POLYPEPTIDES FOR COMPLEMENT INHIBITION

1 . A protein comprising (i) a C3 and/or C3b binding polypeptide and (ii) a VEGF inhibitor, wherein the amino acid sequence of the C3 and/or C3b binding polypeptide has between 4 and 22 substitutions as compared to the Sac7d family consensus sequence of SEQ ID NO: 16, wherein the amino acid sequence of the C3 and/or C3b binding polypeptide comprises amino acids 2-60 of SEQ ID NO: 77, wherein X at positions 2, 3, 4, 6, 15, 17, 18, 31, 37-39, 57, 58, 59 and 61-68 are as set forth below:

Position

Amino Acid

(2) . . . (2)

X is V, A or T

(3) . . . (3)

X is T or K

(4) . . . (4)

X is - or K

(6) . . . (6)

X is R or K

(15) . . . (15)

X is E or Q

(17) . . . (17)

X is D or E

(18) . . . (18)

X is T or I

(31) . . . (31)

X is V or I

(37) . . . (39)

X X X is EGG, DN- or DQ-

(57) . . . (57)

X is M or L

(58) . . . (58)

X is Q, D or E

(59) . . . (59)

X is M, K, or L

(61) . . . (68)

XXXXXXXX is -------K,

EKS--GKK (SEQ ID NO: 82),

EK---QKK (SEQ ID NO: 83),

ARAEREKK (SEQ ID NO: 79),

ARAERE-K (SEQ ID NO: 81),

ARAERE-- (SEQ ID NO: 80),

ARA-EKKK (SEQ ID NO: 84),

E-----KK, ACAEREKK (SEQ

ID NO: 85) or ACA-EKKK

(SEQ ID NO: 86)

and wherein SEQ ID NO: 77 comprises Y at position 25, W at position 44, and at least one of the following:

E, A, or D at position 8;

A at position 9;

T at position 10;

Y, A, or S at position 22;

Q, N, or A at position 23;

S, V, or T at position 27;

E or D at position 30;

A, I, L, V, Y, M, F or H at position 32;

A, T or S at position 34;

T or I at position 42;

A, I, L, V, Y, M, F or H at position 46; and

S at position 48.

2 .- 25 . (canceled)

26 . The protein of claim 1 , wherein SEQ ID NO: 77 comprises:

E, A, or D at position 8;

A at position 9;

T at position 10;

Y, A, or S at position 22;

Q, N, or A at position 23;

S, V, or T at position 27;

E or D at position 30;

L at position 32;

A, T or S at position 34;

T or I at position 42;

Y at position 46; and

S at position 48.

27 . The protein of claim 1 , wherein SEQ ID NO: 77 comprises:

A or D at position 8;

A at position 9;

T at position 10;

A or S at position 22;

N or A at position 23;

V or T at position 27;

D at position 30;

L at position 32;

S at position 34;

I at position 42;

Y at position 46; and

S at position 48.

28 .- 29 . (canceled)

30 . The protein of claim 1 , wherein SEQ ID NO: 77 comprises:

A at position 8;

A at position 9;

T at position 10;

A at position 22;

N at position 23;

V at position 27;

D at position 30;

L at position 32;

S at position 34;

I at position 42;

Y at position 46; and

S at position 48.

31 . The protein of claim 1 , wherein SEQ ID NO: 77 comprises:

D at position 8;

A at position 9;

T at position 10;

S at position 22;

A at position 23;

T at position 27;

D at position 30;

L at position 32;

S at position 34;

I at position 42;

Y at position 46; and

S at position 48.

32 . The protein of claim 1 , wherein the amino acids at positions 2, 3, 4, 6, 15, 17, 18, 31, 37, 38, 39, 57, 58, 59, and 61-68 of SEQ ID NO: 77 are the same as those found at the corresponding position in a protein selected from the group consisting of Sac7d from Sulfolobus acidocaldarius , Sac7e from Sulfolobus acidocaldarius , Sso7d from Sulfolobus solfataricus , Ssh7b from Sulfolobus shibatae , Ssh7a from Sulfolobus shibatae , DBP7 from Sulfolobus tokodaii , Sis7a from Sulfolobus islandicus , Mse7 from Metallosphaera sedula , Mcu7 from Metallosphaera cuprina , Aho7a from Acidianus hospitalis , Aho7b from Acidianus hospitalis , Aho7c from Acidianus hospitalis and Sto7 from Sulfurisphaera tokodaii , when said protein is aligned with SEQ ID NO: 77 with the proviso that the protein may comprise a D17E, N38Q, and/or M59L substitution.

33 .- 36 . (canceled)

37 . The protein of claim 1 , wherein the C3 and/or C3b binding polypeptide comprises amino acids 2-58 of SEQ ID NO: 33.

38 . The protein of claim 1 , wherein the C3 and/or C3b binding polypeptide comprises amino acids 2-58 of SEQ ID NO: 34.

