Granted Patent B2

US 9,132,190 · App. 14/090,778 · Granted Sep 15, 2015

Abstract

Claims (1192)

1. A method for treating a subject having a disease or a disorder characterized by aberrant DLL4 expression or in which DLL4 is detrimental, said method comprising administering to said subject an effective amount of a binding protein capable of binding human DLL4, said binding protein comprising an antigen binding domain comprising six complementarity determining regions (CDRs): CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein:

CDR-H1 is selected from the group consisting of:

residues 31-37 of SEQ ID NO:1;

SEQ ID NO:117;

SEQ ID NO:121;

SEQ ID NO:125;

SEQ ID NO:129;

SEQ ID NO:133;

SEQ ID NO:137;

SEQ ID NO:141;

SEQ ID NO:145;

SEQ ID NO:149;

SEQ ID NO:153;

SEQ ID NO:157;

SEQ ID NO:161;

SEQ ID NO:165;

SEQ ID NO:169;

SEQ ID NO:173;

SEQ ID NO:177;

SEQ ID NO:181;

SEQ ID NO:185;

SEQ ID NO:189;

SEQ ID NO:193;

SEQ ID NO:197;

SEQ ID NO:201;

SEQ ID NO:205;

SEQ ID NO:209;

SEQ ID NO:213;

residues 31-37 of SEQ ID NO:334;

residues 31-37 of SEQ ID NO:336;

residues 31-37 of SEQ ID NO:338;

residues 31-37 of SEQ ID NO:340;

residues 31-37 of SEQ ID NO:342;

residues 31-37 of SEQ ID NO:344;

residues 31-37 of SEQ ID NO:346;

residues 31-37 of SEQ ID NO:348;

residues 31-37 of SEQ ID NO:350;

residues 31-37 of SEQ ID NO:352;

residues 31-37 of SEQ ID NO:354;

residues 31-37 of SEQ ID NO:356;

residues 31-37 of SEQ ID NO:358; and

residues 31-37 of SEQ ID NO:360;

CDR-H2 is selected from the group consisting of:

residues 52-67 of SEQ ID NO:1;

SEQ ID NO:118;

SEQ ID NO:122;

SEQ ID NO:126;

SEQ ID NO:130;

SEQ ID NO:134;

SEQ ID NO:138;

SEQ ID NO:142;

SEQ ID NO:146;

SEQ ID NO:150;

SEQ ID NO:154;

SEQ ID NO:158;

SEQ ID NO:162;

SEQ ID NO:166;

SEQ ID NO:170;

SEQ ID NO:174;

SEQ ID NO:178;

SEQ ID NO:182;

SEQ ID NO:186;

SEQ ID NO:190;

SEQ ID NO:194;

SEQ ID NO:198;

SEQ ID NO:202;

SEQ ID NO:206;

SEQ ID NO:210;

SEQ ID NO:214;

residues 52-67 of SEQ ID NO:334;

residues 52-67 of SEQ ID NO:336;

residues 52-67 of SEQ ID NO:338;

residues 52-67 of SEQ ID NO:340;

residues 52-67 of SEQ ID NO:342;

residues 52-67 of SEQ ID NO:344;

residues 52-67 of SEQ ID NO:346;

residues 52-67 of SEQ ID NO:348;

residues 52-67 of SEQ ID NO:350;

residues 52-67 of SEQ ID NO:352;

residues 52-67 of SEQ ID NO:354;

residues 52-67 of SEQ ID NO:356;

residues 52-67 of SEQ ID NO:358; and

residues 52-67 of SEQ ID NO:360;

CDR-H3 is selected from the group consisting of:

residues 100-110 of SEQ ID NO:1;

SEQ ID NO:119;

SEQ ID NO:123;

SEQ ID NO:127;

SEQ ID NO:131;

SEQ ID NO:135;

SEQ ID NO:139;

SEQ ID NO:143;

SEQ ID NO:147;

SEQ ID NO:151;

SEQ ID NO:155;

SEQ ID NO:159;

SEQ ID NO:163;

SEQ ID NO:167;

SEQ ID NO:171;

SEQ ID NO:175;

SEQ ID NO:179;

SEQ ID NO:183;

SEQ ID NO:187;

SEQ ID NO:191;

SEQ ID NO:195;

SEQ ID NO:199;

SEQ ID NO:203;

SEQ ID NO:207;

SEQ ID NO:211;

SEQ ID NO:215;

residues 100-110 of SEQ ID NO:334;

residues 100-110 of SEQ ID NO:336;

residues 100-110 of SEQ ID NO:338;

residues 100-110 of SEQ ID NO:340;

residues 100-110 of SEQ ID NO:342;

residues 100-110 of SEQ ID NO:344;

residues 100-110 of SEQ ID NO:346;

residues 100-110 of SEQ ID NO:348;

residues 100-110 of SEQ ID NO:350;

residues 100-110 of SEQ ID NO:352;

residues 100-110 of SEQ ID NO:354;

residues 100-110 of SEQ ID NO:356;

residues 100-110 of SEQ ID NO:358; and

residues 100-110 of SEQ ID NO:360;

CDR-L1 is selected from the group consisting of:

residues 23-33 of SEQ ID NO:111;

SEQ ID NO:217;

SEQ ID NO:221;

SEQ ID NO:225;

SEQ ID NO:229;

SEQ ID NO:233;

SEQ ID NO:237;

SEQ ID NO:241;

SEQ ID NO:245;

SEQ ID NO:249;

SEQ ID NO:253;

SEQ ID NO:257;

SEQ ID NO:261;

SEQ ID NO:265;

SEQ ID NO:269;

SEQ ID NO:273;

SEQ ID NO:277;

SEQ ID NO:281;

SEQ ID NO:285;

SEQ ID NO:289;

SEQ ID NO:293;

SEQ ID NO:297;

SEQ ID NO:301;

SEQ ID NO:305;

SEQ ID NO:309;

SEQ ID NO:313;

residues 23-33 of SEQ ID NO:335;

residues 23-33 of SEQ ID NO:337;

residues 23-33 of SEQ ID NO:339;

residues 23-33 of SEQ ID NO:341;

residues 23-33 of SEQ ID NO:343;

residues 24-34 of SEQ ID NO:345;

residues 23-33 of SEQ ID NO:347;

residues 24-34 of SEQ ID NO:349;

residues 24-34 of SEQ ID NO:351;

residues 24-34 of SEQ ID NO:353;

residues 24-34 of SEQ ID NO:355;

residues 23-33 of SEQ ID NO:357;

residues 23-33 of SEQ ID NO:359; and

residues 23-33 of SEQ ID NO:361;

CDR-L2 is selected from the group consisting of:

residues 49-55 of SEQ ID NO:111;

SEQ ID NO:230;

SEQ ID NO:234;

SEQ ID NO:238;

SEQ ID NO:242;

SEQ ID NO:246;

SEQ ID NO:250;

SEQ ID NO:254;

SEQ ID NO:258;

SEQ ID NO:262;

SEQ ID NO:266;

SEQ ID NO:270;

SEQ ID NO:218;

SEQ ID NO:222;

SEQ ID NO:226;

SEQ ID NO:274;

SEQ ID NO:278;

SEQ ID NO:302;

