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Last Updated: March 28, 2024

Claims for Patent: 6,676,941


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Summary for Patent: 6,676,941
Title: Antibody conjugate formulations for selectively inhibiting VEGF
Abstract:Disclosed are antibodies that specifically inhibit VEGF binding to only one (VEGFR2) of the two VEGF receptors. The antibodies effectively inhibit angiogenesis and induce tumor regression, and yet have improved safety due to their specificity. The present invention thus provides new antibody-based compositions, methods and combined protocols for treating cancer and other angiogenic diseases. Advantageous immunoconjugate and prodrug compositions and methods using the new VEGF-specific antibodies are also provided.
Inventor(s): Thorpe; Philip E. (Dallas, TX), Brekken; Rolf A. (Seattle, WA)
Assignee: Board of Regents, The University of Texas System (Austin, TX)
Application Number:09/998,831
Patent Claims:1. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier and at least a first immunoconjugate; wherein said immunoconjugate comprises at least a first anti-VEGF antibody, or antigen-binding fragment thereof, that binds to substantially the same epitope as the monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, operatively attached to at least a first biological agent; and wherein said pharmaceutically acceptable carrier is an ophthalmic formulation or a liposomal formulation.

2. The composition of claim 1, wherein said at least a first antibody is a monoclonal antibody or an antigen-binding fragment thereof.

3. The composition of claim 1, wherein said at least a first antibody is an IgG antibody or an IgM antibody.

4. The composition of claim 1, wherein said at least first antigen-binding fragment is an scFv, Fv, Fab', Fab, diabody, linear antibody or F(ab').sub.2 antigen-binding fragment of an antibody.

5. The composition of claim 1, wherein said at least a first antibody is a dimer, trimer or multimer of said antibody or antigen-binding fragments thereof.

6. The composition of claim 1, wherein said at least a first antibody is a human, humanized or part-human antibody or antigen-binding fragment thereof.

7. The composition of claim 1, wherein said at least a first antibody is a chimeric antibody.

8. The composition of claim 1, wherein said at least a first antibody is a recombinant antibody.

9. The composition of claim 1, wherein said at least first antibody comprises a variable region that includes an amino acid sequence region having the amino acid sequence of SEQ ID NO:7 or SEQ ID NO:9.

10. The composition of claim 1, wherein said at least first antibody is the monoclonal antibody 2C3 produced by hybridoma ATCC PTA 1595.

11. The composition of claim 1, wherein said at least a first antibody is operatively attached to at least a first biological agent that cleaves a substantially inactive prodrug to release a substantially active drug.

12. The composition of claim 11, wherein said at least a first antibody is operatively attached to alkaline phosphatase, arylsulfatase, serratia protease, thermolysin, subtilisin, a carboxypeptidase, a cathepsin, D-alanylcarboxypeptidase, .beta.-galactosidase, neuraminidase, .beta.-lactamase, penicillin amidase or cytosine deaminase that cleaves a substantially inactive prodrug to release a substantially active drug.

13. The composition of claim 1, wherein said at least a first antibody is operatively attached to at least a first therapeutic or diagnostic agent.

14. The composition of claim 13, wherein said at least a first antibody is operatively attached to at least a first therapeutic agent.

15. The composition of claim 14, wherein said at least a first antibody is operatively attached to at least a first and a second therapeutic agents.

16. The composition of claim 15, wherein said at least a first antibody is operatively attached to a plurality of therapeutic agents.

17. The composition of claim 14, wherein said at least a first antibody is operatively attached to at least a first chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent, steroid, antimetabolite, anthracycline, vinca alkaloid, anti-tubulin drug, antibiotic, cytokine, alkylating agent or coagulant.

18. The composition of claim 17, wherein said at least a first antibody is operatively attached to a cytotoxic, cytostatic or anticellular agent capable of killing or suppressing the growth or cell division of endothelial cells.

19. The composition of claim 18, wherein said at least a first antibody is operatively attached to a plant-, fungus- or bacteria-derived toxin.

20. The composition of claim 19, wherein said at least a first antibody is operatively attached to an A chain toxin, a ribosome inactivating protein, .alpha.-sarcin, gelonin, aspergillin, restrictocin, a ribonuclease, an epipodophyllotoxin, diphtheria toxin or Pseudomonas exotoxin.

21. The composition of claim 20, wherein said at least a first antibody is operatively attached to ricin A chain, deglycosylated ricin A chain or gelonin.

22. The composition of claim 17, wherein said at least a first antibody is operatively attached to an anti-angiogenic agent.

