Ligands that have binding specificity for VEGF and/or EGFR and methods of use therefor

• US 20070003549A1
• Filed: 01/11/2006
• Published: 01/04/2007
• Est. Priority Date: 08/24/2004
• Status: Active Grant

• Current Assignee: Domantis Incorporated
• Original Assignee: Domantis Incorporated
• Inventors: Beckmann, Roland, Holmes, Steve, Ignatovich, Olga, de Wildt, Rudolf
• Granted Patent: US 7,696,320 B2
• Time in Patent Office: Days
• US Class Current: 424/145.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 47/6879 the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/40 : against enzymes
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/569 : Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide

Abstract

Disclosed are ligands that have binding specificity for vascular endothelial growth factor (VEGF), for epidermal growth factor receptor (EGFR), or for VEGF and EGFR. Also disclosed are methods of using these ligands. In particular, the use of these ligands for cancer therapy is described.

Claims

1. A ligand that has binding specificity for vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), comprising at least one protein moiety that has a binding site with binding specificity for VEGF and at least one protein moiety that has a binding site with binding specificity for EGFR.

2. The ligand of claim 1 wherein each said protein moiety that has a binding site with binding specificity for VEGF competes for binding to VEGF with an anti-VEGF domain antibody (dAb) selected from the group consisting of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

3. The ligand of claim 1, wherein each said protein moiety that has a binding site with binding specificity for VEGF competes for binding to VEGF with bevacizumab.

4. The ligand of claim 1, wherein each said protein moiety that has a binding site with binding specificity for EGFR competes for binding to EGFR with cetuximab.

5. The ligand of claim 1, wherein each said protein moiety that has a binding site with binding specificity for VEGF competes for binding to VEGF with bevacizumab;

and wherein each said protein moiety that has a binding site with binding specificity for EGFR competes for binding to EGFR with cetuximab.

6. The ligand of claim 1, wherein each protein moiety that has a binding site with binding specificity for VEGF and each protein moiety that has a binding site with binding specificity for EGFR is provided by an antibody fragment.

7. The ligand of claim 6, wherein said antibody fragment is an immunoglobulin single variable domain.

10. The ligand of claim 1, wherein said ligand inhibits binding of epidermal growth factor (EGF) and/or transforming growth factor alpha (TGFalpha) to EGFR.

11. The ligand of claim 1, wherein said ligand inhibits the activity of EGFR.

12. The ligand of claim 1, wherein said ligand inhibits the activity of EGFR without substantially inhibiting binding of epidermal growth factor (EGF) and/or transforming growth factor alpha (TGFalpha) to EGFR.

13. The ligand of claim 1, wherein said ligand inhibits binding of VEGF to vascular endothelial growth factor receptor 1 (VEGFR1) and/or vascular endothelial growth factor receptor 2 (VEGFR2).

14. The ligand of claim 1, wherein said ligand inhibits the activity of VEGF.

15. The ligand of claim 1, wherein said ligand inhibits the activity of VEGF without substantially inhibiting binding of VEGF to vascular endothelial growth factor receptor 1 (VEGFR1) and/or vascular endothelial growth factor receptor 2 (VEGFR2).

22. The ligand of claim 1, wherein said ligand comprises an immunoglobulin single variable domain with binding specificity for VEGF that is a V_HH and/or an immunoglobulin single variable domain with binding specificity for EGFR that is a V_HH.

23. The ligand of claim 1, comprising an immunoglobulin single variable domain with binding specificity for VEGF and an immunoglobulin single variable domain with binding specificity for EGFR that are selected from the group consisting of a human V_H and a human V_L.

24. The ligand of claim 1, wherein said ligand is an IgG-like format comprising two immunoglobulin single variable domains with binding specificity for VEGF, and two immunoglobulin single variable domains with binding specificity for EGFR.

25. The ligand of claim 1, wherein said ligand comprises an antibody Fc region.

52. The ligand of claim 1, wherein said ligand further comprises a toxin.

53. The ligand of claim 1, wherein said toxin is a surface active toxin.

54. The ligand of claim 1, wherein said surface active toxin comprises a free radical generator or a radionuceotlide.

55. The ligand of claim 54, wherein said toxin is a cytotoxin, free radical generator, antimetabolite, protein, polypeptide, peptide, photoactive agent, antisense compound, chemotherapeutic, radionuclide or intrabody.