SEQ ID NO:294;

SEQ ID NO:282;

SEQ ID NO:290;

SEQ ID NO:298;

SEQ ID NO:286;

SEQ ID NO:306;

SEQ ID NO:310;

SEQ ID NO:314;

residues 49-55 of SEQ ID NO:335;

residues 49-55 of SEQ ID NO:337;

residues 49-55 of SEQ ID NO:339;

residues 49-55 of SEQ ID NO:341;

residues 49-55 of SEQ ID NO:343;

residues 50-56 of SEQ ID NO:345;

residues 49-55 of SEQ ID NO:347;

residues 50-56 of SEQ ID NO:349;

residues 50-56 of SEQ ID NO:351;

residues 50-56 of SEQ ID NO:353;

residues 50-56 of SEQ ID NO:355;

residues 49-55 of SEQ ID NO:357;

residues 49-55 of SEQ ID NO:359; and

residues 49-55 of SEQ ID NO:361;

and

CDR-L3 is selected from the group consisting of:

residues 88-96 of SEQ ID NO:111;

SEQ ID NO:231;

SEQ ID NO:235;

SEQ ID NO:239;

SEQ ID NO:243;

SEQ ID NO:247;

SEQ ID NO:251;

SEQ ID NO:255;

SEQ ID NO:259;

SEQ ID NO:263;

SEQ ID NO:267;

SEQ ID NO:271;

SEQ ID NO:219;

SEQ ID NO:223;

SEQ ID NO:227;

SEQ ID NO:275;

SEQ ID NO:279;

SEQ ID NO:303;

SEQ ID NO:295;

SEQ ID NO:283;

SEQ ID NO:291;

SEQ ID NO:299;

SEQ ID NO:287;

SEQ ID NO:307;

SEQ ID NO:311;

SEQ ID NO:315;

residues 88-96 of SEQ ID NO:335;

residues 88-96 of SEQ ID NO:337;

residues 88-96 of SEQ ID NO:339;

residues 88-96 of SEQ ID NO:341;

residues 88-96 of SEQ ID NO:343;

residues 89-97 of SEQ ID NO:345;

residues 88-96 of SEQ ID NO:347;

residues 89-97 of SEQ ID NO:349;

residues 89-97 of SEQ ID NO:351;

residues 89-97 of SEQ ID NO:353;

residues 89-97 of SEQ ID NO:355;

residues 88-96 of SEQ ID NO:357;

residues 88-96 of SEQ ID NO:359; and

residues 88-96 of SEQ ID NO:361.

2. The method according to claim 1 , wherein said binding protein comprises a variable domain CDR set of three CDRs, wherein the variable domain CDR set is selected from the group of variable domain CDR sets consisting of:

