You’re using a public version of DrugPatentWatch with 5 free searches available | Register to unlock more free searches. CREATE FREE ACCOUNT

Last Updated: March 29, 2024

Claims for Patent: 9,403,904


✉ Email this page to a colleague

« Back to Dashboard


Summary for Patent: 9,403,904
Title:Anti-DLL4 antibodies and uses thereof
Abstract: Provided herein are anti-DLL4 antibodies and methods of using anti-DLL4 antibodies as therapeutic agents in diseases or disorders associated with DLL4.
Inventor(s): Smider; Vaughn (San Diego, CA), Mao; Helen Hongyuan (San Diego, CA), Bentley; Cornelia (San Diego, CA), Chase; Tyson (San Diego, CA)
Assignee: Fabrus, Inc. (La Jolla, CA)
Application Number:13/128,236
Patent Claims: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.

2. An antibody or antigen-binding fragment according to claim 1 that is a full-length antibody, optionally a full-length IgG antibody, or an antibody fragment, optionally an antibody fragment selected from the group consisting of a Fab, Fab', F(ab').sub.2, single-chain Fv (scFv), Fv, dsFv, diabody, Fd and Fd' fragment, Fab fragment, Fd fragment, scFv fragment, and a scFab fragment.

3. An antibody or antigen-binding fragment according to claim 1, wherein: a) CDRH2 has the amino acid sequence of SEQ ID NO: 844 except for one of the following sets of differences, I51V/N52L/S53T/G55H, N52L/S53T/G55H, I51E/N52L/S53T/G55H, or I51N/N52L/S53T/G55H; or b) CDRH3 has the amino acid sequence of SEQ ID NO: 851 except for one of the following sets of differences, S98A/S99P/S100F, S98A/S99P/S100F/H102F, or S98A/S99P/S100F/H102Y; or c) CDRH3 has the amino acid sequence of SEQ ID NO: 852 except for the following differences, G96K/G100T; and/or d) CDRL1 has the amino acid sequence of SEQ ID NO: 861 except for the following differences, S28N/S30D/S31H; or e) CDRL2 has the amino acid sequence of SEQ ID NO: 871 except for one of the following sets of differences, S52L/A55S or S52L/A55G; or f) CDRL3 has the amino acid sequence of SEQ ID NO: 882 except for one of the following sets of differences, M92R/S94M or V89L/S94P.

4. An antibody or antigen-binding fragment according to claim 1 that comprises: a) a CDRH2 having the amino acid sequence of SEQ ID NO: 844 except for the difference G55H and a CDRH3 having the amino acid sequence of SEQ ID NO: except for the differences S98A/S99P/S100F/H102F; or b) a CDRH3 having the amino acid sequence of SEQ ID NO:851 except for the differences S98A/S99P/S100F/H102F and a CDRL1 having the amino acid sequence of SEQ ID NO: 861 except for the differences S28N/S30D/S31H; or c) a CDRH2 having the amino acid sequence of SEQ ID NO:844 except for the differences I51V/N52L/S53T/G55H, a CDRH3 having the amino acid sequence of SEQ ID NO:851 except for the differences S98A/S99P/S100F/H102F, and a CDRL1 having the amino acid sequence of SEQ ID NO: 861 except for the differences S28N/S30D/S31H; or d) a CDRH2 having the amino acid sequence of SEQ ID NO:844 except for the differences I51/N52L/S53T/G55H, a CDRH3 having the amino acid sequence of SEQ ID NO:851 except for the differences S98A/S99P/S100F/H102F, a CDRL1 having the amino acid sequence of SEQ ID NO: 861 except for the differences S28N/S30D/S31H, and a CDRL2 having the amino acid sequence of SEQ ID NO:871 except for the differences S52L/A55S; or e) a CDRH1 having the amino acid sequence of SEQ ID NO:831 except for the differences S28R/G35V, a CDRH3 having the amino acid sequence of SEQ ID NO:852 except for the differences G96K/G100T, and a CDRL3 having the amino acid sequence of SEQ ID NO:882 except for the differences M92R/S94M; or f) a CDRH1 having the amino acid sequence of SEQ ID NO:831 except for the differences S28R/G35V, a CDRH3 having the amino acid sequence of SEQ ID NO:852 except for the differences G96K/G100T, and a CDRL3 having the amino acid sequence of SEQ ID NO:882 except for the differences V89L/S94P; or g) a CDRH1 having the amino acid sequence of SEQ ID NO:831 except for the differences S28R/G35V, a CDRH3 having the amino acid sequence of SEQ ID NO:852 except for the differences G96K/G100T, a CDRL2 having the amino acid sequence of SEQ ID NO:872 except for the differences S50G, and a CDRL3 having the amino acid sequence of SEQ ID NO:882 except for the differences V89L/S94P; or h) a CDRH2 comprising the amino acid sequence of SEQ ID NO:844 except for the differences I51V/N52L/S53T/G55H, a CDRH3 comprising the amino acid sequence of SEQ ID NO:851 except for the differences S98A/S99P/S100F/H102F, a CDRL1 comprising the amino acid sequence of SEQ ID NO: 861 except for the differences S28N/S30D/S31H, and a CDRL2 comprising the amino acid sequence of SEQ ID NO:871 except for the differences S52L/A55G.

