Compositions and methods of treating tumors

• US 20020165193A1
• Filed: 03/19/2002
• Published: 11/07/2002
• Est. Priority Date: 03/04/1998
• Status: Active Grant

• Current Assignee: Byeong-Woo Park, Mark Greene, Oʼrourke, Donald M., Ramachandran Murali
• Original Assignee: Byeong-Woo Park, Mark Greene, Oʼrourke, Donald M., Ramachandran Murali
• Inventors: OʼRourke, Donald M., Murali, Ramachandran, Greene, Mark I., Park, Byeong-Woo
• Granted Patent: US 7,625,558 B2
• Time in Patent Office: Days
• US Class Current: 514/44
• 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 comprising the steps of:

administering to said individual a nucleic acid molecule that encodes a protein that dimerizes with said erbB protein and that is deficient in tyrosine kinase activity, and

exposing said individual to a therapeutically effective amount of anti-cancer radiation and/or administering to said individual a therapeutically effective amount of an anti-cancer chemotherapeutic.

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 nucleic acid molecule is the genome of a recombinant virus.

4. A method of treating an individual who has an erbB protein mediated brain tumor comprising the step of:

administering to said individual a nucleic acid molecule that encodes a protein that dimerizes with said erbB protein and is deficient in tyrosine kinase activity.

5. The method of claim 4 wherein said erbB-protein mediated tumor is a mutant EGFR-mediated tumor.

7. A method of inhibiting proliferation of a mutant EGFR-mediated tumor cell comprising the step of delivering to said cell a nucleic acid molecule that encodes a protein that dimerizes with mutant EGFR and is deficient in tyrosine kinase activity.

8. A method of treating an individual who has an erbB protein mediated tumor comprising the steps of:

administering to said individual a composition which inhibits formation of erbB protein dimers that produce elevated tyrosine kinase activity in a tumor cell, and

exposing said individual to a therapeutically effective amount of anti-cancer radiation.

6. The method of claim 14 wherein said individual is exposed to a therapeutically effective amount of anti-cancer radiation and/or administered a therapeutically effective amount of an anti-cancer chemotherapeutic.

9. The method of claim 8 wherein said erbB-protein mediated tumor is a p185-mediated tumor and/or an EGFR-mediated tumor.

10. The method of claim 8 wherein said composition that is administered to a patient comprises a compound that 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.

11. The method of claim 10 wherein said compound that 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 is an antibody.

12. The method of claim 8 wherein said composition that is administered to a patient comprises a compound that competitively interacts with an erbB protein in a tumor cell to competitively inhibit dimer formation with another erbB protein and prevents elevated tyrosine kinase activity.

13. The method of claim 12 wherein said compound that competitively interacts with an erbB protein in a tumor cell to competitively inhibit dimer formation with another erbB protein is a peptide or an antibody.

14. The method of claim 8 wherein said composition that is administered to said tumor cell is a nucleic acid molecule that encodes a protein that competitively interacts with an erbB protein in a tumor cell to competitively inhibit dimer formation with another erbB protein.

15. The method of claim 14 wherein said protein is a mutant or truncated kinase deficient erbB protein.

17. The method of claim 16 wherein said tumor is characterized by tumor cells that have:

a) erbB homodimers that are mutant EGFR homodimers or p185 homodimers; and

/or

b) erbB heterodimers that are p185/EGFR heterodimers, p185/mutant EGFR heterodimers, p185/erbB3 heterodimers;

p185/erbB4 heterodimers or EGFR/mutant EGFR heterodimers.

18. The method of claim 16 wherein said composition that disrupts the kinase activity associated with the multimeric receptor ensemble comprises an active agent selected from the group consisting of antibodies, peptides, and non-proteinaceous kinase inhibitors.

19. The method of claim 16 wherein said composition that disrupts the kinase activity associated with the multimeric receptor ensemble comprises an active agent that is a nucleic acid molecule that encodes a protein or peptide which interacts with a monomeric component of said ensemble to prevent said monomeric component from interacting with a second monomeric component of said ensemble.

16. 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 kinase activity associated with a transformed phenotype, said method comprising the steps of:

a) administering to the individual, a composition that disrupts the kinase activity associated with the multimeric receptor ensemble; and

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

20. 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 kinase activity associated with a transformed phenotype, said method comprising the steps of:

a) administering to the individual, a peptide, non-proteinaceous compound or nucleic acid molecules that encodes a protein that disrupts the kinase activity associated with the multimeric receptor ensemble; and

b) exposing the individual to a therapeutic amount of gamma radiation and/or administering a therapeutic amount of a cytotoxic chemotherapeutic agent to said individual.

21. The method of claim 20 wherein said tumor is characterized by tumor cells that have:

a) erbB homodimers that are mutant EGFR homodimers or p185 homodimers; and

/or

b) erbB heterodimers that are p185/EGFR heterodimers, p185/mutant EGFR heterodimers, p185/erbB3 heterodimers;

p185/erbB4 heterodimers or EGFR/mutant EGFR heterodimers.

22. The method of claim 20 wherein said composition that disrupts the kinase activity associated with the multimeric receptor ensemble comprises an active agent that is a nucleic acid molecule that encodes a protein or peptide which interacts with a monomeric component of said ensemble to prevent said monomeric component from interacting with a second monomeric component of said ensemble.

24. The method of claim 23 wherein said EGFR species is a mutant EGFR.

25. The method of claim 23 wherein said composition that disrupts kinase activity mediated by an EGFR species comprises an active agent that is a nucleic acid molecule that encodes a protein or peptide which interacts with a molecule of an EGFR species to prevent said molecule or from forming a kinase-activity elevating multimeric ensemble with a second molecule.

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

a) administering to the individual, a composition that disrupts kinase activity mediated by an EGFR species; and

b) exposing the individual to a therapeutic amount of gamma radiation and/or administering a therapeutic amount of a cytotoxic chemotherapeutic agent to said individual.