VH E9 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:1

CDR-H2: residues 52-67 of SEQ ID NO:1 and

CDR-H3: residues 100-110 of SEQ ID NO:1

VL E9 CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:111

CDR-L2: residues 49-55 of SEQ ID NO:111 and

CDR-L3: residues 88-96 of SEQ ID NO:111

VH E9.4 CDR Set

CDR-H1: SEQ ID NO:117

CDR-H2: SEQ ID NO:118 and

CDR-H3: SEQ ID NO:119

VL E9.4 CDR Set

CDR-L1: SEQ ID NO:229

CDR-L2: SEQ ID NO:230 and

CDR-L3: SEQ ID NO:231

VH E9.11 CDR Set

CDR-H1: SEQ ID NO:121

CDR-H2: SEQ ID NO:122 and

CDR-H3: SEQ ID NO:123

VL E9.11 CDR Set

CDR-L1: SEQ ID NO:233

CDR-L2: SEQ ID NO:234 and

CDR-L3: SEQ ID NO:235

VH E9.14 CDR Set

CDR-H1: SEQ ID NO:125

CDR-H2: SEQ ID NO:126 and

CDR-H3: SEQ ID NO:127

VL E9.14 CDR Set

CDR-L1: SEQ ID NO:237

CDR-L2: SEQ ID NO:238 and

CDR-L3: SEQ ID NO:239

VH E9.17 CDR Set

CDR-H1: SEQ ID NO:129

CDR-H2: SEQ ID NO:130 and

CDR-H3: SEQ ID NO:131

VL E9.17 CDR Set

CDR-L1: SEQ ID NO:241

CDR-L2: SEQ ID NO:242 and

CDR-L3: SEQ ID NO:243

VH E9.18 CDR Set

CDR-H1: SEQ ID NO:133

CDR-H2: SEQ ID NO:134 and

CDR-H3: SEQ ID NO:135

VL E9.18 CDR Set

CDR-L1: SEQ ID NO:245

CDR-L2: SEQ ID NO:246 and

CDR-L3: SEQ ID NO:247

VH E9.19 CDR Set

CDR-H1: SEQ ID NO:137

CDR-H2: SEQ ID NO:138 and

CDR-H3: SEQ ID NO:139

VL E9.19 CDR Set

CDR-L1: SEQ ID NO:249

CDR-L2: SEQ ID NO:250 and

CDR-L3: SEQ ID NO:251

VH E9.22 CDR Set

CDR-H1: SEQ ID NO:141

CDR-H2: SEQ ID NO:142 and

CDR-H3: SEQ ID NO:143

VL E9.22 CDR Set

CDR-L1: SEQ ID NO:253

CDR-L2: SEQ ID NO:254 and

CDR-L3: SEQ ID NO:255

VH E9.48 CDR Set

CDR-H1: SEQ ID NO:145

CDR-H2: SEQ ID NO:146 and

CDR-H3: SEQ ID NO:147

VL E9.48 CDR Set

CDR-L1: SEQ ID NO:257

CDR-L2: SEQ ID NO:258 and

CDR-L3: SEQ ID NO:259

VH E9.65 CDR Set

CDR-H1: SEQ ID NO:149

CDR-H2: SEQ ID NO:150 and

CDR-H3: SEQ ID NO:151

VL E9.65 CDR Set

CDR-L1: SEQ ID NO:261

CDR-L2: SEQ ID NO:262 and

CDR-L3: SEQ ID NO:263

VH E9.66 CDR Set

CDR-H1: SEQ ID NO:153

CDR-H2: SEQ ID NO:154 and

CDR-H3: SEQ ID NO:155

VL E9.66 CDR Set

CDR-L1: SEQ ID NO:265

CDR-L2: SEQ ID NO:266 and

CDR-L3: SEQ ID NO:267

VH E9.71 CDR Set

CDR-H1: SEQ ID NO:157

CDR-H2: SEQ ID NO:158 and

CDR-H3: SEQ ID NO:159

VL E9.71 CDR Set

CDR-L1: SEQ ID NO:269

CDR-L2: SEQ ID NO:270 and

CDR-L3: SEQ ID NO:271

VH E9.13 CDR Set

CDR-H1: SEQ ID NO:161

CDR-H2: SEQ ID NO:162 and

CDR-H3: SEQ ID NO:163

VL E9.13 CDR Set

CDR-L1: SEQ ID NO:217

CDR-L2: SEQ ID NO:218 and

CDR-L3: SEQ ID NO:219

VH E9.16 CDR Set

CDR-H1: SEQ ID NO:165

CDR-H2: SEQ ID NO:166 and

CDR-H3: SEQ ID NO:167

VL E9.16 CDR Set

CDR-L1: SEQ ID NO:221

CDR-L2: SEQ ID NO:222 and

CDR-L3: SEQ ID NO:223

VH E9.38 CDR Set

CDR-H1: SEQ ID NO:169

CDR-H2: SEQ ID NO:170 and

CDR-H3: SEQ ID NO:171

VL E9.38 CDR Set

CDR-L1: SEQ ID NO:225

CDR-L2: SEQ ID NO:226 and

CDR-L3: SEQ ID NO:227

VH E9.2B CDR Set

CDR-H1: SEQ ID NO:173

CDR-H2: SEQ ID NO:174 and

CDR-H3: SEQ ID NO:175

VL E9.2B CDR Set

CDR-L1: SEQ ID NO:273

CDR-L2: SEQ ID NO:274 and

CDR-L3: SEQ ID NO:275

VH E9.1F CDR Set

CDR-H1: SEQ ID NO:177

CDR-H2: SEQ ID NO:178 and

CDR-H3: SEQ ID NO:179

VL E9.1F CDR Set

CDR-L1: SEQ ID NO:277

CDR-L2: SEQ ID NO:278 and

CDR-L3: SEQ ID NO:279

VH E9.10H CDR Set

CDR-H1: SEQ ID NO:181

CDR-H2: SEQ ID NO:182 and

CDR-H3: SEQ ID NO:183

VL E9.10H CDR Set

CDR-L1: SEQ ID NO:301

CDR-L2: SEQ ID NO:302 and

CDR-L3: SEQ ID NO:303

VH E9.5E CDR Set

CDR-H1: SEQ ID NO:185

CDR-H2: SEQ ID NO:186 and

CDR-H3: SEQ ID NO:187

VL E9.5E CDR Set

CDR-L1: SEQ ID NO:293

CDR-L2: SEQ ID NO:294 and

CDR-L3: SEQ ID NO:295

VH E9.10C CDR Set

CDR-H1: SEQ ID NO:189

CDR-H2: SEQ ID NO:190 and

CDR-H3: SEQ ID NO:191

VL E9.10C CDR Set

CDR-L1: SEQ ID NO:281

CDR-L2: SEQ ID NO:282 and

CDR-L3: SEQ ID NO:283

VH E9.7E CDR Set

CDR-H1: SEQ ID NO:193

CDR-H2: SEQ ID NO:194 and

CDR-H3: SEQ ID NO:195

VL E9.7E CDR Set

CDR-L1: SEQ ID NO:289

CDR-L2: SEQ ID NO:290 and

CDR-L3: SEQ ID NO:291

VH E9.12B CDR Set

CDR-H1: SEQ ID NO:197

CDR-H2: SEQ ID NO:198 and

CDR-H3: SEQ ID NO:199

VL E9.12B CDR Set

CDR-L1: SEQ ID NO:297

CDR-L2: SEQ ID NO:298 and

CDR-L3: SEQ ID NO:299

VH E9.10E CDR Set

CDR-H1: SEQ ID NO:201

CDR-H2: SEQ ID NO:202 and

CDR-H3: SEQ ID NO:203

VL E9.10E CDR Set

CDR-L1: SEQ ID NO:285

CDR-L2: SEQ ID NO:286 and

CDR-L3: SEQ ID NO:287

VH E9.6A CDR Set

CDR-H1: SEQ ID NO:205

CDR-H2: SEQ ID NO:206 and

CDR-H3: SEQ ID NO:207

VL E9.6A CDR Set

CDR-L1: SEQ ID NO:305

CDR-L2: SEQ ID NO:306 and

CDR-L3: SEQ ID NO:307

VH E9.7A CDR Set

CDR-H1: SEQ ID NO:209

CDR-H2: SEQ ID NO:210 and

CDR-H3: SEQ ID NO:211

VL E9.7 A CDR Set

CDR-L1: SEQ ID NO:309

CDR-L2: SEQ ID NO:310 and

CDR-L3: SEQ ID NO:311

VH E9.8H CDR Set

CDR-H1: SEQ ID NO:213

CDR-H2: SEQ ID NO:214 and

CDR-H3: SEQ ID NO:215

VL E9.8H CDR Set

CDR-L1: SEQ ID NO:313

CDR-L2: SEQ ID NO:314 and

CDR-L3: SEQ ID NO:315

VH E9.1 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:334

CDR-H2: residues 52-67 of SEQ ID NO:334 and

CDR-H3: residues 100-110 of SEQ ID NO:334

VL E9.1 CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:335

CDR-L2: residues 49-55 of SEQ ID NO:335 and

CDR-L3: residues 88-96 of SEQ ID NO:335

VH E9-SE1 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:336

CDR-H2: residues 52-67 of SEQ ID NO:336 and

CDR-H3: residues 100-110 of SEQ ID NO:336

VL E9-SE1 CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:337

CDR-L2: residues 49-55 of SEQ ID NO:337 and

CDR-L3: residues 88-96 of SEQ ID NO:337

VH E9-SE2 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:338

CDR-H2: residues 52-67 of SEQ ID NO:338 and

CDR-H3: residues 100-110 of SEQ ID NO:338

VL E9-SE2 CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:339

CDR-L2: residues 49-55 of SEQ ID NO:339 and

CDR-L3: residues 88-96 of SEQ ID NO:339

VH E9-SE3 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:340

CDR-H2: residues 52-67 of SEQ ID NO:340 and

CDR-H3: residues 100-110 of SEQ ID NO:340

VL E9-SE3 CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:341

CDR-L2: residues 49-55 of SEQ ID NO:341 and

CDR-L3: residues 88-96 of SEQ ID NO:341

VH E9-SE4 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:342

CDR-H2: residues 52-67 of SEQ ID NO:342 and

CDR-H3: residues 100-110 of SEQ ID NO:342

