MA35449B1

Binding molecules for bcma and cd3

Abstract

The present invention relates to a binding molecule which is at least bi-specific, comprising a first and a second binding domain, the first binding domain is capable of binding to a Group 3 BCMA epitope and the second binding domain is capable of binding to t lymphocytes CD3 receptor. In addition, the invention relates to a nucleic acid sequence encoding the binding molecule, a vector comprising said nucleic acid sequence and a host cell transformed or transfected with said vector. In addition, the invention relates to a method for producing the binding molecule of the invention, a medical use of said linker molecule and a kit comprising said binding molecule.

MA35449B1, drawing sheet 1 — Sheet 1 of 109

Term

No projected expiry on record.

1 claim: 1 independent, 0 dependent

1
MA 35449Β1 عناصر الحماية ا-جزيء ربط التي هي على الاش ثنائي التحديد يضم نطاق ربط ثاني واول، حيث ان 113 MA 35449Β1 (3)ذطاق ربط ارل قاذر على ربط كتلة الابيتوب 3 من BCMA (CQLRCSSNTPP(TCQRYC) و (ئ)ذطاق ربط ثاني قادر على ربط خليط مستقبل T خلية CD3 و حيث ان كتلة الابيتوب 3 من BCMA تقاربات الى بقايا حمض الامينو 24 الى 41 ، التسلسل كما صور في التسلسل المعرف رقم:1002 . 2- جزيء الربط وفقأ لعنصر الحماية 1، حيث ان نطاق الربط الاول قادر على ربهل ١لابيتوب 3 هن ٠كاك CCRCSSTPPYCQRYC) BCMA). 3- جزيء الربط وفقأ لعنصر الحماية 1 او 2 ، حيث ان نطاق الربط الثاني قادر على رلآ ابسيلون CD3 4- جزيء الربط وفقأ لاي واحد من عناصر الحماية السابقة، حيث ان نطاق ربحد الثاني ^در على ربط بشر. CD3 ومكاك CD3. ج-جزيء الربط وفقأ لاي واحد من عناصر الحماية العايقة - حيث ان نطتق ر. بط الثاني و ااو. الاول مشتق من الجسم المضاد. ح- جزيء الربط وفقأ لعنصر الحماية ج، التي اخنتيرت ، مجموعه تتكون ، 2(SCFv) ء (طاق مفرد scFv ، 2 (mAb نطاق مفرد mAb ، ديابودي و اليجومرات منها. 7- جزيء الربط وفقأ لاي واحد من عناصر الحماية العابقة، حيث ان نطاق ربط الاول يضم منطقة VH تضم CDR-H1, CDR-H2 و CDR-H3 و منطقة VL ت،ضم ,CDR-L1 CDRL2 و CDRL3 مختارة من مجموعة تتكون من : كط صور في CDR-H2 ا1 :SEQ ID NO ى ر ني 1) CDR-H1) -SEQ ID NO: 3, CDR كها صور ني SEQ ID NO: 2, CDR-H3 SEQ ID ى ص في SEQ ID NO: 4, CDRL2 كماصور فى اا :ج :SEQ ID NO ئ ص ني 3-CDR-L و ج :NO كماصورفي SEQ ID NO: 11, CDR-H2 ٤ما صور في 2) CDR-H1) ,13 :SEQ ID NO ك٠ا صور في SEQ ID NO: 12, CDR-H3 كها صور في SEQ ID NO: 14, CDR-L2 ى ص في