23. The composition of claim 22, wherein said at least a first antibody is operatively attached to an angiopoietin or to a second antibody, or antigen binding region thereof, that binds to an angiopoietin.

24. The composition of claim 23, wherein said at least a first antibody is operatively attached to angiopoietin-1 or to a second antibody, or antigen binding region thereof, that binds to angiopoietin-2.

25. The composition of claim 22, wherein said at least a first antibody is operatively attached to angiostatin, vasculostatin, canstatin or maspin.

26. The composition of claim 22, wherein said at least a first antibody is operatively attached to endostatin.

27. The composition of claim 17, wherein said at least a first antibody is operatively attached to an anti-tubulin drug.

28. The composition of claim 27, wherein said at least a first antibody is operatively attached to an anti-tubulin drug selected from the group consisting of colchicine, taxol, vinblastine, vincristine, vindescine and a combretastatin.

29. The composition of claim 17, wherein said at least a first antibody is operatively attached to a coagulant.

30. The composition of claim 29, wherein said at least a first antibody is operatively attached to a coagulant selected from the group consisting of Factor II/IIa, Factor VII/VIIa, Factor IX/IXa, Factor X/Xa, a vitamin K-dependent coagulation factor that lacks the Gla modification, Russell's viper venom Factor .lambda. activator, thromboxane A.sub.2, thromboxane A.sub.2 synthase and .alpha.2-antiplasmin.

31. The composition of claim 29, wherein said at least a first antibody is operatively attached to Tissue Factor, a human Tissue Factor, a mutant Tissue Factor deficient in the ability to activate Factor VII, truncated Tissue Factor or to a dimeric, trimeric or polymeric Tissue Factor or Tissue Factor derivative.

32. The composition of claim 31, wherein said at least a first antibody is operatively attached to truncated Tissue Factor.

33. The composition of claim 13, wherein said at least a first antibody is operatively attached to an imaging or detectable agent.

34. The composition of claim 33, wherein said at least a first antibody is operatively attached to an X-ray detectable compound, a radioactive ion or a nuclear magnetic spin-resonance isotope.

35. The composition of claim 33, wherein said at least a first antibody is operatively attached to biotin, avidin or to an enzyme that generates a colored product upon contact with a chromogenic substrate.

36. The composition of claim 1, wherein said at least a first antibody is operatively attached to said at least a first biological agent as a fusion protein prepared by expressing a recombinant vector that comprises, in the same reading frame, a DNA segment encoding said antibody operatively linked to a DNA segment encoding said biological agent.

37. The composition of claim 1, wherein said at least a first antibody is directly attached to said at least a first biological agent.

38. The composition of claim 13, wherein said at least a first antibody is attached to a second antibody, or antigen binding region thereof, that binds to said therapeutic or diagnostic agent.

39. The composition of claim 14, wherein said at least a first antibody is operatively attached to said at least a first therapeutic agent via a biologically releasable bond or selectively cleavable linker.

40. The composition of claim 39, wherein said at least a first antibody is operatively attached to said at least a first therapeutic agent via a peptide linker that includes a cleavage site for urokinase, pro-urokinase, plasmin, plasminogen, TGF.beta., staphylokinase, Thrombin, Factor IXa, Factor Xa, a metalloproteinase, an interstitial collagenase, a gelatinase or a stromelysin.

41. The composition of claim 1, wherein said pharmaceutically acceptable carrier is an ophthalmic formulation.

42. The composition of claim 41, wherein said composition is formulated for intravitreal or intracameral administration.

43. The composition of claim 1, wherein said composition further comprises a second biological agent.

44. The composition of claim 43, wherein said composition further comprises a second therapeutic agent.

45. The composition of claim 41, wherein said composition comprises a preservative, tonicity agent, antioxidant, stabilizer, wetting agent, clarifying agent or a viscosity-increasing agent.

46. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier and a biologically effective amount of at least a first immunoconjugate; wherein said immunoconjugate comprises at least a first biological agent operatively attached to an anti-VEGF antibody, or antigen-binding fragment thereof, that binds to the same epitope as the monoclonal antibody 2C3 produced by hybridoma ATCC PTA 1595 and that significantly inhibits VEGF binding to the VEGF receptor VEGFR2 (KDR/Flk-1) without significantly inhibiting VEGF binding to the VEGF receptor VEGFR1 (Flt-1); and wherein said pharmaceutically acceptable carrier is an ophthalmic formulation or a liposomal formulation.

47. The composition of claim 1, wherein said pharmaceutically acceptable carrier is a liposomal formulation.

48. The composition of claim 1, wherein said at least a first antibody binds to the same epitope as the monoclonal antibody 2C3 produced by hybridoma ATCC PTA 1595.

49. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier and at least a first immunoconjugate; wherein said immunoconjugate comprises at least a first biological agent operatively attached to at least a first anti-VEGF antibody, or antigen-binding fragment thereof, which effectively compete with the monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, for binding to VEGF; and wherein said pharmaceutically acceptable carrier is an ophthalmic formulation or a liposomal formulation.

50. An ophthalmic preparation comprising an ophthalmic solution or suspension and at least a first immunoconjugate that comprises at least a first anti-VEG antibody, or antigen-binding fragment thereof, that binds to substantially the same epitope as the monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, operatively attached to at least a first biological agent.

51. A liposomal formulation comprising liposomes or nanoparticles and at least a first immunoconjugate that comprises at least a first anti-VEGF antibody, or antigen-binding fragment thereof, that binds to substantially the same epitope as the monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, operatively attached to at least a first biological agent.

52. A kit comprising, in at least a first pharmaceutically acceptable, ophthalmic or liposomal composition: (a) at least a first immunoconjugate comprising at least a first anti-VEGF antibody, or antigen-binding fragment thereof, that binds to substantially the same epitope as the monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, operatively attached to at least a first biological agent; and (b) at least a second biological agent.

53. The kit of claim 52, wherein said at least a second biologic agent is a therapeutic agent.

54. The kit of claim 53, wherein said at least a second therapeutic agent is an anti-angiogenic agent.

55. The kit of claim 54, wherein said at least a second therapeutic agent is endostatin, angiostatin, vasculostatin, canstatin or maspin.

56. The kit of claim 53, wherein said at least a second therapeutic agent is an anti-cancer agent.

57. The kit of claim 56, wherein said at least a second therapeutic agent is a chemotherapeutic agent, radiotherapeutic agent, apoptosis-inducing agent or anti-tubulin drug; or a prodrug or tumor-targeted form thereof.

58. The kit of claim 56, wherein said at least a second therapeutic agent is colchicine, taxol, vinblastine, vincristine, vindescine, a combretastatin, or a prodrug or tumor-targeted form thereof.

59. The kit of claim 56, wherein said at least a second therapeutic agent is a targeting agent-therapeutic agent construct comprising a therapeutic agent operatively linked to at least a first targeting region that binds to an accessible component of a tumor cell or tumor stroma or to a surface-expressed, surface-accessible, surface-localized, cytokine-inducible or coagulant-inducible component of tumor vasculature or intratumoral vasculature.

60. The kit of claim 52, wherein said at least a first immunoconjugate and said at least a second biological agent are comprised within a single ophthalmic or liposomal composition.

61. The kit of claim 52, wherein said at least a first immunoconjugate and said at least a second biological agent are comprised within distinct ophthalmic or liposomal compositions.

62. The kit of claim 52, wherein said at least a second biologic agent is at least one diagnostic component comprised within a composition distinct from said at least a first immunoconjugate.

63. The kit of claim 52, wherein said immunoconjugate comprises said at least a first antibody operatively attached to at least a first cleavage agent or enzyme that cleaves a substantially inactive prodrug to release a substantially active drug.

64. The kit of claim 63, wherein said at least a second biological agent is at least a second substantially inactive prodrug that is cleaved by said at least a first cleavage agent or enzyme to form a substantially active drug.

65. The kit of claim 64, wherein said kit comprises an operably matched cleavage agent or enzyme and substantially inactive prodrug, wherein: (a) the cleavage agent or enzyme is selected from the group consisting of alkaline phosphatase, arylsulfatase, serratia protease, thermolysin, subtilisin, a carboxypeptidase, a cathepsin, D-alanylcarboxypeptidase, .beta.-galactosidase, neuraminidase, .beta.-lactamase, penicillin amidase and cytosine deaminase; and (b) the substantially inactive prodrug is selected from the matched group consisting of a phosphate-containing prodrug, sulfate-containing prodrug, peptide-based prodrug, D-amino acid-modified prodrug, glycosylated prodrug, .beta.-lactam-containing prodrug, optionally substituted phenoxyacetamide- or phenylacetamide-containing prodrug and 5-fluorocytosine.

66. The kit of claim 52, wherein said kit comprises said at least a first immunoconjugate, at least a second therapeutic agent and at least one diagnostic component.

67. The kit of claim 52, wherein said at least a first immunoconjugate is comprised within an ophthalmic composition.

68. The kit of claim 52, wherein said at least a first immunoconjugate is comprised within a liposomal composition.

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