5. An antibody or antigen-binding fragment according to claim 1 that exhibits at least a binding affinity that is 10.sup.-6 M, 10.sup.-7 M, 10.sup.-8 M, 10.sup.-9 M, 10.sup.-10 M, 10.sup.-11 M, or 10.sup.-12 M or lower as measured by surface plasmon resonance (SPR).

6. An antibody or antigen-binding fragment according to claim 1 that is germline-derived, wherein the antibody or antigen-binding fragment optionally comprises: A. a heavy chain variable domain comprising V.sub.H, D.sub.H, and J.sub.H germline segments or modified germline segments and a light chain variable domain comprising V.sub..kappa., and J.sub..kappa.or V.sub..lamda.and J.sub..lamda., germline segments, wherein: a) the V.sub.H germline segment is an IGHV1, an IGHV4, an IGHV5, or an IGHV6 germline segment or allelic variant thereof, optionally an IGHV1-3*01, an IGHV1-3*02, an IGHV1-8*01, an IGHV1-46*01, an IGHV1-46*02, an IGHV1-46*03, an IGHV4-31*01, an IGHV4-31*02, an IGHV4-31*03, an IGHV4-31*04, an IGHV4-31*05, an IGHV4-31*06, an IGHV4-31*07, an IGHV4-31*08, an IGHV4-31*09, an IGHV4-31*10, an IGHV4-34*01, an IGHV4-34*02, an IGHV4-34*03, an IGHV4-34*04, an IGHV4-34*05, an IGHV4-34*06, an IGHV4-34*07, an IGHV4-34*08, an IGHV4-34*09, an IGHV4-34*10, an IGHV4-34*11, an IGHV4-34*12, an IGHV4-34*13, an IGHV5-51*01, an IGHV5-51*02, an IGHV5-51*03, an IGHV5-51*04, an IGHV5-51*05, an IGHV6-1*01, or an IGHV6-1*02 germline segment or a modification or optimized derivative thereof; and b) the D.sub.H germline segment is an IGHD6, an IGHD5, an IGHD4, an IGHD2, an IGHD3, or an IGHD7 germline segment or allelic variant thereof, optionally an IGHD2-2*01, an IGHD2-2*02, an IGHD2-15*01, an IGHD4-23*01, an IGHD6-6*01, an IGHD6-13*01, IGHD5-18*01, IGHD3-3*01, an IGHD3-3*02, an IGHD3-10*01, an IGHD3-10*02, or an IGHD7-27*01 germline segment or a modification or optimized derivative thereof; and c) the J.sub.H germline segment is an IGHJ1, an IGHJ2, an IGHJ4, or an IGHJ6 germline segment or allelic variant thereof, optionally an IGHJ1*01, an IGHJ2*01, an IGHJ4*01, an IGHJ4*02, an IGHJ4*03, an IGHJ6*01, an IGHJ6*02, an IGHJ6*03, or an IGHJ6*04 germline segment or a modification or optimized derivative thereof; and d) the V.sub..kappa. germline segment is an IGKV1, an IGKV2, or an IGKV3 germline segment or allelic variant thereof and the J.sub..kappa. is a IGKJ1 germline segment or allelic variant thereof, optionally an IGKV1-5*01, an IGKV1-5*02, an IGKV1-5*03, an IGKV1-12*01, an IGKV1-12*02, an IGKV2-D-40*01, an IGKV3-11*01, an IGKV3-11*02, an IGKV3-15*01, an IGKV3-20*01, or an IGKV3-20*02 germline segment or a modification or optimized derivative thereof and an IGKJ1*01 germline segment or a modification or optimized derivative thereof; or e) the V.sub..lamda. germline segment is an IGLV2, an IGLV8, an IGLV11, or an IGLV5 germline segment or allelic variant thereof and the J.sub..lamda. germline segment is an IGLJ1 or an IGLJ4 germline segment or allelic variant thereof, optionally an IGLV2-14*01, an IGLV2-14*02, an IGLV2-14*03, an IGLV2-14*04, an IGLV8-61*01, an IGLV8-61*02, an IGLV8-61*03, an IGLV5-48*01, or an IGLV11-55*01 germline segment or a modification or optimized derivative thereof and an IGLJ1*01 or IGLJ4*01 germline segment or a modification or optimized derivative thereof; and/or B. a heavy chain variable domain comprising V.sub.H, D.sub.H, and J.sub.H germline segments or modified germline segments and a light chain variable domain comprising V.sub..kappa. and J.sub..kappa. or V.sub..lamda. and J.sub..lamda. germline segments, wherein: a) the heavy chain variable domain comprises IGHV1-46*01, an IGHD6-6*01, and an IGHJ1*01 germline segments or modified forms thereof and the light chain variable domain comprises IGKV3-11*01 and IGKJ1*01 germline segments or modified forms thereof; or b) the heavy chain variable domain comprises IGHV5-51*03, IGHD5-18*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGLV8-61*01 and IGLJ1*01 germline segments or modified forms thereof; or c) the heavy chain variable domain comprises IGHV6-1*01, IGHD3-3*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGLV5-48*01 and IGLJ4*01 germline segments or a modified forms thereof; or d) the heavy chain variable domain comprises IGHV1-46*01, IGHD6-13*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGKV3-15*01 and IGKJ1*01 germline segments or modified forms thereof; or e) the heavy chain variable domain comprises IGHV4-34*01, IGHD7-27*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGKV1-12*01 and IGKJ1*01 germline segments or modified forms thereof; or f) the heavy chain variable domain comprises IGHV1-46*01, IGHD6-13*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGKV3-20*01 and IGKJ1*01 germline segments or modified forms thereof; or g) the heavy chain variable domain comprises IGHV1-3*02, IGHD4-23*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGKV1-5*01 and IGKJ1*01 germline segments or modified forms thereof; or h) the heavy chain variable domain comprises IGHV1-46*01, IGHD2-15*01, and IGHJ2*01 germline segments or modified forms thereof and the light chain variable domain comprises IGKV1-5*01 and IGKJ1*01 germline segments or modified forms thereof; or i) the heavy chain variable domain comprises IGHV1-46*01, IGHD3-10*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGKV1-5*01 and IGKJ1*01 germline segments or modified forms thereof; or j) the heavy chain variable domain comprises IGHV1-8*01, IGHD2-2*01, and IGHJ6*01 germline segments or modified forms thereof and the light chain variable domain comprises IGKV1-5*01 and IGKJ1*01 germline segments or modified forms thereof; or k) the heavy chain variable domain comprises IGHV1-46*01, IGHD6-13*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGKV2D-40*01 and, IGKJ1*01 germline segments or modified forms thereof; or l) the heavy chain variable domain comprises IGHV4-34*01, IGHD7-27*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGLV2-14*01 and IGLJ4*01 germline segments or modified forms thereof; or m) the heavy chain variable domain comprises IGHV4-31*02, IGHD2-15*01, and IGHJ2*01 germline