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1. WO2011109298 - THERAPEUTIC DLL4 BINDING PROTEINS

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claimed is:

A binding protein capable of binding DLL4, comprising at least one amino acid sequence selected from the group of amino acid sequences consisting of SEQ ID NO: 157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO: 163, and SEQ ID NO: 164.

A binding protein comprising an antigen binding domain wherein the binding protein is capable of binding human DLL4, said antigen binding domain comprising at least one CDR, wherein:

CDR-H1 is selected from the group consisting of:

X1-X2-X3-X4-X5 (SEQ ID NO: 151), wherein;

Xi is N, H, or Y;

X2 is F;

X3 is P;

X4 is M; and

X5 is A or S;

residues 31 -35 of SEQ ID NO 157 (CDR-Hl 38H12) residues 31 -35 of SEQ ID NO 161 (CDR-HI 37D10) ;

residues 31 -35 of SEQ ID NO 163 (CDR-HI 32C7) ;

residues 31 -35 of SEQ ID NO 165 (CDR-HI 14G1) ;

residues 31 -35 of SEQ ID NO 167 (CDR-HI 14A11) ;

residues 31 -35 of SEQ ID NO 169 (CDR-HI 15D6) ;

residues 31 -35 of SEQ ID NO 171 (CDR-HI VH .1 1A11) ; residues 31 -35 of SEQ ID NO 172 (CDR-HI VH . la lAll) ; residues 31 -35 of SEQ ID NO 173 (CDR-HI VH . lb 1A11) ; residues 31 -35 of SEQ ID NO 174 (CDR-HI VH .2a 1A11) ; residues 31 -35 of SEQ ID NO 179 (CDR-HI VH .1 3 8H12) ; residues 31 -35 of SEQ ID NO 180 (CDR-HI VH .1A 38H12) ; residues 31 -35 of SEQ ID NO 181 (CDR-HI VH . lb 38H12) ; residues 31 -35 of SEQ ID NO 182 (CDR-HI VH .2a 38H12) ; residues 31 -35 of SEQ ID NO 187 (CDR-HI hlAUVH.1) ; residues 31 -35 of SEQ ID NO 188 (CDR-HI hlAll . A6) ; residues 31 -35 of SEQ ID NO 189 (CDR-HI hlAll . A8) ; residues 31 -35 of SEQ ID NO 190 (CDR-HI hlAll . C6) ; residues 31 -35 of SEQ ID NO 191 (CDR-HI hlAll . All) ; residues 31 -35 of SEQ ID NO 192 (CDR-HI hlAll . B5) ; residues 31 -35 of SEQ ID NO 193 (CDR-HI hlAll . E12) ;

residues 31-35 of SEQ ID NO: 194 (CDR-H1 hlAll.G3); residues 31-35 of SEQ ID NO: 195 (CDR-H1 hlAll.F5); and residues 31-35 of SEQ ID NO: 196 (CDR-H1 hlAll.H2); CDR-H2 is selected from the group consisting of:

Χ —X2X3X4X5ΧεX7Χθ— —XlO-Xll-Xl2Xl3Xl4Xl5Xl6Xl7 (SEQ

ID NO: 152) , wherein;

Xi is T or S;

X2 is I;

X3 is S;

X4 is S or G;

X5 is S;

X6 is D;

X7 is G, A, D, S, or E;

X8 is T or W;

X9 is T, P, or A;

Xio is Y, s , T, or N;

Xll is Y or I;

X12 is R or G;

Xl3 is D;

Xl4 is S;

Xl5 is V;

Xl6 is K; and

X17 is G;

residues 50 -66 of SEQ ID NO 157 (CDR-H2 38H12) ;

residues 50 -68 of SEQ ID NO 161 (CDR-H2 37D10) ;

residues 50 -66 of SEQ ID NO 163 (CDR-H2 32C7) ;

residues 50 -66 of SEQ ID NO 165 (CDR-H2 14G1) ;

residues 50 -66 of SEQ ID NO 167 (CDR-H2 14A11) ;

residues 50 -66 of SEQ ID NO 169 (CDR-H2 15D6) ;

residues 50 -66 of SEQ ID NO 171 (CDR-H2 VH.1 1A11) ; residues 50 -66 of SEQ ID NO 172 (CDR-H2 VH. la 1A11) ; residues 50 -66 of SEQ ID NO 173 (CDR-H2 VH. lb 1A11) ; residues 50 -66 of SEQ ID NO 174 (CDR-H2 VH.2a 1A11) ; residues 50 -66 of SEQ ID NO 179 (CDR-H2 VH.1 3 8H12) ; residues 50 -66 of SEQ ID NO 180 (CDR-H2 VH.1A 38H12) ; residues 50 -66 of SEQ ID NO 181 (CDR-H2 VH. lb 38H12) ; residues 31 -35 of SEQ ID NO 182 (CDR-HI VH.2a 38H12) ;

residues 50- 66 of SEQ ID NO 187 (CDR-H2 hlAUVH.1) residues 50- 66 of SEQ ID NO 188 (CDR-H2 hlAll A6) ; residues 50- 66 of SEQ ID NO 189 (CDR-H2 hlAll A8) ; residues 50- 66 of SEQ ID NO 190 (CDR-H2 hlAll C6) ; residues 50- 66 of SEQ ID NO 191 (CDR-H2 hlAll All) residues 50- 66 of SEQ ID NO 192 (CDR-H2 hlAll B5) ; residues 50- 66 of SEQ ID NO 193 (CDR-H2 hlAll E12) residues 50- 66 of SEQ ID NO 194 (CDR-H2 hlAll G3) ; residues 50- 66 of SEQ ID NO 195 (CDR-H2 hlAll F5) ; and residues 50- 66 of SEQ ID NO 196 (CDR-H2 hlAll H2) ;

CDR-H3 is selected from the group consisting of:

X1-X2-X3-X4-X5-X6- 7- 8-X9 (SEQ ID NO: 153), wherein;

Xi is G;

X2 is Y

X3 is Y

X4 is N

X5 is S

X6 is P

X7 is F

Xs is A; and

X9 is Y, F, or S;

residues 99-107 of SEQ ID NO:157 (CDR-H3 38H12);

residues 101-111 of SEQ ID NO:161 (CDR-H3 37D10) residues 99-105 of SEQ ID NO: : 163 (CDR-H3

residues 99-105 of SEQ ID NO: : 165 (CDR-H3

residues 99-110 of SEQ ID NO: : 167 (CDR-H3

residues 99-110 of SEQ ID NO: : 169 (CDR-H3

residues 99-107 of SEQ ID NO: : 171 (CDR-H3

residues 99-107 of SEQ ID NO: : 172 (CDR-H3

residues 99-107 of SEQ ID NO: : 173 (CDR-H3

residues 99-107 of SEQ ID NO: : 174 (CDR-H3

residues 99-107 of SEQ ID NO: : 179 (CDR-H3

residues 99-107 of SEQ ID NO: : 180 (CDR-H3

residues 99-107 of SEQ ID NO: : 181 (CDR-H2

residues 99-107 of SEQ ID NO: : 182 (CDR-HI

residues 99-107 of SEQ ID NO: : 187 (CDR-H3

residues 99-107 of SEQ ID NO: : 188 (CDR-H3

residues 99-107 of SEQ ID NO:: 189 (CDR-H3 hlAll .A8) ; residues 99-107 of SEQ ID NO: : 190 (CDR-H3 hlAll .C6) ; residues 99-107 of SEQ ID NO: : 191 (CDR-H3 hlAll .All) residues 99-107 of SEQ ID NO: : 192 (CDR-H3 hlAll .B5) ; residues 99-107 of SEQ ID NO: : 193 (CDR-H3 hlAll .E12) residues 99-107 of SEQ ID NO: : 194 (CDR-H3 hlAll .G3) ; residues 99-107 of SEQ ID NO: : 195 (CDR-H3 hlAll .F5) ; and

residues 99-107 of SEQ ID NO: : 196 (CDR-H3 hlAll .H2) ;

CDR-L1 is selected from the group consisting of:

X1-X2-X3-X4-X5-X6- 7- 8-X9-X10 -X11 (SEQ ID NO: 154), wherein ;

Xl is R;

X2 is A;

X3 is S;

X4 is E or Q;

Xs is D or E;

Xe is I;

X7 is Y or W ;

Xs is s , I, Y

X9 is N;

X10 is L; and

X11 is A;

residues 24 -34 of SEQ ID NO 158 (CDR-Ll 38H12) ;

residues 24 -34 of SEQ ID NO 162 (CDR-LI 37D10) ;

residues 24 -34 of SEQ ID NO 164 (CDR-LI 32C7) ;

residues 24 -34 of SEQ ID NO 166 (CDR-LI 14G1) ;

residues 23 -37 of SEQ ID NO 168 (CDR-LI 14A11) ;

residues 23 -37 of SEQ ID NO 170 (CDR-LI 15D6) ;

residues 24 -34 of SEQ ID NO 175 (CDR-LI VL .1 1A11) ; residues 24 -34 of SEQ ID NO 176 (CDR-LI VL . la 1A11) ; residues 24 -34 of SEQ ID NO 177 (CDR-LI VL . lb 1A11) ; residues 24 -34 of SEQ ID NO 178 (CDR-LI VL .2a 1A11) ; residues 24 -34 of SEQ ID NO 183 (CDR-LI VL .1 3 8H12) ; residues 24 -34 of SEQ ID NO 184 (CDR-LI VL . la 38H12) ; residues 24 -34 of SEQ ID NO 185 (CDR-LI VL . lb 38H12) ; residues 24 -34 of SEQ ID NO 186 (CDR-LI VL .2a 38H12) ; residues 24-34 of SEQ ID NO:: 197 (CDR-Ll hlAHVL.1) ; residues 24 -34 of SEQ ID NO: : 198 (CDR-LI hlAll . A2 ) ; residues 24 -34 of SEQ ID NO: : 199 (CDR-LI hlAll .A12) ; residues 24 -34 of SEQ ID NO: :200 (CDR-LI hlAll .A7) ; residues 24 -34 of SEQ ID NO: : 201 (CDR-LI hlAll .B4) ; residues 24 -34 of SEQ ID NO: : 202 (CDR-LI hlAll . B5); and residues 24 -34 of SEQ ID NO: :203 (CDR-LI hlAll .E12) ;

