CA2462610A1 - Specific binding agents of human angiopoietin-2 - Google Patents

Specific binding agents of human angiopoietin-2 Download PDF

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CA2462610A1
CA2462610A1 CA002462610A CA2462610A CA2462610A1 CA 2462610 A1 CA2462610 A1 CA 2462610A1 CA 002462610 A CA002462610 A CA 002462610A CA 2462610 A CA2462610 A CA 2462610A CA 2462610 A1 CA2462610 A1 CA 2462610A1
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amino acid
acid residue
seq
polypeptide
acceptable salts
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CA2462610C (en
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Jonathan Daniel Oliner
Hosung Min
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Amgen Inc
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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    • C07K2317/00—Immunoglobulins specific features
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2319/00—Fusion polypeptide
    • C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"

Abstract

Disclosed are peptides that bind to Ang-2. Also disclosed are peptibodies comprising the peptides, methods of making such peptides and peptibodies, and methods of treatment using such peptides and peptibodies.

Claims (117)

1. A polypeptide capable of binding Ang-2 wherein said polypeptide comprises the amino acid sequence WDPWT
(SEQ ID NO: 65) and wherein said polypeptide is from 5 to 50 amino acids in length, and physiologically acceptable salts thereof.
2. A polypeptide capable of binding Ang-2, wherein said polypeptide comprises the amino acid sequence WDPWTC
(SEQ ID NO: 66) and physiologically acceptable salts thereof.
3. A polypeptide capable of binding Ang-2, wherein said polypeptide comprises the amino acid sequence Cz2WDPWT
(SEQ 1D NO: 67) wherein z2 is an acidic or neutral polar amino acid residue, and physiologically acceptable salts thereof.
4. The polypeptide according to claim 3, wherein said polypeptide further comprises the amino acid sequence Cz2WDPWTC
(SEQ ID NO: 68) wherein z2 is an acidic or neutral polar amino acid residue, and physiologically acceptable salts thereof.
5. A polypeptide capable of binding Ang-2 comprising an amino acid sequence of the formula:
a1a2a3Ca5WDPWTCa12a13a14 (SEQ ID NO: 69) wherein:
a1l, a2, and a3 are each independently amino acid residues;
a5 is an amino acid residue;
a12 is absent or an amino acid residue;
a13 is absent or a neutral hydrophobic, neutral polar, or a basic amino acid residue;
a14 is a neutral hydrophobic or neutral polar amino acid residue;
and physiologically acceptable salts thereof.
6. The polypeptide according to Claim 5 wherein:
a1 is V, I, P, W, G, S, Q, N, E, K, R, or H;
a2 is V, P, M, G, S, Q, D, E, K, R, or H;
a3 is A, V, P, M, F, T, G, D, E, K, or H;
a8 is A, V, G, Q, N, D, or E;
a12 is S, Q, N, D, E, K, or R;
a13 is L, T, or H;
a14 is V, L, I, W, or M;
and physiologically acceptable salts thereof.
7. The polypeptide according to Claim 5 wherein:
a1 is Q;
a2 is E;
a3 is E;
a5 is D or E;
a12 is D or E;
a13 is H; and a14 is M;
and physiologically acceptable salts thereof.
8. A polypeptide capable of binding Ang-2 comprising an amino acid sequence of the formula:
b1b2b3b4b5b6Cb8WDPWTCb15b16b17b18b19b20 (SEQ ID NO: 70) wherein:
b1 is absent or an amino acid residue;
b2 is absent or a neutral hydrophobic, neutral polar, or a basic amino acid residue;
b3, b4, b5, and b6 are each independently absent or amino acid residues;
b8 is an amino acid residue;
b15 is absent or an amino acid residue;
b16 is absent or a neutral hydrophobic, neutral polar, or a basic amino acid residue;
b17 is absent or a neutral hydrophobic or neutral polar amino acid residue;
b18, b19, and b20 are each independently absent or amino acid residues;
and physiologically acceptable salts thereof.
9. The polypeptide according to Claim 8 wherein:
b1 is absent, or A, V, L, P, W, F, T, G, S, Q, N, K, R, or H;
b2 is absent, or A, V, L, I, P, W, M, T, G, S, Y, N, K, R, or H;
b3 is absent, or A, L, I, P, W, M, T, G, S, Q, N, E, R, or H;
b4 is V, I, P, W, G, S, Q, N, E, K, R, or H;
b5 is V, P, M, G, S, Q, D, E, K, R, or H;
b6 is A, V, P, M, F, T, G, D, E, K, or H;
b8 is A, V, G, Q, N, D, or E;
b15 is S, Q, N, D, E, K, or R;
b16 is L, T, or H;
b17 is V, L, I, W, or M;
b18 is absent, or A, V, L, P, W, F, T, G, Y, Q, D, E, or R;
b19 is absent, or V, L, I, P, T, G, S, Y, Q, N, D, E, or R; and b20 is absent, or V, L, P, W, M, T, G, S, Y, Q, N, D, K, or R;