segments or modified forms thereof and the light chain variable domain comprises IGLV2-14*01 and IGLJ4*01 germline segments or modified forms thereof; or n) the heavy chain variable domain comprises IGHV4-34*01, IGHD7-27*01, and IGHJ4*01 germline segments or modified forms thereof and the light chain variable domain comprises IGLV11-55*01 and IGLJ4*01 germline segments or a modified form thereof; and/or C. a heavy chain variable domain comprising V.sub.H, D.sub.H, and J.sub.H germline segments or modified germline segments and a light chain variable domain comprising V.sub..kappa. and J.sub..kappa. or V.sub..lamda. and J.sub..lamda. germline segments, wherein: a) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 131 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:141; or b) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 132 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:142; or c) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 133 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:143; or d) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 135 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:145; or e) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 137 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:146; or f) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 135 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:144; or g) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 138 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:147; or h) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 136 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:147; or i) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 134 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:147; or j) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 139 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:147; or k) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 135 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:148; or l) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 137 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:149; or m) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 140 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:149; or n) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 137 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:150; or D. a heavy chain variable domain comprising V.sub.H, D.sub.H, and J.sub.H germline segments or modified germline segments and a light chain variable domain comprising V.sub..kappa. and J.sub..kappa. or V.sub..lamda. and J.sub..lamda. germline segments, wherein: a) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 155 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:141; or b) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 156 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:141; or c) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 385 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:142; or E. a heavy chain variable domain comprising V.sub.H, D.sub.H, and J.sub.H germline segments or modified germline segments and a light chain variable domain comprising V.sub..kappa. and J.sub..kappa. or V.sub..lamda. and J.sub..lamda. germline segments, wherein: a) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 384 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:142; or b) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 414 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:142; or c) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 433 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:142; or d) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 433 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:479; or e) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 433 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:537; or f) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 433 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:536; or g) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 131 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:141; or h) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 151 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:141; or i) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 155 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:141; or j) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 156 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:141; or k) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 157 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:141; or l) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 155 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:266; or m) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 219 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:141; or n) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 156 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:343; or o) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 239 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:343; or p) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 239 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:370; or q) the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 134 and the light chain variable domain comprises an amino acid sequence of SEQ ID NO:147; or F. a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 433 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO:537; or G. a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 433 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO:536; or H. a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 239 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO:343; or I. a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 239 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO:370; or J. a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 240 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO:369; or K. a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 240 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO:370.

