Claims for Patent: 7,615,223

Summary for Patent: 7,615,223

Title:	Selected immunoconjugates for binding 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), Ran; Sophia (Riverton, IL)
Assignee:	Board of Regents, The University of Texas System (Austin, TX)
Application Number:	10/642,099
Patent Claims:	1. An immunoconjugate comprising an antibody, or antigen-binding fragment thereof, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer; wherein said antibody or antigen-binding fragment thereof comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (a) 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 (b) 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 immunoconjugate of claim 1, wherein said immunoconjugate comprises said antigen-binding fragment of said antibody operatively attached to a human antibody constant region. 3. The immunoconjugate of claim 1, wherein said antibody is operatively attached to at least a first therapeutic agent. 4. The immunoconjugate of claim 3, wherein said antibody is operatively attached to at least a first chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent, anticellular agent cytotoxin, steroid, antimetabolite, anthracycline, vinca alkaloid, anti-tubulin drug, antibiotic, cytokine, 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. 5. The immunoconjugate of claim 4, wherein said antibody is operatively attached to cyclophosphamide, edelfosine, estramustine, melphalan, fluorouracil, methotrexate, mercaptopurine, UFT, tegafur, uracil, cytarabine, bleomycin, epirubicin, mitomycin, mitoxantrone, camptothecin, irinotecan, topotecan, paclitaxel, cisplatin, octreotide, fludarabine, 5-fluoro-29-deoxyuridine, gemcitabine, hydroxyurea, chlorambucil, nitrogen mustard, mitixantrone, teniposide, colcemid, flavopiridol, staurosporine, 7-hydroxystaurosporine, fenretinide, tamoxifen, finasteride, L-asparaginase, cycloheximide or puromycin. 6. The immunoconjugate of claim 4, wherein said antibody is operatively attached to daunorubicin, doxorubicin, adriamycin, etoposide, actinomycin-D, paclitaxol, colchicine, taxol, vinblastine, vincristine, vindescine, a combretastatin or docetaxel. 7. The immunoconjugate of claim 4, wherein said antibody is operatively attached to 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, dexamethasone or leukemia inhibitory factor. 8. The immunoconjugate of claim 4, wherein said antibody is operatively attached to a plant-, fungus- or bacteria-derived toxin. 9. The immunoconjugate of claim 8, wherein said antibody is operatively attached to an A chain toxin, ricin A chain, deglycosylated ricin A chain, a ribosome inactivating protein, .alpha.-sarcin, gelonin, aspergillin, restrictocin, a ribonuclease, an epipodophyllotoxin, diphtheria toxin or Pseudomonas exotoxin. 10. The immunoconjugate of claim 9, wherein said antibody is operatively attached to gelonin. 11. The immunoconjugate of claim 4, wherein said antibody is operatively attached to the cytokine, interleukin-12 or to the chemokine, LEC. 12. The immunoconjugate of claim 4, wherein said antibody is operatively attached to TNF.alpha.. 13. The immunoconjugate of claim 4, wherein said antibody is operatively attached to the cytokine, interleukin-2 or interferon-.alpha.. 14. The immunoconjugate of claim 3, wherein said antibody is operatively attached to a coagulant. 15. The immunoconjugate of claim 1, wherein said antibody is operatively attached to at least a first diagnostic, imaging or detectable agent. 16. The immunoconjugate of claim 15, wherein said antibody is operatively attached to an X-ray detectable compound, a radioactive ion or a nuclear magnetic spin-resonance isotope. 17. The immunoconjugate of claim 1, wherein said antibody is operatively attached to at least a first agent that cleaves a substantially inactive prodrug to release a substantially active drug. 18. The immunoconjugate of claim 17, wherein said antibody is operatively attached to arylsulfatase, serratia protease, thermolysin, subtilisin, a carboxypeptidase, a cathepsin, D-alanylcarboxypeptidase, .beta.-galactosidase, neuraminidase, .beta.-lactamase, penicillin amidase, cytosine deaminase or alkaline phosphatase that cleaves a substantially inactive prodrug to release a substantially active drug. 19. The immunoconjugate of claim 1, wherein said antibody is attached to at least a first therapeutic, diagnostic, imaging or detectable agent or enzyme by a direct covalent bond, a chemical cross-linker, a biologically releasable bond or selectively cleavable linker or by recombinant expression as a fusion protein. 20. The immunoconjugate of claim 1, wherein said immunoconjugate is comprised in a pharmaceutically acceptable composition. 21. The immunoconjugate of claim 1, wherein said heavy chain variable region has the amino acid sequence of SEQ ID NO:2. 22. The immunoconjugate of claim 1, wherein said light chain variable region has the amino acid sequence of SEQ ID NO:4. 23. The immunoconjugate of claim 1, wherein said antibody, or antigen-binding fragment thereof, 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. 