CDR-L2 is selected from group consisting of:

X1-X2-X3-X4-X5-X6-X7 (SEQ ID NO: 155), wherein;

Xi is D;

X2 is T;

X3 is N or S;

X4 is N, D, S, I, Y, or V;

X5 is L;

X6 is A; and

X7 is D;

residues 50 -56 of SEQ ID NO 158 (CDR-L2 38H12) ;

residues 50 -56 of SEQ ID NO 162 (CDR-L2 37D10) ;

residues 50 -56 of SEQ ID NO 164 (CDR-L2 32C7) ;

residues 50 -56 of SEQ ID NO 166 (CDR-L2 14G1) ;

residues 53 -59 of SEQ ID NO 168 (CDR-L2 14A11) ;

residues 53 -59 of SEQ ID NO 170 (CDR-L2 15D6) ;

residues 50 -56 of SEQ ID NO 175 (CDR-L2 VL .1 1A11) ; residues 50 -56 of SEQ ID NO 176 (CDR-L2 VL . la 1A11) ; residues 50 -56 of SEQ ID NO 177 (CDR-L2 VL. lb 1A11) ; residues 50 -56 of SEQ ID NO 178 (CDR-L2 VL .2a 1A11) ; residues 50 -56 of SEQ ID NO 183 (CDR-L2 VL .1 38H12) ; residues 50 -56 of SEQ ID NO 184 (CDR-L2 VL . la 38H12) ; residues 50 -56 of SEQ ID NO 185 (CDR-L2 VL. lb 38H12) ; residues 50 -56 of SEQ ID NO 186 (CDR-L2 VL .2a 38H12) ; residues 50 -56 of SEQ ID NO 197 (CDR-L2 hlAHVL.1) ; residues 50 -56 of SEQ ID NO 198 (CDR-L2 hlAll .A2) ; residues 50 -56 of SEQ ID NO 199 (CDR-L2 hlAll .A12) ; residues 50 -56 of SEQ ID NO 200 (CDR-L2 hlAll .A7) ; residues 50 -56 of SEQ ID NO 201 (CDR-L2 hlAll .B4) ; residues 50 -56 of SEQ ID NO 202 (CDR-L2 hlAll.B5); and residues 50 -56 of SEQ ID NO 203 (CDR-L2 hlAll .E12) ;

and

CDR-L3 is selected from the group consisting of:

X1-X2-X3-X4-X5-X6- 7- 8-X9 (SEQ ID NO: 156), wherein;

Xi is Q;

X2 is Q;

X3 is Y;

X4 is N, D, or T;

X5 is N, Y, or W;

X6 is Y or V;

X7 is P;

X8 is P; and

X9 is T.

residues 89- 97 of SEQ ID NO: 158 (CDR-L3 38H12) ;

residues 89- 97 of SEQ ID NO: 162 (CDR-L3 37D10) ;

residues 89- 97 of SEQ ID NO: 164 (CDR-L3 32C7) ;

residues 89- 98 of SEQ ID NO: 166 (CDR-L3 14G1) ;

residues 92-100 of SEQ ID NC : 168 (CDP 14A11) ;

residues 92-100 of SEQ ID NC : 170 (CDR 15D6) ;

residues 89- 97 of SEQ ID NO: 175 (CDR-L3 VL .1 1A11) ; residues 89- 97 of SEQ ID NO: 176 (CDR-L3 VL . la 1A11) ; residues 89- 97 of SEQ ID NO: 177 (CDR-L3 VL. lb 1A11) ; residues 89- 97 of SEQ ID NO: 178 (CDR-L3 VL .2a 1A11) ; residues 89- 97 of SEQ ID NO: 183 (CDR-L3 VL .1 38H12) ; residues 89- 97 of SEQ ID NO: 184 (CDR-L3 VL . la 38H12) ; residues 89- 97 of SEQ ID NO: 185 (CDR-L3 VL. lb 38H12) ; residues 89- 97 of SEQ ID NO: 186 (CDR-L3 VL .2a 38H12) ; residues 89- 97 of SEQ ID NO: 197 (CDR-L3 hlAHVL.1) ; residues 89- 97 of SEQ ID NO: 198 (CDR-L3 hlAll .A2) ; residues 89- 97 of SEQ ID NO: 199 (CDR-L3 hlAll .A12) ; residues 89- 97 of SEQ ID NO: 200 (CDR-L3 hlAll .A7) ; residues 89- 97 of SEQ ID NO: 201 (CDR-L3 hlAll .B4) ; residues 89- 97 of SEQ ID NO: 202 (CDR-L3 hlAll.B5); and residues 89- 97 of SEQ ID NO: 203 (CDR-L3 hlAll .E12) .

The binding protein according to claim 2, wherein said at least one CDR comprises amino acid sequence selected from the group consisting of:

residues 31-35 of SEQ ID NO: 157 (CDR-Hl 38H12); residues 50-66 of SEQ ID NO:157 (CDR-H2 38H12); residues 99-107 of SEQ ID NO:157 (CDR-H3 38H12); residues 24-34 of SEQ ID NO:158 (CDR-L1 38H12); residues 50-56 of SEQ ID NO:158 (CDR-L2 38H12); residues 89-97 of SEQ ID NO:158 (CDR-L3 38H12); residues 31-35 of SEQ ID NO: 159 (CDR-Hl 1A11); residues 50-66 of SEQ ID NO:159 (CDR-H2 1A11); residues 99-107 of SEQ ID NO:159 (CDR-H3 1A11); residues 24-34 of SEQ ID NO:160 (CDR-L1 1A11); residues 50-56 of SEQ ID NO:160 (CDR-L2 1A11); residues 89-97 of SEQ ID NO:160 (CDR-L3 1A11); residues 31-35 of SEQ ID NO:161 (CDR-Hl 37D10); residues 50-68 of SEQ ID NO:161 (CDR-H2 37D10); residues 101-111 of SEQ ID NO:161 (CDR-H3 37D10); residues 24-34 of SEQ ID NO: 162 (CDR-L1 37D10); residues 50-56 of SEQ ID NO: 162 (CDR-L2 37D10); residues 89-97 of SEQ ID NO: 162 (CDR-L3 37D10); residues 31-35 of SEQ ID NO: 163 (CDR-Hl 32C7); residues 50-66 of SEQ ID NO:163 (CDR-H2 32C7); residues 99-105 of SEQ ID NO:163 (CDR-H3 32C7); residues 24-34 of SEQ ID NO: 164 (CDR-L1 32C7); residues 50-56 of SEQ ID NO: 164 (CDR-L2 32C7); residues 89-98 of SEQ ID NO: 164 (CDR-L3 32C7); residues 31-35 of SEQ ID NO:165 (CDR-Hl 14G1); residues 50-66 of SEQ ID NO:165 (CDR-H2 14G1); residues 99-105 of SEQ ID NO:165 (CDR-H3 14G1); residues 24-34 of SEQ ID NO:166 (CDR-L1 14G1); residues 50-56 of SEQ ID NO:166 (CDR-L2 14G1); residues 89-98 of SEQ ID NO:166 (CDR-L3 14G1); residues 31-35 of SEQ ID NO:167 (CDR-Hl 14A11); residues 50-66 of SEQ ID NO:167 (CDR-H2 14A11); residues 99-110 of SEQ ID NO:167 (CDR-H3 14A11); residues 23-37 of SEQ ID NO: 168 (CDR-L1 14A11); residues 53-59 of SEQ ID NO:168 (CDR-L2 14A11); residues 92-100 of SEQ ID NO: 168 (CDR-L3 14A11); residues 31-35 of SEQ ID NO:169 (CDR-Hl 15D6); residues 50-66 of SEQ ID NO: 169 (CDR-H2 15D6); residues 99-110 of SEQ ID NO: 169 (CDR-H3 15D6); residues 23-37 of SEQ ID NO:170 (CDR-L1 15D6); residues 53-59 of SEQ ID NO: 170 (CDR-L2 15D6); residues 92-100 of SEQ ID NO: 170 (CDR-L3 15D6); residues 31-35 of SEQ ID NO: 171 (CDR-Hl VH.l 1A11); residues 50-66 of SEQ ID NO: 171 (CDR-H2 VH.l 1A11); residues 99-107 of SEQ ID NO: 171 (CDR-H3 VH.l 1A11); residues 31-35 of SEQ ID NO: 172 (CDR-Hl VH.la 1A11); residues 50-66 of SEQ ID NO:172 (CDR-H2 VH.la 1A11); residues 99-107 of SEQ ID NO:172 (CDR-H3 VH.la 1A11); residues 31-35 of SEQ ID NO:173 (CDR-Hl VH.lb 1A11);

residues 50-66 of SEQ ID NO:173 (CDR-H2 VH.lb 1A11); residues 99-107 of SEQ ID NO: 173 (CDR-H3 VH.lb 1A11); residues 31-35 of SEQ ID NO: 174 (CDR-Hl VH.2a 1A11); residues 50-66 of SEQ ID NO:174 (CDR-H2 VH.2a 1A11); residues 99-107 of SEQ ID NO:174 (CDR-H3 VH.2a 1A11); residues 24-34 of SEQ ID