CDR-E1 ;16 :SEQ ID NO كها صور في 13-CDR و 15 :SEQ ID NO كط صور في SEQ ID NO: 21, CDR-H2 ك٠ا دور في 3) CDR-H1) ,23 :SEQ ID NO كها صور في SEQ ID NO: 22, CDR-H3 114 IK 35449Β1 CDR-L1 كما صور ني SEQ ID NO: 24, CDRL2 كما صور في SEQ ID NO: 25 و CDR-13 كعا صور في SEQ ID NO: 26: (4) CDR-H1 ى ص في SEQ ID NO: 31, CDR-H2 كمأ صول في SEQ ID NO: 32, CDR-H3 كها صور في SEQ ID NO: 33, CDRLI ش١ ص في SEQ ID NO: 34, CDRL2 كم١ صول في SEQ ID NO: 35 و CDRL3 ى دور في SEQ ID NO: 36;(5) CDR-H1 كما صوز في SEQ ID NO: 41, CDR-H2 كها صور في SEQ ID NO: 42, CDR-H3 كما صور في SEQ ID NO: 43, CDRLI ى ص في SEQ ID NO: 44, CDRL2 كها صول في SEQ ID NO: 45 و CDRL3 كها صور في SEQ ID NO: 46;(6) CDR-H1 ى ص في SEQ ID NO: 51, CDR-H2 كهاصورفي SEQ ID NO: 52, CDR-H3 كها ص في SEQ ID NO: 53, CDR-L1 ى ص في SEQ ID NO: 54, CDR-L2 كهاصول في SEQ ID NO: 55وCDRL3 ى ر ني SEQ ID NO: 56;(7) CDR-H1 كما صور في SEQ ID NO: 61, CDR-H2 كعاصورفي SEQ ID NO: 62, CDR-H3 كها صور ني SEQ ID NO: 63, CDR-11 ى س فى SEQ ID NO: 64, CDRL2 ى ص في SEQ ID NO: 65 و CDR-L3 كما صور قي SEQ ID NO: 66;(8) CDR-H1 كماصور في SEQ ID NO 71, CDR-H2 كمامرر في SEQ ID NO: 72, CDR-H3 كها صول ني SEQ ID NO: 73, CDR-E1 كما صور فى SEQ ID NO: 74, CDR-E2 كعا صور في SEQ ID NO: 75 و CDR-L3 كها صور قي SEQ ID NO: 76;(9) CDR-H1 ى م۶ر في SEQ ID NO: 161, CDR-H2 ى ص في SEQ ID NO: 162, CDR-H3 كها صور في SEQ ID NO: 163, CDR-11 ى ص في SEQ ID NO: 164, CDRL2 كهاصورفي SEQ ID NO: 165 و CDR-13 س۶ر فى SEQ ID NO: 166;115 UK 35449Β1 (10) CDR-ΗΙ كعاصورفي SEQ ID NO: 171. CDR-H2 كما صور في SEQ ID NO: 172, CDR-H3 كما صور في SEQ ID NO: 173, CDR-11 ٤ما صور في SEQ ID NO: 174, CDR-L2 ٤ما صور في SEQ ID NO: 175 و CDR-L3 كما مو-ر في SEQ ID NO: 176;(11 ) CDR-ΗΙ كما صور في SEQ ID NO: 181, CDR-H2 كما صور في SEQ ID NO: 182, CDR-H3 كما صور في SEQ ID NO: 183, CDR-ΕΙ ى ص في SEQ ID NO: 184, CDRL2 كماصولفي SEQ ID NO: 185 jCDR-L.3 كما صور في SEQ ID NO: 186;(12) CDR-H1 كماصورفي SEQ ID NO: 191, CDR-H2 سدش SEQ ID NO: 192, CDR-H3 ى ص في SEQ ID NO: 193, CDR-L1 ى ص في SEQ ID NO: 194, CDR-L2 رفي^ SEQ ID NO: 195 .