7. An antibody or antigen-binding fragment according to claim 1, wherein the antibody or antigen-binding fragment (i) exhibits affinity for human DLL4 expressed on the surface of a cell, optionally on the surface of an endothelial cell, and/or (ii) modulates an activity of human DLL4, optionally as an agonist or antagonist, wherein such modulation optionally comprises inhibiting Notch activation.

8. An antibody or antigen-binding fragment according to claim 1, wherein the antibody or antigen-binding fragment specifically binds to an epitope within an EGF domain of DLL4, optionally within the EGF2 to EGF4 domains of DLL4, optionally within the EGF3 to EGF4 domain or in EGF2 domain of DLL4.

9. An antibody or antigen-binding fragment according to claim 1, wherein the antibody or antigen-binding fragment specifically binds to a human DLL4 epitope within amino acids 283 to 360 of human DLL4 set forth in SEQ ID NO:114, wherein the antibody or antigen-binding fragment comprises: A. at least one heavy chain variable domain and at least one light chain variable domain, wherein: a) each heavy chain variable domain comprises (i) a CDRH1 having an amino acid sequence GYSFTSYWIG (SEQ ID NO:831); (ii) a CDRH2 having an amino acid sequence IIYPGDSDTRYSPSFQG (SEQ ID NO:845); and (iii) a CDRH3 having an amino acid sequence RGYSYGYDYFDY(SEQ ID NO:852); and b) each light chain variable domain comprises (i) a CDRL1 having an amino acid sequence GLSSGSVSTSYYPS(SEQ ID NO:862); (ii) a CDRL2 having an amino acid sequence STNTRSS (SEQ ID NO:872); and (iii) a CDRL3 having an amino acid sequence VLYMGSGISYV (SEQ ID NO:882); wherein the antibody or antigen-binding antibody fragment is optionally a full-length antibody, optionally a full-length IgG antibody, or an antibody fragment selected from the group consisting of a Fab, Fab', F(ab').sub.2, single-chain Fv (scFv), Fv, dsFv, diabody, Fd and Fd' fragment, Fab fragment, Fd fragment, scFv fragment, and a scFab fragment; or B. at least one 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) CDRH1 comprises a modification of amino acid sequence SEQ ID NO:831, wherein one or more amino acids are different at positions S28, F29, T30, W33, I34, and/or G35 as compared to the corresponding positions in SEQ ID NO:831, wherein optionally one or more of the differences is selected from the group consisting of S28A, S28R, S28K, S28N, F29A, T30A, W33A, I34A, G35T, G35A and G35V; b) CDRH2 comprises a modification of amino acid sequence SEQ ID NO:845, wherein one or more amino acids are different at positions I50, I51, Y52, P52a, D54, S55, D56, and/or T57 as compared to the corresponding positions in SEQ ID NO:845, wherein optionally one or more of the differences is selected from the group consisting of I50A, I51A, Y52A, P52aA, D54A, S55G, D56A, T57D, and T57A; c) CDRH3 comprises a modification of amino acid sequence SEQ ID NO:852, wherein one or more amino acids are different at positions R95, G96, Y97, S98, Y99, G100, Y100a, D100b, and/or D101 as