VL E9-SE4 CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:343

CDR-L2: residues 49-55 of SEQ ID NO:343 and

CDR-L3: residues 88-96 of SEQ ID NO:343

VH E9-SE5 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:344

CDR-H2: residues 52-67 of SEQ ID NO:344 and

CDR-H3: residues 100-110 of SEQ ID NO:344

VL E9-SE5 CDR Set

CDR-L1: residues 24-34 of SEQ ID NO:345

CDR-L2: residues 50-56 of SEQ ID NO:345 and

CDR-L3: residues 89-97 of SEQ ID NO:345

VH E9-SE6 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:346

CDR-H2: residues 52-67 of SEQ ID NO:346 and

CDR-H3: residues 100-110 of SEQ ID NO:346

VL E9-SE6 CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:347

CDR-L2: residues 49-55 of SEQ ID NO:347 and

CDR-L3: residues 88-96 of SEQ ID NO:347

VH E9-SE7 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:348

CDR-H2: residues 52-67 of SEQ ID NO:348 and

CDR-H3: residues 100-110 of SEQ ID NO:348

VL E9-SE7 CDR Set

CDR-L1: residues 24-34 of SEQ ID NO:349

CDR-L2: residues 50-56 of SEQ ID NO:349 and

CDR-L3: residues 89-97 of SEQ ID NO:349

VH E9-SE8 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:350

CDR-H2: residues 52-67 of SEQ ID NO:350 and

CDR-H3: residues 100-110 of SEQ ID NO:350

VL E9-SE8 CDR Set

CDR-L1: residues 24-34 of SEQ ID NO:351

CDR-L2: residues 50-56 of SEQ ID NO:351 and

CDR-L3: residues 89-97 of SEQ ID NO:351

VH E9-FR1 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:352

CDR-H2: residues 52-67 of SEQ ID NO:352 and

CDR-H3: residues 100-110 of SEQ ID NO:352

VL E9-FR1 CDR Set

CDR-L1: residues 24-34 of SEQ ID NO:353

CDR-L2: residues 50-56 of SEQ ID NO:353 and

CDR-L3: residues 89-97 of SEQ ID NO:353

VH E9-FR2 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:354

CDR-H2: residues 52-67 of SEQ ID NO:354 and

CDR-H3: residues 100-110 of SEQ ID NO:354

VL E9-FR2 CDR Set

CDR-L1: residues 24-34 of SEQ ID NO:355

CDR-L2: residues 50-56 of SEQ ID NO:355 and

CDR-L3: residues 89-97 of SEQ ID NO:355

VH E9.71 CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:356

CDR-H2: residues 52-67 of SEQ ID NO:356 and

CDR-H3: residues 100-110 of SEQ ID NO:356

VL E9.71 CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:357

CDR-L2: residues 49-55 of SEQ ID NO:357 and

CDR-L3: residues 88-96 of SEQ ID NO:357

VH E9.71(M) CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:358

CDR-H2: residues 52-67 of SEQ ID NO:358 and

CDR-H3: residues 100-110 of SEQ ID NO:358

VL E9.71(M) CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:359

CDR-L2: residues 49-55 of SEQ ID NO:359 and

CDR-L3: residues 88-96 of SEQ ID NO:359

VH E9.71(L) CDR Set

CDR-H1: residues 31-37 of SEQ ID NO:360

CDR-H2: residues 52-67 of SEQ ID NO:360 and

CDR-H3: residues 100-110 of SEQ ID NO:360

and

VL E9.71(L) CDR Set

CDR-L1: residues 23-33 of SEQ ID NO:361

CDR-L2: residues 49-55 of SEQ ID NO:361 and

CDR-L3: residues 88-96 of SEQ ID NO:361.

3. The method according to claim 2 , wherein said binding protein comprises at least two variable domain CDR sets selected from the group consisting of:

VH E9 CDR Set and VL E9 CDR Set,

VH E9.4 CDR Set and VL E9.4 CDR Set,

VH E9.11 CDR Set and VL E9.11 CDR Set,

VH E9.14 CDR Set and VL E9.14 CDR Set,

VH E9.17 CDR Set and VL E9.17 CDR Set,

VH E9.18 CDR Set and VL E9.18 CDR Set,

VH E9.19 CDR Set and VL E9.19 CDR Set,

VH E9.22 CDR Set and VL E9.22 CDR Set,

VH E9.48 CDR Set and VL E9.48 CDR Set,

VH E9.65 CDR Set and VL E9.65 CDR Set,

VH E9.66 CDR Set and VL E9.66 CDR Set,

VH E9.71 CDR Set and VL E9.71 CDR Set,

VH E9.13 CDR Set and VL E9.13 CDR Set,

VH E9.16 CDR Set and VL E9.16 CDR Set,

VH E9.38 CDR Set and VL E9.38 CDR Set,

VH E9.2B CDR Set and VL E9.2B CDR Set,

VH E9.1F CDR Set and VL E9.1F CDR Set,

VH E9.10H CDR Set and VL E9.10H CDR Set,

VH E9.5E CDR Set and VL E9.5E CDR Set,

VH E9.10C CDR Set and VL E9.10C CDR Set,

VH E9.7E CDR Set and VL E9.7E CDR Set,

VH E9.12B CDR Set and VL E9.12B CDR Set,

VH E9.10E CDR Set and VL E9.10E CDR Set,

VH E9.6A CDR Set and VL E9.6A CDR Set,

VH E9.7A CDR Set and VL E9.7A CDR Set,

VH E9.8H CDR Set and VL E9.8H CDR Set,

VH E9-SE1 CDR Set and VL E9-SE1 CDR Set,

VH E9-SE2 CDR Set and VL E9-SE2 CDR Set,

VH E9-SE3 CDR Set and VL E9-SE3 CDR Set,

VH E9-SE4 CDR Set and VL E9-SE4 CDR Set,

VH E9-SE5 CDR Set and VL E9-SE5 CDR Set,

VH E9-SE6 CDR Set and VL E9-SE6 CDR Set,

VH E9-SE7 CDR Set and VL E9-SE7 CDR Set,

VH E9-SE8 CDR Set and VL E9-SE8 CDR Set,

VH E9-FR1 CDR Set and VL E9-FR1 CDR Set,

VH E9-FR2 CDR Set and VL E9-FR2 CDR Set,

VH E9.71 CDR Set and VL E9.71 CDR Set,

VH E9.71(M) CDR Set and VL E9.71(M) CDR Set, and

VH E9.71(L) CDR Set and VL E9.71(L) CDR Set.

4. The method according to claim 1 , wherein said binding protein further comprises a human acceptor framework, said human acceptor framework comprising an amino acid sequence selected from the group consisting of:

SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62,

SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98.

5. The method according to claim 4 , wherein said human acceptor framework further comprises at least one amino acid substitution relative to a human germline acceptor framework at a 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 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 CDR1 and a Kabat-defined first heavy chain framework.

6. The method according to claim 5 , wherein said key residue is selected from the group consisting of: 2H, 4H, 24H, 26H, 27H, 29H, 34H, 35H, 37H, 39H, 44H, 45H, 47H, 48H, 49H, 50H, 51H, 58H, 59H, 60H, 63H, 67H, 69H, 71H, 73H, 76H, 78H, 91H, 93H, 94H, 2L, 4L, 25L, 29L, 27bL, 33L, 34L, 36L, 38L, 43L, 44L, 46L, 47L, 48L, 49L, 55L, 58L, 62L, 64L, 71L, 87L, 89L, 90L, 91L, 94L, and 95L.

7. The method according to claim 1 , wherein said binding protein comprises at least one variable domain having amino acid sequence selected from the group consisting of: SEQ ID NOS:1, 111, 116, 228, 120, 232, 124, 236, 128, 240, 132, 244, 136, 248, 140, 252, 144, 256, 148, 260, 152, 264, 156, 268, 160, 216, 164, 220, 168, 224, 172, 272, 176, 276, 180, 300, 184, 292, 188, 280, 192, 288, 196, 296, 200, 284, 204, 304, 208, 308, 212, 312, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, and 361.

