claim 11, wherein the antibody disrupts ligand independent erbB kinase activity.

26. A method of treating an individual who has an erbB protein mediated tumor which method comprises steps of:

(a) administering to said individual a pharmaceutical composition comprising an antibody which inhibits formation of erbB protein dimers that produce elevated tyrosine kinase activity in a tumor cell of said individual; and

(b) after a time sufficient for said antibody to inhibit the tyrosine kinase activity associated with dimerization of erbB proteins in the tumor cell and thereby inhibit the growth of the tumor cell and increase sensitivity of the tumor cell to radiation, exposing said individual to a therapeutically effective amount of anti-cancer radiation, wherein the radiation is administered beginning within 72 hours after administration of the pharmaceutical composition.

28. The method according to claim 26 or 27, wherein the radiation is administered beginning within 1 to 10 hours after administration of the pharmaceutical composition.

29. The method according to claim 26 or 27, wherein the radiation is administered beginning within 3 hours after administration of the pharmaceutical composition.

30. The method according to claim 26 or 27, wherein the radiation is administered beginning within 24 hours after administration of the pharmaceutical composition.

31. The method according to claim 26 or 27, wherein the radiation is administered beginning with 1 -10 minutes after administration of the pharmaceutical composition.

32. The method according to any one of claims 26 to 31 wherein the radiation is administered as multiple doses.

27. A method of treating an individual who has an erbB protein mediated tumor which method comprises steps of:

(a) administering to said individual a pharmaceutical composition comprising an antibody which inhibits formation of erbB protein dimers that produce elevated tyrosine kinase activity in a tumor cell of said individual wherein the tumor cell is characterized by a transformed phenotype; and

(b) after a time sufficient for said antibody to inhibit the tyrosine kinase activity associated with dimerization of erbB proteins in the tumor cell and thereby reverse the transformed phenotype of the tumor cell so as to increase sensitivity of the tumor cell to radiation, exposing said individual to a therapeutically effective amount of anti-cancer radiation, wherein the radiation is administered beginning within 72 hours after administration of the pharmaceutical composition.