HUMANIZED ANTI-EGFL7 ANTIBODIES AND METHODS USING SAME

1 . A nucleic acid encoding an anti-EGFL7 antibody, the antibody comprising a variable domain comprising the following hypervariable region (HVR) sequences:

(i) HVR-L1 comprising KX 1 SX 2 SX 3 DYX 4 GDSYX 5 S, wherein X 1 is A or R; X 2 is H or Q; X 3 is G or V; X 4 is selected from the group consisting of D, L, R, S, and W; and X 5 is M or V (SEQ ID NO: 210);

(ii) HVR-L2 comprising GASX 1 X 2 EX 3 , wherein X 1 is N or Y; X 2 is selected from the group consisting of L, R and Y; and X 3 is Q or S (SEQ ID NO: 211);

(iii) HVR-L3 comprising QQNNEX 1 PX 2 T, wherein X 1 is D or E; and X 2 is F or Y (SEQ ID NO: 212);

(iv) HVR-H1 comprising GX 1 X 2 X 3 X 4 TYGX 5 S, wherein X 1 is H or V; X 2 is R or T; X 3 is selected from the group consisting of F, G, R, and S; X 4 is selected from the group consisting of D, G, R, and T; and X 5 is M or Y (SEQ ID NO: 213);

(v) HVR-H2 comprising GWINX 1 X 2 SGVPTX 3 AX 4 X 5 X 6 X 7 X 8 , wherein X 1 is selected from the group consisting of I, M, T, and W; X 2 is H or R; X 3 is selected from group consisting of I, M, T, and Y; X 4 is D or H; X 5 is selected from group consisting of D, M and T; X 6 is F or Y; X 7 is K or S; and X 8 is G or R (SEQ ID NO: 214, and

(vi) HVR-H3 comprising AX 1 LGSX 2 AVDX 3 , wherein X 1 is N or R; X 2 is selected from the group consisting of C, R, H, and Y; and X 3 is A or Y (SEQ ID NO: 215).

2 . A nucleic acid encoding an anti-EGFL7 antibody, the antibody comprising the following HVR sequences: HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 37-43, HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 44-47, HVR-L3 comprising the amino acid sequence SEQ ID NO: 48, HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 49-57, HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 58-73, and HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 74-77.

3 . The nucleic acid of claim 1 , wherein HVR-L1 comprises the amino acid sequence KASQSVDYSGDSYMS (SEQ ID NO: 234), HVR-L2 comprises the amino acid sequence GASYRES (SEQ ID NO: 235), HVR-L3 comprises the amino acid sequence QQNNEEPYT (SEQ ID NO: 236), HVR-H1 comprises the amino acid sequence GHTFTTYGMS (SEQ ID NO: 34), HVR-H2 comprises the amino acid sequence GWINTHSGVPTYADDFKG (SEQ ID NO: 35), and HVR-H3 comprises the amino acid sequence ARLGSYAVDY (SEQ ID NO: 237).

4 . The nucleic acid of claim 1 , wherein the heavy chain comprises the following framework sequences: FR-H1 comprises EX 1 QLVESGGGLVQPGGSLRLSCAAS, wherein X 1 is I or V (SEQ ID NO: 216); FR-H2 comprises WVRQAPGKGLEWX 1 , wherein X 1 is I, M, or V (SEQ ID NO: 217); FR-H3 comprises RFTX 1 SX 2 DX 3 SX 4 X 5 TX 6 YLQMNSLRAEDTAVYX 7 CAR, wherein X 1 is F or I; X 2 is L or R; X 3 is N or T, X 4 is selected from the group consisting of A, E, K and T; X 5 is N or S; X 6 is selected from the group consisting of A, L, M, T and V; and X 7 is F or Y (SEQ ID NO: 218); and FR-H4 comprises WGQGTLVTVSS (SEQ ID NO: 219).

5 . The nucleic acid of claim 4 , wherein the heavy chain comprises the following framework sequences: FR-H1 comprises EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 197); FR-H2 comprises WVRQAPGKGLEWV (SEQ ID NO: 198); FR-H3 comprises RFTISX 1 DNSKNTX 2 YLQMNSLRAEDTAVYYCAR, wherein X 1 L or R; X 2 is selected from the group consisting of A, L, M, T and V (SEQ ID NO: 220); and FR-H4 comprises WGQGTLVTVSS (SEQ ID NO: 200).

6 . The nucleic acid of claim 4 , wherein the heavy chain comprises the following framework sequences: FR-H1 comprises EIQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 238); FR-H2 comprises WVRQAPGKGLEWM (SEQ ID NO: 239); FR-H3 comprises RFTISX 1 DNSKSTX 2 YLQMNSLRAEDTAVYFCAR, wherein X 1 L or R; X 2 is selected from the group consisting of A, L, M, T and V (SEQ ID NO: 240); and FR-H4 comprises WGQGTLVTVSS (SEQ ID NO: 219).