NO:175 (CDR-L1 VL.l 1A11); residues 50-56 of SEQ ID NO:175 (CDR-L2 VL.l 1A11); residues 89-97 of SEQ ID NO: 175 (CDR-L3 VL.l 1A11); residues 24-34 of SEQ ID NO:176 (CDR-L1 VL.la 1A11); residues 50-56 of SEQ ID NO:176 (CDR-L2 VL.la 1A11); residues 89-97 of SEQ ID NO:176 (CDR-L3 VL.la 1A11); residues 24-34 of SEQ ID NO: 177 (CDR-L1 VL.lb 1A11); residues 50-56 of SEQ ID NO: 177 (CDR-L2 VL.lb 1A11); residues 89-97 of SEQ ID NO:177 (CDR-L3 VL.lb 1A11); residues 24-34 of SEQ ID NO:178 (CDR-L1 VL.2a 1A11); residues 50-56 of SEQ ID NO:178 (CDR-L2 VL.2a 1A11); residues 89-97 of SEQ ID NO:178 (CDR-L3 VL.2a 1A11); residues 31-35 of SEQ ID NO: 179 (CDR-H1 VH.l 38H12); residues 50-66 of SEQ ID NO:179 (CDR-H2 VH.l 38H12); residues 99-107 of SEQ ID NO:179 (CDR-H3 VH.l 38H12); residues 31-35 of SEQ ID NO:180 (CDR-H1 VH.1A 38H12); residues 50-66 of SEQ ID NO:180 (CDR-H2 VH.1A 38H12); residues 99-107 of SEQ ID NO: 180 (CDR-H3 VH.1A 38H12); residues 31-35 of SEQ ID NO:181 (CDR-H1 VH.lb 38H12); residues 50-66 of SEQ ID NO: 181 (CDR-H2 VH.lb 38H12); residues 99-107 of SEQ ID NO:181 (CDR-H3 VH.lb 38H12); residues 31-35 of SEQ ID NO: 182 (CDR-H1 VH.2a 38H12); residues 50-66 of SEQ ID NO: 182 (CDR-H2 VH.2a 38H12); residues 99-107 of SEQ ID NO:182 (CDR-H3 VH.2a 38H12);

residues 24-34 of SEQ ID NO:183 (CDR-L1 VL.l 38H12); residues 50-56 of SEQ ID NO: 183 (CDR-L2 VL. l 38H12); residues 89-97 of SEQ ID NO: 183 (CDR-L3 VL.l 38H12); residues 24-34 of SEQ ID NO:184 (CDR-L1 VL.la 38H12); residues 50-56 of SEQ ID NO:184 (CDR-L2 VL.la 38H12); residues 89-97 of SEQ ID NO: 184 (CDR-L3 VL.la 38H12); residues 24-34 of SEQ ID NO:185 (CDR-L1 VL.lb 38H12); residues 50-56 of SEQ ID NO:185 (CDR-L2 VL.lb 38H12); residues 89-97 of SEQ ID NO: 185 (CDR-L3 VL.lb 38H12); residues 24-34 of SEQ ID NO: 186 (CDR-L1 VL.2a 38H12); residues 50-56 of SEQ ID NO: 186 (CDR-L2 VL.2a 38H12); residues 89-97 of SEQ ID NO:186 (CDR-L3 VL.2a 38H12); residues 31-35 of SEQ ID NO:187 (CDR-H1 hi Al l VH.l), residues 50-66 of SEQ ID NO: 187 (CDR-H2 hi Al l VH.l); residues 99-107 of SEQ ID NO: 187 (CDR-H3 hi Al l VH.l); residues 31-35 of SEQ ID NO: 188 (CDR-H1 hlAl l.A6), residues 50-66 of SEQ ID NO: 188 (CDR-H2

MA11.A6); residues 99-107 of SEQ ID NO:188 (CDR-H3 hlAl l .A6); residues 31-35 of SEQ ID NO: 189 (CDR-H1 MA11.A8), residues 50-66 of SEQ ID NO: 189 (CDR-H2 hlAl l.A8); residues 99-107 of SEQ ID NO:189 (CDR-H3 MA11.A8); residues 31-35 of SEQ ID NO: 190 (CDR-H1 hlAl l .C6), residues 50-66 of SEQ ID NO: 190 (CDR-H2 MA11.C6); residues 99-107 of SEQ ID NO:190 (CDR-H3 hlAl l .C6); residues 31-35 of SEQ ID NO:191 (CDR-H1 hlAl l .Al l), residues 50-66 of SEQ ID NO:191 (CDR- H2 hlAl l .Al l); residues 99-107 of SEQ ID NO: 191 (CDR-H3 hlAl l.Al l); residues 31-35 of SEQ ID NO:192 (CDR-H1 hlAl l .B5), residues 50-66 of SEQ ID NO: 192 (CDR-H2 hlAll.B5); residues 99-107 of SEQ ID NO: 192 (CDR-H3 hlAll.B5); residues 31-35 of SEQ ID NO:193 (CDR-H1 hlAll.E12), residues 50-66 of SEQ ID NO:193 (CDR-H2 hlAll.E12); residues 99-107 of SEQ ID NO:193 (CDR-H3 hlAll.E12); residues 31-35 of SEQ ID NO:194 (CDR-H1 hlAll.G3), residues 50-66 of SEQ ID NO:194 (CDR-H2 hlAll.G3); residues 99-107 of SEQ ID NO:194 (CDR-H3 hlAll.G3); residues 31-35 of SEQ IDNO:195 (CDR-H1 hlAll.F5), residues 50-66 of SEQ ID NO: 195 (CDR-H2 hlAll.F5); residues 99-107 of SEQ ID NO: 195 (CDR-H3 hlAll.F5); residues 31-35 of SEQ ID NO: 196 (CDR-Hl hlAll.H2), residues 50-66 of SEQ IDNO:196 (CDR-H2 hlAll.H2); residues 99-107 of SEQ ID NO: 196 (CDR-H3 hlAll.H2); residues 24-34 of SEQ ID NO: 197 (CDR-L1 hlAllVL.l), residues 50-56 of SEQ IDNO:197 (CDR-L2 hlAl 1VL.1); residues 89-97 of SEQ ID NO: 197 (CDR-L3 hlAllVL.l); residues 24-34 of SEQ ID NO:198 (CDR-L1 hlAll.A2), residues 50-56 of SEQ IDNO:198 (CDR-L2

MA11.A2); residues 89-97 of SEQ ID NO:198 (CDR-L3 hlAll.A2); residues 24-34 of SEQ ID NO:199 (CDR-L1 hlAll.A12), residues 50-56 of SEQ ID NO:199 (CDR-L2 hlAll.A12); residues 89-97 of SEQ ID NO:199 (CDR-L3 hlAll.A12); residues 24-34 of SEQ ID NO:200 (CDR-L1 hlAl 1.A7), residues 50-56 of SEQ ID NO:200 (CDR-L2 hlAl 1.A7); residues 89-97 of SEQ ID NO:200 (CDR-L3 hlAl 1.A7);

residues 24-34 of SEQ IDNO:201 (CDR-L1 hlAll.B4), residues 50-56 of SEQ ID NO:201 (CDR-L2 hlAll.B4); residues 89-97 of SEQ IDNO:201 (CDR-L3

MA11.B4); residues 24-34 of SEQ ID NO:202 (CDR-L1 hlAll.B5), residues 50-56 of SEQ ID NO:202 (CDR-L2 hi Al 1.B5); residues 89-97 of SEQ ID NO:202 (CDR-L3 hlAll.B5); residues 24-34 of SEQ ID NO:203 (CDR-L1 hlAll.E12), residues 50-56 of SEQ ID NO:203 (CDR-L2 hlAll.E12); and residues 89-97 of SEQ ID NO:203 (CDR-L3hlAll.E12).

The binding protein according to claim 2, wherein said binding protein comprises at least three CDRs.

The binding protein according to claim 4, wherein said at least three CDRs are selected from a variable domain CDR set selected from the group consisting of:

VH38H12CDR Set

CDR-H1: residues 31-35 of SEQ IDNO:157

CDR-H2: residues 50-66 of SEQ IDNO:157

CDR-H3 residues 99-107 of SEQ ID NO: 157

VL38H12CDR Set

CDR-L1: residues 24-34 of SEQ IDNO:158

CDR-L2: residues 50-56 of SEQ ID NO: 158 CDR-L3: residues 89-97 of SEQ ID NO: 158 VH 1A11 CDR Set

CDR-H1 : residues 31-35 o f SEQ ID NO: 159 CDR-H2: residues 50-66 of SEQ ID NO: 159 CDR-H3: residues 99-107 of SEQ ID NO:159 VL 1A11 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO: 160 CDR-L2: residues 50-56 of SEQ ID NO:160 CDR-L3 : residues 89-97 of SEQ ID NO: 160 VH 37D10 CDR Set

CDR-H1 : residues 31 -35 o f SEQ ID NO: 161 CDR-H2: residues 50-68 of SEQ ID NO:161 CDR-H3: residues 101-11 1 of SEQ ID NO: 161 VL 37D10 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO:162 CDR-L2: residues 50-56 of SEQ ID NO: 162 CDR-L3: residues 89-97 of SEQ ID NO: 162 VH 32C7 CDR Set

CDR-H1 : residues 31-35 o f SEQ ID NO: 163 CDR-H2: residues 50-66 of SEQ ID NO: 163 CDR-H3: residues 99-105 of SEQ ID NO:163 VL 32C7 CDR Set

CDR-L 1 : residues 24-34 of SEQ ID NO: 164 CDR-L2: residues 50-56 of SEQ ID NO: 164 CDR-L3: residues 89-98 of SEQ ID NO: 164 VH 14G1 CDR Set

CDR-H1 : residues 31-35 o f SEQ ID NO: 165 CDR-H2: residues 50-66 of SEQ ID NO:165 CDR-H3: residues 99-105 of SEQ ID NO:165 VL 14G1 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO: 166 CDR-L2: residues 50-56 of SEQ ID NO:166 CDR-L3: residues 89-97 of SEQ ID NO: 166 VH 14A11 CDR Set

CDR-H1 : residues 31 -35 o f SEQ ID NO: 167 CDR-H2: residues 50-66 of SEQ ID NO: 167 CDR-H3: residues 99-110 of SEQ ID NO:167 VL 14A11 CDR Set

CDR-L1 : residues 23-37 of SEQ ID NO: 168 CDR-L2: residues 53-59 of SEQ ID NO:168 CDR-L3: residues 92-100 of SEQ ID NO: 168 VH 15D6 CDR Set

CDR-H1 : residues 31 -35 o f SEQ ID NO: 169 CDR-H2: residues 50-66 of SEQ ID NO:169 CDR-H3: residues 99-1 10 of SEQ ID NO: 169 VL 15D6 CDR Set

CDR-L1 : residues 23-37 of SEQ ID NO:170 CDR-L2: residues 53-59 of SEQ ID NO: 170 CDR-L3: residues 92-100 of SEQ ID NO: 170 VH VH.l 1A11 CDR Set

CDR-H1 : residues 31-35 o f SEQ ID NO: 171 CDR-H2: residues 50-66 of SEQ ID NO:171 CDR-H3: residues 99-107 of SEQ ID NO:171 VH VH.la 1A11 CDR Set

CDR-H1 : residues 31-35 of SEQ ID NO:172 CDR-H2: residues 50-66 of SEQ ID NO: 172 CDR-H3: residues 99-107 of SEQ ID NO: 172 VH VH.lb 1A11 CDR Set