8. The method according to claim 7 , wherein said binding protein comprises two variable domains, wherein said two variable domains have amino acid sequences selected from the group consisting of: SEQ ID NOS:1 and 111, SEQ ID NOS:116 and 228, SEQ ID NOS:120 and 232, SEQ ID NOS:124 and 236, SEQ ID NOS: 128 and 240, SEQ ID NOS: 132 and 244, SEQ ID NOS: 136 and 248, SEQ ID NOS:140 and 252, SEQ ID NOS:144 and 256, SEQ ID NOS:148 and 260, SEQ ID NOS:152 and 264, SEQ ID NOS:156 and 268, SEQ ID NOS: 160 and 216, SEQ ID NOS: 164 and 220, SEQ ID NOS:168 and 224, SEQ ID NOS:172 and 272, SEQ ID NOS:176 and 276, SEQ ID NOS:180 and 300, SEQ ID NOS:184 and 292, SEQ ID NOS:188 and 280, SEQ ID NOS:192 and 288, SEQ ID NOS:196 and 296, SEQ ID NOS:200 and 284, SEQ ID NOS:204 and 304, SEQ ID NOS:208 and 308, SEQ ID NOS:212 and 312, SEQ ID NOS:334 and 335, SEQ ID NOS:336 and 337, SEQ ID NOS:338 and 339, SEQ ID NOS:340 and 341, SEQ ID NOS:342 and 343, SEQ ID NOS:344 and 345, SEQ ID NOS:346 and 347, SEQ ID NOS:348 and 349, SEQ ID NOS:350 and 351, SEQ ID NOS:352 and 353, SEQ ID NOS:354 and 355, SEQ ID NOS:356 and 357, SEQ ID NOS:358 and 359, and SEQ ID NOS:360 and 361.

9. The method according to claim 8 , wherein the binding protein further comprises a heavy chain immunoglobulin constant domain selected from the group consisting of: a human IgM constant domain; a human IgG1 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.

10. The method according to claim 9 , wherein said heavy chain immunoglobulin constant domain is a human IgG1 constant domain, said human IgG1 constant domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:3.

11. The method according to claim 8 , wherein the binding protein further comprises a light chain immunoglobulin constant domain, wherein said light chain immunoglobulin constant domain is a human Ig kappa constant domain, said Ig kappa constant domain comprising amino acid sequence SEQ ID NO:4.

12. The method according to claim 8 , wherein the binding protein further comprises a light chain immunoglobulin constant domain, wherein said light chain immunoglobulin constant domain is a human Ig lambda constant domain, said Ig lambda constant domain comprising amino acid sequence SEQ ID NO:5.

13. The method according to claim 1 , wherein said binding protein is selected from the group consisting of: an immunoglobulin molecule, an scFv, a monoclonal antibody, a human antibody, a chimeric antibody, a humanized antibody, a single domain antibody, a Fab fragment, a Fab′ fragment, an F(ab′)2, an Fv, a disulfide linked Fv, a single domain antibody, a diabody, a multispecific antibody, a bispecific antibody, a dual variable domain immunoglobulin (DVD-Ig) binding protein, and a dual specific antibody.

14. The method according to claim 1 , wherein said binding protein comprises:

an Ig constant heavy region having an amino acid sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:3;

an Ig constant light region having an amino acid sequence selected from the group consisting of SEQ ID NO:4 and SEQ ID NO:5;

an Ig variable heavy region having an amino acid sequence selected from the group consisting of:

SEQ ID NOS:1, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, and 360; and

an Ig variable light region having an amino acid sequence selected from the group consisting of:

SEQ ID NOS:111, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 216, 220, 224, 272, 276, 300, 292, 280, 288, 296, 284, 304, 308, 312, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, and 361.

15. The method according to claim 14 , wherein the binding protein comprises:

an Ig variable heavy region comprising the amino acid sequence of SEQ ID NO:156, and

an Ig variable light region comprising the amino acid sequence of SEQ ID NO:268.

16. The method of claim 15 , wherein the binding protein further comprises:

a heavy chain immunoglobulin constant domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:3, and

a light chain immunoglobulin constant domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:4 and SEQ ID NO:5.

17. The method according to claim 14 , wherein the binding protein comprises:

an Ig variable heavy region comprising the amino acid sequence of SEQ ID NO:360, and

an Ig variable light region comprising the amino acid sequence of SEQ ID NO:361.

18. The method of claim 17 , wherein the binding protein further comprises:

a heavy chain immunoglobulin constant domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:3, and

a light chain immunoglobulin constant domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:4 and SEQ ID NO:5.

19. The method according to claim 14 , wherein the binding protein comprises:

an Ig variable heavy region comprising the amino acid sequence of SEQ ID NO:156, and

an Ig variable light region comprising the amino acid sequence of SEQ ID NO:359.

20. The method of claim 19 , wherein the binding protein further comprises:

a heavy chain immunoglobulin constant domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:3, and

a light chain immunoglobulin constant domain comprising an amino acid sequence selected from the group consisting of SEQ ID:NO 4 and SEQ ID NO:5.

21. The method of claim 1 , 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.

22. The method of claim 21 , wherein the binding protein is capable of blocking DLL4 interaction with Notch-1 and Notch-4.

23. The method of claim 1 , wherein the binding protein is capable of modulating a biological function of DLL4.

24. The method of claim 1 , wherein said binding protein is capable of neutralizing a DLL4.

25. The method of claim 1 , wherein said binding protein is capable of reducing angiogenesis.

26. The method of claim 1 , wherein said binding protein has a dissociation constant (KD) 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 −11 M; at most about 10- 12 M; and at most about 10 −13 M.

27. The method of claim 1 , wherein said binding protein has an on rate selected from the group consisting of: at least about 10 2 M −1 s −1 ; at least about 10 3 M −1 s- 1 ; at least about 10 4 M −1 s- 1 ; at least about 10 5 M −1 s −1 ; and at least about 10 6 M −1 s −1 .

28. The method of claim 1 , wherein said binding protein has an off rate selected from the group consisting of: at most about 10- 3 s- 1 ; at most about 10 −4 s −1 ; at most about 10 −5 s −1 ; and at most about 10 −6 s −1 .

29. The method of claim 1 , wherein said binding protein is administered as a binding protein construct, said binding protein construct being selected from the group consisting of:

an immunoglobulin molecule,

a monoclonal antibody,

a chimeric antibody,

a CDR-grafted antibody,

a humanized antibody,

a Fab,

a Fab′,

a F(ab′)2,

a Fv,

a disulfide linked Fv,

a scFv,

a single domain antibody,

a diabody,

a multispecific antibody,

a dual specific antibody,

a dual variable domain immunoglobulin (DVD-Ig) binding protein, and

a bispecific antibody.

30. The method of claim 1 , wherein said binding protein is administered as a binding protein construct, said binding protein construct being conjugated to a therapeutic or cytotoxic agent.

31. The method of claim 1 , wherein said binding protein is administered as a pharmaceutical composition, said pharmaceutical composition comprising the binding protein and a pharmaceutically acceptable carrier.

32. The method of claim 31 , wherein said pharmaceutical composition further comprises at least one additional therapeutic agent, said additional therapeutic agent selected from the group consisting of an antibody or fragment thereof capable of binding human VEGFR2; an antibody or fragment thereof capable of binding human VEGFR1, an antibody or fragment thereof capable of binding human VEGF; methotrexate; an antibody or fragment thereof capable of binding human TNF; angiogenesis inhibitors; kinase inhibitors; co-stimulation molecule blockers; adhesion molecule blockers; anti-cytokine antibody or functional fragment thereof; methotrexate; corticosteroids; cyclosporine; rapamycin; FK506; and non-steroidal anti-inflammatory agents.