compared to the corresponding positions in SEQ ID NO:852, wherein optionally one or more of the differences is selected from the group consisting of R95A, G96K, G96R, G96L, G96D, G96T, Y97A, Y97H, S98A, Y99A, G100A, G100D, G100L, G100P, G100R, G100M, G100K, G100S, G100R, G100T, Y100aA, D100bA and D101A, and wherein optionally the differences are G96K/G100T; d) CDRL1 comprises a modification of amino acid sequence SEQ ID NO:862, wherein one or more amino acids are different at positions G24, L25, S26, S27, G27a, S27b, V27c, S28, T29, S30, Y31, Y32, and/or P33 as compared to the corresponding positions in SEQ ID NO:862, wherein optionally one or more of the differences is selected from the group consisting of G24A, G24R, G24L, L25A, S26A, S27A, G27aA, S27bA, V27cA, S28A, T29A, S30A, Y31A, Y32A, and P33A; e) CDRL2 comprises a modification of amino acid sequence SEQ ID NO:872, wherein one or more amino acids are different at positions S50, T51, N52, T53, R54, S55 and S56 as compared to the corresponding positions in SEQ ID NO:872, wherein optionally one or more of the differences is selected from the group consisting of 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 S56A; and f) CDRL3 comprises a modification of amino acid sequence SEQ ID NO:882, wherein one or more amino acids are different at positions V89, L90, Y91, M92, G93, S94, G95, I95a, and/or S95b as compared to the corresponding positions in SEQ ID NO:882, wherein optionally one or more of the differences is selected from the group consisting of 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 S95bA, and wherein optionally the differences are M92R/S94M or V89L/S94P; or C. at least one at least one heavy chain variable domain and at least one light chain variable domain, wherein each heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 433 and each light chain variable domain comprises an amino acid sequence of SEQ ID NO:537.

10. A composition comprising a carrier, optionally a pharmaceutically acceptable carrier, and an isolated antibody or antigen-binding antibody fragment according to claim 1, wherein the composition is optionally formulated into a formulation for single dose administration or as a sustained release formulation, wherein the formulation is a gel, ointment, cream, paste, suppository, flush, liquid, suspension, aerosol, tablet, pill, or powder, which formulation is optionally suitable for systemic, parenteral, topical, oral, mucosal, intranasal, subcutaneous, aerosolized, intravenous, bronchial, pulmonary, vaginal, vulvovaginal, or esophageal administration, and wherein the composition is optionally further combined with anti-angiogenic agent, optionally an antagonist of vascular endothelial growth factor (VEGF), wherein the VEGF antagonist optionally is an anti-VEGF antibody or antigen-binding antibody fragment, wherein the anti-VEGF antibody optionally is bevacizumab.

Make Better Decisions: Try a trial or see plans & pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.