CDR-H1 : residues 31 -35 of SEQ ID NO: 173 CDR-H2: residues 50-66 of SEQ ID NO:173 CDR-H3: residues 99-107 of SEQ ID NO:173 VH VH.2a 1A1 1 CDR Set

CDR-H1 : residues 31-35 of SEQ ID NO:174 CDR-H2: residues 50-66 of SEQ ID NO:174 CDR-H3: residues 99-107 of SEQ ID NO: 174 VL VL.l 1A1 1 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO:175 CDR-L2: residues 50-56 of SEQ ID NO:175 CDR-L3: residues 89-97 of SEQ ID NO: 175 VL VL.la 1A11 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO: 176 CDR-L2: residues 50-56 of SEQ ID NO:176 CDR-L3: residues 89-97 of SEQ ID NO: 176 VL VL.lb 1A11 CDR Set

CDR-L1 : residues 24-34 of SEQ ID O:177 CDR-L2: residues 50-56 of SEQ ID NO: 177 CDR-L3: residues 89-97 of SEQ ID NO: 177 VL VL.2a 1A11 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO: 178 CDR-L2: residues 50-56 of SEQ ID NO: 178 CDR-L3: residues 89-97 of SEQ ID NO: 178 VH VH.l 38H12 CDR Set

CDR-H1 : residues 31-35 of SEQ ID NO: 179 CDR-H2: residues 50-66 of SEQ ID NO:179 CDR-H3: residues 99-107 of SEQ ID NO:179 VH VH. la 38H12 CDR Set

CDR-H1 : residues 31-35 of SEQ ID NO: 180 CDR-H2: residues 50-66 of SEQ ID NO: 180 CDR-H3 : residues 99- 107 of SEQ ID NO: 180 VH VH.lb 38H12 CDR Set

CDR-H1 : residues 31-35 of SEQ ID NO:181 CDR-H2: residues 50-66 of SEQ ID NO: 181 CDR-H3: residues 99-107 of SEQ ID NO:181 VH VH.2a 38H12 CDR Set

CDR-H1 : residues 31 -35 of SEQ ID NO: 182 CDR-H2: residues 50-66 of SEQ ID NO: 182 CDR-H3: residues 99-107 of SEQ ID NO:182 VL VL.l 38H12 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO: 183 CDR-L2: residues 50-56 of SEQ ID NO: 183 CDR-L3: residues 89-97 of SEQ ID NO: 183 VL VL. la 38H12 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO: 184 CDR-L2: residues 50-56 of SEQ ID NO: 184 CDR-L3: residues 89-97 of SEQ ID NO: 184 VL VL.lb 38H12 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO: 185 CDR-L2: residues 50-56 of SEQ ID NO: 185 CDR-L3: residues 89-97 of SEQ ID NO: 185 VL VL.2a 38H12 CDR Set

CDR-L1: residues 24-34 of SEQ ID NO: 186 CDR-L2: residues 50-56 of SEQ IDNO:186 CDR-L3 : residues 89-97 of SEQ ID NO: 186 VH hAllVH.l CDR Set

CDR-H1: residues 31-35 of SEQ ID NO: 187 CDR-H2: residues 50-66 of SEQ ID NO: 187 CDR-H3: residues 99-107 of SEQ ID NO: 187 VHhAll.A6 CDR Set

CDR-H1: residues 31-35 of SEQ ID NO: 188 CDR-H2: residues 50-66 of SEQ ID NO: 188 CDR-H3 : residues 99- 107 of SEQ ID NO: 188 VHhAll.A8 CDR Set

CDR-H1: residues 31-35 of SEQ ID NO: 189 CDR-H2: residues 50-66 of SEQ ID NO: 189 CDR-H3: residues 99-107 of SEQ ID NO:189 VHhAll.C6 CDR Set

CDR-H1: residues 31-35 of SEQ ID NO: 190 CDR-H2: residues 50-66 of SEQ ID NO: 190 CDR-H3: residues 99-107 of SEQ IDNO:190 VHhAll.AH CDR Set

CDR-H1: residues 31-35 of SEQ ID NO:191 CDR-H2: residues 50-66 of SEQ IDNO:191 CDR-H3: residues 99-107 of SEQ IDNO:191 VHhAll.B5 CDR Set

CDR-H1: residues 31-35 of SEQ IDNO:192 CDR-H2: residues 50-66 of SEQ IDNO:192 CDR-H3: residues 99-107 of SEQ ID NO: 192 VH hAll.E12CDRSet

CDR-H1: residues 31-35 of SEQ IDNO:193 CDR-H2: residues 50-66 of SEQ ID NO: 193 CDR-H3: residues 99-107 of SEQ ID NO: 193 VHhAll.G3 CDR Set

CDR-H1: residues 31-35 of SEQ ID NO: 194 CDR-H2: residues 50-66 of SEQ ID NO: 194 CDR-H3: residues 99-107 of SEQ ID NO:194 VHhAll.F5 CDR Set

CDR-H1: residues 31-35 of SEQ ID NO: 195 CDR-H2: residues 50-66 of SEQ IDNO:195 CDR-H3 : residues 99- 107 of SEQ ID NO: 195 VHhAll.H2 CDR Set

CDR-H1: residues 31-35 of SEQ IDNO:196 CDR-H2: residues 50-66 of SEQ ID NO: 196 CDR-H3: residues 99-107 of SEQ ID NO: 196 VLhlAllVL.l CDR Set

CDR-L1: residues 24-34 of SEQ ID NO: 197 CDR-L2: residues 50-56 of SEQ IDNO:197 CDR-L3: residues 89-97 of SEQ ID NO: 197 VLhlAll.A2 CDR Set

CDR-L1: residues 24-34 of SEQ IDNO:198 CDR-L2: residues 50-56 of SEQ IDNO:198 CDR-L3 : residues 89-97 of SEQ ID NO: 198 VLhlAll.A12 CDR Set

CDR-L1: residues 24-34 of SEQ IDNO:199 CDR-L2: residues 50-56 of SEQ IDNO:199 CDR-L3: residues 89-97 of SEQ ID NO: 199 VLhlAll.A7 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO:200 CDR-L2: residues 50-56 of SEQ ID NO:200 CDR-L3 : residues 89-97 of SEQ ID NO:200 VLhlAll.B4 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO:201 CDR-L2: residues 50-56 of SEQ IDNO:201 CDR-L3: residues 89-97 of SEQ IDNO:201 VLhlAll.B5 CDR Set

CDR-L1 : residues 24-34 of SEQ ID NO:202 CDR-L2: residues 50-56 of SEQ IDNO:202 CDR-L3 : residues 89-97 of SEQ ID NO:202 and

VLhlAll.E12CDR Set

CDR-L1: residues 24-34 of SEQ IDNO:203 CDR-L2: residues 50-56 of SEQ IDNO:203 CDR-L3: residues 89-97 of SEQ IDNO:.203

6. The binding protein according to claim 5, comprising CDRs from at least two variable domain CDR sets.

7. The binding protein according to claim 6, wherein said at least two variable domain CDR sets are a pair of CDR sets selected from the group consisting of:

VH 38H12 CDR Set and VL 38H12 CDR Set,

VH 1 Al 1 CDR Set and VL 1A11 CDR Set,

VH 37D10 CDR Set and VL 37D10 CDR Set,

VH 32C7 CDR Set and VL 32C7 CDR Set,

VH 14G1 Set and VL 14G1 CDR Set,

VH 14A11 CDR Set and VL 14A11 CDR Set,

VH 15D6 CDR Set and VL 15D6 CDR Set,

VH VH.l 1A11 CDR Set and VL VL.l 1A11 CDR Set,

VH VH.l 1A11 CDR Set and VL VL.la 1A11 CDR Set,

VH VH.l 1A11 CDR Set and VL VL.lb 1A11 CDR Set,

VH VH.l 1A11 CDR Set and VL VL.2a 1A11 CDR Set,

VH VH.la 1A11 CDR Set and VL VL.l 1A11 CDR Set,

VH VH.la 1A11 CDR Set and VL VL.la 1A11 CDR Set,

VH VH.la 1A11 CDR Set and VL VL.lb 1A11 CDR Set,

VH VH.la 1A11 CDR Set and VL VL.2a 1A11 CDR Set,

VH VH.lb 1A11 CDR Set and VL VL.1 1A11 CDR Set,

VH VH.lb 1A11 CDR Set and VL VL.la 1A11 CDR Set,

VH VH.lb 1A11 CDR Set and VL VL.lb 1A11 CDR Set,

VH VH.lb 1A11 CDR Set and VL VL.2a 1A11 CDR Set,

VH VH.2a 1A11 CDR Set and VL VL.l 1A11 CDR Set,

VH VH.2a 1A11 CDR Set and VL VL.la 1A11 CDR Set,

VH VH.2a 1A11 CDR Set and VL VL.lb 1A11 CDR Set,

VH VH.2a 1 Al 1 CDR Set and VL VL.2a 1A11 CDR Set,

VH VH.l 38H 12 CDR Set and VL VL.l 38H 12 CDR Set,

VH VH.l 38H12 CDR Set and VL VL.la 38H12 CDR Set,

VH VH.l 38H12 CDR Set and VL VL.lb 38H12 CDR Set,

VH VH.l 38H12 CDR Set and VL VL.2a 38H12 CDR Set,

VH VH.la 38H12 CDR Set and VL VL.l 38H12 CDR Set,

VH VH.la 38H12 CDR Set and VL VL. la 38H12 CDR Set,

VH VH.la 38H12 CDR Set and VL VL. lb 38H12 CDR Set,

VH VH.la 38H12 CDR Set and VL VL.2a 38H12 CDR Set,

VH VH.lb 38H12 CDR Set and VL VL.l 38H12 CDR Set,

VH VH.lb 38H12 CDR Set and VL VL.la 38H12 CDR Set, VH VH.lb 38H12 CDR Set and VL VL.lb 38H12 CDR Set,

VH VH.lb 38H12 CDR Set and VL VL.2a 38H12 CDR Set,

VH VH.2a 38H12 CDR Set and VL VL.l 38H12 CDR Set,

VH VH.2a 38H12 CDR Set and VL VL. la 38H12 CDR Set,

VH VH.2a 38H12 CDR Set and VL VL. lb 38H12 CDR Set,

VH VH.2a 38H12 CDR Set and VL VL.2a 38H12 CDR Set,

VH hlAl 1.A6 CDR Set and VL hlAl 1VL.1 CDR Set,

VH hi Al 1.C6 CDR Set and VL hi Al 1 VL.l CDR Set,

VH hi Al l. Al l CDR Set and VL hi Al l VL.l CDR Set,

VH hi Al 1.A8 CDR Set and VL hlAl 1VL.1 CDR Set,

VH hlAl lVH.l CDR Set and VL hlAl l.B4 CDR Set,

VH hlAl 1VH.1 CDR Set and VL hlAl 1.A7 CDR Set,

VH hi Al 1VH.1 CDR Set and VL hlAl 1.A12 CDR Set,

VH hlAl 1VH.1 CDR Set and VL hlAl 1.A2 CDR Set,

VH MA11.B5 CDR Set and VL MA11.B5 CDR Set,

VH hi Al 1.E12 CDR Set and VL hlAl 1.E12 CDR Set,

VH hi Al 1.G3 CDR Set and VL hi Al 1.E12 CDR Set,

VH hi Al 1.F5 CDR Set and VL hlAl 1.E12 CDR Set, and

VH hi Al 1.H2 CDR Set and VL hi Al 1.E12 CDR Set.

