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1. An isolated antibody or antigen-binding fragment thereof that specifically binds to human DLL4, wherein the antibody comprises at least one heavy chain variable domain and at least one light chain variable domain, wherein each heavy chain variable domain comprises three complementary determining regions (CDRs), CDRH1, CDRH2, and CDRH3, and each light chain variable domain comprises three CDRs, CDRL1, CDRL2, and CDRL3, wherein:
a) CDRH3 has an amino acid sequence selected from the group consisting of EEYSSSSAEYFQH (SEQ ID NO:851), RGYSYGYDYFDY (SEQ ID NO:852), EYYDFWSGYYTDYFDY (SEQ ID NO:853), EGYSSSWYDYFDY (SEQ ID NO:854), ANWGDYFDY (SEQ ID NO:855), DDYGGNSDYFDY (SEQ ID NO:856), EGYCSGGSCYS (SEQ ID NO:857), EYYYGSGSYYNDYFDY (SEQ ID NO:858), GCYCSSTSCYADYYYYYGMDV (SEQ ID NO:859), GSCYSYWYFDL (SEQ ID NO:860), SEQ ID NO:851 except that the amino acid residue at position(s) E96, Y97, S98, S99, S100, S100a, A100b, E100c, Q101, and/or H102 is different than the corresponding residue in SEQ ID NO: 851, wherein the different amino acid residue in SEQ ID NO: 851 is E96A, Y97A, S98A, S98Q, S98V, S98I, S98G, S99P, S99A, S99L, S99W, S99F, S99N, S99H, S99C, S99G, S100F, S100A, S100G, S100C, S100H, S100L, S100R, S100aA, A100bE, E100cA, Q101A, H102A, H102S, H102F, and/or H102Y, and SEQ ID NO: 852 except that the amino acid residue at position(s) R95, G96, Y97, S98, Y99, G100, Y100a, D100b, and/or D101 is different than the corresponding residue in SEQ ID NO: 852, wherein the different amino acid residue in SEQ ID NO: 852 is R95A, G96K, G96R, G96L, G96D, G96T, Y97A, Y97H, S98A, Y99A, G100A, G100D, G100L, G100P, G100R, G100M, G100K, G100S, G100R, G100T, Y100aA, D100bA, and/or D101A; b) CDRH2 has an amino acid sequence selected from the group consisting of IINPSGGSTSYAQKFQG (SEQ ID NO:844), IIYPGDSDTRYSPSFQG (SEQ ID NO:845), RTYYRSKWYNDYAVSVKS (SEQ ID NO:846), EINHSGSTNYNPSLKS (SEQ ID NO:847), INSNAGNGNTKYSQEFQG (SEQ ID NO: 848), WMNPNSGNTGYAQKFQG (SEQ ID NO:849), YIYYSGSTYYNPSLKS (SEQ ID NO:850), SEQ ID NO: 844 except that the amino acid residue at position(s) I50, I51, N52, P52a, S53, G54, G55, G56, T57, and/or S58 is different than the corresponding residue in SEQ ID NO: 844, wherein the different amino acid residue in SEQ ID NO: 844 is I50A, I50T, I51A, I51T, I51V, I51N, I51R, I51W, I51S, I51G, I51V, I51E, I51H, I51Y, N52A, N52V, N52G, N52T, N52P, N52L, N52W, N52Y, N52V, N52S, N52Q, N52K, P52aA, P52aM, P52aE, P52aH, P52aY, P52aT, P52aN, P52aR, P52aW, P52aS, P52aG, S53A, S53I, S53E, S53R, S53G, S53T, S53L, S53V, S53N, S53P, G54A, G54W, G54D, G55A, G55V, G55E, G55S, G55K, G55T, G55L, G55R, G55H, G55I, G55W, S58A, T57A, and/or S58A, and SEQ ID NO: 845 except that the amino acid residue at position(s) I50, I51, Y52, P52a, D54, S55, D56 and/or T57 is different than the corresponding residue in SEQ ID NO: 845, wherein the different amino acid residue in SEQ ID NO: 845 is 150A, I51A, Y52A, P52aA, D54A, S55G, D56A, T57D, and/or T57A; c) CDRH1 has an amino acid sequence selected from the group consisting of GYTFTSYYMH (SEQ ID NO: 830), GYSFTSYWIG (SEQ ID NO:831), GDSVSSNSAA (SEQ ID NO:832), GGSFSGYYWS (SEQ ID NO:833), GYTFTSYAMH (SEQ ID NO:834), GYTFTSYAIN (SEQ ID NO:835), GGSISSGGYY (SEQ ID NO:836), SEQ ID NO: 830 except that the amino acid residue at position(s) T28, F29, T30, S31, and/or Y33 is different than the corresponding residue in SEQ ID NO:830, wherein the different amino acid residue in SEQ ID NO: 830 is T28A, F29A, T30A, S31A, and/or Y33A, and SEQ ID NO: 831 except that the amino acid residue at position(s) S28, F29, T30, W33, I34, and/or G35 is different than the corresponding residue in SEQ ID NO: 831, wherein the different amino acid residue in SEQ ID NO: 831 is S28A, S28R, S28K, S28N, F29A, T30A, W33A, I34A, G35T, G35A, and/or G35V; d) CDRL3 has an amino acid sequence selected