and physiologically acceptable salts thereof.
10. The polypeptide according to Claim 8 wherein:
b1 is absent, or P, or T;
b2 is absent, or I, or N;
b3 is absent, or R, or I;
b4 is Q;
b5 is E;
b6 is E;
b8 is D or E;
b15 is D or E;
b16 is H;
b17 is M;
b18 is absent, or W, or P;
b19 is absent, or G, or E; and b20 is absent, or V, or K.
and physiologically acceptable salts thereof.
11. A polypeptide comprising at least one amino acid sequence selected from the group consisting of SEQ ID NO: 4, and SEQ ID NO: 76 to SEQ ID
NO: 118, inclusive, wherein said polypeptide is capable of binding to Ang-2, and physiologically acceptable salts thereof;

PEPTIDE ~SEQ ID NO. ~PEPTIDE SEQUENCE

Con4-44 76 PIRQEECDWDPWTCEHMWEV
Con4-40 77 TNIQEECEWDPWTCDHMPGK
Con4-4 78 WYEQDACEWDPWTCEHMAEV
Con4-31 79 NRLQEVCEWDPWTCEHMENV
Con4-C5 80 AATQEECEWDPWTCEHMPRS
Con4-42 81 LRHQEGCEWDPWTCEHMFDW
Con4-35 82 VPRQKDCEWDPWTCEHMYVG
Con4-43 83 SISHEECEWDPWTCEHMQVG
Con4-49 84 WAAQEECEWDPWTCEHMGRM
Con4-27 85 TWPQDKCEWDPWTCEHMGST
Con4-48 86 GHSQEECGWDPWTCEHMGTS
Con4-46 87 QHWQEECEWDPWTCDHMPSK
Con4-41 88 NVRQEKCEWDPWTCEHMPVR
Con4-36 89 KSGQVECNWDPWTCEHMPRN
Con4-34 90 VKTQEHCDWDPWTCEHMREW
Con4-28 91 AWGQEGCDWDPWTCEHMLPM
Con4-39 92 PVNQEDCEWDPWTCEHMPPM
Con4-25 93 RAPQEDCEWDPWTCAHMDIK
Con4-50 94 HGQNMECEWDPWTCEHMFRY
Con4-38 95 PRLQEECVWDPWTCEHMPLR
Con4-29 96 RTTQEKCEWDPWTCEHMESQ
Con4-47 97 QTSQEDCVWDPWTCDHMVSS
Con4-20 98 QVIGRPCEWDPWTCEHLEGL
Con4-45 99 WAQQEECAWDPWTCDHMVGL
Con4-37 100 LPGQEDCEWDPWTCEHMVRS
Con4-33 101 PMNQVECDWDPWTCEHMPRS
AC2-Con4 102 FGWSHGCEWDPWTCEHMGST
Con4-32 103 KSTQDDCDWDPWTCEHMVGP
Con4-17 104 GPRISTCQWDPWTCEHMDQL
Con4-8 105 STIGDMCEWDPWTCAHMQVD
AC4-Con4 106 VLGGQGCEWDPWTCRLLQGW

