Claims for Patent: 7,572,448

Summary for Patent: 7,572,448

Title:	Combined cancer treatment methods using selected antibodies to aminophospholipids
Abstract:	Disclosed are surprising discoveries concerning the role of anionic phospholipids and aminophospholipids in tumor vasculature and in viral entry and spread, and compositions and methods for utilizing these findings in the treatment of cancer and viral infections. Also disclosed are advantageous antibody, immunoconjugate and duramycin-based compositions and combinations that bind and inhibit anionic phospholipids and aminophospholipids, for use in the safe and effective treatment of cancer, viral infections and related diseases.
Inventor(s):	Thorpe; Philip E. (Dallas, TX), Huang; Xianming (Dallas, TX), Ran; Sophia (Riverton, IL)
Assignee:	Board of Regents, The University of Texas System (Austin, TX)
Application Number:	10/642,058
Patent Claims:	1. A method for treating an animal with cancer, comprising administering to said animal a therapeutically effective amount of a first anti-cancer agent; and further comprising: (a) subjecting said animal to surgery or radiotherapy; or (b) administering to said animal a therapeutically effective amount of at least a second anti-cancer agent; wherein said first anti-cancer agent is a purified antibody, or antigen-binding fragment thereof, that comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (i) a heavy chain variable region that comprises variable heavy (VH) CDR1, VH CDR2 and VH CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VH CDR1 has the amino acid sequence of SEQ ID NO:10, said VH CDR2 has the amino acid sequence of SEQ ID NO:11 and said VH CDR3 has the amino acid sequence of SEQ ID NO:12; and (ii) a light chain variable region that comprises a variable light (VL) CDR1, VL CDR2 and VL CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VL CDR1 has the amino acid sequence of SEQ ID NO:13, said VL CDR2 has the amino acid sequence of SEQ ID NO:14 and said VL CDR3 has the amino acid sequence of SEQ ID NO:15. 2. The method of claim 1, wherein said animal is a human patient. 3. The method of claim 1, wherein said first anti-cancer agent is administered to said animal via intravenous administration. 4. The method of claim 1, wherein said antibody, or said antigen-binding fragment thereof, binds to the luminal surface of blood vessels of the vascularized tumor. 5. The method of claim 1, wherein a therapeutically effective amount of at least a second anti-cancer agent is administered to said animal. 6. The method of claim 5, wherein said at least a second anti-cancer agent is a chemotherapeutic agent, radiotherapeutic agent, cytokine, anti-angiogenie agent, apoptosis-inducing agent, anticetlular agent, cytotoxin, steroid, antimetabolite, anthracycline, vinca alkaloid, antibiotic, chemokine, topoisomerase inhibitor, taxane, DNA cross-linking agent, intercalating agent, microtubule-directed agent, kinase inhibitor, farnesyl transferase inhibitor, hormone, hormone antagonist, DNA fragmenting agent, protein synthesis inhibitor, glucocorticoid, LHRH antagonist or alkylating agent. 7. The method of claim 6, wherein said at least a second anti-cancer agent is gemcitabine, taxol, vincristine, vinblastine, a combretastatin, doxorubicin, etoposide or actinomycin-D. 8. The method of claim 6, wherein said at least a second anti-cancer agent is docetaxel. 9. The method of claim 6, wherein said at least a second anti-cancer agent is cyclophosphamide, edelfosine, estramustine, meiphalan, fluorouracil, methotrexate, mercaptopurine, UFT, tegafur, uracil, cytarabine, bleomycin, epirubicin, mitomycin, mitoxantrone, camptothecin, irinotecan, topotecan, paclitaxel, cisplatin, octreotide, fludarabine, 5-fluoro-29-deoxyuridine, gemeitabine, hydroxyurea, ehlorambucil, nitrogen mustard, mitixantrone, teniposide, colcemid, flavopiridol, staurosporine, 7-hydroxystaurosporine, fenretinide, tamoxifen, finasteride, L-asparaginase, cycloheximide or puromycin. 10. The method of claim 6, wherein said at least a second anti-cancer agent is angiostatin, endostatin, a 16 kDa prolactin fragment, a laminin peptide, a fibronectin peptide, a tissue metalloproteinase inhibitor, a plasminogen activator inhibitor, TGF-.beta.1, IFN-.beta., IFN-.gamma., an ELR-CXC chemokine, SDF-1, MIG, platelet factor 4, IP-10, thrombospondin, SPARC, 2-Methoxyoestradiol, proliferin-related protein, suramin, thalidomide, cortisone, linomide, fumagillin, a retinoid, CM101, dexarnethasone or leukemia inhibitory factor. 11. The method of claim 5, wherein said at least a second anti-cancer agent is an anti-tubulin drug, a calcium flux inducing agent, a calcium ionophore or an inflammatory cytokine. 12. The method of claim 5, wherein said at least a second anti-cancer agent is an antibody or an antibody-therapeutic agent construct that binds to a tumor cell, an intracellular antigen released from a necrotic tumor cell or to a component of tumor vasculature. 13. The method of claim 12, wherein said at least a second anti-cancer agent is an anti-tumor cell immunotoxin. 14. The method of claim 5, wherein said at least a second anti-cancer agent is administered to said animal simultaneously with said first anti-cancer agent. 