Chemotherapeutic methods and compositions

• US 9,107,935 B2
• Filed: 01/05/2010
• Issued: 08/18/2015
• Est. Priority Date: 01/06/2009
• Status: Active Grant

• Current Assignee: Gilead Biologics, Inc. (Gilead Sciences Inc.)
• Original Assignee: Gilead Biologics, Inc. (Gilead Sciences Inc.)
• Inventors: Smith, Victoria, Holzer, Alison Kay
• Primary Examiner(s): Halvorson, Mark
• Assistant Examiner(s): Xiao, Yan
• Application Number:
  US12/652,687
• Publication Number:
  US 20100209415A1
• Time in Patent Office: 2,051 Days
• Field of Search: 514/1.1, 514/44.A, 514/44.R, 424/94.4, 424/139.1, 424/130.1
• US Class Current: 1/1
• 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 31/282 Platinum compounds
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/14 interfering N.A.

Abstract

Disclosed herein are methods and compositions for enhancing the cell-killing activity of anti-neoplastic agents by inhibiting the activity of a lysyl oxidase-type enzyme. Also disclosed are methods for screening for chemotherapeutic agents, and for molecules that enhance the activity of chemotherapeutic agents, using cells grown on an extracellular matrix.

Claims

1. A method for enhancing the cell killing activity of an anti-neoplastic agent, the method comprising:

contacting a cell that is resistant to the anti-neoplastic agent with the anti-neoplastic agent and an inhibitor of LOXL2, wherein the anti-neoplastic agent is a nucleic acid;

wherein the cell is growing in the presence of an extracellular matrix containing collagen and the inhibitor is an antibody that specifically binds to LOXL2,

whereby the cell killing activity of the anti-neoplastic agent is enhanced.

2. The method of claim 1, wherein the cell is in culture.

3. The method of claim 1, wherein the cell is present in a tumor.

4. The method of claim 1, wherein the nucleic acid is a siRNA.

5. The method of claim 1, wherein the collagen comprises type I collagen.

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

17. The method of claim 1, wherein the antibody is an antibody fragment.

18. The method of claim 17, wherein the antibody fragment is selected from the group consisting of scFv, Fab, and Fab₂ fragments.

19. The method of claim 1, wherein the antibody is human or humanized.

6. A method for killing a malignant cell, the method comprising:

contacting the malignant cell with an anti-neoplastic agent and an inhibitor of LOXL2, wherein the anti-neoplastic agent is a nucleic acid;

wherein the malignant cell is growing in the presence of an extracellular matrix containing collagen and the inhibitor is an antibody that specifically binds to LOXL2,

whereby the malignant cell is killed.

7. The method of claim 6, wherein the malignant cell is in culture.

8. The method of claim 6, wherein the malignant cell is present in a tumor.

9. The method of claim 6, wherein the nucleic acid is a siRNA.

10. The method of claim 6, wherein the collagen comprises type I collagen.

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

21. The method of claim 6, wherein the antibody is an antibody fragment.

22. The method of claim 21, wherein the antibody fragment is selected from the group consisting of scFv, Fab, and Fab₂ fragments.

23. The method of claim 6, wherein the antibody is human or humanized.

11. A method for reversing resistance of a malignant cell to an anti-neoplastic agent, the method comprising:

contacting the malignant cell, which is resistant to the anti-neoplastic agent, with the anti-neoplastic agent and an inhibitor of LOXL2, wherein the anti-neoplastic agent is a nucleic acid,

wherein the malignant cell is growing in the presence of an extracellular matrix containing collagen and the inhibitor is an antibody that specifically binds to LOXL2,

whereby the resistance of the malignant cell to the anti-neoplastic agent is reversed.

12. The method of claim 11, wherein the malignant cell is in culture.

13. The method of claim 11, wherein the malignant cell is present in a tumor.

14. The method of claim 11, wherein the nucleic acid is a siRNA.

15. The method of claim 11, wherein the collagen comprises type I collagen.

24. The method of claim 11, wherein the antibody is monoclonal.

25. The method of claim 11, wherein the antibody is an antibody fragment.

26. The method of claim 25, wherein the antibody fragment is selected from the group consisting of scFv, Fab, and Fab₂ fragments.

27. The method of claim 11, wherein the antibody is human or humanized.