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Last Updated: September 25, 2020

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Claims for Patent: 6,416,758

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Summary for Patent: 6,416,758
Title: Antibody conjugate kits 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.
Inventor(s): Thorpe; Philip E. (Dallas, TX), Brekken; Rolf A. (Seattle, WA)
Assignee: Board of Regents, The University of Texax System (Austin, TX)
Application Number:09/561,526
Patent Claims:1. A kit comprising, in at least a first composition:

(a) at least a first immunoconjugate comprising at least a first biological agent operatively attached to at least a first anti-VEGF antibody, or antigen-binding fragment thereof, wherein said anti-VEGF antibody, or antigen-binding fragment thereof, effectively competes with the monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, for binding to VEGF; and

(b) at least a second biological agent.

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

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

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

5. The kit of claim 1, wherein said at least a first antibody of said immunoconjugate is a chimeric antibody or a recombinant antibody.

6. The kit of claim 1, wherein said at least a first antibody of said immunoconjugate 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.

7. The kit of claim 1, wherein said at least a first antibody of said immunoconjugate is the monoclonal antibody 2C3 produced by hybridoma ATCC PTA 1595.

8. The kit of claim 1, wherein said immunoconjugate comprises said at least a first antibody operatively attached to at least a first therapeutic or diagnostic agent.

9. The kit of claim 8, wherein said immunoconjugate comprises said at least a first antibody operatively attached to at least a first therapeutic agent.

10. The kit of claim 9, wherein said immunoconjugate comprises said at least a first antibody operatively attached to two or more therapeutic agents.

11. The kit of claim 9, wherein said immunoconjugate comprises said at least a first antibody 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.

12. The kit of claim 11, wherein said immunoconjugate comprises said at least a first antibody operatively attached to a cytotoxic, cytostatic or anticellular agent capable of killing or suppressing the growth or cell division of endothelial cells.

13. The kit of claim 12, wherein said immunoconjugate comprises said at least a first antibody operatively attached to a plant-, fungus- or bacteria-derivedtoxin.

14. The kit of claim 13, wherein said immunoconjugate comprises said at least a first antibody operatively attached to 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.

15. The kit of claim 11, wherein said immunoconjugate comprises said at least a first antibody operatively attached to an anti-angiogenic agent.

16. The kit of claim 15, wherein said immunoconjugate comprises said at least a first antibody operatively attached to an angiopoietin, angiostatin, vasculostatin, canstatin or maspin.

17. The kit of claim 15, wherein said immunoconjugate comprises said at least a first antibody operatively attached to endostatin.

18. The kit of claim 11, wherein said immunoconjugate comprises said at least a first antibody operatively attached to an anti-tubulin drug.

19. The kit of claim 18, wherein said immunoconjugate comprises said at least a first antibody operatively attached to an anti-tubulin drug selected from the group consisting of colchicine, taxol, vinblastine, vincristine, vindescine and a combretastatin.

20. The kit of claim 11, wherein said immunoconjugate comprises said at least a first antibody operatively attached to a coagulant.

21. The kit of claim 20, wherein said immunoconjugate comprises said at least a first antibody 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, truncated Tissue Factor or Tissue Factor derivative.

22. The kit of claim 8, wherein said immunoconjugate comprises said at least a first antibody operatively attached to an imaging or detectable agent.

23. The kit of claim 22, wherein said immunoconjugate comprises said at least a first antibody operatively attached to an X-ray detectable compound, a radioactive ion, a nuclear magnetic spin-resonance isotope, biotin, avidin or to an enzyme that generates a colored product upon contact with a chromogenic substrate.

24. The kit of claim 1, wherein said immunoconjugate comprises said at least a first antibody operatively attached to at least a first biological agent that cleaves a substantially inactive prodrug to release a substantially active drug.

25. The kit of claim 1, wherein said immunoconjugate comprises said at least a first antibody 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.

26. The kit of claim 8, wherein said immunoconjugate comprises said at least a first antibody attached to a second antibody, or antigen binding region thereof, that binds to said therapeutic or diagnostic agent.

27. The kit of claim 9, wherein said immunoconjugate comprises said at least a first antibody operatively attached to said at least a first therapeutic agent via a biologically releasable bond or selectively cleavable linker.

28. The kit of claim 27, wherein said immunoconjugate comprises said at least a first antibody 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.

29. The kit of claim 1, wherein said at least a second biological agent is at least a second therapeutic agent.

30. The kit of claim 29, wherein said at least a second therapeutic agent is an anti-cancer agent.

31. The kit of claim 30, wherein said at least a second therapeutic agent is a chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent or anti-tubulin drug; or a prodrug or tumor-targeted form thereof.