15. The method of claim 5, wherein said at least a second anti-cancer agent is administered to said animal sequential to said first anti-cancer agent. 16. The method of claim 15, wherein said at least a second anti-cancer agent is administered to said animal prior to said anti-cancer agent. 17. The method of claim 16, wherein said at least a second anti-cancer agent injures, causes preapoptotic changes or induces apoptosis in the endothelium of the blood vessels of said vascularized tumor. 18. The method of claim 17, wherein said at least a second anti-cancer agent is taxol, vincristine, vinblastine, neomycin, a podophyllotoxin, TNF-.alpha., angiostatin, endostatin, vasculostatin, an .alpha..sub.v.beta..sub.3 antagonist, a calcium-flux inducing agent or a calcium ionophore. 19. The method of claim 17, wherein said at least a second anti-cancer agent is a combretastatin, paclitaxol or docetaxel. 20. The method of claim 15, wherein said at least a second anti-cancer agent is administered to said animal subsequent to said anti-cancer agent. 21. The method of claim 20, wherein said at least a second anti-cancer agent is an anti-tumor cell inununotoxin or an anti-angiogenic agent. 22. The method of claim 1, wherein said animal is subjected to surgery or radiotherapy and wherein a therapeutically effective amount of a chemotherapeutic agent is administered to said animal. 23. The method of claim 1, wherein an image of said cancer is first obtained by administering to said animal a diagnostically effective amount of a detectably-labeled construct comprising said first antibody operatively attached to a detectable label. 24. The method of claim 1, wherein said heavy chain variable region has the amino acid sequence of SEQ ID NO:2. 25. The method of claim 1, wherein said light chain variable region has the amino acid sequence of SEQ ID NO:4. 26. The method of claim 1, wherein said purified antibody comprises a heavy chain variable region that has the amino acid sequence of SEQ ID NO:2 and a light chain variable region that has the amino acid sequence of SEQ ID NO:4. 27. The method of claim 1, wherein said first anti-cancer agent is said antigen-binding fragment of said antibody. 28. The method of claim 27, wherein said antigen-binding fragment of said antibody is operatively attached to a human antibody constant region. 29. A method for treating an animal with cancer, comprising administering to said animal a combined therapeutically effective amount of a first anti-cancer agent and at least a second anti-cancer agent; wherein said first anti-cancer agent is a purified antibody. or antigen-binding fragment thereof, that comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (i) a heavy chain variable region that comprises variable heavy (VH) CDR1, VH CDR2 and VH CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VH CDR1 has the amino acid sequence of SEQ ID NO:10, said VH CDR2 has the amino acid sequence of SEQ ID NO:11 and said VH CDR3 has the amino acid sequence of SEQ liD NO:12; and (ii) a light chain variable region that comprises a variable light (VL) CDR1, VL CDR2 and VL CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VL CDR1 has the amino acid sequence of SEQ ID NO:13, said VL CDR2 has the amino acid sequence of SEQ ID NO:14 and said VL CDR3 has the amino acid sequence of SEQ ID NO:15. 30. The method of claim 29, wherein said at least a second anti-cancer agent is docetaxel. 31. The method of claim 29, wherein said animal is a human patient. 32. The method of claim 29, wherein said first anti-cancer agent is said antigen-binding fragment of said antibody. 33. The method of claim 32, wherein said antigen-binding fragment of said antibody is operatively attached to a human antibody constant region. 34. A method for inhibiting angiogenesis, comprising administering to an animal having a disease associated with angiogenesis a combined therapeutically effective amount of a first therapeutic agent and at least a second therapeutic agent; wherein said first therapeutic agent is a purified antibody, or antigen-binding fragment thereof, that comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (i) a heavy chain variable region that comprises variable heavy (VH) CDR1, VH CDR2 and VH CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VH CDR1 has the amino acid sequence of SEQ ID NO:10, said VH CDR2 has the amino acid sequence of SEQ ID NO11 and said VH CDR3 has the amino acid sequence of SEQ ID NO: 12; and (ii) a light chain variable region that comprises a variable light (VL) CDR1, VL CDR2 and VL CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VL CDR1 has the amino acid sequence of SEQ ID NO:13, said VL CDR2 has the amino acid sequence of SEQ ID NO:14 and said VL CDR3 has the amino acid sequence of SEQ ID NO:15. 35. The method of claim 34, wherein said animal has cancer. 36. The method of claim 34, wherein said heavy chain variable region has the amino acid sequence of SEQ ID NO:2. 37. The method of claim 34, wherein said light chain variable region has the amino acid sequence of SEQ ID NO:4. 