24. A composition comprising a biologically effective amount of an immunoconjugate that comprises an antibody, or antigen-binding fragment thereof, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer; wherein said antibody or antigen-binding fragment thereof comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (a) 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 (b) 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. 25. The composition of claim 24, wherein said immunoconjugate comprises said antigen-binding fragment of said antibody operatively attached to a human antibody constant region. 26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an immunoconjugate that comprises an antibody, or antigen-binding fragment thereof, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer; wherein said antibody or antigen-binding fragment thereof comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (a) a heavy chain variable region that comprises variable heavy (VH) CDR 1, 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 (b) 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. 27. The pharmaceutical composition of claim 26, wherein said immunoconjugate comprises said antigen-binding fragment of said antibody operatively attached to a human constant domain. 28. An immunoconjugate comprising an antibody operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer; wherein said antibody comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (a) a heavy chain variable region that comprises a variable heavy (VH) CDR1, VH CDR2 and VH CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said variable heavy (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 (b) 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 variable light (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. 29. The immunoconjugate of claim 28, wherein said immunoconjugate is comprised in a pharmaceutically acceptable composition. 30. The immunoconjugate of claim 28, wherein said heavy chain variable region has the amino acid sequence of SEQ ID NO:2. 31. The immunoconjugate of claim 28, wherein said light chain variable region has the amino acid sequence of SEQ ID NO:4. 32. The immunoconjugate of claim 28, wherein said 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. 33. The immunoconjugate of claim 28, wherein said antibody comprises a human constant domain. 34. An immunoconjugate comprising the monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545, or an antigen-binding fragment thereof, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer. 35. The immunoconjugate of claim 34, wherein said immunoconjugate comprises said monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 36. The immunoconjugate of claim 34, wherein said immunoconjugate comprises said antigen-binding fragment of said monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 37. The immunoconjugate of claim 36, 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. 38. The immunoconjugate of claim 34, wherein said antibody or antigen-binding fragment thereof is operatively attached to at least a first chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent, anticellular agent, cytotoxin, steroid, antimetabolite, anthracycline, ymca alkaloid, anti-tubulin drug, antibiotic, cytokine, chemokine, plant-derived toxin, fungus-derived toxin, bacteria-derived toxin or a coagulant. 39. A composition comprising a biologically effective amount of an immunoconjugate comprising an antibody operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer; wherein said antibody comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (a) a heavy chain variable region that comprises a variable heavy (VH) CDR 1, VH CDR2 and VH CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said variable heavy (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 (b) 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 variable light (VL) CDR1 has the amino acid sequence of SEQ ID NO:13, said VL CDR2 that has the amino acid sequence of SEQ ID NO:14 and said VL CDR3 that has the amino acid sequence of SEQ ID NO:15. 40. The composition of claim 38, wherein said composition is a pharmaceutically acceptable composition. 41. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an immunoconjugate comprising an antibody operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer; wherein said antibody comprises at least two variable regions that each comprises three CDRs, wherein said two variable regions are: (a) a heavy chain variable region that comprises a variable heavy (VH) CDR1, VH CDR2 and VH CDR3 from the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, wherein said variable heavy (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 (b) 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 variable light (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. 