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US 2011/0217237 A1Published application
Therapeutic dll4 binding proteins
AssigneeAbbott Laboratories
InventorsMing-Jiu Chen, Chung-Ming Hsieh, Jijie Gu, Susan E. Morgan-Lappe, Yingchun Li
Life of this patent
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Abstract
DLL4 binding proteins are described herein, including antibodies, CDR-grafted antibodies, humanized antibodies, and DLL4 binding fragments thereof, proteins that bind DLL4 with high affinity, and DLL4 binding proteins that neutralize DLL4 and/or VEGF activity. The DLL4 binding proteins are useful for treating or preventing cancers and tumors and especially for treating or preventing tumor angiogenesis.
Claims117
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;
- X1 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-H1 38H12);
- residues 31-35 of SEQ ID NO:161 (CDR-H1 37D10);
- residues 31-35 of SEQ ID NO:163 (CDR-H1 32C7);
- residues 31-35 of SEQ ID NO:165 (CDR-H1 14G1);
- residues 31-35 of SEQ ID NO:167 (CDR-H1 14A11);
- residues 31-35 of SEQ ID NO:169 (CDR-H1 15D6);
- residues 31-35 of SEQ ID NO:171 (CDR-H1 VH.1 1A11);
- residues 31-35 of SEQ ID NO:172 (CDR-H1 VH.1a 1A11);
- residues 31-35 of SEQ ID NO:173 (CDR-H1 VH.1b 1A11);
- residues 31-35 of SEQ ID NO:174 (CDR-H1 VH.2a 1A11);
- residues 31-35 of SEQ ID NO:179 (CDR-H1 VH.1 38H12);
- residues 31-35 of SEQ ID NO:180 (CDR-H1 VH.1A 38H12);
- residues 31-35 of SEQ ID NO:181 (CDR-H1 VH.1b 38H12);
- residues 31-35 of SEQ ID NO:182 (CDR-H1 VH.2a 38H12);
- residues 31-35 of SEQ ID NO:187 (CDR-H1 h1A11VH.1);
- residues 31-35 of SEQ ID NO:188 (CDR-H1 h1A11.A6);
- residues 31-35 of SEQ ID NO:189 (CDR-H1 h1A11.A8);
- residues 31-35 of SEQ ID NO:190 (CDR-H1 h1A11.C6);
- residues 31-35 of SEQ ID NO:191 (CDR-H1 h1A11.A11);
- residues 31-35 of SEQ ID NO:192 (CDR-H1 h1A11.B5);
- residues 31-35 of SEQ ID NO:193 (CDR-H1 h1A11.E12);
- residues 31-35 of SEQ ID NO:194 (CDR-H1 h1A11.G3);
- residues 31-35 of SEQ ID NO:195 (CDR-H1 h1A11.F5);
- and
- residues 31-35 of SEQ ID NO:196 (CDR-H1 h1A11.H2);
- CDR-H2 is selected from the group consisting of:
- X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17 (SEQ ID NO:152), wherein;
- X1 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;
- X10 is Y, S, T, or N;
- X11 is Y or I;
- X12 is R or G;
- X13 is D;
- X14 is S;
- X15 is V;
- X16 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.1a 1A11);
- residues 50-66 of SEQ ID NO:173 (CDR-H2 VH.1b 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 38H12);
- residues 50-66 of SEQ ID NO:180 (CDR-H2 VH.1A 38H12);
- residues 50-66 of SEQ ID NO:181 (CDR-H2 VH.1b 38H12);