38. The method of claim 34, wherein said purified antibody comprises a heavy chain variable region that has the amino acid sequence of SEQ ID NO:2 and a light chain variable region that has the amino acid sequence of SEQ ID NO:4. 39. The method of claim 34, wherein said animal is a human patient. 40. The method of claim 34, wherein said first therapeutic agent is said antigen-binding fragment of said antibody. 41. The method of claim 40, wherein said antigen-binding fragment of said antibody is operatively attached to a human antibody constant region. 42. A method for treating an animal with cancer, comprising administering to said animal a therapeutically effective amount of a first anti-cancer agent, wherein said first anti-cancer agent is purified monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, or an antigen-binding fragment thereof; and further comprising: (a) subjecting said animal to surgery or radiotherapy; or (b) administering to said animal a therapeutically effective amount of at least a second anti-cancer agent. 43. The method of claim 42, wherein said first anti-cancer agent is an antigen-binding fragment of said monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 44. The method of claim 43, wherein said antigen-binding fragment of said monoelonal antibody 3G4, produced by hybridoma ATCC PTA 4545, is operatively attached to a human antibody constant region. 45. The method of claim 42, wherein said animal is a human patient. 46. The method of claim 42, wherein said first anti-cancer agent is the monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 47. A method for treating an animal with cancer, comprising administering to said animal a combined therapeutically effective amount of a first anti-cancer agent, wherein said first anti-cancer agent is purified monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545, or an antigen-binding fragment thereof; and at least a second anti-cancer agent. 48. The method of claim 47, wherein said first anti-cancer agent is the monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 49. The method of claim 47, wherein said first anti-cancer agent is an antigen-binding fragment of said monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 50. The method of claim 49, wherein said antigen-binding fragment of said monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, is operatively attached to a human antibody constant region. 51. The method of claim 47, wherein said animal is a human patient. 52. A method for treating an animal with cancer, comprising administering to said animal a combined therapeutically effective amount of a first anti-cancer agent, wherein said first anti-cancer agent is purified monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, and at least a second anti-cancer agent. 53. A method for inhibiting angiogenesis, comprising administering to an animal having a disease associated with angiogenesis a combined therapeutically effective amount of a first therapeutic agent, wherein said first therapeutic agent is purified monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, or an antigen-binding fragment thereof, and at least a second therapeutic agent. 54. The method of claim 53, wherein said first therapeutic agent is an antigen-binding fragment of said monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 55. The method of claim 54, wherein said antigen-binding fragment of said monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, is operatively attached to a human antibody constant region. 56. The method of claim 53, wherein said animal has cancer. 57. The method of claim 53, wherein said animal is a human patient. 58. The method of claim 53, wherein said first therapeutic agent is the monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 59. A method for treating an animal with cancer, comprising administering to said animal a therapeutically effective amount of a first anti-cancer agent and further comprising: (a) subjecting said animal to surgery or radiotherapy; or (b) administering to said animal a therapeutically effective amount of at least a second anti-cancer agent; wherein said first anti-cancer agent is a purified antibody that comprises at least two variable regions that each comprises thee CDRs, wherein said two variable regions are: (i) a heavy chain variable region that comprises variable heavy (VH) CDR1, VH CDR2 and VH CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VH CDR1 has the amino acid sequence of SEQ ID NO:10, said VH CDR2 has the amino acid sequence of SEQ ID NO:11 and said VH CDR3 has the amino acid sequence of SEQ ID NO:12; and (ii) a light chain variable region that comprises a variable light (VL) CDR1, VL CDR2 and VL CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VL CDR1 has the amino acid sequence of SEQ ID NO:13, said VL CDR2 has the amino acid sequence of SEQ ID NO:14 and said VL CDR3 has the amino acid sequence of SEQ ID NO:15. 