56. The ligand of claim 1, wherein said ligand further comprises a half-life extending moiety.

57. The ligand of claim 56, wherein said half-life extending moiety is a polyalkylene glycol moiety, serum albumin or a fragment thereof, transferrin receptor or a transferrin-binding portion thereof, or a moiety comprising a binding site for a polypeptide that enhances half-life in vivo.

58. The ligand of claim 57, wherein said half-life extending moiety is an moiety comprising a binding site for a polypeptide that enhances half-life in vivo, said moiety being selected from the group consisting of an affibody, an SpA domain, an LDL receptor class A domain, an EGF domain, and an avimer.

59. The ligand of claim 57, wherein said half-life extending moiety is a polyethylene glycol moiety.

60. The ligand of claim 57, wherein said half-life extending moiety is an antibody or antibody fragment comprising a binding site for serum albumin or neonatal Fc receptor.

61. The ligand of claim 60, wherein said antibody or antibody fragment comprising a binding site for serum albumin or neonatal Fc receptor is an antibody fragment, and said antibody fragment is an immunoglobulin single variable domain comprising a binding site for serum albumin comprising a binding site for serum albumin.

62. The ligand of claim 61, wherein said immunoglobulin single variable domain comprising a binding site for serum albumin competes for binding to human serum albumin with a dAb selected from the group consisting of DOM7m-16 (SEQ ID NO:

473), DOM7m-12 (SEQ ID NO;

     474), DOM7m-26 (SEQ ID NO;

     475), DOM7r-1 (SEQ ID NO;

     476), DOM7r-3 (SEQ ID NO;

     477), DOM7r-4 (SEQ ID NO;

     478), DOM7r-5 (SEQ ID NO;

     479), DOM7r-7 (SEQ ID NO;

     480), DOM7r-8 (SEQ ID NO;

     481), DOM7h-2 (SEQ ID NO;

     482), DOM7h-3 (SEQ ID NO;

     483), DOM7h-4 (SEQ ID NO;

     484), DOM7h-6 (SEQ ID NO;

     485), DOM7h-1 (SEQ ID NO;

     486), DOM7h-7 (SEQ ID NO;

     487), DOM7h-22 (SEQ ID NO;

     489), DOM7h-23 (SEQ ID NO;

     490), DOM7h-24 (SEQ ID NO;

     491), DOM7h-25 (SEQ ID NO;

     492), DOM7h-26 (SEQ ID NO;

     493), DOM7h-21 (SEQ ID NO;

     494), DOM7h-27 (SEQ ID NO;

     495), DOM7h-8 (SEQ ID NO;

     496), DOM7r-13 (SEQ ID NO;

     497), DOM7r-14 (SEQ ID NO;

     498), DOM7r-15 (SEQ ID NO;

     499), DOM7r-16 (SEQ ID NO;

     500), DOM7r-17 (SEQ ID NO;

     501), DOM7r-18 (SEQ ID NO;

     502), DOM7r-19 (SEQ ID NO;

     503), DOM7r-20 (SEQ ID NO;

     504), DOM7r-21 (SEQ ID NO;

     505), DOM7r-22 (SEQ ID NO;

     506), DOM7r-23 (SEQ ID NO;

     507), DOM7r-24 (SEQ ID NO;

     508), DOM7r-25 (SEQ ID NO;

     509), DOM7r-26 (SEQ ID NO;

     510), DOM7r-27 (SEQ ID NO;

     511), DOM7r-28 (SEQ ID NO;

     512), DOM7r-29 (SEQ ID NO;

     513), DOM7r-30 (SEQ ID NO;

     514), DOM7r-31 (SEQ ID NO;

     515), DOM7r-32 (SEQ ID NO;

     516), and DOM7r-33 (SEQ ID NO;

     517).