Con4-1 107 VLGGQGCQWDPWTCSHLEDG
Con4-C1 108 TTIGSMCEWDPWTCAHMQGG
Con4-21 109 TKGKSVCQWDPWTCSHMQSG
Con4-C2 110 TTIGSMCQWDPWTCAHMQGG
Con4-18 111 WVNEVVCEWDPWTCNHWDTP
Con4-19 112 VVQVGMCQWDPWTCKHMRLQ
Con4-16 113 AVGSQTCEWDPWTCAHLVEV
Con4-11 114 QGMKMFCEWDPWTCAHIVYR
Con4-C4 115 TTIGSMCQWDPWTCEHMQGG
Con4-23 116 TSQRVGCEWDPWTCQHLTYT
Con4-15 117 QWSWPPCEWDPWTCQTVWPS
Con4-9 118 GTSPSFCQWDPWTCSHMVQG
TN8-Con4 4 QEECEWDPWTCEHM
12. A fusion polypeptide comprising at least one peptide according to Claims 1, 5, 8, or 11 and a vehicle, wherein said fusion polypeptide is capable of binding to Ang-2, and physiologically acceptable salts thereof.
13. The fusion polypeptide according to claim 12 wherein said vehicle is at least one of an Fc domain, polyethylene glycol, a lipid, a cholesterol group, a carbohydrate, and an oligosaccharide.
14. The polypeptide according to Claims 1, 5, 8, or 11 which is cyclic.
15. A dimer or multimer of the polypeptides according to Claims 1, 5, 8, or 11.
16. A composition of matter having the formula:
(X1)a-F1-(X2)b and multimers thereof, wherein:
F1 is a vehicle;
X1 and X2 are each independently selected from -(L1)c-P1;
-(L1)c-P1-(L2)d-P2;
-(L1)c-P1-(L2)d-P2-(L3)e-P3; and -(L1)c-P1-(L2)d-P2-(L3)e-P3-(L4)f-P4;
wherein one or more of P1, P2, P3, and P4 each independently comprise a polypeptide selected from the group consisting of:
(a) the amino acid sequence WDPWT (SEQ ID NO: 65), wherein said polypeptide is from 5 to 50 amino acids in length;
(b) the amino acid sequence WDPWTC (SEQ ID NO: 66), (c) the amino acid sequence Cz2WDPWT (SEQ ID NO: 67), and (d) the amino acid sequence Cz2WDPWTC (SEQ ID NO: 68), wherein z2 is an acidic or neutral polar amino acid residue;
L1, L2, L3, and L4 are each independently linkers; and a, b, c, d, e, and f are each independently 0 or 1, provided that at least one of a and b is 1;
and physiologically acceptable salts thereof.
17. The composition of matter according to claim 16 wherein z2 is A, V, G, Q, N, D, or E.
18. The composition of matter according to claim 16 wherein one or more of P1, P2, P3, and P4 each independently comprise a polypeptide selected from the group consisting of SEQ ID NO: 4, and SEQ ID NO: 76 to SEQ ID
NO: 118 inclusive.
19. The composition of matter of Claim 16 of the formulae:

or and physiologically acceptable salts thereof.
20. The composition of matter of Claim 16 of the formula:
F1-(L1)c-P1 and physiologically acceptable salts thereof.
21. The composition of matter of Claim 16 of the formula:
F1-(L1)c-P1-(L2)d-P2 and physiologically acceptable salts thereof.
22. The composition of matter of Claim 16 of the formula:
P1-(Li)c-F1-(L2)d-P2 and physiologically acceptable salts thereof.
23. The composition of matter of Claim 16, wherein F1 is an Fc domain or fragment thereof.
24. The composition of matter of Claim 16 wherein F1 comprises the amino acid sequence of SEQ ID NO: 60.
25. A polynucleotide encoding a composition of matter according to Claim 1, 5, 8, or 11.
26. An expression vector comprising the polynucleotide of Claim 25.
27. A host cell comprising the expression vector of Claim 26.
28. The host cell according to Claim 27 wherein the cell is a prokaryotic cell.
29. The host cell according to Claim 28 wherein the cell is an E. coli cell.
30. The host cell according to Claim 27 wherein the cell is a eukaryotic cell.
31. A polypeptide capable of binding Ang-2 comprising an amino acid sequence of the formula:
Pc2Dc4Lc6c7c8LY
(SEQ ID NO: 71) wherein c2 is a neutral hydrophobic amino acid residue c4 is a A, D, or E
c6 is an acidic amino acid residue c7 is an amino acid residue; and c8 is a neutral hydrophobic, neutral polar, or basic amino acid residue;
and physiologically acceptable salts thereof.
32. The polypeptide according to claim 31 wherein c2 is L or M.
33. The polypeptide according to claim 31 wherein c6 is D or E.
34. A polypeptide capable of binding Ang-2 comprising an amino acid sequence of the formula:
d1d2d3d4Pd6Dd8Ld10d11d12LY d15d16d17d18d19d20d21d22 (SEQ ID NO: 72) wherein, d1 is absent, or an amino acid residue;
d2 is absent, or a neutral polar, acidic, or a basic amino acid residue;
d3 is absent, or a neutral hydrophobic or neutral polar amino acid residue;
d4 is absent, or an amino acid residue;