60. A method for treating an animal with cancer, comprising administering to said animal a therapeutically effective amount of a first anti-cancer agent and further comprising: (a) subjecting said animal to surgery or radiotherapy; or (b) administering to said animal a therapeutically effective amount of at least a second anti-cancer agent; wherein said first anti-cancer agent is a purified antibody, or antigen-binding fragment thereof, that comprises at least two variable regions that each comprises three CDRs, wherein at least one of said variable regions is: (i) a heavy chain variable region from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, which has the amino acid sequence of SEQ ID NO:2; or (ii) a light chain variable region from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, which has the amino acid sequence of SEQ ID NO:4. 61. The method of claim 60, wherein said purified antibody comprises said heavy chain variable region. 62. The method of claim 60, wherein said purified antibody comprises said heavy chain variable region and said light chain variable region. 63. The method of claim 60, wherein said purified antibody comprises said light chain variable region. 64. A method for inhibiting angiogenesis, comprising administering to an animal having a disease associated with angiogenesis a combined therapeutically effective amount of a first therapeutic agent and at least a second therapeutic agent; wherein said first therapeutic agent is a purified antibody that comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (i) a heavy chain variable region that comprises variable heavy (VH) CDR1, VH CDR2 and VH CDR3 from the monoctonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VH CDR1 has the amino acid sequence of SEQ ID NO: 10, said VH CDR2 has the amino acid sequence of SEQ ID NO:11 and said VH CDR3 has the amino acid sequence of SEQ ID NO:12; and (ii) a light chain variable region that comprises a variable light (VL) CDR1, VL CDR2 and VL CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VL CDR1 has the amino acid sequence of SEQ ID NO: 13, said VL CDR2 has the amino acid sequence of SEQ ID NO:14 and said VL CDR3 has the amino acid sequence of SEQ if) NO:15. 65. A method for inhibiting angiogenesis, comprising administering to an animal having a disease associated with angiogenesis a combined therapeutically effective amount of a first therapeutic agent and at least a second therapeutic agent; wherein said first therapeutic agent is a purified antibody, or antigen-binding fragment thereof, that comprises at least two variable regions that each comprises three CDRs, wherein at least one of said variable regions is: (i) a heavy chain variable region from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, which has the amino acid sequence of SEQ ID NO:2; or (ii) a light chain variable region from the monoelonal antibody 3G4, produced by hybridoma ATCC PTA 4545, which has the amino acid sequence of SEQ ID NO:4. 66. The method of claim 65, wherein said purified antibody comprises said heavy chain variable region. 67. The method of claim 65, wherein said purified antibody comprises said light chain variable region. 68. The method of claim 65, wherein said purified antibody comprises said heavy chain variable region and said light chain variable region. 69. A method for treating an animal with cancer, comprising administering to said animal a combined therapeutically effective amount of a first anti-cancer agent and at least a second anti-cancer agent; wherein said first anti-cancer agent is a purified antibody that comprises at least two variable regions that each comprises thee CDRs, wherein said two variable regions are: (i) a heavy chain variable region that comprises variable heavy (VH) CDR1, VH CDR2 and VH CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VH CDR1 has the amino acid sequence of SEQ ID NO:10, said VH CDR2 has the amino acid sequence of SEQ ID NO:11 and said VH CDR3 has the amino acid sequence of SEQ ID NO:12; and (ii) a light chain variable region that comprises a variable light (VL) CDR1, VL CDR2 and VL CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said VL CDRI has the amino acid sequence of SEQ ID NO:13, said VL CDR2 has the amino acid sequence of SEQ ID NO:14 and said VL CDR3 has the amino acid sequence of SEQ ID NO:15. 70. A method for treating an animal with cancer, comprising administering to said animal a combined therapeutically effective amount of a first anti-cancer agent and at least a second anti-cancer agent; wherein said first anti-cancer agent is a purified antibody, or antigen-binding fragment thereof, that comprises at least two variable regions that each comprises three CDRs, wherein at least one of said variable regions is: (i) a heavy chain variable region from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, which has the amino acid sequence of SEQ ID NO:2; or (ii) a light chain variable region from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, which has the amino acid sequence of SEQ ID NO:4. 71. The method of claim 70, wherein said purified antibody comprises said heavy chain variable region. 72. The method of claim 70, wherein said purified antibody comprises said light chain variable region. 73. The method of claim 70, wherein said purified antibody comprises said heavy chain variable region and said light chain variable region.

Details for Patent 7,572,448

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2022-07-15