8. The binding protein according to claim 4, further comprising a human acceptor framework sequence.

9. The binding protein according to claim 5, further comprising a human acceptor framework sequence.

10. The binding protein according to claim 6, further comprising a human acceptor framework sequence.

11. The binding protein according to claim 7, further comprising a human acceptor framework sequence.

12. The binding protein according to claim 8, wherein said human acceptor framework sequence is selected from the group of acceptor sequences listed in Tables 3 and 4.

13. The binding protein according to claim 9, wherein said human acceptor framework sequence is selected from the group of acceptor sequences listed in Tables 3 and 4.

14. The binding protein according to claim 10, wherein said human acceptor framework sequence is selected from the group of acceptor sequences listed in Tables 3 and 4

15. The binding protein according to claim 11, wherein said human acceptor framework sequence is selected from the group of acceptor sequences listed in Tables 3 and 4.

16. The binding protein according to claim 8, wherein said human acceptor framework sequence is selected from any framework sequence in a variable region sequence selected from the group consisting of:

The binding protein according to claim 9, wherein said human acceptor framework sequence is selected from any framework sequence in a variable region sequence selected from the group consisting of:

SEQ ID NO: 177 SEQ ID NO: 186 SEQ ID NO: 194 SEQ ID NO:202 VL.lb 1A11 VL .2a VH hlAll . G3 VL hlAll.B5

SEQ ID NO: 178 SEQ ID NO: 187 SEQ ID NO: 195 SEQ ID NO:203 VL.2a 1A11 VH hlAUVH.1 VH hlAll . F5 VL hlAll.E12

SEQ ID NO: 179

VH.l 38H12

18. The binding protein according to claim 10, wherein said human acceptor framework sequence is selected from any framework sequence in a variable region sequence selected from the group consisting of:

The binding protein according to claim 11 , wherein said human acceptor framework sequence is selected from any framework sequence in a variable region sequence selected from the group consisting of:

20. The binding protein according to claim 8, wherein said binding protein comprises at least one acceptor framework sequence selected from the group consisting of:

heavy chain framework- 1 (H-FR1):

E-V-Q-L-V-E-S-G-G-G-L-V-Q-P-G-G-S-L-R-L-S-C-A-A-S-G-F-T-F-X30 (SEQ ID NO: 143), wherein X30 is S, R, or G;

heavy chain framework-2 (H-FR2): W-V-R-Q-A-P-G-K-G-L-E-W-V-A (SEQ ID NO: 144);

heavy chain framework-3 (H-FR3):

R-F-T-I-S-R-D-N-A-K-X11-S-L-Y-L-Q-M-N-S-L-R-A-E-D-T-A-V-Y-Y-C-X31-R (SEQ ID NO: 145), wherein;

¾ i is N or S; and

X31 is A or S;

heavy chain framework-4 (H-FR4): W-G-Q-G-T-L-V-T-V-S-S (SEQ ID NO: 146); light chain framework-1 (L-FR1):

D-I-Q-M-T-Q-S-P-S-S-L-S-A-S-V-G-D-R-V-T-I-T-C (SEQ ID NO: 147);

light chain framework-2 (L-FR2): W-Y-Q-Q-K-P-G-K-X9-P-K-L-L-I-X15 (SEQ ID

NO: 148), wherein;

X9 is A or S; and

Xi5 is F or Y;

light chain framework-3 (L-FR3):

G-V-P-S-R-F-S-G-S-G-S-G-T-D-X15-T-L-T-I-S-S-L-Q-P-E-D-F-A-T-Y-Y-C (SEQ ID NO: 149), wherein;

Xi5 is F or S; and

light chain framework-4 (L-FR4): F-G-Q-G-T-K-L-E-I-K (SEQ ID NO: 150).

21. The binding protein according to claim 9, wherein said binding protein comprises at least one acceptor framework sequence selected from the group consisting of:

heavy chain framework-1 (H-FR1):

E-V-Q-L-V-E-S-G-G-G-L-V-Q-P-G-G-S-L-R-L-S-C-A-A-S-G-F-T-F-X30 (SEQ ID NO: 143), wherein X30 is S, R, or G;

heavy chain framework-2 (H-FR2): W-V-R-Q-A-P-G-K-G-L-E-W-V-A (SEQ ID NO: 144);

heavy chain framework-3 (H-FR3):

R-F-T-I-S-R-D-N-A-K-X11-S-L-Y-L-Q-M-N-S-L-R-A-E-D-T-A-V-Y-Y-C-X31-R (SEQ ID NO: 145), wherein;

¾ i is N or S; and

X31 is A or S;

heavy chain framework-4 (H-FR4): W-G-Q-G-T-L-V-T-V-S-S (SEQ ID NO: 146); light chain framework-1 (L-FR1):

D-I-Q-M-T-Q-S-P-S-S-L-S-A-S-V-G-D-R-V-T-I-T-C (SEQ ID NO: 147);

light chain framework-2 (L-FR2): W-Y-Q-Q-K-P-G-K-X9-P-K-L-L-I-X15 (SEQ ID

NO: 148), wherein;

X9 is A or S; and

Xi5 is F or Y;

light chain framework-3 (L-FR3):

G-V-P-S-R-F-S-G-S-G-S-G-T-D-Xi5-T-L-T-I-S-S-L-Q-P-E-D-F-A-T-Y-Y-C (SEQ ID NO: 149), wherein;

Xi5 is F or S; and

light chain framework-4 (L-FR4): F-G-Q-G-T-K-L-E-I-K (SEQ ID NO: 150).

The binding protein according to claim 10, wherein said binding protein comprises at least one acceptor framework sequence selected from the group consisting of:

heavy chain framework-1 (H-FR1):

E-V-Q-L-V-E-S-G-G-G-L-V-Q-P-G-G-S-L-R-L-S-C-A-A-S-G-F-T-F-X30 (SEQ ID NO: 143), wherein X30 is S, R, or G;

heavy chain framework-2 (H-FR2): W-V-R-Q-A-P-G-K-G-L-E-W-V-A (SEQ ID NO: 144);

heavy chain framework-3 (H-FR3):

R-F-T-I-S-R-D-N-A-K-X11-S-L-Y-L-Q-M-N-S-L-R-A-E-D-T-A-V-Y-Y-C-X31-R (SEQ ID NO: 145), wherein;

¾ i is N or S; and

X31 is A or S;

heavy chain framework-4 (H-FR4): W-G-Q-G-T-L-V-T-V-S-S (SEQ ID NO: 146); light chain framework-1 (L-FR1):

D-I-Q-M-T-Q-S-P-S-S-L-S-A-S-V-G-D-R-V-T-I-T-C (SEQ ID NO: 147);

light chain framework-2 (L-FR2): W-Y-Q-Q-K-P-G-K-X9-P-K-L-L-I-X15 (SEQ ID

NO: 148), wherein;

X9 is A or S; and

Xi5 is F or Y;

light chain framework-3 (L-FR3):

G-V-P-S-R-F-S-G-S-G-S-G-T-D-Xi5-T-L-T-I-S-S-L-Q-P-E-D-F-A-T-Y-Y-C (SEQ ID NO: 149), wherein;

Xi5 is F or S; and

light chain framework-4 (L-FR4): F-G-Q-G-T-K-L-E-I-K (SEQ ID NO: 150).

23. The binding protein according to claim 11, wherein said binding protein comprises at least one acceptor framework sequence selected from the group consisting of:

heavy chain framework- 1 (H-FR1):

E-V-Q-L-V-E-S-G-G-G-L-V-Q-P-G-G-S-L-R-L-S-C-A-A-S-G-F-T-F-X30 (SEQ ID NO: 143), wherein X30 is S, R, or G;

heavy chain framework-2 (H-FR2): W-V-R-Q-A-P-G-K-G-L-E-W-V-A (SEQ ID NO: 144);

heavy chain framework-3 (H-FR3):

R-F-T-I-S-R-D-N-A-K-X11-S-L-Y-L-Q-M-N-S-L-R-A-E-D-T-A-V-Y-Y-C-X31-R (SEQ ID NO: 145), wherein;

¾ i is N or S; and

X31 is A or S;

heavy chain framework-4 (H-FR4): W-G-Q-G-T-L-V-T-V-S-S (SEQ ID NO: 146); light chain framework-1 (L-FR1):

D-I-Q-M-T-Q-S-P-S-S-L-S-A-S-V-G-D-R-V-T-I-T-C (SEQ ID NO: 147);

light chain framework-2 (L-FR2): W-Y-Q-Q-K-P-G-K-X9-P-K-L-L-I-X15 (SEQ ID

NO: 148), wherein;

X9 is A or S; and

Xi5 is F or Y;

light chain framework-3 (L-FR3):

G-V-P-S-R-F-S-G-S-G-S-G-T-D-Xi5-T-L-T-I-S-S-L-Q-P-E-D-F-A-T-Y-Y-C (SEQ ID NO: 149), wherein;


light chain framework-4 (L-FR4): F-G-Q-G-T-K-L-E-I-K (SEQ ID NO: 150).