42. A composition comprising a biologically effective amount of an immunoconjugate comprising the monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545, or an antigen-binding fragment thereof, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer. 43. The composition of claim 42, wherein said immunoconjugate comprises said monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 44. The composition of claim 42, wherein said immunoconjugate comprises said antigen-binding fragment of said monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 45. The composition of claim 44, 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. 46. The composition of claim 42, wherein said antibody or antigen-binding fragment thereof is operatively attached to at least a first chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent, anticellular agent, cytotoxin, steroid, antimetabolite, anthracycline, vinca alkaloid, anti-tubulin drug, antibiotic, cytokine, chemokine, plant-derived toxin, fungus-derived toxin, bacteria-derived toxin or a coagulant. 47. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an immunoconjugate comprising the monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545, or an antigen-binding fragment thereof, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer. 48. The pharmaceutical composition of claim 47, wherein said immunoconjugate comprises said monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 49. The pharmaceutical composition of claim 47, wherein said immunoconjugate comprises said antigen-binding fragment of said monoclonal antibody 3G4 produced by hybridoma ATCC PTA 4545. 50. The pharmaceutical composition of claim 47, 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 pharmaceutical composition of claim 47, wherein said antibody or antigen-binding fragment thereof is operatively attached to at least a first chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent, anticellular agent, cytotoxin, steroid, antimetabolite, anthracycline, vinca alkaloid, anti-tubulin drug, antibiotic, cytokine, chemokine, plant-derived toxin, fungus-derived toxin, bacteria-derived toxin or a coagulant. 52. An immunoconjugate comprising an antibody, or antigen-binding fragment thereof, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer; wherein said antibody or antigen-binding fragment thereof comprises at least two variable regions that each comprises three CDRs, wherein at least one of said variable regions is: (a) 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 (b) 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. 53. The immunoconjugate of claim 52, wherein said antibody or antigen-binding fragment thereof comprises said heavy chain variable region. 54. The immunoconjugate of claim 52, wherein said antibody or antigen-binding fragment thereof comprises said light chain variable region. 55. The immunoconjugate of claim 52, wherein said antibody or antigen-binding fragment thereof comprises said heavy chain variable region and said light chain variable region. 56. An immunoconjugate comprising the monoclonal antibody 3G4, produced by hybridoma ATCC PTA 4545, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer. 57. A composition comprising a biologically effective amount of an immunoconjugate that comprises an antibody, or antigen-binding fragment thereof, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer; wherein said antibody or antigen-binding fragment thereof comprises at least two variable regions that each comprises three CDRs, wherein at least one of said variable regions is: (a) 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 (b) 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. 58. The composition of claim 57, wherein said antibody or antigen-binding fragment thereof comprises said heavy chain variable region. 59. The composition of claim 57, wherein said antibody or antigen-binding fragment thereof comprises said light chain variable region. 60. The composition of claim 57, wherein said antibody or antigen-binding fragment thereof comprises said heavy chain variable region and said light chain variable region. 61. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an immunoconjugate that comprises an antibody, or antigen-binding fragment thereof, operatively attached to at least a first therapeutic, diagnostic, imaging or detectable agent, enzyme, chelating agent, biochemical cross-linker or peptide spacer; wherein said antibody or antigen-binding fragment thereof comprises at least two variable regions that each comprises three CDRs, wherein at least one of said variable regions is: (a) 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 (b) 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. 62. The pharmaceutical composition of claim 61, wherein said antibody or antigen-binding fragment thereof comprises said heavy chain variable region. 63. The pharmaceutical composition of claim 61, wherein said antibody or antigen-binding fragment thereof comprises said light chain variable region. 64. The pharmaceutical composition of claim 61, wherein said antibody or antigen-binding fragment thereof comprises said heavy chain variable region and said light chain variable region.

Details for Patent 7,615,223

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