و CDR-13 كما صور في SEQ ID NO: 196;(13) CDR-H1 كما صور ني SEQ ID NO: 201, CDR-H2 كما صور في SEQ ID NO: 202, CDR-H3 كها صول ني SEQ ID NO: 203, CDR-11 ى ص في SEQ ID NO: 204, CDR-L2 كهاصورفي SEQ ID NO: 205 و CDR-E3 ى ص في SEQ ID NO: 206;(14) CDR-H1 ى س في SEQ ID NO: 211, CDR-H2 كهاصورفي SEQ ID NO: 212, CDR-H3 ص صول في SEQ ID NO: 213, CDR-11 ى ص في SEQ ID ΝΟ:214 , CDR-L2 كهاصورفي SEQ ID NO: 215 و CDR-L3 ى ص فى SEQ ID NO: 216;(15) CDR-H1 ى ص في SEQ ID NO: 221, CDR-H2 كهاصوزفي SEQ ID NO: 222, CDR-H3 كها ددر ص SEQ ID NO: 223, CDR-E1 كها س ني SEQ ID NO: 224, CDR-L2 كهاصورفي SEQ ID NO: 225 و CDR-13 ى ص في SEQ ID NO: 226;(16) CDR-H1 ى ص ني SEQ ID NO: 311, CDR-H2 كما صور في SEQ ID NO: 312, CDR-H3 كها س في SEQ ID NO: 313, /-// 116 1 35449Β1 CDR-L1 كها صور في SEQ ID NO: 314, CDR-E2 كماصورفي SEQ ID NO: 315 و CDR-L.3 كها صرر في SEQ ID NO: 315;(17) CDR-H1 ى صور في SEQ ID NO: 321, CDR-H2 كما صور في SEQ ID NO: 322, CDR-H3 كها صور في SEQ ID NO: 323, CDR-11 ى س في SEQ ID NO: 324, CDRL2 ىصرمب٤ SEQ ID NO: 325 و CDR-13 كها صور ض SEQ ID NO: 326: (18) CDR-H1 كط صور فى SEQ ID NO: 331, CDR-H2 كما صور في SEQ ID NO: 332, CDR-H3 ى ص في SEQ ID NO: 333, CDRLI ى ص في SEQ ID NO: 334, CDRL2 كهاسفي SEQ ID NO: 335 و CDR-13 كما صول في SEQ ID NO: 336;(19) CDR-H1 كما صور في SEQ ID NO: 341, CDR-H2 كما صور في SEQ ID NO: 342, CDR-H3 كها ر في SEQ ID NO: 343, CDR-L1 كعاصورفي SEQ ID NO: 344, CDR-E2 كما صور في SEQ ID NO: 345 و CDR-L3 ى ر ني SEQ ID NO: 346;(20) CDR-H1 كما صور في SEQ ID NO: 351, CDR-H2 كما صور في SEQ ID NO: 352, CDR-H3 كما صور في SEQ ID NO: 353, CDR-L1 كعا صور ني SEQ ID NO: 354, CDR-E2 كما صور فى SEQ ID NO: 355 و CDR-E3 كهاصورفي SEQ ID NO: 356;(21) CDR-H1 كما صور في SEQ ID NO: 361, CDR-H2 كماصورفي SEQ ID NO: 362, CDR-H3 كا صور ني SEQ ID NO: 363, CDR-L1 ى ص في SEQ ID NO: 364, CDRL2 ى ص في SEQ ID NO: 365 و CDR-L3 كا هيرر في SEQ ID NO: 366;(22) CDR-H1 سور في SEQ ID NO: 371CDR-H2 ك٠اصورلي SEQ ID NO: 372, CDR-H3 كها صول.ل فى SEQ ID NO: 373, CDR-E1 كما صور في SEQ ID NO: 374, CDR-12 كما صور في SEQ ID NO: 375 و CDR-13 ى ص فى SEQ ID NO: 376;117 IK 35449Β1 (23) CDR-H1 ى صور ني SEQ ID NO: 381, CDR-H2 سدفى SEQ ID NO: 382, CDR-H3 كها صور في SEQ ID NO: 383, CDRL ئ ص فى SEQ ID NO: 384, CDR-L2 كم١ صول فى SEQ ID NO: 385 و CDR-E3 ى س فى SEQ ID NO: 386;(24) CDR-H1 كما صور في SEQ ID NIO: 581, CDR-H2 كما صور في SEQ ID NO: 582, CDR-H3 كها صول في SEQ ID NO: 583, CDR-L1 كما هبرر فى SEQ ID NO: 584, CDR-L2 سذ في SEQ ID NO: 585 و CDR-L3 ى مور فى SEQ ID NO: 586;(25) CDR-H1 ٤طسفي SEQ ID NO: 591, CDR-H2 كاصورفى SEQ ID NO: 592, CDR-H3 كهاسش SEQ ID NO: 593, CDR-11 ى ص فى SEQ ID NO: 594, CDR-L2 كهاصور فى SEQ ID NO: 595 .