33. The method of claim 1 , wherein the disease or 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, hemangiomas, melanomas, sarcomas, brain tumor, nerve cancer, eye tumor, meninges cancer, solid tumors from hematopoietic malignancies, tumor metastases, ocular neovascularization, edema, rheumatoid arthritis, multiple sclerosis, atheroscleorotic plaques, Crohn's disease, inflammatory bowel disease, refractory ascites, psoriasis, sarcoidosis, arterial arteriosclerosis, sepsis, peptic ulcers, burns, and pancreatitis, polycystic ovarian disease (POD), endometriosis, uterine fibroids, benign prostate hypertrophy, and other angiogenesis independent and dependent diseases characterized by abberant DLL4 activity.

34. The method according to claim 33 , wherein the disease or disorder is a primary cancer or a metastatic cancer.

35. The method according to claim 33 , wherein the urinary tract cancer is selected from the group consisting of renal cancer, bladder cancer, and urothelium cancer.

36. The method according to claim 33 , wherein the female genital tract cancer is selected from the group consisting of cervical cancer, uterine cancer, ovarian cancer, choriocarcinoma, and gestational trophoblastic disease.

37. The method according to claim 33 , wherein the male genital tract cancer is selected from the group consisting of prostate cancer, seminal vesicles cancer, testicular cancer, and germ cell tumor.

38. The method according to claim 33 , wherein the endocrine gland cancer is selected from the group consisting of thyroid cancer, adrenal cancer, and pituitary gland cancer.

39. The method according to claim 33 , wherein the sarcoma is selected from the group consisting of a bone sarcoma, a soft tissue sarcoma, and Kaposi's sarcoma.

40. The method according to claim 33 , 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 meningiomas.

41. The method according to claim 33 , 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 lymphoma.

42. The method according to claim 33 , wherein the ocular neovascularization is selected from the group consisting of diabetic blindness, a retinopathy, an age induced macular degeneration, and a rubeosis.

43. The method according to claim 33 , wherein the disease or disorder is a non-small cell lung cancer.

44. The method according to claim 43 , wherein the tumor size in the treated subject is at least 50% smaller than the tumor size in a control subject not treated with said binding protein.

45. A method of treating a subject having a disease or a disorder characterized by aberrant DLL4 expression or in which DLL4 is detrimental, said method comprising administering to said subject an effective amount of a binding protein in combination with at least one additional agent, said at least one additional agent selected from the group consisting of an antibody or fragment thereof capable of binding human VEGFR2; an antibody or fragment thereof capable of binding human VEGFR1, an antibody or fragment thereof capable of binding human VEGF; methotrexate; an antibody or fragment thereof capable of binding human TNF; corticosteroids; cyclosporine; rapamycin; FK506; and non-steroidal anti-inflammatory agents; wherein said binding protein comprises an antigen binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein:

CDR-H1 is selected from the group consisting of:

residues 31-37 of SEQ ID NO:1;

SEQ ID NO:117;

SEQ ID NO:121;

SEQ ID NO:125;

SEQ ID NO:129;

SEQ ID NO:133;

SEQ ID NO:137;

SEQ ID NO:141;

SEQ ID NO:145;

SEQ ID NO:149;

SEQ ID NO:153;

SEQ ID NO:157;

SEQ ID NO:161;

SEQ ID NO:165;

SEQ ID NO:169;

SEQ ID NO:173;

SEQ ID NO:177;

SEQ ID NO:181;

SEQ ID NO:185;

SEQ ID NO:189;

SEQ ID NO:193;

SEQ ID NO:197;

SEQ ID NO:201;

SEQ ID NO:205;

SEQ ID NO:209;

SEQ ID NO:213;

residues 31-37 of SEQ ID NO:334;

residues 31-37 of SEQ ID NO:336;

residues 31-37 of SEQ ID NO:338;

residues 31-37 of SEQ ID NO:340;

residues 31-37 of SEQ ID NO:342;

residues 31-37 of SEQ ID NO:344;

residues 31-37 of SEQ ID NO:346;

residues 31-37 of SEQ ID NO:348;

residues 31-37 of SEQ ID NO:350;

residues 31-37 of SEQ ID NO:352;

residues 31-37 of SEQ ID NO:354;

residues 31-37 of SEQ ID NO:356;

residues 31-37 of SEQ ID NO:358; and

residues 31-37 of SEQ ID NO:360;

CDR-H2 is selected from the group consisting of:

residues 52-67 of SEQ ID NO:1;

SEQ ID NO:118;

SEQ ID NO:122;

SEQ ID NO:126;

SEQ ID NO:130;

SEQ ID NO:134;

SEQ ID NO:138;

SEQ ID NO:142;

SEQ ID NO:146;

SEQ ID NO:150;

SEQ ID NO:154;

SEQ ID NO:158;

SEQ ID NO:162;

SEQ ID NO:166;

SEQ ID NO:170;

SEQ ID NO:174;

SEQ ID NO:178;

SEQ ID NO:182;

SEQ ID NO:186;

SEQ ID NO:190;

SEQ ID NO:194;

SEQ ID NO:198;

SEQ ID NO:202;

SEQ ID NO:206;

SEQ ID NO:210;

SEQ ID NO:214;

residues 52-67 of SEQ ID NO:334;

residues 52-67 of SEQ ID NO:336;

residues 52-67 of SEQ ID NO:338;

residues 52-67 of SEQ ID NO:340;

residues 52-67 of SEQ ID NO:342;

residues 52-67 of SEQ ID NO:344;

residues 52-67 of SEQ ID NO:346;

residues 52-67 of SEQ ID NO:348;

residues 52-67 of SEQ ID NO:350;

residues 52-67 of SEQ ID NO:352;

residues 52-67 of SEQ ID NO:354;

residues 52-67 of SEQ ID NO:356;

residues 52-67 of SEQ ID NO:358; and

residues 52-67 of SEQ ID NO:360;

CDR-H3 is selected from the group consisting of:

residues 100-110 of SEQ ID NO:1;

SEQ ID NO:119;

SEQ ID NO:123;

SEQ ID NO:127;

SEQ ID NO:131;

SEQ ID NO:135;

SEQ ID NO:139;

SEQ ID NO:143;

SEQ ID NO:147;

SEQ ID NO:151;

SEQ ID NO:155;

SEQ ID NO:159;

SEQ ID NO:163;

SEQ ID NO:167;

SEQ ID NO:171;

SEQ ID NO:175;

SEQ ID NO:179;

SEQ ID NO:183;

SEQ ID NO:187;

SEQ ID NO:191;

SEQ ID NO:195;

SEQ ID NO:199;

SEQ ID NO:203;

SEQ ID NO:207;

SEQ ID NO:211;

SEQ ID NO:215;

residues 100-110 of SEQ ID NO:334;

residues 100-110 of SEQ ID NO:336;

residues 100-110 of SEQ ID NO:338;

residues 100-110 of SEQ ID NO:340;

residues 100-110 of SEQ ID NO:342;

residues 100-110 of SEQ ID NO:344;

residues 100-110 of SEQ ID NO:346;

residues 100-110 of SEQ ID NO:348;

residues 100-110 of SEQ ID NO:350;

residues 100-110 of SEQ ID NO:352;

residues 100-110 of SEQ ID NO:354;

residues 100-110 of SEQ ID NO:356;

residues 100-110 of SEQ ID NO:358; and

residues 100-110 of SEQ ID NO:360;