7 . The nucleic acid of claim 1 , wherein the light chain comprises the following framework sequences: FR-L1 comprises DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 201), FR-L2 comprises WYQQKPGKAPKLLIY (SEQ ID NO: 202), FR-L3 comprises GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 203), FR-L4 comprises FGQGTKVEIK (SEQ ID NO: 221) or FGQGTKVEIKR (SEQ ID NO: 204).

8 . The nucleic acid of claim 1 , wherein the light chain comprises the variable domain sequence of 4F11.v17 as shown in FIG. 15 (SEQ ID NO: 82) or the variable domain sequence of 4F11.v22 as shown in FIG. 15 (SEQ ID NO: 83).

9 . The nucleic acid of claim 1 , wherein the heavy chain comprises the variable domain sequence of 4F11.v17 as shown in FIG. 16 (SEQ ID NO: 84) or the variable domain sequence of 4F11.v22 as shown in FIG. 16 (SEQ ID NO: 85).

10 . The nucleic acid of claim 1 , wherein the light chain comprises the variable domain sequence of 4F11.v17 as shown in FIG. 15 (SEQ ID NO: 82) and the heavy chain comprises the variable domain sequence of 4F11.v17 as shown in FIG. 16 (SEQ ID NO: 84).

11 . The nucleic acid of claim 1 , wherein the light chain comprises the variable domain sequence of 4F11.v22 as shown in FIG. 15 (SEQ ID NO: 83) and the heavy chain comprises the variable domain sequence of 4F11.v22 as shown in FIG. 16 (SEQ ID NO: 85).

12 . The nucleic acid of claim 1 , wherein at least a portion of the framework sequence is a human consensus framework sequence.

13 . The nucleic acid of claim 14 , comprising human κ subgroup 1 consensus framework sequence or heavy chain human subgroup III consensus framework sequence.

14 . A nucleic acid encoding an anti-EGFL7 antibody, the antibody comprising a variable domain comprising the following HVR sequences:

(i) HVR-L1 comprising X 1 X 2 X 3 X 4 X 5 X 6 VX 7 X 8 X 9 X 10 ITYLX 11 , wherein X 1 is selected from the group consisting of L, Q, R, S, and T; X 2 is selected from the group consisting of P, T, and W; X 3 is H or S; X 4 is D or Q; X 5 is G or S; X 6 is L or V; X 7 is H or P; X 8 is selected from the group consisting of I, L, P, T, and Y; X 9 is selected from the group consisting of N, Q or S; X 10 is selected from the group consisting of A, G, and S; and X 11 is G or H (SEQ ID NO: 222);

(ii) HVR-L2 comprising RVSNX 1 X 2 S, wherein X 1 is D or R; and X 2 is selected from the group consisting of A, G, F, I, and T (SEQ ID NO: 223);

(iii) HVR-L3 comprising X 1 QSX 2 X 3 VPLT, wherein X 1 is selected from the group consisting of A, G, I, K, L, N, T, and V; X 2 is C or T; and X 3 is F or H (SEQ ID NO: 224);

(iv) HVR-H1 comprising GYX 1 X 2 X 3 DX 4 YX 5 N, wherein X 1 is N or T; X 2 is F or V;

X 3 is selected from the group consisting of I, M, R, and S; X 4 is selected from the group consisting of Y, Q, and K; and X 5 is I or M (SEQ ID NO: 225);

(v) HVR-H2 comprising GDINX 1 X 2 X 3 X 4 X 5 X 6 HX 7 X 8 X 9 X 10 X 11 X 12 X 13 , wherein X 1 is selected from the group consisting of A, L, N, and P; X 2 is selected from the group consisting of D, L, and R; X 3 is selected from the group consisting of G, K, N, R, S, and Y; X 4 is G or S; X 5 is selected from the group consisting of G, I, K, R, S, T, and V; X 6 is selected from the group consisting of G, R, and T; X 7 is selected from the group consisting of I, V, L, and Y; X 8 is N or S; X 9 is selected from the group consisting of A, N, and Q; X 10 is K or V; X 11 is F or Q; X 12 is K or T; and X 13 is selected from the group consisting of G, H, R, and S (SEQ ID NO: 226); and

(vi) HVR-H3 comprising X 1 REGVYHX 2 YDDYAX 3 DY, wherein X 1 is selected from the group consisting of A, N, and T; X 2 is D or P; and X 3 is M or W (SEQ ID NO: 227).

