Therapeutic DLL4 binding proteins

US 9,132,190 B2
Filed: 11/26/2013
Issued: 09/15/2015
Est. Priority Date: 08/29/2009
Status: Active Grant

First Claim

Patent Images

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;

andCDR-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.

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Abstract

Improved DLL4 binding proteins are described, including antibodies, CDR-grafted antibodies, human antibodies, and DLL4 binding fragments thereof, proteins that bind DLL4 with high affinity, and DLL4 binding proteins that neutralize DLL4 activity. The DLL4 binding proteins are useful for treating or preventing cancers and tumors and especially for treating or preventing tumor angiogenesis, and/or other angiogenesis-dependent diseases such as ocular neovascularization, or angiogenesis-independent diseases characterized by aberrant DLL4 expression or activity such as autoimmune disorders including multiple sclerosis.

151 Citations

46 Claims

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;
  
  andCDR-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.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)
- - 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 SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      1CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      1 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      1VL E9 CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      111CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      111 andCDR-L3;
      
      residues 88-96 of SEQ ID NO;
      
      111VH E9.4 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      117CDR-H2;
      
      SEQ ID NO;
      
      118 andCDR-H3;
      
      SEQ ID NO;
      
      119VL E9.4 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      229CDR-L2;
      
      SEQ ID NO;
      
      230 andCDR-L3;
      
      SEQ ID NO;
      
      231VH E9.11 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      121CDR-H2;
      
      SEQ ID NO;
      
      122 andCDR-H3;
      
      SEQ ID NO;
      
      123VL E9.11 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      233CDR-L2;
      
      SEQ ID NO;
      
      234 andCDR-L3;
      
      SEQ ID NO;
      
      235VH E9.14 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      125CDR-H2;
      
      SEQ ID NO;
      
      126 andCDR-H3;
      
      SEQ ID NO;
      
      127VL E9.14 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      237CDR-L2;
      
      SEQ ID NO;
      
      238 andCDR-L3;
      
      SEQ ID NO;
      
      239VH E9.17 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      129CDR-H2;
      
      SEQ ID NO;
      
      130 andCDR-H3;
      
      SEQ ID NO;
      
      131VL E9.17 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      241CDR-L2;
      
      SEQ ID NO;
      
      242 andCDR-L3;
      
      SEQ ID NO;
      
      243VH E9.18 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      133CDR-H2;
      
      SEQ ID NO;
      
      134 andCDR-H3;
      
      SEQ ID NO;
      
      135VL E9.18 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      245CDR-L2;
      
      SEQ ID NO;
      
      246 andCDR-L3;
      
      SEQ ID NO;
      
      247VH E9.19 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      137CDR-H2;
      
      SEQ ID NO;
      
      138 andCDR-H3;
      
      SEQ ID NO;
      
      139VL E9.19 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      249CDR-L2;
      
      SEQ ID NO;
      
      250 andCDR-L3;
      
      SEQ ID NO;
      
      251VH E9.22 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      141CDR-H2;
      
      SEQ ID NO;
      
      142 andCDR-H3;
      
      SEQ ID NO;
      
      143VL E9.22 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      253CDR-L2;
      
      SEQ ID NO;
      
      254 andCDR-L3;
      
      SEQ ID NO;
      
      255VH E9.48 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      145CDR-H2;
      
      SEQ ID NO;
      
      146 andCDR-H3;
      
      SEQ ID NO;
      
      147VL E9.48 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      257CDR-L2;
      
      SEQ ID NO;
      
      258 andCDR-L3;
      
      SEQ ID NO;
      
      259VH E9.65 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      149CDR-H2;
      
      SEQ ID NO;
      
      150 andCDR-H3;
      
      SEQ ID NO;
      
      151VL E9.65 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      261CDR-L2;
      
      SEQ ID NO;
      
      262 andCDR-L3;
      
      SEQ ID NO;
      
      263VH E9.66 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      153CDR-H2;
      
      SEQ ID NO;
      
      154 andCDR-H3;
      
      SEQ ID NO;
      
      155VL E9.66 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      265CDR-L2;
      
      SEQ ID NO;
      
      266 andCDR-L3;
      
      SEQ ID NO;
      
      267VH E9.71 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      157CDR-H2;
      
      SEQ ID NO;
      
      158 andCDR-H3;
      
      SEQ ID NO;
      
      159VL E9.71 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      269CDR-L2;
      
      SEQ ID NO;
      
      270 andCDR-L3;
      
      SEQ ID NO;
      
      271VH E9.13 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      161CDR-H2;
      
      SEQ ID NO;
      
      162 andCDR-H3;
      
      SEQ ID NO;
      
      163VL E9.13 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      217CDR-L2;
      