و CDR-13 كها صور فى SEQ ID NO: 596;(26) CDR-H1 كما صور في SEQ ID NO: 601, CDR-H2 كما صور في SEQ ID NO: 602, CDR-H3 كها صور فى SEQ ID NO: 603, CDR-E1 ى ص في SEQ ID NO: 604, CDRL2 كهاصورفى SEQ ID NO: 605 و CDR-L3 ى في SEQ ID NO: 606;(27) CDR-H1 كها ص في SEQ ID NO: 611, CDR-H2 كمأصورفي SEQ ID NO: 612, CDR-H3 ش١ ص فى SEQ ID NO: 613, CDR-11 كعا صور في SEQ ID NO: 614, CDR-L2 كما صور في SEQ ID NO: 615 و CDR-L3 ى صور فى SEQ ID NO: 616;(28) CDR-H1 ى ص فى SEQ ID NO: 621, CDR-H2 كماصورفى SEQ ID NO: 622, CDR-H3 ى س في SEQ ID NO: 623, CDR-11 كما صور فى SEQ ID NO: 624, CDR-12 كما صور في SEQ ID NO: 625 و CDR-E3 ى ص فى SEQ ID NO: 626;(29) CDR-H1 كه-ا ص فى SEQ ID NO: 631, CDR-H2 كما صور فى SEQ ID NO: 632, CDR-H3 ى س في SEQ ID NO: 633, 118 i/J/f 1 35449Β1 CDR-L1 ى ۵برر فى SEQ ID NO: 634) CDR-L2 كمأصورفى SEQ ID NO: 635 و CDR-I3 كفا صور في SEQ ID NO: 636: (30) CDR-ΗΙ كما صور في SEQ ID NO: 641, CDR-H2 كما صور في SEQ ID NO: 642ا CDR-H3 كها هبرر فى SEQ ID NO: 643ا CDR-L1 كما صوز فى SEQ ID NO: 644, CDR-L2 كعاصورفي SEQ ID NO: 645 و CDR-13 كها صول فى SEQ ID NO: 646;(31) CDR-H1 ى ص في SEQ ID NO: ا51ج CDR-H2 كهاصورفى SEQ ID NO: 652, CDR-H3 ى ر في SEQ ID NO: 653, CDRLI ى ص في SEQ ID NO: 654, CDRL2 ى ص في SEQ ID NO: 655 CDRL3 ى صو.ر فى SEQ ID NO: 656;(32) CDR-H1 ى ص في SEQ ID NO: 661, CDR-H2 SEQ ID NO: 662, CDR-H3 كهاصورلي SEQ ID NO: 663, CDR-L1 ى ص في SEQ ID NO: 664, CDRL2 كماصوزفي SEQ ID NO: 665 و CDR-13 كهاصورفى SEQ ID NO: 666;(33) CDR-H1 ى ص في SEQ ID NO: 671, CDR-H2 كعاصورفي SEQ ID NO: 672, CDR-H3 كماً صوز فى SEQ ID NO: 673, CDRLI ى ص فى SEQ ID NO: 674, CDRL2 كماصولفي SEQ ID NO: 675 و CDR-13 ى مبرر في SEQ ID NO: 676;(34) CDR-H1 ى ص فى SEQ ID NO: 681, CDR-H2 كماهبررفي SEQ ID NO: 682, CDR-H3 ى س فى SEQ ID NO: 683, CDRLI ى ص في SEQ ID NO: 684, CDR-L2 كهاصورش SEQ ID NO: 685 و CDR-13 ىهررفي SEQ ID NO: 686;(35) CDR-H1 ى ددور فى SEQ ID NO: 691, CDR-H2 كعاصورش SEQ ID NO: 692, CDR-H3 كما مور في SEQ ID NO: 693, CDRLI ى ص فى SEQ ID NO: 694, CDR-L2 ى مبرر في SEQ ID NO: 695 و CDR-13 ى ر في SEQ ID NO: 696;119 MA 35449Β1 (36) CDR-H1 كم١ صور. ني SEQ ID NO: 701, CDR-H2 كمأصورش SEQ ID NO: 702, CDR-H3 كها مدور ني SEQ ID NO: 703, CDRLI كما صور في SEQ ID NO: 704, CDR-12 كما صور فى SEQ ID NO: 705 .