Targeted chimeric molecules for cancer therapy

• US 20060263368A1
• Filed: 01/10/2006
• Published: 11/23/2006
• Est. Priority Date: 01/10/2005
• Status: Abandoned Application

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Research & Development Foundation
• Inventors: Rosenblum, Michael G., Ellington, Andrew D.
• Application Number:
  US11/329,362
• Publication Number:
  US 20060263368A1
• Time in Patent Office: Days
• US Class Current: 424/155.100
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6859 the tumour determinant being from liver or pancreas cancer cell
• 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 16/30 from tumour cells
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

The present invention concerns chimeric cancer therapeutic molecules comprising a targeting moiety and an anti-cell proliferation moiety. The anti-cell proliferation moiety may comprise a cytotoxic agent or an apoptosis-inducing factor, in specific embodiments. In particular embodiments, the anti-cell proliferation mechanism of the chimeric molecules comprises apoptotic pathways. In additional embodiments, the chimeric molecules of the present invention provide sensitivity to chemotherapy in a cell that is resistant to the chemotherapy.

Claims

1. A method of conferring or restoring chemosensitivity to one or more chemotherapy-resistant cancer cells in an individual, comprising delivering to the individual a therapeutically effective amount of a chimeric molecule comprising a cell-specific targeting moiety and an anti-cell proliferation moiety.

2. The method of claim 1, wherein the cell-specific targeting moiety is further defined as a cancer cell-targeting moiety.

3. The method of claim 2, wherein the cancer cell-targeting moiety is further defined as an antibody, a growth factor, a hormone, a peptide, an aptamer, or a cytokine.

4. The method of claim 3, wherein the antibody is further defined as a full-length antibody, chimeric antibody, Fab′

, Fab, F(ab′

)2, single domain antibody (DAB), Fv, single chain Fv (scFv), minibody, diabody, triabody, or a mixture thereof.

5. The method of claim 4, wherein the antibody is a scFv.

6. The method of claim 3, wherein the antibody is an anti-HER-2/neu antibody.

7. The method of claim 6, wherein the HER-2/neu antibody is scFv23.

8. The method of claim 3, wherein the antibody is an anti-gp240 antigen antibody.

9. The method of claim 8, wherein the anti-gp240 antigen antibody comprises scFvMEL.

10. The method of claim 3, wherein the cancer cell-targeting moiety comprises one or more growth factors.

11. The method of claim 10, wherein the growth factor is transforming growth factor, epidermal growth factor, insulin-like growth factor, fibroblast growth factor, heregulin, platelet-derived growth factor, vascular endothelial growth factor, or hypoxia inducible factor.

12. The method of claim 3, wherein the cancer cell-targeting moiety comprises one or more hormones.

13. The method of claim 12, wherein the hormone is human chorionic gonadotropin, gonadotropin releasing hormone, an androgen, an estrogen, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, growth hormone, adrenocorticotropic hormone, antidiuretic hormone, oxytocin, thyrotropin-releasing hormone, growth hormone releasing hormone, corticotropin-releasing hormone, somatostatin, dopamine, melatonin, thyroxine, calcitonin, parathyroid hormone, glucocorticoids, mineralocorticoids, adrenaline, noradrenaline, progesterone, insulin, glucagon, amylin, erythropoitin, calcitriol, calciferol, atrial-natriuretic peptide, gastrin, secretin, cholecystokinin, neuropeptide Y, ghrelin, PYY_3-36, insulin-like growth factor-1, leptin, thrombopoietin, angiotensinogen, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, or, IL-36.

14. The method of claim 3, wherein the cancer cell-targeting moiety comprises one or more cytokines.

15. The method of claim 14, wherein the cytokine is IL1, IL2, IL3, IL4, IL5, IL6, IL7, IL8, IL9, IL10, IL11, IL12, IL13, IL14, IL15, IL-16, IL-17, IL-18, granulocyte-colony stimulating factor, macrophage-colony stimulating factor, granulocyte-macrophage colony stimulating factor, leukemia inhibitory factor, erythropoietin, granulocyte macrophage colony stimulating factor, oncostatin M, leukemia inhibitory factor, IFN-γ

, IFN-α

, IFN-β

, LT-β

, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, TGF-β

, IL 1α

, IL-1β

, IL-1 RA, MIF, IGIF, or a mixture thereof.

16. The method of claim 1, wherein the anti-cell proliferation moiety is further defined as an apoptosis-inducing moiety or a cytotoxic agent.

17. The method of claim 16, wherein the apoptosis-inducing moiety is a granzyme, a Bcl-2 family member, cytochrome C, or a caspase.

18. The method of claim 17, wherein the granzyme is granzyme A, granzyme B, granzyme C, granzyme D, granzyme E, granzyme F, granzyme G, granzyme H, granzyme I, granzyme J, granzyme K, granzyme L, granzyme M, or granzyme N.