      SEQ ID NO;
      
      218 andCDR-L3;
      
      SEQ ID NO;
      
      219VH E9.16 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      165CDR-H2;
      
      SEQ ID NO;
      
      166 andCDR-H3;
      
      SEQ ID NO;
      
      167VL E9.16 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      221CDR-L2;
      
      SEQ ID NO;
      
      222 andCDR-L3;
      
      SEQ ID NO;
      
      223VH E9.38 CDR SetCDR-H1;
      
      SEQ ID NO;
      
      169CDR-H2;
      
      SEQ ID NO;
      
      170 andCDR-H3;
      
      SEQ ID NO;
      
      171VL E9.38 CDR SetCDR-L1;
      
      SEQ ID NO;
      
      225CDR-L2;
      
      SEQ ID NO;
      
      226 andCDR-L3;
      
      SEQ ID NO;
      
      227VH E9.2B CDR SetCDR-H1;
      
      SEQ ID NO;
      
      173CDR-H2;
      
      SEQ ID NO;
      
      174 andCDR-H3;
      
      SEQ ID NO;
      
      175VL E9.2B CDR SetCDR-L1;
      
      SEQ ID NO;
      
      273CDR-L2;
      
      SEQ ID NO;
      
      274 andCDR-L3;
      
      SEQ ID NO;
      
      275VH E9.1F CDR SetCDR-H1;
      
      SEQ ID NO;
      
      177CDR-H2;
      
      SEQ ID NO;
      
      178 andCDR-H3;
      
      SEQ ID NO;
      
      179VL E9.1F CDR SetCDR-L1;
      
      SEQ ID NO;
      
      277CDR-L2;
      
      SEQ ID NO;
      
      278 andCDR-L3;
      
      SEQ ID NO;
      
      279VH E9.10H CDR SetCDR-H1;
      
      SEQ ID NO;
      
      181CDR-H2;
      
      SEQ ID NO;
      
      182 andCDR-H3;
      
      SEQ ID NO;
      
      183VL E9.10H CDR SetCDR-L1;
      
      SEQ ID NO;
      
      301CDR-L2;
      
      SEQ ID NO;
      
      302 andCDR-L3;
      
      SEQ ID NO;
      
      303VH E9.5E CDR SetCDR-H1;
      
      SEQ ID NO;
      
      185CDR-H2;
      
      SEQ ID NO;
      
      186 andCDR-H3;
      
      SEQ ID NO;
      
      187VL E9.5E CDR SetCDR-L1;
      
      SEQ ID NO;
      
      293CDR-L2;
      
      SEQ ID NO;
      
      294 andCDR-L3;
      
      SEQ ID NO;
      
      295VH E9.10C CDR SetCDR-H1;
      
      SEQ ID NO;
      
      189CDR-H2;
      
      SEQ ID NO;
      
      190 andCDR-H3;
      
      SEQ ID NO;
      
      191VL E9.10C CDR SetCDR-L1;
      
      SEQ ID NO;
      
      281CDR-L2;
      
      SEQ ID NO;
      
      282 andCDR-L3;
      
      SEQ ID NO;
      
      283VH E9.7E CDR SetCDR-H1;
      
      SEQ ID NO;
      
      193CDR-H2;
      
      SEQ ID NO;
      
      194 andCDR-H3;
      
      SEQ ID NO;
      
      195VL E9.7E CDR SetCDR-L1;
      
      SEQ ID NO;
      
      289CDR-L2;
      
      SEQ ID NO;
      
      290 andCDR-L3;
      
      SEQ ID NO;
      
      291VH E9.12B CDR SetCDR-H1;
      
      SEQ ID NO;
      
      197CDR-H2;
      
      SEQ ID NO;
      
      198 andCDR-H3;
      
      SEQ ID NO;
      
      199VL E9.12B CDR SetCDR-L1;
      
      SEQ ID NO;
      
      297CDR-L2;
      
      SEQ ID NO;
      
      298 andCDR-L3;
      
      SEQ ID NO;
      
      299VH E9.10E CDR SetCDR-H1;
      
      SEQ ID NO;
      
      201CDR-H2;
      
      SEQ ID NO;
      
      202 andCDR-H3;
      
      SEQ ID NO;
      
      203VL E9.10E CDR SetCDR-L1;
      
      SEQ ID NO;
      
      285CDR-L2;
      
      SEQ ID NO;
      
      286 andCDR-L3;
      
      SEQ ID NO;
      
      287VH E9.6A CDR SetCDR-H1;
      
      SEQ ID NO;
      
      205CDR-H2;
      
      SEQ ID NO;
      
      206 andCDR-H3;
      
      SEQ ID NO;
      