32. The kit of claim 31, wherein said at least a second therapeutic agent is an angiopoietin, endostatin, angiostatin, vasculostatin, canstatin, maspin, colchicine, taxol, vinblastine, vincristine, vindescine, a combretastatin, or a prodrug or tumor-targeted form thereof.

33. The kit of claim 30, 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, tumor stroma, tumor vasculature or intratumoral vasculature.

34. The kit of claim 33, wherein said at least a second therapeutic agent is a targeting agent-therapeutic agent construct comprising said targeting region operatively linked to Tissue Factor, truncated Tissue Factor or a Tissue Factor derivative or to an antibody, or antigen-binding fragment thereof, that binds to Tissue Factor, truncated Tissue Factor or a Tissue Factor derivative.

35. The kit of claim 30, wherein said at least a second therapeutic agent is a substantially inactive prodrug that is cleavable to form a substantially active drug.

36. The kit of claim 29, wherein said kit comprises two or more second therapeutic agents.

37. The kit of claim 29, wherein said at least a first immunoconjugate and said at least a second therapeutic agent are comprised within a single composition.

38. The kit of claim 29, wherein said at least a first immunoconjugate and said at least a second therapeutic agent are comprised within distinct compositions.

39. The kit of claim 1, wherein said at least a second biological agent is at least one diagnostic component comprised within a composition distinct from said at least a first immunoconjugate.

40. The kit of claim 39, wherein said at least one diagnostic component is a tumor diagnostic component that comprises at least a first binding region that binds to an accessible component of a tumor cell, tumor vasculature or tumor stroma, operatively attached to an in vivo diagnostic imaging agent or to a reporter agent directly or indirectly detectable by an in vitro diagnostic test.

41. The kit of claim 1, wherein said kit comprises, within distinct compositions:

(a) at least a first immunoconjugate, wherein said at least a first antibody of said immunoconjugate is operatively attached to at least a first cleavage agent or enzyme; and

(b) at least one substantially inactive prodrug, wherein said prodrug is cleaved by said at least a first cleavage agent or enzyme to form a substantially active drug.

42. The kit of claim 41, wherein said kit comprises an operably matched first cleavage agent or enzyme and substantially inactive prodrug, wherein:

(a) said first 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) said 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.

43. The kit of claim 1, wherein said at least a first immunoconjugate or said at least a second biological agent is comprised in a pharmaceutically acceptable composition.

44. The kit of claim 43, wherein said at least a first immunoconjugate and said at least a second biological agent are each comprised in a pharmaceutically acceptable composition.

45. The kit of claim 43, wherein said pharmaceutically acceptable composition is formulated for intravenous administration.

46. The kit of claim 1, wherein said kit comprises said at least a first immunoconjugate, at least a second therapeutic agent and at least one diagnostic component.

47. A kit comprising:

(a) a biologically effective amount of at least a first immunoconjugate comprising at least a first biological agent operatively attached to at least a first anti-VEGF antibody, or antigen-binding fragment thereof; wherein said anti-VEGF antibody, or antigen-binding fragment thereof, effectively competes with the monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, for binding to VEGF and 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

(b) a biologically effective amount of at least a second biological agent.

48. A composition comprising at least a first immunoconjugate comprising at least a first biological agent operatively attached to at least a first anti-VEGF antibody, or antigen-binding fragment thereof; wherein said anti-VEGF antibody, or antigen-binding fragment thereof, effectively competes with the monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, for binding to VEGF.

49. The composition of claim 48, wherein said at least a first antibody is an IgG antibody or an IgM antibody.

50. An immunoconjugate comprising at least a first biological agent operatively attached to at least a first anti-VEGF antibody, or antigen-binding fragment thereof; wherein said anti-VEGF antibody, or antigen-binding fragment thereof, effectively competes with the monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, for binding to VEGF.

Details for Patent 6,416,758

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Microbix Biosystems KINLYTIC urokinase INJECTABLE;INJECTION 021846 001 1978-01-16   Start Trial Board of Regents, The University of Texax System (Austin, TX) 2019-04-28 DISCN search
Microbix Biosystems KINLYTIC urokinase INJECTABLE;INJECTION 021846 002 1978-01-16   Start Trial Board of Regents, The University of Texax System (Austin, TX) 2019-04-28 DISCN search
Microbix Biosystems KINLYTIC urokinase INJECTABLE;INJECTION 021846 003 1978-01-16   Start Trial Board of Regents, The University of Texax System (Austin, TX) 2019-04-28 DISCN search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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