63. The ligand of claim 61, wherein said immunoglobulin single variable domain comprising a binding site for serum albumin comprises an amino acid sequence that has at least 85% amino acid sequence identity with the amino acid sequence of a dAb selected from the group consisting of DOM7m-16 (SEQ ID NO:

473), DOM7m-12 (SEQ ID NO;

     474), DOM7m-26 (SEQ ID NO;

     475), DOM7r-1 (SEQ ID NO;

     476), DOM7r-3 (SEQ ID NO;

     477), DOM7r-4 (SEQ ID NO;

     478), DOM7r-5 (SEQ ID NO;

     479), DOM7r-7 (SEQ ID NO;

     480), DOM7r-8 (SEQ ID NO;

     481), DOM7h-2 (SEQ ID NO;

     482), DOM7h-3 (SEQ ID NO;

     483), DOM7h-4 (SEQ ID NO;

     484), DOM7h-6 (SEQ ID NO;

     485), DOM7h-1 (SEQ ID NO;

     486), DOM7h-7 (SEQ ID NO;

     487), DOM7h-22 (SEQ ID NO;

     489), DOM7h-23 (SEQ ID NO;

     490), DOM7h-24 (SEQ ID NO;

     491), DOM7h-25 (SEQ ID NO;

     492), DOM7h-26 (SEQ ID NO;

     493), DOM7h-21 (SEQ ID NO;

     494), DOM7h-27 (SEQ ID NO;

     495), DOM7h-8 (SEQ ID NO;

     496), DOM7r-13 (SEQ ID NO;

     497), DOM7r-14 (SEQ ID NO;

     498), DOM7r-15 (SEQ ID NO;

     499), DOM7r-16 (SEQ ID NO;

     500), DOM7r-17 (SEQ ID NO;

     501), DOM7r-18 (SEQ ID NO;

     502), DOM7r-19 (SEQ ID NO;

     503), DOM7r-20 (SEQ ID NO;

     504), DOM7r-21 (SEQ ID NO;

     505), DOM7r-22 (SEQ ID NO;

     506), DOM7r-23 (SEQ ID NO;

     507), DOM7r-24 (SEQ ID NO;

     508), DOM7r-25 (SEQ ID NO;

     509), DOM7r-26 (SEQ ID NO;

     510), DOM7r-27 (SEQ ID NO;

     511), DOM7r-28 (SEQ ID NO;

     512), DOM7r-29 (SEQ ID NO;

     513), DOM7r-30 (SEQ ID NO;

     514), DOM7r-31 (SEQ ID NO;

     515), DOM7r-32 (SEQ ID NO;

     516), and DOM7r-33 (SEQ ID NO;

     517).

69. A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of ligand of claim 1 or 45.

70. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of ligand of claim 1 or 45 and a chemotherapeutic agent.

75. A method of administering to a subject anti-VEGF treatment and anti-EGFR treatment, the method comprising simultaneous administration of an anti-VEGF treatment and an anti-EGFR treatment by administering to said subject a therapeutically effective amount of a ligand of claim 1.

76. A composition comprising a ligand of claim 1 or 45 and a physiologically acceptable carrier.

79. A drug delivery device comprising the composition of claim 76.

80. A drug delivery device for simultaneously administering to a subject anti-VEGF treatment and anti-EGFR treatment, the device comprising a ligand of claim 1.

87. An isolated or recombinant nucleic acid encoding a ligand of claim 1 or 45.

88. A vector comprising the recombinant nucleic acid of claim 87.

89. A host cell comprising the recombinant nucleic acid of claim 87.

90. A method for producing a ligand comprising maintaining the host cell of claim 89 under conditions suitable for expression of said nucleic acid or vector, whereby a ligand is produced.

8. A ligand that has binding specificity for vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), comprising at least one immunoglobulin single variable domain with binding specificity for VEGF and at least one immunoglobulin single variable domain with binding specificity for EGFR, wherein

each said immunoglobulin single variable domain with binding specificity for VEGF competes for binding to VEGF with an anti-VEGF domain antibody (dAb) selected from the group consisting of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

9. The ligand of claim 8, wherein each said immunoglobulin single variable domain with binding specificity for VEGF comprises an amino acid sequence that has at least about 85% amino acid sequence identity with the amino acid sequence of a dAb selected from the group consisting of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

16-21. -21. (canceled)

26. A ligand that has binding specificity for vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), comprising at least one immunoglobulin single variable domain with binding specificity for VEGF and at least one immunoglobulin single variable domain with binding specificity for EGFR, wherein

each said immunoglobulin single variable domain with binding specificity for VEGF competes for binding to VEGF with an anti-VEGF domain antibody (dAb) selected from the group consisting of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123); and

each said immunoglobulin single variable domain with binding specificity for EGFR competes for binding to EGFR with cetuximab.