      207VL E9.6A CDR SetCDR-L1;
      
      SEQ ID NO;
      
      305CDR-L2;
      
      SEQ ID NO;
      
      306 andCDR-L3;
      
      SEQ ID NO;
      
      307VH E9.7A CDR SetCDR-H1;
      
      SEQ ID NO;
      
      209CDR-H2;
      
      SEQ ID NO;
      
      210 andCDR-H3;
      
      SEQ ID NO;
      
      211VL E9.7 A CDR SetCDR-L1;
      
      SEQ ID NO;
      
      309CDR-L2;
      
      SEQ ID NO;
      
      310 andCDR-L3;
      
      SEQ ID NO;
      
      311VH E9.8H CDR SetCDR-H1;
      
      SEQ ID NO;
      
      213CDR-H2;
      
      SEQ ID NO;
      
      214 andCDR-H3;
      
      SEQ ID NO;
      
      215VL E9.8H CDR SetCDR-L1;
      
      SEQ ID NO;
      
      313CDR-L2;
      
      SEQ ID NO;
      
      314 andCDR-L3;
      
      SEQ ID NO;
      
      315VH E9.1 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      334CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      334 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      334VL E9.1 CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      335CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      335 andCDR-L3;
      
      residues 88-96 of SEQ ID NO;
      
      335VH E9-SE1 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      336CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      336 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      336VL E9-SE1 CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      337CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      337 andCDR-L3;
      
      residues 88-96 of SEQ ID NO;
      
      337VH E9-SE2 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      338CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      338 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      338VL E9-SE2 CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      339CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      339 andCDR-L3;
      
      residues 88-96 of SEQ ID NO;
      
      339VH E9-SE3 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      340CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      340 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      340VL E9-SE3 CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      341CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      341 andCDR-L3;
      
      residues 88-96 of SEQ ID NO;
      
      341VH E9-SE4 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      342CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      342 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      342VL E9-SE4 CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      343CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      343 andCDR-L3;
      
      residues 88-96 of SEQ ID NO;
      
      343VH E9-SE5 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      344CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      344 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      344VL E9-SE5 CDR SetCDR-L1;
      
      residues 24-34 of SEQ ID NO;
      
      345CDR-L2;
      
      residues 50-56 of SEQ ID NO;
      
      345 andCDR-L3;
      
      residues 89-97 of SEQ ID NO;
      
      345VH E9-SE6 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      346CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      346 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      346VL E9-SE6 CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      347CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      347 andCDR-L3;
      
      residues 88-96 of SEQ ID NO;
      
      347VH E9-SE7 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      348CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      348 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      348VL E9-SE7 CDR SetCDR-L1;
      
      residues 24-34 of SEQ ID NO;
      
      349CDR-L2;
      
      residues 50-56 of SEQ ID NO;
      
      349 andCDR-L3;
      
      residues 89-97 of SEQ ID NO;
      
      349VH E9-SE8 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      350CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      350 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      350VL E9-SE8 CDR SetCDR-L1;
      
      residues 24-34 of SEQ ID NO;
      
      351CDR-L2;
      
      residues 50-56 of SEQ ID NO;
      
      351 andCDR-L3;
      
      residues 89-97 of SEQ ID NO;
      
      351VH E9-FR1 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      352CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      352 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      352VL E9-FR1 CDR SetCDR-L1;
      
      residues 24-34 of SEQ ID NO;
      
      353CDR-L2;
      
      residues 50-56 of SEQ ID NO;
      
      353 andCDR-L3;
      
      residues 89-97 of SEQ ID NO;
      
      353VH E9-FR2 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      354CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      354 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      354VL E9-FR2 CDR SetCDR-L1;
      
      residues 24-34 of SEQ ID NO;
      
      355CDR-L2;
      
      residues 50-56 of SEQ ID NO;
      
      355 andCDR-L3;
      
      residues 89-97 of SEQ ID NO;
      
      355VH E9.71 CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      356CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      356 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      356VL E9.71 CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      357CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      357 andCDR-L3;
      
      residues 88-96 of SEQ ID NO;
      
      357VH E9.71(M) CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      358CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      358 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      358VL E9.71(M) CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      359CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      359 andCDR-L3;
      
      residues 88-96 of SEQ ID NO;
      
      359VH E9.71(L) CDR SetCDR-H1;
      
      residues 31-37 of SEQ ID NO;
      
      360CDR-H2;
      
      residues 52-67 of SEQ ID NO;
      
      360 andCDR-H3;
      
      residues 100-110 of SEQ ID NO;
      
      360andVL E9.71(L) CDR SetCDR-L1;
      
      residues 23-33 of SEQ ID NO;
      