39 . A protein comprising (i) a C3 and/or C3b binding polypeptide and (ii) a VEGF inhibitor, wherein the C3 and/or C3b binding polypeptide comprises amino acids 2-58 of the sequence MVKVKFXXXGEEKEVXTSKIXXVXRXGKXVXFTYDDXGKXGXGXVXEKDAPKELLD MLARAEREKK (SEQ ID NO: 65), wherein each X independently represents any amino acid, and wherein SEQ ID NO: 65 comprises:

(i) D or E at position 16;

(ii) E or Q at position 37; and

(iii) Y at position 24, W at position 42, or both.

40 . The protein of claim 39 , wherein SEQ ID NO: 65 comprises Y at position 24 and W at position 42.

41 . The protein of claim 40 , wherein SEQ ID NO: 65 comprises:

A, I, L, V, Y, M, F or H at position 31;

A, T or S at position 33;

T or I at position 40; and

A, I, L, V, Y, M, F or H at position 44.

42 .- 58 . (canceled)

59 . The protein of claim 39 , wherein SEQ ID NO: 65 comprises:

E, A, or D at position 7;

A at position 8;

T at position 9;

Y, A, or S at position 21;

Q, N, or A at position 22;

Y at position 24;

S, V, or T at position 26;

E or D at position 29;

A, I, L, V, Y, M, F or H at position 31;

A, T or S at position 33;

T or I at position 39;

W at position 42;

A, I, L, V, Y, M, F or H at position 44; and

S at position 46.

60 .- 62 . (canceled)

63 . The protein of claim 39 , wherein SEQ ID NO: 65 comprises:

A or D at position 7;

A at position 8;

T at position 9;

A or S at position 21;

N or A at position 22;

Y at position 24;

V or T at position 26;

D at position 29;

L at position 31;

S at position 33;

I at position 40;

W at position 42;

Y at position 44; and

S at position 46.

64 .- 66 . (canceled)

67 . The protein of claim 39 , wherein SEQ ID NO: 65 comprises:

D at position 7;

A at position 8;

T at position 9;

S at position 21;

A at position 22;

Y at position 24;

T at position 26;

D at position 29;

L at position 31;

S at position 33;

I at position 40;

W at position 42;

Y at position 44; and

S at position 46.

68 .- 70 . (canceled)

71 . The protein of claim 39 , wherein the C3 and/or C3b binding polypeptide comprises amino acids 2-58 of SEQ ID NO: 33.

72 . The protein of claim 39 , wherein the C3 and/or C3b binding polypeptide comprises amino acids 2-58 of SEQ ID NO: 34.

73 . (canceled)

74 . A protein comprising (i) a C3 and/or C3b binding polypeptide comprising amino acids 2-58 of any one of SEQ ID NOs: 22, 23, or 24,

wherein the amino acid sequence comprises D or A at position 7, A at position 8, T at position 9, S or A at position 21, A or N at position 22, Y at position 24, T or V at position 26, D at position 29, L at position 31, S at position 33, I at position 40, W at position 42, Y at position 44, and S at position 46 and (ii) a VEGF inhibitor.

75 .- 81 . (canceled)

82 . The protein of claim 1 , wherein the VEGF inhibitor comprises an antibody fragment selected from the group consisting of a Fab, F(ab′) 2 , Fv, scFv, or a single domain antibody (e.g., a nanobody).

83 . The protein of claim 82 , wherein the antibody fragment is a Fab comprising a VL domain, a CL domain, a VH domain, and a CH1 domain.

84 . The protein of claim 83 , comprising the C3 and/or C3b binding polypeptide fused directly or indirectly to one, two, three, or four of:

(i) the VL of the Fab;

(ii) the CL of the Fab;

(iii) the VH of the Fab; or

(iv) the CH1 of the Fab.

85 .- 86 . (canceled)

87 . The protein of claim 82 , wherein the antibody fragment comprises a heavy chain fragment having the amino acid sequence of SEQ ID NO: 36 and a light chain having the amino acid sequence of SEQ ID NO: 35, optionally wherein the protein comprises (i) SEQ ID NO: 35 and either SEQ ID NO: 38, SEQ ID NO: 40, or SEQ ID NO: 56 or (ii) SEQ ID NO: 36 and either SEQ ID NO: 37, SEQ ID NO: 39, or SEQ ID NO: 55.

88 .- 94 . (canceled)

95 . The protein of claim 82 , further comprising a half-life extending polypeptide, optionally wherein the protein has a structure depicted in FIG. 11 , FIG. 12 , FIG. 13 , or FIG. 14 .

96 . A nucleic acid encoding the protein of claim 1 .

97 .- 98 . (canceled)

99 . A pharmaceutical composition comprising the protein of claim 1 and a pharmaceutically acceptable carrier.

100 . A method of treating a subject having or at risk of a complement-mediated disorder, the method comprising administering to the subject a composition comprising an effective amount of the protein of claim 1 .

101 .- 117 . (canceled)

118 . The method of claim 100 , wherein the composition is administered to the eye of a subject suffering from an eye disorder.

119 .- 136 . (canceled)