d6 is a neutral hydrophobic amino acid residue;
d8 is a A, D, or E;
d10 is an acidic amino acid residue;
d11 is an amino acid residue;
d12 is a neutral hydrophobic, neutral polar, or basic amino acid residue;
d15 is absent, or a neutral polar, acidic, or a basic amino acid residue;
d16 is absent, or a neutral polar, acidic, or a basic amino acid residue;
d17 is absent, or a neutral hydrophobic, or neutral polar amino acid residue;
d18 is absent, or a neutral hydrophobic, or neutral polar amino acid residue;
d19 is absent, or a neutral hydrophobic, neutral polar, or basic amino acid residue;
d20 is absent, or an amino acid residue;
d21 is absent, or a neutral polar, acidic, or a basic amino acid residue;
d22 is absent, or a neutral hydrophobic, neutral polar, or basic amino acid residue;
and physiologically acceptable salts thereof.
35. The polypeptide according to Claim 34 wherein:
d1 is T, S, Q, R, or H;
d2 is T, Q, N, or K;
d3 is F;
d4 is M, Q, E, or K;
d6 is L or M;
d8 is D or E;
d10 is E;
d11 is Q or E;
d12 is T or R;
d15 Y, D, E, or K;
d16 is Q;
d17 is W or F;
d18 is L, I, M, or T;

d19 is L, F, or Y;
d20 is Q, D, or E;
d21 is absent, Q, or H;
d22 is absent, A, L, G, S, or R;
and physiologically acceptable salts thereof.
36. A polypeptide comprising at least one amino acid sequence selected from the group consisting of SEQ ID NO: 6, and SEQ ID NO: 119 to SEQ ID
NO: 142, inclusive, wherein said polypeptide is capable of binding to Ang-2, and physiologically acceptable salts thereof;

Peptide SEQ ID NO. Peptide Sequence
37. A fusion polypeptide comprising at least one peptide according to Claims 31, 34, or 36 and a vehicle, wherein said fusion polypeptide is capable of binding to Ang-2, and physiologically acceptable salts thereof.
38. The fusion polypeptide according to Claim 37 wherein said vehicle is at least one of an Fc domain, polyethylene glycol, a lipid, a cholesterol group, a carbohydrate, and an oligosaccharide.
39. The polypeptide according to Claim 31, 34, or 36 which is cyclic.
40. A dimer or multimer of the polypeptides according to Claims 31, 34, or 36.
41. A composition of matter having the formula:
(X1)a-F1-(X2)b and multimers thereof, wherein:
F1 is a vehicle;
X1 and X2 are each independently selected from -(L1)c-P1;
-(L1)c-P1-(L2)d-P2;
-(L1)c-P1-(L2)d-P2-(L3)e-P3; and -(L1)c-P1-(L2)d-P2-(L3)e-p3-(L4)f-P4;
wherein one or more of P1, P2, P3, and P4 each independently comprise a polypeptide according to claim 31, 34, or 36;