      361CDR-L2;
      
      residues 49-55 of SEQ ID NO;
      
      361 andCDR-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, andVH 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 DLL4a 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, andan 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, anda 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, andan 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, anda 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, andan 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, anda 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^−
      
      7M;
      
      at most about 10^−
      
      8M;
      
      at most about 10^−
      
      9M;
      
      at most about 10^−
      
      10M;
      
      at most about 10^−
      
      11M;
      
      at most about 10-¹²M; and
      
      at most about 10^−
      
      13M.
  - 27. The method of claim 1, wherein said binding protein has an on rate selected from the group consisting of:
    - at least about 10²M^−
      
      1s^−
      
      1;
      
      at least about 10³M^−
      
      1s-¹;
      
      at least about 10⁴M^−
      
      1s-¹;
      
      at least about 10⁵M^−
      
      1s^−
      
      1; and
      
      at least about 10⁶M^−
      
      1s^−
      
      1.
  - 28. The method of claim 1, wherein said binding protein has an off rate selected from the group consisting of:
    - at most about 10-³s-¹;
      
      at most about 10^−
      
      4s^−
      
      1;
      
      at most about 10^−
      
      5s^−
      
      1; and
      
      at most about 10^−
      
      6s^−
      
      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, anda 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;
  
  andCDR-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;
  
  andCDR-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.

Specification

Resources

Litigation Campaign Assessment

Current Assignee
Alvaria Cayman
Original Assignee
Abbvie Incorporated
Inventors
Benatuil, Lorenzo, Boghaert, Erwin R., Gu, Jijie, Harris, Maria, Hickson, Jonathan A., Hsieh, Chung-Ming, Kutskova, Yuliya, Li, Yingchun, Liu, Zhihong, Morgan-Lappe, Susan
Primary Examiner(s)
Goddard, Laura B
Assistant Examiner(s)
Natarajan, Meera

Application Number

US14/090,778
Publication Number

US 20140093521A1
Time in Patent Office

658 Days
Field of Search

None
US Class Current

1/1
CPC Class Codes

A61K 2039/505   comprising antibodies

A61K 39/3955   against proteinaceous mater...

A61K 45/06   Mixtures of active ingredie...

A61P 1/04   for ulcers, gastritis or re...

A61P 1/16   for liver or gallbladder di...

A61P 1/18   for pancreatic disorders, e...

A61P 11/00   Drugs for disorders of the ...

A61P 11/04   for throat disorders

A61P 13/02   of urine or of the urinary ...

A61P 13/08   of the prostate

A61P 13/10   of the bladder

A61P 13/12   of the kidneys

A61P 15/00   Drugs for genital or sexual...

A61P 17/00   Drugs for dermatological di...

A61P 17/02   for treating wounds, ulcers...

A61P 17/06   Antipsoriatics

A61P 19/02   for joint disorders, e.g. a...

A61P 21/00   Drugs for disorders of the ...

A61P 25/00   Drugs for disorders of the ...

A61P 27/02   Ophthalmic agents

A61P 29/00 : Non-central analgesic, anti...

A61P 31/04 : Antibacterial agents

A61P 35/00 : Antineoplastic agents

A61P 35/02 : specific for leukemia

A61P 35/04 : specific for metastasis

A61P 43/00 : Drugs for specific purposes...

A61P 5/00 : Drugs for disorders of the ...

A61P 7/10 : Antioedematous agents; Diur...

A61P 9/00 : Drugs for disorders of the ...

A61P 9/10 : for treating ischaemic or a...

A61P 9/14 : Vasoprotectives; Antihaemor...

C07K 14/47 : from mammals

C07K 16/18 : against material from anima...

C07K 16/22 : against growth factors ; ag...

C07K 2317/21 : from primates, e.g. man

C07K 2317/33 : Crossreactivity, e.g. for s...

C07K 2317/565 : Complementarity determining...

C07K 2317/567 : Framework region [FR]

C07K 2317/73 : Inducing cell death, e.g. a...

C07K 2317/76 : Antagonist effect on antige...

C07K 2317/92 : Affinity (KD), association ...

C07K 2317/94 : Stability, e.g. half-life, ...

C07K 7/06 : having 5 to 11 amino acids

C07K 7/08 : having 12 to 20 amino acids...

View All

Therapeutic DLL4 binding proteins

First Claim

7 Assignments

0 Petitions

Accused Products

Abstract

151 Citations

46 Claims

Specification

Solutions

Use Cases

Quick Links

Therapeutic DLL4 binding proteins

First Claim

7 Assignments

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

Subscription Required

Abstract

151 Citations

46 Claims

Specification

Subscription Required

Solutions

Use Cases

Quick Links