- residues 31-35 of SEQ ID NO:182 (CDR-H1 VH.2a 38H12);
- residues 50-66 of SEQ ID NO:187 (CDR-H2 h1A11VH.1);
- residues 50-66 of SEQ ID NO:188 (CDR-H2 h1A11.A6);
- residues 50-66 of SEQ ID NO:189 (CDR-H2 h1A11.A8);
- residues 50-66 of SEQ ID NO:190 (CDR-H2 h1A11.C6);
- residues 50-66 of SEQ ID NO:191 (CDR-H2 h1A11.A11);
- residues 50-66 of SEQ ID NO:192 (CDR-H2 h1A11.B5);
- residues 50-66 of SEQ ID NO:193 (CDR-H2 h1A11.E12);
- residues 50-66 of SEQ ID NO:194 (CDR-H2 h1A11.G3);
- residues 50-66 of SEQ ID NO:195 (CDR-H2 h1A11.F5);
- and
- residues 50-66 of SEQ ID NO:196 (CDR-H2 h1A11.H2);
- CDR-H3 is selected from the group consisting of:
- X1-X2-X3-X4-X5-X6-X7-X8-X9 (SEQ ID NO:153), wherein;
- X1 is G;
- X2 is Y;
- X3 is Y;
- X4 is N;
- X5 is S;
- X6 is P;
- X7 is F;
- X8 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 32C7);
- residues 99-105 of SEQ ID NO:165 (CDR-H3 14G1);
- residues 99-110 of SEQ ID NO:167 (CDR-H3 14A11);
- residues 99-110 of SEQ ID NO:169 (CDR-H3 15D6);
- residues 99-107 of SEQ ID NO:171 (CDR-H3 VH.1 1A11);
- residues 99-107 of SEQ ID NO:172 (CDR-H3 VH.1a 1A11);
- residues 99-107 of SEQ ID NO:173 (CDR-H3 VH.1b 1A11);
- residues 99-107 of SEQ ID NO:174 (CDR-H3 VH.2a 1A11);
- residues 99-107 of SEQ ID NO:179 (CDR-H3 VH.1 38H12);
- residues 99-107 of SEQ ID NO:180 (CDR-H3 VH.1A 38H12);
- residues 99-107 of SEQ ID NO:181 (CDR-H2 VH.1b 38H12);
- residues 99-107 of SEQ ID NO:182 (CDR-H1 VH.2a 38H12);
- residues 99-107 of SEQ ID NO:187 (CDR-H3 h1A11VH.1);
- residues 99-107 of SEQ ID NO:188 (CDR-H3 h1A11.A6);
- residues 99-107 of SEQ ID NO:189 (CDR-H3 h1A11.A8);
- residues 99-107 of SEQ ID NO:190 (CDR-H3 h1A11.C6);
- residues 99-107 of SEQ ID NO:191 (CDR-H3 h1A11.A11);
- residues 99-107 of SEQ ID NO:192 (CDR-H3 h1A11.B5);
- residues 99-107 of SEQ ID NO:193 (CDR-H3 h1A11.E12);
- residues 99-107 of SEQ ID NO:194 (CDR-H3 h1A11.G3);
- residues 99-107 of SEQ ID NO:195 (CDR-H3 h1A11.F5);
- and
- residues 99-107 of SEQ ID NO:196 (CDR-H3 h1A11.H2);
- CDR-L1 is selected from the group consisting of:
- X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 (SEQ ID NO:154), wherein;
- X1 is R;
- X2 is A;
- X3 is S;
- X4 is E or Q;
- X5 is D or E;
- X6 is I;
- X2 is Y or W;
- X8 is S, I, Y, N, or R;
- X9 is N;
- X10 is L;
- and
- X11 is A;
- residues 24-34 of SEQ ID NO:158 (CDR-L1 38H12);
- residues 24-34 of SEQ ID NO:162 (CDR-L1 37D10);
- residues 24-34 of SEQ ID NO:164 (CDR-L1 32C7);
- residues 24-34 of SEQ ID NO:166 (CDR-L1 14G1);
- residues 23-37 of SEQ ID NO:168 (CDR-L1 14A11);
- residues 23-37 of SEQ ID NO:170 (CDR-L1 15D6);
- residues 24-34 of SEQ ID NO:175 (CDR-L1 VL.1 1A11);