CDR-L1 is selected from the group consisting of:

residues 23-33 of SEQ ID NO:111;

SEQ ID NO:217;

SEQ ID NO:221;

SEQ ID NO:225;

SEQ ID NO:229;

SEQ ID NO:233;

SEQ ID NO:237;

SEQ ID NO:241;

SEQ ID NO:245;

SEQ ID NO:249;

SEQ ID NO:253;

SEQ ID NO:257;

SEQ ID NO:261;

SEQ ID NO:265;

SEQ ID NO:269;

SEQ ID NO:273;

SEQ ID NO:277;

SEQ ID NO:281;

SEQ ID NO:285;

SEQ ID NO:289;

SEQ ID NO:293;

SEQ ID NO:297;

SEQ ID NO:301;

SEQ ID NO:305;

SEQ ID NO:309;

SEQ ID NO:313;

residues 23-33 of SEQ ID NO:335;

residues 23-33 of SEQ ID NO:337;

residues 23-33 of SEQ ID NO:339;

residues 23-33 of SEQ ID NO:341;

residues 23-33 of SEQ ID NO:343;

residues 24-34 of SEQ ID NO:345;

residues 23-33 of SEQ ID NO:347;

residues 24-34 of SEQ ID NO:349;

residues 24-34 of SEQ ID NO:351;

residues 24-34 of SEQ ID NO:353;

residues 24-34 of SEQ ID NO:355;

residues 23-33 of SEQ ID NO:357;

residues 23-33 of SEQ ID NO:359; and

residues 23-33 of SEQ ID NO:361;

CDR-L2 is selected from the group consisting of:

residues 49-55 of SEQ ID NO:111;

SEQ ID NO:230;

SEQ ID NO:234;

SEQ ID NO:238;

SEQ ID NO:242;

SEQ ID NO:246;

SEQ ID NO:250;

SEQ ID NO:254;

SEQ ID NO:258;

SEQ ID NO:262;

SEQ ID NO:266;

SEQ ID NO:270;

SEQ ID NO:218;

SEQ ID NO:222;

SEQ ID NO:226;

SEQ ID NO:274;

SEQ ID NO:278;

SEQ ID NO:302;

SEQ ID NO:294;

SEQ ID NO:282;

SEQ ID NO:290;

SEQ ID NO:298;

SEQ ID NO:286;

SEQ ID NO:306;

SEQ ID NO:310;

SEQ ID NO:314;

residues 49-55 of SEQ ID NO:335;

residues 49-55 of SEQ ID NO:337;

residues 49-55 of SEQ ID NO:339;

residues 49-55 of SEQ ID NO:341;

residues 49-55 of SEQ ID NO:343;

residues 50-56 of SEQ ID NO:345;

residues 49-55 of SEQ ID NO:347;

residues 50-56 of SEQ ID NO:349;

residues 50-56 of SEQ ID NO:351;

residues 50-56 of SEQ ID NO:353;

residues 50-56 of SEQ ID NO:355;

residues 49-55 of SEQ ID NO:357;

residues 49-55 of SEQ ID NO:359; and

residues 49-55 of SEQ ID NO:361;

and

CDR-L3 is selected from the group consisting of:

residues 88-96 of SEQ ID NO:111;

SEQ ID NO:231;

SEQ ID NO:235;

SEQ ID NO:239;

SEQ ID NO:243;

SEQ ID NO:247;

SEQ ID NO:251;

SEQ ID NO:255;

SEQ ID NO:259;

SEQ ID NO:263;

SEQ ID NO:267;

SEQ ID NO:271;

SEQ ID NO:219;

SEQ ID NO:223;

SEQ ID NO:227;

SEQ ID NO:275;

SEQ ID NO:279;

SEQ ID NO:303;

SEQ ID NO:295;

SEQ ID NO:283;

SEQ ID NO:291;

SEQ ID NO:299;

SEQ ID NO:287;

SEQ ID NO:307;

SEQ ID NO:311;

SEQ ID NO:315;

residues 88-96 of SEQ ID NO:335;

residues 88-96 of SEQ ID NO:337;

residues 88-96 of SEQ ID NO:339;

residues 88-96 of SEQ ID NO:341;

residues 88-96 of SEQ ID NO:343;

residues 89-97 of SEQ ID NO:345;

residues 88-96 of SEQ ID NO:347;

residues 89-97 of SEQ ID NO:349;

residues 89-97 of SEQ ID NO:351;

residues 89-97 of SEQ ID NO:353;

residues 89-97 of SEQ ID NO:355;

residues 88-96 of SEQ ID NO:357;

residues 88-96 of SEQ ID NO:359; and

residues 88-96 of SEQ ID NO:361.

46. A method for reducing human DLL4 activity in a subject, said method comprising administering to said subject an effective amount of a binding protein capable of binding human DLL4 such that human DLL4 activity in said subject is reduced, said binding protein comprising an antigen binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein:

CDR-H1 is selected from the group consisting of:

residues 31-37 of SEQ ID NO:1;

SEQ ID NO:117;

SEQ ID NO:121;

SEQ ID NO:125;

SEQ ID NO:129;

SEQ ID NO:133;

SEQ ID NO:137;

SEQ ID NO:141;

SEQ ID NO:145;

SEQ ID NO:149;

SEQ ID NO:153;

SEQ ID NO:157;

SEQ ID NO:161;

SEQ ID NO:165;

SEQ ID NO:169;

SEQ ID NO:173;

SEQ ID NO:177;

SEQ ID NO:181;

SEQ ID NO:185;

SEQ ID NO:189;

SEQ ID NO:193;

SEQ ID NO:197;

SEQ ID NO:201;

SEQ ID NO:205;

SEQ ID NO:209;

SEQ ID NO:213;

residues 31-37 of SEQ ID NO:334;

residues 31-37 of SEQ ID NO:336;

residues 31-37 of SEQ ID NO:338;

residues 31-37 of SEQ ID NO:340;

residues 31-37 of SEQ ID NO:342;

residues 31-37 of SEQ ID NO:344;

residues 31-37 of SEQ ID NO:346;

residues 31-37 of SEQ ID NO:348;

residues 31-37 of SEQ ID NO:350;

residues 31-37 of SEQ ID NO:352;

residues 31-37 of SEQ ID NO:354;

residues 31-37 of SEQ ID NO:356;

residues 31-37 of SEQ ID NO:358; and

residues 31-37 of SEQ ID NO:360;

CDR-H2 is selected from the group consisting of:

residues 52-67 of SEQ ID NO:1;

SEQ ID NO:118;

SEQ ID NO:122;

SEQ ID NO:126;

SEQ ID NO:130;

SEQ ID NO:134;

SEQ ID NO:138;

SEQ ID NO:142;

SEQ ID NO:146;

SEQ ID NO:150;

SEQ ID NO:154;

SEQ ID NO:158;

SEQ ID NO:162;

SEQ ID NO:166;

SEQ ID NO:170;