L1, L2, L3, and L4 are each independently linkers; and a, b, c, d, e, and f are each independently 0 or 1, provided that at least one of a and b is 1;
and physiologically acceptable salts thereof.
42. The composition of matter of claim 41 wherein one or more of P1, P2, P3, and P4 each independently comprise a polypeptide selected from the group consisting of SEQ ID NO: 6, and SEQ ID NO: 119 to SEQ ID NO: 142, inclusive.
43. The composition of matter of Claim 41 of the formulae:

or and physiologically acceptable salts thereof.
44. The composition of matter of Claim 41 of the formula:
F1-(L1)c-P1 and physiologically acceptable salts thereof.
45. The composition of matter of Claim 41 of the formula:
F1-(L1)c-P1-(L2)d-P2 and physiologically acceptable salts thereof.
46. The composition of matter of Claim 41 of the formula:
P1-(L1)c-F1-(L2)d-P2 and physiologically acceptable salts thereof.
47. The composition of matter of Claim 41, wherein F1 is an Fc domain or fragment thereof.
48. The composition of matter of Claim 41 wherein F1 comprises the amino acid sequence of SEQ ID NO: 60.
49. A polynucleotide encoding a polypeptide according to any of Claims 31, 34, or 36.
50. An expression vector comprising the polynucleotide of Claim 49.
51. A host cell comprising the expression vector of Claim 50.
52. The host cell according to Claim 51 wherein the cell is a prokaryotic cell.
53. The host cell according to Claim 52 wherein the cell is an E. coli cell.
54. The host cell according to Claim 51 wherein the cell is a eukaryotic cell.
55. A polypeptide capable of binding Ang-2 comprising an amino acid sequence of the formula:) RPe3e4e5e6e7G
(SEQ ID NO: 73) wherein e3 is a neutral polar amino acid residue;
e4 is an acidic amino acid residue;
e5 is a neutral polar or an acidic amino acid residue;
e6 is a neutral hydrophobic amino acid residue;
e7 is a neutral hydrophobic amino acid residue;
and physiologically acceptable salts thereof.
56. The polypeptide according to claim 55 wherein e3 is Y or C.
57. The polypeptide according to claim 55 wherein e4 is D or E.
58. The polypeptide according to claim 55 wherein e6 is I or M.
59. A polypeptide capable of binding Ang-2 comprising an amino acid sequence of the formula:

f1f2f3f4RPf7f8f9f10f11Gf13f14f15f16f17f18f19f20 (SEQ ID NO: 74) wherein, f1 is a neutral hydrophobic or neutral polar amino acid residue;
f2 is a neutral hydrophobic or neutral polar amino acid residue;
f3 is a neutral polar or acidic amino acid residue;
f4 is a neutral hydrophobic or neutral polar amino acid residue;
f7 is a neutral polar amino acid residue;
f8 is an acidic amino acid residue;
f9 is a neutral polar or acidic amino acid residue;
f10 is a neutral hydrophobic amino acid residue;
f11 is a neutral hydrophobic amino acid residue;
f13 is a neutral hydrophobic or neutral polar amino acid residue;
f14 is a neutral hydrophobic or neutral polar amino acid residue;
f15 is a neutral polar amino acid residue;
f16 is a neutral polar amino acid residue;
f17 is a neutral polar or acidic amino acid residue;
f18 is a neutral hydrophobic or basic amino acid residue;
f19 is a neutral hydrophobic or neutral polar amino acid residue; and f20 is a neutral hydrophobic or neutral polar amino acid residue;
and physiologically acceptable salts thereof.
60. The polypeptide according to Claim 59 wherein:
f1 is S, A, or G;
f2 is G, Q, or P;
f3 is Q, G, or D;

f4 is L, M, or Q;
f7 is C or Y;
f8 is E or D;
f9 is E, G, or D;
f10 is I or M;
f11 is F or L;
f13 is C or W;
f14 is G or P;
f15 T or N;
f16 is Q, Y, or K;
f17 is N, D, or Q;
f18 is L, V, W, or R;
f19 is A, Q, Y, or I; and f20 is L, A, G, or V;
and physiologically acceptable salts thereof.
61. A polypeptide comprising at least one amino acid sequence selected from the group consisting of SEQ ID NO: 3, and SEQ ID NO: 143 to SEQ ID
NO: 148, inclusive, wherein said polypeptide is capable of binding to Ang-2, and physiologically acceptable salts thereof;