from the group consisting of QQRSNWPPWT (SEQ ID NO:881), VLYMGSGISYV (SEQ ID NO:882), MIWHSSASFV (SEQ ID NO: 883), QQYNNWPPWT (SEQ ID NO: 884), QANSFPPWT (SEQ ID NO:885), QQYGSSPPWT (SEQ ID NO: 886), QQYNSYSPWT (SEQ ID NO:887), MQRIEFPSWT (SEQ ID NO: 888), SSYTSSSTLFV (SEQ ID NO: 889), QVYESSANFV (SEQ ID NO: 890), SEQ ID NO: 881 except that the amino acid residue at position(s) R91, S92, N93, and/or W94 is different than the corresponding amino acid residue in SEQ ID NO: 881, wherein the different amino acid residue in SEQ ID NO: 881 is R91P, R91L, R91G, S92P, S92A, S92Q, S92V, S92T, S92R, S92G, S92V, S92M, S92N, S92C, N93Y, N93S, N93H, N93Q, W94R, W94S, W94T, W94L, W94P, and/or W94M, and SEQ ID NO: 882 except that the amino acid residue at position(s) V89, L90, Y91, M92, G93, S94, G95, I95a, and/or S95b is different than the corresponding amino acid residue in SEQ ID NO: 882, wherein the different amino acid residue in SEQ ID NO: 882 is V89A, V89P, V89T, V89S, V89L, V89R, V89C, V89E, V89W, V89N, V89I, V89G, V89H, L90A, Y91A, M92A, M92E, M92S, M92G, M92L, M92P, M92V, M92D, M92R, M92N, M92T, M92F, G93A, S94A, S94W, S94G, S94P, S94R, S94L, S94M, S94E, S94V, G94A, I95aA, and/or S95bA; e) CDRL2 has an amino acid sequence selected from the group consisting of DASNRAT (SEQ ID NO:871), STNTRSS (SEQ ID NO: 872), YYSDSSK (SEQ ID NO:873), GASTRAT (SEQ ID NO:874), AASSLQS (SEQ ID NO:875), GASSRAT (SEQ ID NO: 876), DASSLGS (SEQ ID NO:877), TLSYRAS (SEQ ID NO:878), EVSNRPS (SEQ IDNO:879), HYSDSDK (SEQ ID NO:880), SEQ ID NO: 871 except that the amino acid residue at position(s) D50, A51, S52, N53, R54, A55, and/or T56 is different than the corresponding residue in SEQ ID NO: 871, wherein the different amino acid residue in SEQ ID NO: 871 is D50A, A51T, S52A, S52L, S52T, S52R, S52S, S52W, S52N, S52P, S52M, N53A, N53E, N53G, N53M, N53C, N53H, N53P, R54A, A55T, A55R, A55C, A55S, A55G, and/or T56A, and SEQ ID NO: 872 except that the amino acid residue at position(s) S50, T51, N52, T53, R54, S55, and/or S56 is different than the corresponding residue in SEQ ID NO: 872, wherein the different amino acid residue in SEQ ID NO: 872 is S50A, S50F, S50G, S50C, S50R, S50L, S50M, S50V, S50P, S50T, S50H, S50Q, S50N, S50K, S50D, S50E, S50W, T51A, T51F, T51L, T51I, T51M, T51V, T51S, T51P, T51Y, T51H, T51Q, T51N, T51K, T51D, T51E, T51W, T51R, T51G, N52A T53A, R54A, R54I, R54Y, R54D, R54G, S55A, S55F, S55L, S55I, S55M, S55V, S55P, S55T, S55Y, S55H, S55Q, S55N, S55K, S55D, S55E, S55W, S55R, S55G, and/or S56A; and f) CDRL1 has an amino acid sequence selected from the group consisting of RASQSVSSYLA (SEQ ID NO: 861), GLSSGSVSTSYYPS (SEQ ID NO:862), TLRSGINLGSYRIF (SEQ ID NO:863), RASQSVSSNLA (SEQ ID NO:864), RASQGISSWLA (SEQ ID NO:865), RASQVSSSYLA (SEQ ID NO:866), RASQSISSWLA (SEQ ID NO:867), RSSQSLLDSDDGNTYLD (SEQ ID NO:868), TGTSSDVGGTNYVS (SEQ ID NO:869), TLSSDLSVGGKNMF (SEQ ID NO:870), SEQ ID NO: 861 except that the amino acid residue at position(s) R24, Q27, S28, S30, S31, and/or Y32 is different than the corresponding residue in SEQ ID NO: 861, wherein the different amino acid residue in SEQ ID NO: 861 is R24G, Q27L, S28P, S28G, S28K, S28V, S28F, S28P, S28T, S28L, S28Q, S28A, S28N, S28H, S28I, S28R, S28W, S28M S28E, S30N, S30W, S30R, S30L, S30O, S30D, S30L, S30T, S30P, S30Y, S30Q, S30A, S30G, S30V, S31K, S31T, S31N, S31K, S31L, S31M, S31F, S31I, S31V, S31H, S31A, S31P, S31D, S31R, S31Y, S31Q, S31E, S31G, Y32V, and/or Y32S, and SEQ ID NO: 862 except that the amino acid residue at position(s) G24, L25, S26, S27, G27a, S27b, V27c, S28, T29, S30, Y31, Y32, and/or P33 is different than the corresponding residue in SEQ ID NO: 862, wherein the different amino acid residue in SEQ ID NO: 862 is G24A, G24R, G24L, L25A, S26A, S27A, G27aA, S27bA, V27cA, S28A, T29A, S30A, Y31A, Y32A, and/or P33A; wherein the antibody or antigen-binding fragment optionally is isolated. |