24. The binding protein according to claim 2, wherein said binding protein comprises a human acceptor framework sequence and at least one variable domain having an amino acid sequence selected from the group consisting of:


SEQ ID NO: 175 SEQ ID NO:192

VL VL .1 1A11 VH hlAll .B5

SEQ ID NO: 176 SEQ ID NO:193

VL VL . la 1A11 VH hlAll .E12

SEQ ID NO: 177 SEQ ID NO:194

VL VL . lb VH hlAll . G3

SEQ ID NO: 178 SEQ ID NO:195

VL VL.2a 1A11 VH hlAll . F5

SEQ ID NO: 179 SEQ ID NO:196

VH VH.1 38H12 VH hlAll .H2

SEQ ID NO: 180 SEQ ID NO:197

VH VH. la 38H12 VL hlAllVL.l

SEQ ID NO: 181 SEQ ID NO:198

VH VH. lb 38H12 VL hlAll.A2

SEQ ID NO: 182 SEQ ID NO:199

VH VH.2a 38H12 VL hlAll.A12

SEQ ID NO: 183 SEQ ID NO:200

VL VL .1 38H12 VL hlAll.A7

SEQ ID NO: 184 SEQ ID NO:201

VL VL . la 38H12 VL hlAll.B4

SEQ ID NO: 185 SEQ ID NO:202

VL VL . lb 38H12 VL hlAll.B5

SEQ ID NO: 186 SEQ ID NO:203

VL VL.2a 38H12 VL hlAll.E12

SEQ ID NO: 187

VH hlAllVH.l

The binding protein according to claim 24, wherein said binding protein comprises two variable domains, wherein said two variable domains have amino acid sequences selected from the group consisting of:

12)

SEQ ID NO : 172 and SEQ ID SEQ ID NO: 182 and SEQ ID

NO: 177 NO: 184

VH.la and VL . lb 1A11 (Table VH.2a and VL.la (Table 16)

12)

SEQ ID NO : 172 and SEQ ID SEQ ID NO: 182 and SEQ ID

NO: 178 NO: 185

VH.la and VL . 2a 1A11 (Table VH.2a and VL . lb (Table 16)

12)

SEQ ID NO : 173 and SEQ ID SEQ ID NO: 182 and SEQ ID

NO: 175 NO: 186

VH.lb and VL . 1 1A11 (Table VH.2a and VL.2a (Table 16)

12)

SEQ ID NO : 173 and SEQ ID SEQ ID NO: 188 and SEQ ID

NO: 176 NO: 197

VH.lb and VL . la 1A11 (Table hlAll.A6 VH and hlAllVL.l

12) Tables 20/21

SEQ ID NO : 173 and SEQ ID SEQ ID NO: 190 and SEQ ID

NO: 177 NO: 197

VH.lb and VL . lb 1A11 (Table hlAll.C6 VH and hlAllVL.l

12) Tables 20/21

SEQ ID NO : 173 and SEQ ID SEQ ID NO: 191 and SEQ ID

NO: 178 NO: 197

VH.lb and VL . 2a 1A11 (Table hlAll.All VH and hlAllVL.l

12) Tables 20/21

SEQ ID NO : 174 and SEQ ID SEQ ID NO: 189 and SEQ ID

NO: 175 NO: 197

VH.2a and VL . 1 1A11 (Table hlAll.A8 VH and hlAll VL.l

12) Tables 20/21

SEQ ID NO : 174 and SEQ ID SEQ ID NO: 187 and SEQ ID

NO: 176 NO: 201

VH.2a and VL . la 1A11 (Table hlAllVH.l and hlAll.B4 VL

12) Tables 20/21

SEQ ID NO : 174 and SEQ ID SEQ ID NO: 187 and SEQ ID

NO: 177 NO: 200

VH.2a and VL . lb 1A11 (Table hlAllVH.l and hlAll.A7 VL

12) Tables 20/21

SEQ ID NO : 174 and SEQ ID SEQ ID NO: 187 and SEQ ID

NO: 178 NO: 199

VH.2a and VL . 2a 1A11 (Table hlAllVH.l and hlAll.A12 VL

12) Tables 20/21

SEQ ID NO : 179 and SEQ ID SEQ ID NO: 187 and SEQ ID

NO: 183 NO: 198

VH.1 and VL .1 38H12 (Table hlAllVH.l VH and hlAll.A2

16) VL

Tables 20/21

SEQ ID NO : 179 and SEQ ID SEQ ID NO: 192 and SEQ ID

NO: 184 NO: 202

VH.1 and VL . la 38H12 (Table hlAll.B5 VH and hlAll.B5 VL

16) Tables 20/21

SEQ ID NO : 179 and SEQ ID SEQ ID NO: 193 and SEQ ID

NO: 185 NO: 203

VH.1 and VL . lb 38H12 (Table hlAll.E12 VH and hlAll.E12

16) VL

Tables 20/21

SEQ ID NO: 179 and SEQ ID SEQ ID NO: 194 and SEQ ID NO: 186 NO : 203

VH.l and VL.2a 38H12 (Table hlAll.G3 VH and hlAll.E12 16) VL

Tables 20/21

SEQ ID NO: 180 and SEQ ID SEQ ID NO: 195 and SEQ ID NO: 183 NO : 203

VH.la and VL .1 38H12 (Table hlAll.F5 VH and hlAll.E12 16) VL

Tables 20/21

SEQ ID NO: 180 and SEQ ID SEQ ID NO: 196 and SEQ ID NO: 184 NO : 203

VH.la and VL.la 38H12 (Table hlAll.H2 VH and hlAll.E12 16) VL

Tables 20/21

SEQ ID NO: 180 and SEQ ID

NO: 185

VH.la and VL . lb 38H12 (Table

16)

26. The binding protein according to claim 8, wherein said human acceptor framework sequence comprises at least one Framework Region amino acid substitution at a key residue, said key residue selected from the group consisting of:

a residue adjacent to a CDR;

a glycosylation site residue;

a rare residue;

a residue capable of interacting with human DLL4;

a residue capable of interacting with a CDR;

a canonical residue;

a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone; and

a residue in a region that overlaps between a Chothia-defined variable heavy chain CDRl and a Kabat-defined first heavy chain framework.

27. The binding protein according to claim 11 , wherein said human acceptor framework sequence comprises at least one Framework Region amino acid substitution at a key residue, said key residue selected from the group consisting of:

a residue adjacent to a CDR;

a glycosylation site residue;

a rare residue;

a residue capable of interacting with human DLL4;

a residue capable of interacting with a CDR;

a canonical residue;

a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone; and

a residue in a region that overlaps between a Chothia-defmed variable heavy chain CDRl and a Kabat-defmed first heavy chain framework.

28. The binding protein according to claim 25, wherein said human acceptor framework sequence comprises at least one Framework Region amino acid substitution at a key residue, said key residue selected from the group consisting of:

a residue adjacent to a CDR;

a glycosylation site residue;

a rare residue;

a residue capable of interacting with human DLL4;

a residue capable of interacting with a CDR;

a canonical residue;

a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone; and

a residue in a region that overlaps between a Chothia-defmed variable heavy chain CDRl and a Kabat-defmed first heavy chain framework.

29. The binding protein according to claim 26, wherein the binding protein comprises a consensus human variable domain sequence.

30. The binding protein according to claim 27, wherein the binding protein comprises a consensus human variable domain sequence.

31. The binding protein according to claim 28, wherein the binding protein comprises a consensus human variable domain sequence.

32. The binding protein according to claim 8, wherein said human acceptor framework comprises at least one framework region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to a sequence of a human germline acceptor framework and comprises at least 70 amino acid residues identical to the human germline acceptor framework.

33. The binding protein according to claim 11 , wherein said human acceptor framework comprises at least one framework region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to a sequence of a human germline acceptor framework and comprises at least 70 amino acid residues identical to the human germline acceptor framework.

34. The binding protein according to claim 25, wherein said human acceptor framework comprises at least one framework region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to a sequence of a human germline acceptor framework and comprises at least 70 amino acid residues identical to the human germline acceptor framework.

35. The binding protein according to claim 2, wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:


VH VH.2a 1A11 VL hlAll.A2

SEQ ID NO: 175 SEQ ID NO:199

VL VL .1 1A11 VL hlAll.A12

SEQ ID NO: 176 SEQ ID NO:200

VL VL . la 1A11 VL hlAll.A7

SEQ ID NO: 177 SEQ ID NO:201

VL VL . lb VL hlAll.B4

SEQ ID NO: 178 SEQ ID NO:202

VL VL.2a 1A11 VL hlAll.B5

SEQ ID NO: 179 SEQ ID NO:203

VH VH.1 38H12 VL hlAll.E12

SEQ ID NO: 180

VH VH. la 38H12

The binding protein according to claim 35, wherein said binding protein comprises two variable domains, wherein said two variable domains have amino acid sequences selected from the group consisting of:

NO: 175 NO: 185

VH. la and VL .1 VH.2a and VL . lb 38H12

SEQ ID NO: 172 and SEQ ID SEQ ID NO: 182 and SEQ ID NO: 176 NO : 186

VH. la and VL . la VH.2a and VL.2a 38H12

SEQ ID NO: 172 and SEQ ID SEQ ID NO: 188 and SEQ ID NO: 177 NO: 197

VH. la and VL . lb hlAll.A6 VH and hlAllVL.l

SEQ ID NO: 172 and SEQ ID SEQ ID NO: 190 and SEQ ID NO: 178 NO: 197

VH. la and VL .2a hlAll.C6 VH and hlAllVL.l

SEQ ID NO: 173 and SEQ ID SEQ ID NO: 191 and SEQ ID NO: 175 NO: 197

VH. lb and VL .1 hlAll.All VH and hlAllVL.l

SEQ ID NO: 173 and SEQ ID SEQ ID NO: 189 and SEQ ID NO: 176 NO: 197

VH. lb and VL . la hlAll.A8 VH and hlAll VL.l

SEQ ID NO: 173 and SEQ ID SEQ ID NO: 187 and SEQ ID NO: 177 NO : 201

VH. lb and VL . lb hlAllVH.l and hlAll.B4 VL

SEQ ID NO: 173 and SEQ ID SEQ ID NO: 187 and SEQ ID NO: 178 NO : 200

VH. lb and VL .2a hlAllVH.l and hlAll.A7 VL

SEQ ID NO: 174 and SEQ ID SEQ ID NO: 187 and SEQ ID NO: 175 NO: 199

VH.2a and VL .1 hlAllVH.l and hlAll.A12 VL

SEQ ID NO: 174 and SEQ ID SEQ ID NO: 187 and SEQ ID NO: 176 NO : 198

VH.2a and VL . la hlAllVH.l VH and hlAll.A2

VL

SEQ ID NO: 174 and SEQ ID SEQ ID NO: 192 and SEQ ID NO: 177 NO : 202

VH.2a and VL . lb hlAll.B5 VH and hlAll.B5 VL

SEQ ID NO: 174 and SEQ ID SEQ ID NO: 193 and SEQ ID NO: 178 NO : 203

VH.2a and VL.2a hlAll.E12 VH and hlAll.E12

VL

SEQ ID NO: 179 and SEQ ID SEQ ID NO: 194 and SEQ ID NO: 183 NO: 203

VH.1 and VL .1 38H12 hlAll.G3 VH and hlAll.E12

VL

SEQ ID NO: 179 and SEQ ID SEQ ID NO: 195 and SEQ ID NO: 184 NO : 203

VH.1 and VL . la 38H12 hlAll.F5 VH and hlAll.E12

VL

SEQ ID NO: 179 and SEQ ID SEQ ID NO: 196 and SEQ ID NO: 185 NO : 203

VH.1 and VL . lb 38H12 hlAll.H2 VH and hlAll.E12

VL

37. The DLL4 binding protein according to claim 2, wherein said binding protein is capable of blocking DLL4 interaction with a Notch protein.