و CDR-13 ش١سفي SEQ ID NO: 706؛ (37) CDR-H1 كعاصرفي SEQ ID NO: 711, CDR-H2 كهاصورني SEQ ID NO: 712, CDR-H3 كها هرر فى SEQ ID NO: 713, CDR-11 ئ س في SEQ ID NO: 714, CDR-L2 كها صول في SEQ ID NO: 715 و CDR-13 ى ^ر في SEQ ID NO: 716: (38) CDR-H1 ى صور في SEQ ID NO: 721, CDR-H2 كما صور في SEQ ID NO: 722, CDR-H3 ى ص فى SEQ ID NO: 723, CDRLI ى ص في SEQ ID NO: 724, CDRL2 كمأصورفي SEQ ID NO: 725CDRL3 ى ر في SEQ ID NO: 726;(39) CDR-H1 ٤ما ر فى SEQ ID NO: 731, CDR-H2 رفي^ SEQ ID NO: 732, CDR-H3 كها صو.ر في SEQ ID NO: 733, CDR-L1 ئ هور فى SEQ ID NO: 734, CDRL2 كهاصورفى SEQ ID NO: 735 و CDR-L3 كها مور ص SEQ ID NO: 736;(40) CDR-H1 كهاصورفي SEQ ID NO: 741, CDR-H2 صور فى SEQ ID NO: 742, CDR-H3 ك۵ا صور في SEQ ID NO: 743, CDRLI كما صور في SEQ ID NO: 744, CDR-L2 كما صور في SEQ ID NO: 745 و CDR-13 كها صو.ر فى SEQ ID NO: 746;(41) CDR-H1 كهاصور نيSEQ ID NO: 751, CDR-H2 كماصورفي SEQ ID NO: 752, CDR-H3 كها صور في SEQ ID NO: 753, CDR-11 ى س فى SEQ ID NO: 754, CDRL2 كما ر في SEQ ID NO: 755 و CDR-L3 ئ صور قى SEQ ID NO: 756;(42) CDR-H1 كا س في SEQ ID NO: 761, CDR-H2 كعاصورفي SEQ ID NO: 762, CDR-H3 كها صور فى SEQ ID NO: 763, 120 ½// MA 35449Β1 CDR-L1 ى ص في SEQ ID NO: 764, CDR-L2 كما۵بررقي SEQIDNO: 765 و CDR-L3 ص صور فى SEQ ID NO: 766;(43) CDR-Hكا ص في ٦ SEQ ID NO: 771, CDR-H2 كهاصورفي SEQ ID NO: 772, CDR-H3 كها صور في SEQ ID NO: 773) CDR-11 كما صور في SEQ ID NO: 774, CDRL2 كهاسفى SEQ ID NO: 775 و CDR-13 كعاصورفي SEQ ID NO: 776;(44) CDR-Hكماهورفي ٦ SEQ ID NO: 781, CDR-H2 كما صور في SEQ ID NO: 762, CDR-H3 كها صور ر SEQ ID NO: 783, CDR-L1 ى ص في SEQ ID NO: 784, CDRL2 كها ص ني SEQ ID NO: 785 و CDR-13 ى'صفي SEQ ID NO: 786;(45) CDR-H1 كعاصورفي SEQ ID NO: 791, CDR-H2 كعاصورفي SEQ ID NO: 792, CDR-H3 كها صور في SEQ ID NO: 793, CDR-L1 ى ص في SEQ ID NO: 794, CDRL2 كماصولش SEQ ID NO: 795 و CDR-L3 كئصور فى SEQ ID NQ: 796;(46) CDR-H1 ئ ص فى SEQ ID NO: 801, CDR-H2 كعاصور في SEQ ID NO: 802, CDR-H3 صور في li SEQ ID NO: 803, CDR-11 ى ر فى SEQ ID NO: 804, CDR-L2 ى صور في SEQ ID NO: 805 و CDR-E3 كما صور في SEQ ID NO: 806;(47) CDR-H1 كما صور في SEQ ID NO: 811, CDR-H2 كعاهررفى SEQ ID NO: 812, CDR-H3 كما صور في SEQ ID NO: 813, CDR-11 شا مبرر في SEQ ID NO: 814, CDR-L2 ى صور في SEQ ID NO: 815 و CDR-L3 ى ص فى SEQ ID NO: 816;(48) CDR-H1 كهامبرر فى SEQ ID NO: 821, CDR-H2 كعاصور فى SEQ ID NO: 822, CDR-H3 كما صوز في SEQ ID NO: 823, CDR-11 كعا صور فى SEQ ID NO: 824, CDR-L2 ش١سني SEQ ID NO: 825 و CDR-L3 كعا صو ر فى