19. The method of claim 18, wherein the granzyme is granzyme B.

20. The method of claim 17, wherein the Bcl-2 family member is Bax, Bak, Bcl-Xs, Bad, Bid, Bik, Hrk, or Bok.

21. The method of claim 17, wherein the caspase is caspase-1, caspase-2 caspase-3, caspase-4, caspase-5, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10, caspase-11, caspase-12, caspase-13, or caspase-14.

22. The method of claim 16, wherein the cytotoxic agent is TNF-α

, gelonin, Prodigiosin, a ribosome-inhibiting protein (RIP), Pseudomonas exotoxin, Clostridium difficile Toxin B, Helicobacter pylori VacA, Yersinia enterocolitica YopT, Violacein, diethylenetriaminepentaacetic acid, irofulven, Diptheria Toxin, mitogillin, ricin, botulinum toxin, cholera toxin, or saporin 6.

23. The method of claim 16, wherein the cytotoxic agent is recombinant.

24. The method of claim 1, wherein the cell-specific targeting moiety and the anti-cell proliferation moiety are chemically conjugated.

25. The method of claim 1, wherein the cell-specific targeting moiety and the anti-cell proliferation moiety are comprised in a fusion polypeptide.

26. The method of claim 1, wherein the cell-specific targeting moiety and the anti-cell proliferation moiety are connected by a linker.

27. The method of claim 1, wherein the chemotherapy-resistant cancer cell is further defined as HER-2/neu overexpressing, resistant to TNF-α

, Nf-κ

B-overexpressing, Nf-κ

B signaling-defective, or a combination thereof.

28. The method of claim 1, wherein the chemotherapy-resistant cells are resistant to one or more classes of chemotherapeutic agents.

29. The method of claim 28, wherein the classes of chemotherapeutic agents are selected from the group consisting of alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant alkyloids, taxanes, and hormonal agents.

30. The method of claim 1, wherein the chemotherapy-resistant cells are resistant to one or more of 5-fluorouracil, cisplatin, etoposide, doxorubicin, or gemcitabine.

31. The method of claim 1, further comprising an additional cancer therapy for the individual.

32. The method of claim 31, wherein the additional cancer therapy is chemotherapy, surgery, radiation, gene therapy, hormone therapy, immunotherapy, or a combination thereof.

33. The method of claim 32, wherein the chemotherapy and the chimeric molecule are administered concomitantly.

34. The method of claim 32, wherein the chemotherapy and the chimeric molecule are administered in succession.

35. The method of claim 34, wherein the chimeric molecule is administered prior to the chemotherapy.

36. The method of claim 34, wherein the chimeric molecule is administered subsequent to the chemotherapy.

37. The method of claim 32, wherein the chemotherapy and the chimeric molecule provide a synergistic effect on the cancer cell.

38. The method of claim 32, wherein the chemotherapy and the chimeric molecule provide an additive effect on the cancer cell.

39. The method of claim 32, wherein the chimeric molecule is further defined as neoadjuvant surgical therapy.

40. The method of claim 32, wherein the chimeric molecule is further defined as postadjuvant surgical therapy.

41. The method of claim 1, wherein the chimeric molecule is scFvMEL/GrB.

42. The method of claim 1, wherein the chimeric molecule is scFv23/TNF-α

.

43. The method of claim 1, wherein the chimeric molecule is scFvMEL/TNF-α

.

44. A method of sensitizing one or more cancer cells in an individual to a chemotherapy, comprising administering to the individual a therapeutically effective amount of a chimeric molecule, said chimeric molecule comprising a cell-targeting moiety and an anti-cell proliferation moiety.

45. A method of inducing apoptosis in one or more TNF-resistant cancer cells in an individual, comprising administering to the individual a therapeutically effective amount of a chimeric molecule, said chimeric molecule comprising a cell-specific targeting moiety and an anti-cell proliferation moiety.

46. A method of inducing apoptosis in one or more HER-2/neu overexpressing cancer cells in an individual, comprising administering to the individual a therapeutically effective amount of a chimeric molecule, said chimeric molecule comprising a cell-specific targeting moiety and an anti-cell proliferation moiety.

47. A method of inducing apoptosis in one or more gp240 antigen-positive cells in an individual, comprising administering to the individual a therapeutically effective amount of a chimeric molecule, said chimeric molecule comprising a cell-specific targeting moiety and an anti-cell proliferation moiety.

48. A method of treating cancers in an individual that are Her-2/neu overexpressing and Nf-κ

B overexpressing, comprising administering to the individual a therapeutically effective amount of a chimeric molecule, said chimeric molecule comprising a cell-specific targeting moiety and an anti-cell proliferation moiety.

49. A method of treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of at least one chemotherapeutic agent, wherein said agent acts by interrupting NF-κ

B signaling, and a chimeric molecule, said chimeric molecule comprising a cell-specific targeting moiety and an anti-cell proliferation moiety.