38. The DLL4 binding protein according to claim 36, wherein the binding protein is capable of blocking DLL4 interaction with a Notch protein selected from the group consisting of Notch- 1, Notch-2, Notch-3, Notch-4, and combinations thereof.

39. The DLL4 binding protein according to claim 2, wherein said binding protein is capable of modulating a biological function of DLL4.

40. The DLL4 binding protein according to claim 2, wherein said binding protein is capable of neutralizing a biological function of DLL4.

41. The DLL4 binding protein according to claim 2, wherein said binding protein is capable of inhibiting VEGFR2 activity, VEGFR1 activity, or both.

42. The DLL4 binding protein according to claim 2, wherein said binding protein is capable of diminishing the ability of DLL4 to bind to its receptor.

43. The DLL4 binding protein according to claim 2, wherein said binding protein is capable of inhibiting normal angiogenesis.

44. The DLL4 binding protein according to claim 2, wherein said binding protein has an on rate constant (Kon) to DLL4 selected from the group consisting of: at least about 102M"V l; at least about 103M_1s_1; at least about 104M_1s_1; at least about 105M_1s_1; and at least about 106M_1s_1, as measured by surface plasmon resonance.

45. The DLL4 binding protein according to claim 8, wherein said binding protein has an on rate constant (Kon) to DLL4 selected from the group consisting of: at least about 102M"V l; at least about 103M_1s_1; at least about 104M_1s_1; at least about 105M_1s_1; and at least about 106M_1s_1, as measured by surface plasmon resonance.

46. The DLL4 binding protein according to claim 24, wherein said binding protein has an on rate constant (Kon) to DLL4 selected from the group consisting of: at least about 102M"V l; at least about 103M_1s_1; at least about 104M_1s_1; at least about 105M_1s_1; and at least about 106M_1s_1, as measured by surface plasmon resonance.

47. The DLL4 binding protein according to claim 2, wherein said binding protein has an off rate constant (Koff) to DLL4 selected from the group consisting of: at most about 10~3s_1; at most about lO'V1; at most about lO'V1; and at most about 10~6s_1, as measured by surface plasmon resonance.

48. The DLL4 binding protein according to claim 8, wherein said binding protein has an off rate constant (Koff) to DLL4 selected from the group consisting of: at most about 10~3s_1; at most about lO'V1; at most about lO'V1; and at most about 10~6s_1, as measured by surface plasmon resonance.

49. The DLL4 binding protein according to claim 24, wherein said binding protein has an off rate constant (Koff) to DLL4 selected from the group consisting of: at most about 10'V1; at most about lO'V1; at most about lO'V1; and at most about 10~6s_1, as measured by surface plasmon resonance.

50. The DLL4 binding protein according to claim 2, wherein said binding protein has a

dissociation constant (KD) to DLL4 selected from the group consisting of: at most about 10"7 M; at most about 10"8 M; at most about 10"9 M; at most about 10"10 M; at most about 10"n M; at most about 10"12 M; and at most 10"13 M.

51. The DLL4 binding protein according to claim 8, wherein said binding protein has a

dissociation constant (KD) to DLL4 selected from the group consisting of: at most about 10"7 M; at most about 10"8 M; at most about 10"9 M; at most about 10"10 M; at most about 10"n M; at most about 10"12 M; and at most 10"13 M.

52. The DLL4 binding protein according to claim 24, wherein said binding protein has a dissociation constant (KD) to DLL4 selected from the group consisting of: at most about 10"7 M; at most about 10"8 M; at most about 10"9 M; at most about 10"10 M; at most about 10"n M; at most about 10"12 M; and at most 10"13 M.

53. An antibody construct comprising a binding protein described in claim 2, said antibody construct further comprising a linker polypeptide or an immunoglobulin constant domain.

54. The antibody construct according to claim 53, selected from the group consisting of:

an immunoglobulin molecule,

a monoclonal antibody,

a chimeric antibody,

a CDR-grafted antibody,

a Fab,

a Fab',

a F(ab')2,

an Fv,

a disulfide linked Fv,

an scFv,

a single domain antibody,

a diabody,

a multispecific antibody,

a dual specific antibody, and

a bispecific antibody.

55. The antibody construct according to claim 53, wherein said antibody construct comprises a heavy chain immunoglobulin constant domain selected from the group consisting of: a human IgM constant domain,

a human IgGl constant domain,

a human IgG2 constant domain,

a human IgG3 constant domain,

a human IgG4 constant domain,

a human IgE constant domain,

and

a human IgA constant domain.

56. The antibody construct according to claim 53, comprising an immunoglobulin constant domain having an amino acid sequence selected from the group consisting of:

SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and combinations thereof.

57. An antibody conjugate comprising an antibody construct as described in any one of claims 53-56, said antibody conjugate further comprising an agent selected from the group consisting of: an imaging agent, a therapeutic agent, a cytotoxic agent, and an immunoadhesion molecule.

58. The antibody conjugate according to claim 57, wherein said agent is an imaging agent selected from the group consisting of a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin.

59. The antibody conjugate according to claim 57, wherein said imaging agent is a radiolabel selected from the group consisting of: 3H 14C 35S, 90Y, 99Tc, mIn, 1251, 131I, 177Lu, 166Ho, and 153Sm.

60. The antibody conjugate according to claim 57, wherein said agent is a therapeutic or cytotoxic agent selected from the group consisting of: an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, a toxin, and an apoptotic agent.

61. The antibody construct according to claim 53, wherein said binding protein possesses a human glycosylation pattern.

62. The antibody conjugate according to claim 57, wherein said binding protein possesses a human glycosylation pattern.

63. The binding protein according to claim 4, wherein said binding protein exists as a

crystal.

64. The antibody construct according to claim 53, wherein said antibody construct exists as a crystal.

65. The antibody conjugate according to claim 57, wherein said antibody construct exists as a crystal.

66. The binding protein according to claim 63, wherein said crystal is a carrier-free

pharmaceutical controlled release crystal.

67. The antibody construct according to claim 64, wherein said crystal is a carrier-free

pharmaceutical controlled release crystal.

68. The antibody conjugate according to claim 65, wherein said crystal is a carrier-free pharmaceutical controlled release crystal.

69. The binding protein according to claim 63, wherein said binding protein crystal has a greater half life in vivo than the soluble counterpart of the binding protein.

70. The antibody construct according to claim 64, wherein said antibody construct crystal has a greater half life in vivo than the soluble counterpart of the antibody construct.

71. The antibody conjugate according to claim 65, wherein said antibody conjugate crystal has a greater half life in vivo than the soluble counterpart of the antibody conjugate.

72. The binding protein according to claim 63, wherein said binding protein crystal retains biological activity of the non-crystal form of the binding protein.

73. The antibody construct according to claim 64, wherein said antibody construct crystal retains biological activity of the non-crystal form of the antibody construct.

74. The antibody conjugate according to claim 65, wherein said antibody conjugate crystal retains biological activity of the non-crystal form of the antibody conjugate.

75. An isolated nucleic acid encoding a binding protein amino acid sequence described in claim 2.

76. An isolated nucleic acid encoding a polypeptide selected from the group consisting of: a polypeptide comprising a heavy chain variable domain, wherein the heavy chain variable domain comprises one or more of a CDR-H1, a CDR-H2, and a CDR-H3 as described in claim 2; a polypeptide comprising a light chain variable domain, wherein the light chain variable domain comprises one or more of a CDR-L1, a CDR-L2, and a CDR-L3 as described in claim 2; and a combination of both polypeptides.

77. A vector comprising the isolated nucleic acid according to claim 76.

78. The vector according to claim 77, wherein the vector is selected from the group consisting of: pcDNA, pTT, pTT3, pEFBOS, pBV, pJV, and pBJ.

79. A host cell comprising the vector described in claim 77.

80. The host cell according to claim 79, wherein said host cell is a prokaryotic cell.

81. The host cell according to claim 80, wherein said host cell is Escherichia coli.

82. The host cell according to claim 79, wherein said host cell is a eukaryotic cell.

83. The host cell according to claim 82, wherein said eukaryotic cell is selected from the group consisting of: a protist cell, an animal cell, a plant cell, and a fungal cell.

84. The host cell according to claim 83, wherein said eukaryotic cell is an animal cell selected from the group consisting of: a mammalian cell, an avian cell, and an insect cell.

85. The host cell according to claim 84, wherein said mammalian cell is a CHO cell.

86. The host cell according to claim 84, wherein said mammalian cell is a COS cell.

87. The host cell according to claim 83, wherein said fungal cell is Saccharomyces cerevisiae.

88. The host cell according to claim 84, wherein said insect cell is an Sf9 cell.

89. A method of producing a binding protein that binds human DLL4, comprising culturing the host cell as described in claim 79 in a culture medium under conditions sufficient to produce a binding protein that binds human DLL4.