27. The ligand of claim 26, wherein each said immunoglobulin single variable domain with binding specificity for VEGF comprises an amino acid sequence that has at least about 85% amino acid sequence identity with the amino acid sequence of a dAb selected from the group consisting of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

29. The ligand of claim 26, wherein said ligand inhibits binding of epidermal growth factor (EGF) and/or transforming growth factor alpha (TGFalpha) to EGFR.

30. The ligand of claim 26, wherein said ligand inhibits the activity of EGFR.

31. The ligand of claim 26, wherein said ligand inhibits the activity of EGFR without substantially inhibiting binding of epidermal growth factor (EGF) and/or transforming growth factor alpha (TGFalpha) to EGFR.

32. The ligand of claim 26, wherein said ligand inhibits binding of VEGF to vascular endothelial growth factor receptor 1 (VEGFR1) and/or vascular endothelial growth factor receptor 2 (VEGFR2).

33. The ligand of claim 26, wherein said ligand inhibits the activity of VEGF.

34. The ligand of claim 26, wherein said ligand inhibits the activity of VEGF without substantially inhibiting binding of VEGF to vascular endothelial growth factor receptor 1 (VEGFR1) and/or vascular endothelial growth factor receptor 2 (VEGFR2).

41. The ligand of claim 26 wherein said ligand comprises an immunoglobulin single variable domain with binding specificity for VEGF that is a V_HH and/or an immunoglobulin single variable domain with bining specificity for EGFR that is a V_HH.

42. The ligand of claim 26, wherein each said immunoglobulin single variable domain with binding specificity for VEGF and each said immunoglobulin single variable domain with binding specificity for EGFR are selected from the group consisting of a human V_H and a human V_L.

43. The ligand of claim 26, wherein said ligand is an IgG-like format comprising two immunoglobulin single variable domains with binding specificity for VEGF, and two immunoglobulin single variable domains with binding specificity for EGFR.

44. The ligand of claim 26, wherein said ligand comprises an antibody Fc region.

28. A ligand that has binding specificity for vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), comprising a first immunoglobulin single variable domain with binding specificity for VEGF and a second immunoglobulin single variable domain with binding specificity for EGFR, wherein

said first immunoglobulin single variable domain competes for binding to VEGF with bevacizumab;

and

said second immunoglobulin single variable domain competes for binding to EGFR with cetuximab.

35-40. -40. (canceled)

45. A ligand that has binding specificity for vascular endothelial growth factor (VEGF), comprising at least one immunoglobulin single variable domain with binding specificity for VEGF, wherein each said immunoglobulin single variable domain with binding specificity for VEGF competes for binding to VEGF with an anti-VEGF domain antibody (dAb) selected from the group consisting of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

46. The ligand of claim 45, wherein said ligand inhibits binding of VEGF to vascular endothelial growth factor receptor 1 (VEGFR1) and/or vascular endothelial growth factor receptor 2 (VEGF2).

49. The ligand of claim 45 wherein said ligand comprises an immunoglobulin single variable domain with binding specificity for VEGF that is a V_HH.

50. The ligand of claim 45, comprising an immunoglobulin single variable domain with binding specificity for VEGF is independently selected from the group consisting of a human V_H and a human V_L.

51. The ligand of claim 45, wherein each said immunoglobulin single variable domain with binding specificity for VEGF comprises an amino acid sequence that has at least about 85% amino acid sequence identity with the amino acid sequence of a dAb selected from the group consisting of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

47-48. -48. (canceled)

64-68. -68. (canceled)

71-74. -74. (canceled)

77-78. -78. (canceled)

81-86. -86. (canceled)

91. (canceled)

92. A composition comprising a single domain antibody polypeptide construct that antagonizes human VEGF binding to a receptor, wherein said single domain antibody polypeptide construct comprises a CDR3 sequence that is the same that the sequence of CDR3 of a dAb selected from the group consisting of TAR15-1, TAR15-3, TAR15-4, TAR15-9, TAR15-10, TAR15-11, TAR15-12, TAR15-13, TAR15-14, TAR15-15, TAR15-16, TAR15-17, TAR15-18, TAR15-19, TAR15-20, TAR15-22, TAR15-5, TAR15-6, TAR15-7, TAR15-8, TAR15-23, TAR15-24, TAR15-25, TAR15-26, TAR15-27, TAR15-29, and TAR15-30.