15 . A nucleic acid encoding an anti-EGFL7 antibody, the antibody comprising the following HVR sequences: HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 106-124 and 243-246, HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 125-129, HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 130-145, HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 146-153, HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154-187 and 247, and HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 188-192.

16 . The nucleic acid of claim 14 , wherein HVR-L1 comprises the amino acid sequence RTSQSLVHINAITYLH (SEQ ID NO: 241), HVR-L2 comprises the amino acid sequence RVSNRFS (SEQ ID NO: 101), HVR-L3 comprises the amino acid sequence GQSTHVPLT (SEQ ID NO: 131), HVR-H1 comprises the amino acid sequence GYTFIDYYMN (SEQ ID NO: 103), HVR-H2 comprises the amino acid sequence GDINLDNSGTHYNQKFKG (SEQ ID NO: 242), and HVR-H3 comprises the amino acid sequence AREGVYHDYDDYAMDY (SEQ ID NO: 105).

17 . The nucleic acid of claim 14 , wherein the heavy chain comprises the following framework sequences: FR-H1 comprises EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 197); FR-H2 comprises WVRQAPGKGLEWX 1 , wherein X 1 is I or V (SEQ ID NO: 228); FR-H3 comprises RX 1 TX 2 SX 3 DX 4 SX 5 X 6 TX 7 YX 8 QMNSLRAEDTAVYYC, wherein X 1 is F or V; X 2 is I or L; X 3 is selected from the group consisting of L, R, and V; X 4 is K or N; X 5 is selected from the group consisting of K, N, R, and S; X 6 is N or S; X 7 is selected from the group consisting of A, L, and V; and X 8 is L or M (SEQ ID NO: 229); and FR-H4 comprises WGQGTLVTVSS (SEQ ID NO: 200).

18 . The nucleic acid of claim 17 , wherein the heavy chain comprises the following framework sequences: FR-H1 comprises EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 197); FR-H2 comprises WVRQAPGKGLEWV (SEQ ID NO: 198); FR-H3 comprises RFTISRDX 1 SKNTX 2 YLQMNSLRAEDTAVYYCAR, wherein X 1 is N or K; and X 2 is selected from the group consisting of A, L, and V (SEQ ID NO: 230); and FR-H4 comprises WGQGTLVTVSS (SEQ ID NO: 200).

19 . The nucleic acid of claim 14 , wherein the light chain comprises the following framework sequences: FR-L1 comprises DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 201), FR-L2 comprises WYQQKPGKAPKLLIY (SEQ ID NO: 202), FR-L3 comprises GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 203), FR-L4 comprises FGQGTKVEIK (SEQ ID NO: 221) or FGQGTKVEIKR (SEQ ID NO: 204).

20 . The nucleic acid of claim 14 , wherein the light chain comprises the variable domain sequence of 18F7.v6 as shown in FIG. 27 (SEQ ID NO: 193) or the variable domain sequence of 18F7.v6k as shown in FIG. 27 (SEQ ID NO: 194).

21 . The nucleic acid of claim 14 , wherein the heavy chain comprises the variable domain sequence of 18F7.v6 as shown in FIG. 28 (SEQ ID NO: 195) or the variable domain sequence of 18F7.v6k as shown in FIG. 28 (SEQ ID NO: 196).

22 . The nucleic acid of claim 14 , wherein the light chain comprises the variable domain sequence of 18F7.v6 as shown in FIG. 27 (SEQ ID NO: 193) and the heavy chain comprises the variable domain sequence of 18F7.v6 as shown in FIG. 28 (SEQ ID NO: 195).

23 . The nucleic acid of claim 14 , wherein the light chain comprises the variable domain sequence of 18F7.v6k as shown in FIG. 27 (SEQ ID NO: 194) and the heavy chain comprises the variable domain sequence of 18F7.v6k as shown in FIG. 28 (SEQ ID NO: 196).

24 . The nucleic acid of claim 14 , wherein at least a portion of the framework sequence is a human consensus framework sequence.

25 . The nucleic acid of claim 24 , comprising human κ subgroup 1 consensus framework sequence or heavy chain human subgroup III consensus framework sequence.

26 . The nucleic acid of claim 1 or 14 , wherein said antibody is a bispecific antibody.

27 . The nucleic acid of claim 26 , wherein said bispecific antibody binds to vascular endothelial growth factor (VEGF).

28 . A vector comprising the nucleic acid of claim 1 or 14 .

29 . A host cell comprising the nucleic acid claim 1 or 14 .

30 . A method for making an anti-EGFL7 antibody, said method comprising (a) expressing a vector of claim 28 in a suitable host cell, and (b) recovering the antibody.

31 . The method of claim 30 , wherein the host cell is prokaryotic.

32 . The method of claim 30 , wherein the host cell is eukaryotic.