90. A DLL4 binding protein produced according to the method of claim 89.

91. A composition for the release of a binding protein said composition comprising:

(a) a formulation, wherein said formulation comprises a crystallized binding protein according as described in any one of claims 63-65, and an ingredient; and

(b) at least one polymeric carrier.

92. The composition according to claim 93, wherein said polymeric carrier is a polymer selected from one or more of the group consisting of: poly (acrylic acid), poly

(cyanoacrylates), poly (amino acids), poly (anhydrides), poly (depsipeptide), poly (esters), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (b- hydroxybutryate), poly (caprolactone), poly (dioxanone), poly (ethylene glycol), poly ((hydroxypropyl) methacrylamide, poly [(organo)phosphazene], poly (ortho esters), poly (vinyl alcohol), poly (vinylpyrrolidone), maleic anhydride- alkyl vinyl ether copolymers, pluronic polyols, albumin, alginate, cellulose and cellulose derivatives, collagen, fibrin, gelatin, hyaluronic acid, oligosaccharides, glycaminoglycans, sulfated polysaccharides, blends and copolymers thereof.

93. The composition according to claim 91, wherein said ingredient is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β- cyclodextrin, methoxypolyethylene glycol and polyethylene glycol.

94. A method for treating a mammal comprising the step of administering to the mammal an effective amount of the composition as described in claim 91.

95. A pharmaceutical composition comprising a DLL4 binding protein as described in claim 2, and a pharmaceutically acceptable carrier.

96. The pharmaceutical composition of claim 95, further comprising at least one additional agent for treating a disorder in which DLL4 activity is detrimental.

97. The pharmaceutical composition of claim 95, wherein said additional agent is selected from the group consisting of: a therapeutic agent; an imaging agent; an antineoplastic agent; a chemotherapeutic agent; an angiogenesis inhibitor; an anti-VEGF antibody; an anti-EGFR antibody; an anti-cMet antibody; an anti-ErbB3 antibody; an anti-HER2 antibody; an anti-CD20 antibody; aflibercept; a kinase inhibitor; a co-stimulation molecule blocker; an anti-B7.2 antibody; a CTLA4-Ig; an adhesion molecule blocker; an anti-E selectin antibody; an anti-L selectin antibody; an anti-cytokine antibody or functional fragment thereof; an anti-IL-18 antibody; an anti-TNF antibody; anti-IL-6 antibody; methotrexate; a corticosteroid; a cyclosporin; a rapamycin; FK506; a DNA alkylating agent; cisplatin; carboplatin; an anti-tubulin agent; paclitaxel; docetaxel; doxorubicin; gemcitabine; gemzar; an anthracycline; adriamycin; a topoisiomersase I inhibitor; a topoisomerase II inhibitor; 5-fluorouracil (5-FU); leucovorin; irinotecan; a receptor tyrosine kinase inhibitor, an apoptosis inhibitor; a Bcl2/Bclx inhibitor; erlotinib, gefitinib, a COX-2 inhibitor, celecoxib, cyclosporin; rapamycin; a detectable label or reporter molecule; a TNF antagonist; an antirheumatic; a muscle relaxant; a narcotic; an analgesic; an anesthetic; a sedative; a local anesthetic; a neuromuscular blocker; an antimicrobial agent; an antipsoriatic agent; a corticosteroid; an anabolic steroid; an erythropoietin; an immunization; an immunoglobulin; an immunosuppressive agent; a growth hormone; a hormone replacement drug; a radiopharmaceutical drug; an antidepressant; an antipsychotic drug; a stimulant; an asthma medication; a beta agonist; an inhaled steroid; an epinephrine; an epinephrine analog thereof; a cytokine; and a cytokine antagonist.

98. A method for reducing human DLL4 activity comprising contacting human DLL4 with the binding protein as described in claim 2 such that human DLL4 activity is reduced.

99. A method for reducing human DLL4 activity in a human subject suffering from a disorder in which DLL4 activity is detrimental, comprising administering to the human subject a binding protein as described in claim 2 such that human DLL4 activity in the human subject is reduced.

100. A method for treating a subject for a disease or a disorder in which DLL4 activity is detrimental by administering to the subject a DLL4 binding protein as described in claim 2 such that treatment is achieved.

101. The method of claim 100, wherein said disorder is selected from the group consisting of: breast cancer, colon cancer, rectal cancer, lung cancer, oropharynx cancer, hypopharynx cancer, esophageal cancer, stomach cancer, pancreas cancer, liver cancer, gallbladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, female genital tract cancer, male genital tract cancer, endocrine gland cancer, skin cancer, hemangioma, melanoma, sarcoma, brain tumor, nerve cancer, eye tumor, meninges cancer, solid tumors from hematopoietic malignancy, tumor metastases, ocular neovascularization, edema, rheumatoid arthritis, atherosclerotic plaques, Crohn's disease, inflammatory bowel disease, refractory ascites, psoriasis, sarcoidosis, arterial arteriosclerosis, sepsis, peptic ulcers, burns, pancreatitis, polycystic ovarian disease (POD), endometriosis, uterine fibroid, benign prostate hypertrophy, T-cell acute lymphoblastic leukemia (T-ALL), cerebral autosomal dominant arteriopathy with subcortical infarcts and

leukoencephalopathy (CADASIL), multiple sclerosis (MS), tetralogy of Fallot (TOF), Alagille syndrome (AS), macular degeneration and age-related macular degeneration diseases, and other angiogenesis independent and dependent diseases characterized by aberrant DLL4 activity.

102. The method according to Claim 101, wherein the disorder is a primary and metastatic cancer.

103. The method according to Claim 101, wherein the urinary tract cancer is selected from the group consisting of renal cancer, bladder cancer, and urothelium cancer.

104. The method according to Claim 101, wherein the female genital tract cancer is selected from the group consisting of cervical cancer, uterine cancer, ovarian cancer,

choriocarcinoma, and gestational trophoblastic disease.

105. The method according to Claim 101, wherein the male genital tract cancer is selected from the group consisting of prostate cancer, seminal vesicles cancer, testicular cancer, and germ cell tumor.

106. The method according to Claim 101, wherein the endocrine gland cancer is selected from the group consisting of thyroid cancer, adrenal cancer, and pituitary gland cancer.

107. The method according to Claim 101, wherein the sarcoma is selected from the group consisting of a bone sarcoma, a soft tissue sarcoma, and Kaposi's sarcoma.

108. The method according to Claim 101, wherein the meninges cancer is selected from the group consisting of an astrocytoma, a glioma, a glioblastoma, a retinoblastoma, a neuroma, a neuroblastoma, a Schwannoma, and a meningioma.

109. The method according to Claim 101, wherein the solid tumor from a hematopoietic

malignancy is a leukemia, a Hodgkin's leukemia, a non-Hodgkin's leukemia, a lymphoma, a Hodgkin's lymphoma, and a non-Hodgkin's lymphomas.

110. The method according to Claim 101, wherein the ocular neovascularization is selected from the group consisting of diabetic blindness, a retinopathy, an age-related macular degeneration, and a rubeosis.

111. The method according to Claim 101, wherein said administering to the subject is by at least one mode selected from the group consisting of: parenteral, subcutaneous, intramuscular, intravenous, intraarterial, intraarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar,

intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic,

intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.

112. A method of treating a patient suffering from a disorder in which DLL4 is

detrimental comprising the step of administering a DLL4 binding protein as described in claim 2 before, concurrent with, or after the administration of a therapeutically effective amount of a second agent, wherein the second agent is selected from the group consisting of an antibody or fragment thereof capable of binding human VEGFR2; methotrexate; an antibody or fragment thereof capable of binding human TNF; a corticosteroid; a cyclosporine; a rapamycin; FK506; a non-steroidal anti-inflammatory agent (NSAID); a radiotherapeutic agent; an antineoplastic agent; a chemotherapeutic agent; a DNA alkylating agent; cisplatin; carboplatin; an anti-tubulin agent; paclitaxel; docetaxel; taxol; doxorubicin; gemcitabine; gemzar; an anthracycline; adriamycin; a topoisomerase I inhibitor; a topoisomerase II inhibitor; 5-fluorouracil (5-FU); leucovorin; irinotecan; a receptor tyrosine kinase inhibitor; erlotinib; gefitinib; a COX-2 inhibitor; celecoxib; a kinase inhibitor; an angiogenesis inhibitor; an anti-VEGF antibody;

aflibercept; a co-stimulation molecule blocker; an anti-B7.1 antibody; an anti-B7.2 antibody; a CTLA4-Ig; an anti-CD20 antibody; an adhesion molecule blocker; an anti- LFA-1 antibody; an anti-E selectin antibody; and anti-L selectin antibody; a small molecule inhibitor; an anti-cytokine antibody or functional fragment thereof; an anti-IL- 18 antibody; anti-TNF antibody; an anti-IL-6 antibody; an anti-cytokine receptor antibody; a detectable label or reporter; a TNF antagonist; an antirheumatic; a muscle relaxant; a narcotic; an analgesic; an anesthetic; a sedative; a local anesthetic; a neuromuscular blocker; an antimicrobial agent; an antipsoriatic drug; a corticosteroid; an anabolic steroid; an erythropoietin; an immunization; an immunoglobulin; an immunosuppressive agent; a growth hormone; a hormone replacement drug; a radiopharmaceutical drug; an antidepressant; an antipsychotic drug; a stimulant; an asthma medication; a beta agonist; an inhaled steroid; an epinephrine; an epinephrine analog; a cytokine; and a cytokine antagonist.

113. A binding protein according to claim 2, wherein said binding protein is an antibody.

114. The antibody according to claim 113, wherein the antibody is selected from the group consisting of a monoclonal antibody, a full-length tetrameric immunoglobulin, an IgG molecule, an IgGi molecule, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, and an affinity matured antibody.

115. The antibody according to claim 114, wherein the antibody is a monoclonal antibody.

116. The binding protein according to claim 36, wherein said two variable domains have the amino acid sequences selected from the group consisting of:

SEQ ID NO: 188 and SEQ ID NO: 197,

SEQ ID NO: 190 and SEQ ID NO: 197, and

SEQ ID NO: 191 and SEQ ID NO: 197.

117. The binding protein according to claim 36, wherein said two variable domains have the amino acid sequences of SEQ ID NO: 181 and SEQ ID NO: 185.