Antibody compositions for selectively inhibiting VEGF

• US 6,342,219 B1
• Filed: 04/28/2000
• Issued: 01/29/2002
• Est. Priority Date: 04/28/1999
• Status: Expired due to Term

• Current Assignee: Junglebyte Pte Limited, Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Thorpe, Philip E., Brekken, Rolf A.
• Primary Examiner(s): Chan, Christina Y.
• Assistant Examiner(s): Huynh, Phuong N.
• Application Number:
  US09/561,500
• Time in Patent Office: 641 Days
• Field of Search: 424/130.1, 424/133.1, 424/134.1, 424/135.1, 424/141.1, 424/142.1, 424/143.1, 424/145.1, 435/810, 435/69.1, 435/335, 530/387.1, 530/387.3, 530/388.1, 530/388.15, 530/388.23, 530/391.1, 530/391.3, 530/391.5, 530/391.7, 530/809, 530/864, 530/865, 530/866
• US Class Current: 424/145.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6815 Enzymes
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6845 the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/10 for accommodation disorders, e.g. myopia
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/52 : Cytokines; Lymphokines; Interferons
• CPC Class Codes: C07K 16/22 : against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/24 : against cytokines, lymphokines or interferons
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 5/101 : the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: Y10S 435/81 : Packaged device or kit
• CPC Class Codes: Y10S 530/809 : Fused cells, e.g. hybridoma
• CPC Class Codes: Y10S 530/864 : Monoclonal
• CPC Class Codes: Y10S 530/865 : Human
• CPC Class Codes: Y10S 530/866 : involving immunoglobulin or antibody fragment, e.g. fab', fab, fv, fc, heavy chain or light chain

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.

Claims

1. A composition comprising at least a first purified 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.

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 a first antigen-binding fragment is an scFv, Fv, Fab′

, Fab, diabody, linear antibody or F(ab′

)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 fragment 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 6, wherein said at least a first antibody comprises an antigen-binding region of said antibody operatively attached to a human antibody framework or constant region.

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

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

10. The composition of claim 1, wherein said at least a 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.

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

12. The composition of claim 1, wherein said composition is a pharmaceutically acceptable composition.

13. The composition of claim 12, wherein said composition is formulated for intravenous administration.

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

15. The composition of claim 14, wherein said composition further comprises a second therapeutic agent.

26. 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.

27. The composition of claim 1, wherein said composition comprises said at least a first antibody and a pharmaceutically acceptable carrier.

16. A composition comprising at least a first purified, unconjugated 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.

17. A composition comprising at least a first purified anti-VEGF antibody, or antigen-binding fragment thereof, prepared by a process comprising immunizing an animal with a composition comprising at least a first immunogenic VEGF component and selecting from the immunized animal an antibody-producing cell that produces an antibody that substantially cross-reacts with the monoclonal antibody 2C3 produced by hybridoma ATCC PTA 1595.

18. The composition of claim 17, wherein the immunized animal is a transgenic mouse that comprises a human antibody library and wherein the antibody selected is a human antibody.

19. The composition of claim 17, wherein antibody-encoding nucleic acids are obtained from the selected antibody-producing cell and expressed to produce said antibody.

20. A composition comprising a biologically effective amount of a purified 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).

21. A pharmaceutical composition comprising a biologically effective amount of at least a first purified 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.

22. A purified 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.

23. A monoclonal antibody 2C3, produced by hybridoma ATCC PTA 1595, or an antigen-binding fragment of said monoclonal antibody.

24. A hybridoma that produces a monoclonal anti-VEGF antibody that binds to substantially the same epitope as the monoclonal antibody 2C3 produced by hybridoma ATCC PTA 1595.

25. A method for preparing an anti-VEGF antibody that binds to substantially the same epitope as the monoclonal antibody 2C3 produced by hybridoma ATCC PTA 1595, comprising administering to an animal an immunizing composition comprising at least a first immunogenic VEGF component and selecting from the immunized animal an antibody that substantially cross-reacts with the monoclonal antibody 2C3 produced by hybridoma ATCC PTA 1595.

28. A composition comprising at least a first purified 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.

29. A kit comprising, in at least a first composition, at least a first purified 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;

and at least a second biological agent.

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

31. The kit of claim 30, wherein said at least a second therapeutic agent is a non-tumor targeted anti-angiogenic agent.

32. The kit of claim 31, wherein said at least a second therapeutic agent is an anti-angiogenic agent selected from the group consisting of angiostatin, endostatin, vasculostatin, canstatin and maspin.

33. The kit of claim 31, wherein said at least a second therapeutic agent is an anti-angiogenic agent listed in Table D.

34. The kit of claim 30, wherein said at least a second therapeutic agent is an angiopoictin or a tumor-targeted angiopoietin.

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

36. The kit of claim 35, wherein said at least a second therapeutic agent is a chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent or anti-tubulin drug;

a prodrug form of a chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent or anti-tubulin drug;

or a tumor-targeted chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent or anti-tubulin drug.

37. The kit of claim 36, wherein said at least a second therapeutic agent is angiopoietin-1, angiopoietin-2, endostatin, angiostatin, vasculostatin, canstatin or maspin, or a prodrug or tumor-targeted form thereof.

38. The kit of claim 36, wherein said at least a second therapeutic agent is an anti-tubulin drug selected from the group consisting of colchicine, taxol, vinblastine, vincristine, vindescine and a combretastatin;

or a tumor-targeted anti-tubulin drug selected from the group consisting of colchicine, taxol, vinblastine, vincristine, vindescine and a combretastatin.

39. The kit of claim 35, 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.

40. The kit of claim 39, wherein said at least a first targeting region is at least a first targeting antibody, or an antigen-binding fragment thereof.

41. The kit of claim 39, wherein said at least a first targeting region is operatively linked to a cytotoxic agent, anti-angiogenic agent, apoptosis-inducing agent, anti-tubulin drug or coagulant.

42. The kit of claim 41, wherein said at least a first targeting region is operatively linked to deglycosylated ricin A chain, gelonin, 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.

43. The kit of claim 29, wherein said kit comprises at least a second and third biological agent.

44. The kit of claim 29, wherein said at least a first antibody and said at least a second biological agent are comprised within a single composition.

45. The kit of claim 29, wherein said at least a first antibody and said at least a second biological agent are comprised within distinct compositions.

46. The kit of claim 29, wherein said at least a first antibody and said at least a second biological agent are comprised in one or more pharmaceutically acceptable compositions.

47. The kit of claim 29, 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 antibody.

48. The kit of claim 47, 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.

49. The kit of claim 29, wherein said kit comprises said at least a first antibody, at least a second therapeutic agent and at least one diagnostic component.

50. A medicinal cocktail comprising, in a pharmaceutically acceptable form, a combined therapeutically effective amount of at least a first unconjugated anti-VEGF antibody that binds to substantially the same epitope as the monoclonal antibody 2C3 produced by hybridoma ATCC PTA 1595, or an antigen-binding fragment of said anti-VEGF antibody, and at least a second anti-angiogenic agent.