100. A composition of claim 92 wherein said single domain antibody polypeptide construct comprises a tetravalent, dual-specific antibody polypeptide construct comprising:

a) a first copy of a first fusion protein comprising a single domain antibody polypeptide that binds a first epitope, fused to an IgG heavy chain constant domain;

b) a second copy of said first fusion protein;

c) a first copy of a second fusion protein comprising a single domain antibody polypeptide that binds a second epitope, fused to a light chain constant domain;

d) a second copy of said second fusion protein;

wherein said first and said second copies of said first fusion protein are disulfide bonded to each other via their respective IgG heavy chain constant domains, and

wherein said light chain constant domain of said first copy of said second fusion protein is disulfide bonded to the IgG heavy chain constant domain of said first copy of said first fusion protein, and

wherein said light chain constant domain of said second copy of second fusion protein is disulfide bonded to the IgG heavy chain constant domain of said second copy of said first fusion protein, and

wherein said polypeptide construct binds said first and said second epitopes.

101. The composition of claim 100 wherein said first and/or said second epitope is a VEGF epitope.

93. A composition comprising a single domain antibody polypeptide construct that antagonizes human VEGF binding to a receptor, wherein said single domain antibody polypeptide construct comprises an amino acid sequence selected from the group consisting of TAR15-1, TAR15-3, TAR15-4, TAR15-9, TAR15-10, TAR15-11, TAR15-12, TAR15-13, TAR15-14, TAR15-15, TAR15-16, TAR15-17, TAR15-18, TAR15-19, TAR15-20, TAR15-22, TAR15-5, TAR15-6, TAR15-7, TAR15-8, TAR15-23, TAR15-24, TAR15-25, TAR15-26, TAR15-27, TAR15-29, and TAR15-30 or a sequence at least 85% identical thereto.

94-99. -99. (canceled)

102. An immunoglobulin single variable domain polypeptide that binds VEGF, wherein the polypeptide has an amino acid sequence that is identical to the amino acid sequence of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123), or differs from the amino acid sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123) at no more than 25 amino acid positions and has a CDR1 sequence that has at least 50% identity to the CDR1 sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

103. An immunoglobulin single variable domain polypeptide that binds to VEGF, wherein the polypeptide has an amino acid sequence that is identical to the amino acid sequence of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123), or differs from the amino acid sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123) at no more than 25 amino acid positions and has a CDR2 sequence that has at least 50% identity to the CDR2 sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

104. An immunoglobulin single variable domain polypeptide that binds VEGF, wherein the polypeptide has an amino acid sequence that is identical to the amino acid sequence of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123), or differs from the amino acid sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123) at no more than 25 amino acid positions and has a CDR3 sequence that has at least 50% identity to the CDR3 sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

105-107. -107. (canceled)

108. An immunoglobulin single variable domain polypeptide that binds VEGF, wherein the dAb has an amino acid sequence that is identical to the amino acid sequence of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123), or differs from the amino acid sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123) at no more than 25 amino acid positions and has a CDR1 sequence that has at least 50% identity to the CDR1 sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123) and has a CDR2 sequence that has at least 50% identity to the CDR2 sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123) and has a CDR3 sequence that has at least 50% identity to the CDR3 sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).

109-114. -114. (canceled)

115. A VEGF antagonist having a CDR1 sequence that has at least 50% identity to the CDR1 sequence of TAR15-6 (SEQ ID NO:

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123) and a CDR2 sequence that has at least 50% identity to the CDR2 sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123) and a CDR3 sequence that has at least 50% identity to the CDR3 sequence of TAR15-6 (SEQ ID NO;

117), TAR15-8 (SEQ ID NO;

119), and TAR15-26 (SEQ ID NO;

123).