SEQ ID NO:174;

SEQ ID NO:178;

SEQ ID NO:182;

SEQ ID NO:186;

SEQ ID NO:190;

SEQ ID NO:194;

SEQ ID NO:198;

SEQ ID NO:202;

SEQ ID NO:206;

SEQ ID NO:210;

SEQ ID NO:214;

residues 52-67 of SEQ ID NO:334;

residues 52-67 of SEQ ID NO:336;

residues 52-67 of SEQ ID NO:338;

residues 52-67 of SEQ ID NO:340;

residues 52-67 of SEQ ID NO:342;

residues 52-67 of SEQ ID NO:344;

residues 52-67 of SEQ ID NO:346;

residues 52-67 of SEQ ID NO:348;

residues 52-67 of SEQ ID NO:350;

residues 52-67 of SEQ ID NO:352;

residues 52-67 of SEQ ID NO:354;

residues 52-67 of SEQ ID NO:356;

residues 52-67 of SEQ ID NO:358; and

residues 52-67 of SEQ ID NO:360;

CDR-H3 is selected from the group consisting of:

residues 100-110 of SEQ ID NO:1;

SEQ ID NO:119;

SEQ ID NO:123;

SEQ ID NO:127;

SEQ ID NO:131;

SEQ ID NO:135;

SEQ ID NO:139;

SEQ ID NO:143;

SEQ ID NO:147;

SEQ ID NO:151;

SEQ ID NO:155;

SEQ ID NO:159;

SEQ ID NO:163;

SEQ ID NO:167;

SEQ ID NO:171;

SEQ ID NO:175;

SEQ ID NO:179;

SEQ ID NO:183;

SEQ ID NO:187;

SEQ ID NO:191;

SEQ ID NO:195;

SEQ ID NO:199;

SEQ ID NO:203;

SEQ ID NO:207;

SEQ ID NO:211;

SEQ ID NO:215;

residues 100-110 of SEQ ID NO:334;

residues 100-110 of SEQ ID NO:336;

residues 100-110 of SEQ ID NO:338;

residues 100-110 of SEQ ID NO:340;

residues 100-110 of SEQ ID NO:342;

residues 100-110 of SEQ ID NO:344;

residues 100-110 of SEQ ID NO:346;

residues 100-110 of SEQ ID NO:348;

residues 100-110 of SEQ ID NO:350;

residues 100-110 of SEQ ID NO:352;

residues 100-110 of SEQ ID NO:354;

residues 100-110 of SEQ ID NO:356;

residues 100-110 of SEQ ID NO:358; and

residues 100-110 of SEQ ID NO:360;

CDR-L1 is selected from the group consisting of:

residues 23-33 of SEQ ID NO:111;

SEQ ID NO:217;

SEQ ID NO:221;

SEQ ID NO:225;

SEQ ID NO:229;

SEQ ID NO:233;

SEQ ID NO:237;

SEQ ID NO:241;

SEQ ID NO:245;

SEQ ID NO:249;

SEQ ID NO:253;

SEQ ID NO:257;

SEQ ID NO:261;

SEQ ID NO:265;

SEQ ID NO:269;

SEQ ID NO:273;

SEQ ID NO:277;

SEQ ID NO:281;

SEQ ID NO:285;

SEQ ID NO:289;

SEQ ID NO:293;

SEQ ID NO:297;

SEQ ID NO:301;

SEQ ID NO:305;

SEQ ID NO:309;

SEQ ID NO:313;

residues 23-33 of SEQ ID NO:335;

residues 23-33 of SEQ ID NO:337;

residues 23-33 of SEQ ID NO:339;

residues 23-33 of SEQ ID NO:341;

residues 23-33 of SEQ ID NO:343;

residues 24-34 of SEQ ID NO:345;

residues 23-33 of SEQ ID NO:347;

residues 24-34 of SEQ ID NO:349;

residues 24-34 of SEQ ID NO:351;

residues 24-34 of SEQ ID NO:353;

residues 24-34 of SEQ ID NO:355;

residues 23-33 of SEQ ID NO:357;

residues 23-33 of SEQ ID NO:359; and

residues 23-33 of SEQ ID NO:361;

CDR-L2 is selected from the group consisting of:

residues 49-55 of SEQ ID NO:111;

SEQ ID NO:230;

SEQ ID NO:234;

SEQ ID NO:238;

SEQ ID NO:242;

SEQ ID NO:246;

SEQ ID NO:250;

SEQ ID NO:254;

SEQ ID NO:258;

SEQ ID NO:262;

SEQ ID NO:266;

SEQ ID NO:270;

SEQ ID NO:218;

SEQ ID NO:222;

SEQ ID NO:226;

SEQ ID NO:274;

SEQ ID NO:278;

SEQ ID NO:302;

SEQ ID NO:294;

SEQ ID NO:282;

SEQ ID NO:290;

SEQ ID NO:298;

SEQ ID NO:286;

SEQ ID NO:306;

SEQ ID NO:310;

SEQ ID NO:314;

residues 49-55 of SEQ ID NO:335;

residues 49-55 of SEQ ID NO:337;

residues 49-55 of SEQ ID NO:339;

residues 49-55 of SEQ ID NO:341;

residues 49-55 of SEQ ID NO:343;

residues 50-56 of SEQ ID NO:345;

residues 49-55 of SEQ ID NO:347;

residues 50-56 of SEQ ID NO:349;

residues 50-56 of SEQ ID NO:351;

residues 50-56 of SEQ ID NO:353;

residues 50-56 of SEQ ID NO:355;

residues 49-55 of SEQ ID NO:357;

residues 49-55 of SEQ ID NO:359; and

residues 49-55 of SEQ ID NO:361;

and

CDR-L3 is selected from the group consisting of:

residues 88-96 of SEQ ID NO:111;

SEQ ID NO:231;

SEQ ID NO:235;

SEQ ID NO:239;

SEQ ID NO:243;

SEQ ID NO:247;

SEQ ID NO:251;

SEQ ID NO:255;

SEQ ID NO:259;

SEQ ID NO:263;

SEQ ID NO:267;

SEQ ID NO:271;

SEQ ID NO:219;

SEQ ID NO:223;

SEQ ID NO:227;

SEQ ID NO:275;

SEQ ID NO:279;

SEQ ID NO:303;

SEQ ID NO:295;

SEQ ID NO:283;

SEQ ID NO:291;

SEQ ID NO:299;

SEQ ID NO:287;

SEQ ID NO:307;

SEQ ID NO:311;

SEQ ID NO:315;

residues 88-96 of SEQ ID NO:335;

residues 88-96 of SEQ ID NO:337;

residues 88-96 of SEQ ID NO:339;

residues 88-96 of SEQ ID NO:341;

residues 88-96 of SEQ ID NO:343;

residues 89-97 of SEQ ID NO:345;

residues 88-96 of SEQ ID NO:347;

residues 89-97 of SEQ ID NO:349;

residues 89-97 of SEQ ID NO:351;

residues 89-97 of SEQ ID NO:353;

residues 89-97 of SEQ ID NO:355;

residues 88-96 of SEQ ID NO:357;

residues 88-96 of SEQ ID NO:359; and

residues 88-96 of SEQ ID NO:361.

Assignments (8)