Peptide SEQ ID NO: Sequence Con1-1 143 AGGMRPYDGMLGWPNYDVQA
Con1-2 144 QTWDDPCMHILGPVTWRRCI
Con1-3 145 APGQRPYDGMLGWPTYQRIV
Con1-4 146 SGQLRPCEEIFGCGTQNLAL
Con1-5 147 FGDKRPLECMFGGPIQLCPR
Con1-6 148 GQDLRPCEDMFGCGTKDWYG
Con1 3 KRPCEEIFGGCTYQ
62. A fusion polypeptide comprising at least one polypeptide according to Claims 55, 59, or 61 and a vehicle, wherein said fusion polypeptide is capable of binding to Ang-2, and physiologically acceptable salts thereof.
63. The fusion polypeptide according to claim 62 wherein said vehicle is at least one of an Fc domain, polyethylene glycol, a lipid, a cholesterol group, a carbohydrate, and an oligosaccharide.
64. The polypeptide according to Claim 55, 59, or 61 which is cyclic.
65. A dimer or multimer of the compounds according to Claims 55, 59, or 61.
66. A composition of matter having the formula:
(X1)a -F1-(X2)b and multimers thereof, wherein:
F1 is a vehicle;
X1 and X2 are each independently selected from -(L1)c-P1 -(L1)c-P1-(L2)d-P2;

-(L1)c-P1-(L2)d -P2-(L3)e -P3; and -(L1)c-P1-(L2)d -P2-(L3)e-P3-(L4)f-P4;
wherein one or more of P1, P2, P3, and P4 each independently comprise a polypeptide according to Claim 55, 59, or 61;
L1, L2, L3, and L4 are each independently linkers; and a, b, c, d, e, and f are each independently 0 or 1, provided that at least one of a and bis 1;
and physiologically acceptable salts thereof.
67. The composition of matter of claim 66 wherein one or more of P1, P2, P3, and P4 each independently comprise a polypeptide selected from the group consisting of SEQ ID NO: 3, and SEQ ID NO: 143 to SEQ ID NO: 148, inclusive.
68. The composition of matter of Claim 66 of the formulae:

or and physiologically acceptable salts thereof.
69. The composition of matter of Claim 66 of the formula:
F1-(L1)c-P1 and physiologically acceptable salts thereof.
70. The composition of matter of Claim 66 of the formula:
F1-(L1)c-P1-(L2)d -P2 and physiologically acceptable salts thereof.
71. The composition of matter of Claim 66 of the formula:
P1-(L1)c-F1-(L2)d-P2 and physiologically acceptable salts thereof.
72. The composition of matter of Claim 66, wherein F1 is an Fc domain or fragment thereof.
73. The composition of matter of Claim 66 wherein F1 comprises the amino acid sequence of SEQ ID NO: 60.
74. A polynucleotide encoding a polypeptide according to any of Claims Claims 55, 59, or 61.
75. An expression vector comprising the polynucleotide of Claim 74.
76. A host cell comprising the expression vector of Claim 75.
77. The host cell according to Claim 76 wherein the cell is a prokaryotic cell.
78. The host cell according to Claim 77 wherein the cell is an E. coli cell.
79. The host cell according to Claim 76 wherein the cell is a eukaryotic cell.
80. A polypeptide capable of binding Ang-2 comprising an amino acid sequence of the formula:

Cg2Gg4g5DPFTg10GCg13 (SEQ ID NO: 75) wherein g2 is an acidic amino acid residue;
g4 is a neutral hydrophobic amino acid residue;
g5 is E, D, or Q;
g10 is a neutral hydrophobic or neutral polar amino acid residue;
g13 is an acidic residue;
and physiologically acceptable salts thereof.
81. The polypeptide according to claim 80 wherein g2 is E or D.
82. The polypeptide according to claim 80 wherein g4 is V or M.
83. The polypeptide according to claim 80 wherein g10 is F or Q.
84. The polypeptide according to claim 80 wherein g13 is D or E.
85. A polypeptide capable of binding Ang-2 comprising an amino acid sequence of the formula:

h1h2h3h4Ch6Gh8h9DPFTh14GCh17h18h19h20 (SEQ ID NO: 158) wherein, h1 is absent or a neutral hydrophobic, neutral polar, or a basic amino acid residue;
h2 is a neutral hydrophobic or neutral polar amino acid residue;
h3 is an acidic amino acid residue;
h4 is a neutral hydrophobic or neutral polar amino acid residue;
h6 is an acidic amino acid residue;
h8 is a neutral hydrophobic amino acid residue;
h9 is E, D, or Q;
h14 is a neutral hydrophobic or neutral polar amino acid residue;
h17 is an acidic amino acid residue;
h18 is a neutral hydrophobic, neutral polar, or a basic amino acid residue;
h19 is a neutral hydrophobic or neutral polar amino acid residue; and h20 is absent or an amino acid residue;
and physiologically acceptable salts thereof.
86. The polypeptide according to Claim 85 wherein:
h1 is absent, or A, L, M, G, K, or H;

h2 is L, F, or Q;
h3 is D or E;
h4 is W or Y;
h6 is D or E;
h8 is V or M;
h14 is F or Q;
h17 is D or E;
h18 is M, Y, N, or K;
h19 is L or Q; and h20 is absent or M, T, G, S, D, K, or R;
and physiologically acceptable salts thereof.
87. A polypeptide comprising at least one amino acid sequence selected from the group consisting of SEQ ID NO: 5, and SEQ ID NO: 149 to SEQ ID
NO: 157, inclusive, wherein said polypeptide is capable of binding to Ang-2, and physiologically acceptable salts thereof;

Peptide SEQ ID NO: Sequence
88. A fusion polypeptide comprising at least one peptide according to Claim 80, 85, or 87, and a vehicle, wherein said fusion polypeptide is capable of binding to Ang-2, and physiologically acceptable salts thereof.
89. The fusion polypeptide according to Claim 88 wherein said vehicle is at least one of an Fc domain, polyethylene glycol, a lipid, a cholesterol group, a carbohydrate, and an oligosaccharide.
90. The polypeptide according to Claim 80, 85, or 87 which is cyclic.
91. A dimer or multimer of the polypeptides according to Claims 80, 85, or 87.
92. A composition of matter having the formula:

(X1)a -F1-(X2)b and multimers thereof, wherein:
F1 is a vehicle;
X1 and X2 are each independently selected from -(L1)c -P1;
-(L1)c -P1-(L2)d-P2;
-(L1)c -P1-(L2)d-P2-(L3)e -P3; and -(L1)c -P1-(L2)d-P2-(L3)e P3-(L4)F -p4;
wherein one or more of P1, p2, p3, and P4 each independently comprise a polypeptide according to Claim 80, 85, or 87;
L1, L2, L3, and L4 are each independently linkers; and a, b, c, d, e, and f are each independently 0 or 1, provided that at least one of a and b is 1;
and physiologically acceptable salts thereof.
93. The composition of matter of claim 92 wherein one or more of P1, P2, P3, and P4 each independently comprise a polypeptide selected from the group consisting of SEQ ID NO: 5, and SEQ ID NO: 149 to SEQ ID NO: 157, inclusive.
94. The composition of matter of Claim 92 of the formulae:

or and physiologically acceptable salts thereof.
95. The composition of matter of Claim 92 of the formula:

F1-(L1)c -P1 and physiologically acceptable salts thereof.
96. The composition of matter of Claim 92 of the formula:

F1-(L1)c-P1-(L2)d-P2 and physiologically acceptable salts thereof.
97. The composition of matter of Claim 92 of the formula:

P1-(L1)c-F1-(L2)d-P2 and physiologically acceptable salts thereof.
98. The composition of matter of Claim 92, wherein F1 is an Fc domain or fragment thereof.
99. The composition of matter of Claim 92 wherein F1 comprises the amino acid sequence of SEQ ID NO: 60.
100. A polynucleotide encoding a polypeptide according to any of Claims 80, 85, or 87.
101. An expression vector comprising the polynucleotide of Claim 100.
102. A host cell comprising the expression vector of Claim 101.
103. The host cell according to Claim 102 wherein the cell is a prokaryotic cell.
104. The host cell according to Claim 103 wherein the cell is an E. coli cell.
105. The host cell according to Claim 102 wherein the cell is a eukaryotic cell.
106. A polypeptide according to any of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID
NO: 3, or SEQ ID NO: 4, or a variant thereof.
107. A polypeptide according to any of SEQ ID NO: 5, SEQ ID NO: 6, or SEQ
ID NO: 7, or a variant thereof.
108. A composition of matter having the formula:

(X1)q-F1-(X2)r and multimers thereof, wherein:
F1 is a vehicle;
X1 and X2 are each independently selected from -(L1)s-P1;
-(L1)s-P1-(L2)t-P2;
-(L1)s -P1-(L2)t-P2-(L3)u-P3; and -(L1)s-P1-(L2)t-P2-(L3)u-P3-(L4)v-P4;
wherein one or more of P1, P2, P3, and P4 each independently comprise a polypeptide selected from the group consisting of:
(a) the amino acid sequence WDPWT (SEQ ID NO: 65), wherein said polypeptide is from 5 to 50 amino acids in length;
(b) the amino acid sequence WDPWTC (SEQ ID NO: 66);

(c) the amino acid sequence Cz2WDPWT (SEQ ID NO: 67), wherein z2 is an acidic or neutral polar amino acid residue;
(d) the amino acid sequence Cz2WDPWTC (SEQ ID NO: 68), wherein z2 is an acidic or neutral polar amino acid residue;
(e) the amino acid sequence Pc2Dc4Lc6c7c8LY (SEQ ID NO: 71) wherein c2 is a neutral hydrophobic amino acid residue; c4 is a A, D, or E; c6 is an acidic amino acid residue; c7 is an amino acid residue; and c8 is a neutral hydrophobic, neutral polar, or basic amino acid residue;
(f) the amino acid sequence RPe3e4e5e6e7G (SEQ ID NO: 73) wherein e3 is a neutral polar amino acid residue; e4 is an acidic amino acid residue; e5 is a neutral polar or an acidic amino acid residue; e6 is a neutral hydrophobic amino acid residue; and e7 is a neutral hydrophobic amino acid residue;
(g) the amino acid sequence Cg2Gg4g5DPFTg10GCg13 (SEQ ID NO: 75) wherein g2 is an acidic amino acid residue; g4 is a neutral hydrophobic amino acid residue; g5 is a neutral polar or an acidic amino acid residue;
g10 is a neutral hydrophobic or neutral polar amino acid residue; and g13 is an acidic residue;
(h) A polypeptide of SEQ ID NO: 1;
(i) A polypeptide of SEQ ID NO: 2; and (j) A polypeptide of SEQ ID NO: 7;
L1, L2, L3, and L4 are each independently linkers; and q, r, s, t, u, and v are each independently 0 or 1, provided that at least one of q and r is 1;
and physiologically acceptable salts thereof.
109. A pharmaceutical composition comprising an effective amount of a composition according to Claims 1, 31, 55, or 80 in admixture with a pharmaceutically acceptable carrier thereof.~
110. A method of inhibiting undesired angiogenesis in a mammal comprising administering a therapeutically effective amount of the composition according to Claim 12, 16, 37, 41, 62, 66, 88, or 92.
111. A method of treating angiogenesis in a subject, said method comprising administering an effective amount of a composition of Claim 12, 16, 37, 41, 62, 66, 88, or 92.
112. A method of modulating angiogenesis in a mammal comprising administering a therapeutically effective amount of the composition according to Claim 12, 16, 37, 41, 62, 66, 88, or 92.
113. A method of inhibiting tumor growth characterized by undesired angiogenesis in a mammal comprising administering a therapeutically effective amount of the composition according to Claim 12, 16, 37, 41, 62, 66, 88, or 92.
114. A method of treating cancer in a mammal comprising administering a therapeutically effective amount of the composition according to Claim 12, 16, 37, 41, 62, 66, 88, or 92 and a chemotherapeutic agent.
115. The method according to claim 114 wherein the chemotherapeutic agent is at least one of 5-FU, CPT-11, and Taxotere.
116. A method of modulating at least one of vascular permeability or plasma leakage in a mammal comprising administering a therapeutically effective amount of the composition according to Claim 12, 16, 37, 41, 62, 66, 88, or 92.
117. A method of treating at least one of ocular neovascular disease, obesity, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, inflammatory disorders, atherosclerosis, endometriosis, neoplastic disease, bone-related disease, or psoriasis in a mammal comprising administering a therapeutically effective amount of the composition according to Claim 12, 16, 37, 41, 62, 66, 88, or 92.
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