- residues 24-34 of SEQ ID NO:176 (CDR-L1 VL.1a 1A11);
- residues 24-34 of SEQ ID NO:177 (CDR-L1 VL.1b 1A11);
- residues 24-34 of SEQ ID NO:178 (CDR-L1 VL.2a 1A11);
- residues 24-34 of SEQ ID NO:183 (CDR-L1 VL.1 38H12);
- residues 24-34 of SEQ ID NO:184 (CDR-L1 VL.1a 38H12);
- residues 24-34 of SEQ ID NO:185 (CDR-L1 VL.1b 38H12);
- residues 24-34 of SEQ ID NO:186 (CDR-L1 VL.2a 38H12);
- residues 24-34 of SEQ ID NO:197 (CDR-L1 h1A11VL.1);
- residues 24-34 of SEQ ID NO:198 (CDR-L1 h1A11.A2);
- residues 24-34 of SEQ ID NO:199 (CDR-L1 h1A11.A12);
- residues 24-34 of SEQ ID NO:200 (CDR-L1 h1A11.A7);
- residues 24-34 of SEQ ID NO:201 (CDR-L1 h1A11.B4);
- residues 24-34 of SEQ ID NO:202 (CDR-L1 h1A11.B5);
- and
- residues 24-34 of SEQ ID NO:203 (CDR-L1 h1A11.E12);
- CDR-L2 is selected from group consisting of:
- X1-X2-X3-X4-X5-X6-X7 (SEQ ID NO:155), wherein;
- X1 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.1a 1A11);
- residues 50-56 of SEQ ID NO:177 (CDR-L2 VL.1b 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.1a 38H12);
- residues 50-56 of SEQ ID NO:185 (CDR-L2 VL.1b 38H12);
- residues 50-56 of SEQ ID NO:186 (CDR-L2 VL.2a 38H12);
- residues 50-56 of SEQ ID NO:197 (CDR-L2 h1A11VL.1);
- residues 50-56 of SEQ ID NO:198 (CDR-L2 h1A11.A2);
- residues 50-56 of SEQ ID NO:199 (CDR-L2 h1A11.A12);
- residues 50-56 of SEQ ID NO:200 (CDR-L2 h1A11.A7);
- residues 50-56 of SEQ ID NO:201 (CDR-L2 h1A11.B4);
- residues 50-56 of SEQ ID NO:202 (CDR-L2 h1A11.B5);
- and
- residues 50-56 of SEQ ID NO:203 (CDR-L2 h1A11.E12);
- and
- CDR-L3 is selected from the group consisting of:
- X1-X2-X3-X4-X5-X6-X7-X8-X9 (SEQ ID NO:156), wherein;
- X1 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 NO:168 (CDR-L3 14A11);
- residues 92-100 of SEQ ID NO:170 (CDR-L3 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.1a 1A11);
- residues 89-97 of SEQ ID NO:177 (CDR-L3 VL.1b 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.1a 38H12);
- residues 89-97 of SEQ ID NO:185 (CDR-L3 VL.1b 38H12);
- residues 89-97 of SEQ ID NO:186 (CDR-L3 VL.2a 38H12);
- residues 89-97 of SEQ ID NO:197 (CDR-L3 h1A11VL.1);
- residues 89-97 of SEQ ID NO:198 (CDR-L3 h1A11.A2);
- residues 89-97 of SEQ ID NO:199 (CDR-L3 h1A11.A12);
- residues 89-97 of SEQ ID NO:200 (CDR-L3 h1A11.A7);
- residues 89-97 of SEQ ID NO:201 (CDR-L3 h1A11.B4);
- residues 89-97 of SEQ ID NO:202 (CDR-L3 h1A11.B5);
- and
- residues 89-97 of SEQ ID NO:203 (CDR-L3 h1A11.E12).
215 more elements
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-hydroxybutyrate), 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.
Dependencies are inferred from the claim text.