SEQ ID NO: 826;121 1 35449Β1 (49) CDR-H1 ى صور فى SEQ ID NO: 831, CDR-H2 كمأصورفى SEQ ID NO: 832, CDR-H3 كعاصورفي SEQ ID NO: 833, CDR-L1 شا صور في SEQ ID NO: 834, CDR-L2 في jf ك٠ا SEQ ID NO: 835 و CDR-I3 ٠عةىسفي ID NO: 836;(50) CDR-H1 كما صور ني SEQ ID NO: 961, CDR-H2 كما صور في SEQ ID NO: 962, CDR-H3 ى ص في SEQ ID NO: 963, CDR-L1 ى ر في SEQ ID NO: 964, CDR-L2 كها صول فى SEQ ID NO: 965 و CDR-L3 كماصورفى SEQ ID NO: 966;(51) CDR-H1 كها صور في SEQ ID NO: 971, CDR-H2 كعاصورش SEQ ID NO: 972, CDR-I-I3 كها صور ض SEQ ID NO: 973, CDR-11 ى ص في SEQ ID NO: 974, CDRL2 كهاصورفي SEQ ID NO: 975 و CDR-E3 0عجىسفي ID NO: 976;(52) CDR-H1 كاهرر فى SEQ ID NO: 981, CDR-H2 كمأصورفي SEQ ID NO: 982, CDR-H3 في Jr كها SEQ ID NO: 983, CDR-L1 ى ص في SEQ ID NO: 984, CDRL2 كهاصورفى SEQ ID NO: 985 و CDR-L3 ى في SEQ ID NO: 986;و (53) CDR-H1 SEQ ID NO: 991, CDR-H2 ى صور فى SEQ ID NO: 992, CDR-H3 ٤ما صور نى SEQ ID NO: 993, CDR-L1 ى ص في SEQ ID NO: 994, CDRL2 كى١ىررفي SEQ ID NO: 995 CDR-L3 كما صور في SEQ ID NO: 996. ج_ جزيء الربط وفقأ لاي راحد من عناصر الحماية السابقة، حيث ان نطاق ربط يضم منطقة كما صور في VH مختار من مجموعة تتكون من مناطق VH SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 27, SEQ ID NO: 37, SEQ ID NO: 47, SEQ ID NO: 57, SEQ ID NO: 67, SEQ ID NO: 77, SEQ ID NO: 167, SEQ ID NO: 177, SEQ ID NO: 187, SEQ ID NO: 197, SEQ ID NO: 207, SEQ ID NO: 217, SEQ ID NO: 227, 122 MA 35449Β1 SEQfD NO: 317, SEQ ID NO: 327, SEQ ID NO: 337, SEQ ID NO: 347, SEQ ID NO: 357, SEQ ID NO: 3ا7ج SEQ ID NO: 377, SEQ ID NO: 387, SEQ ID NO: 587, SEQ ID NO: 597, SEQ ID NO: 607, SEQ ID NO: 617, SEQ ID NO: 627, SEQ ID NO: 637, SEQ ID NO: 647, SEQ ID NO: 657, SEQ ID NO: 667, SEQ ID NO: 677, SEQ ID NO: 687, SEQ ID NO: 697, SEQ ID NO: 707, SEQ ID NO: 717, SEQ ID NO: 727, SEQ ID NO: 737, SEQ ID NO: 747, SEQ ID NO: 757, SEQ ID NO: 767, SEQ ID NO: 777, SEQ ID NO: 787, SEQ ID NO: 797, SEQ ID NO: 807, SEQ ID NO: 817, SEQ ID NO: 827, SEQ ID NO: 837, SEQ ID NO: 967, SEQ ID NO: 977, SEQ ID NO: 987, jSEQ ID NO: 997 ج_جزيء الربط وفقأ لاي واحد مز عناصر الحماية التابقة، حيث ان نطاق الربط يضم منحلقة كما صور في VL مختار من مجموعة تتكون من مناطق VL SEQID NO: 8, SEQ ID NO: 18, SEQ ID NO: 28, SEQ ID NO: 38, SEQ ID NO: 48, SEQ ID NO: 58, SEQ ID NO: 68, SEQ ID NO: 78, SEQ ID NO: 168, SEQ ID NO: 178, SEQ ID NO: 00 00 SEQ ID NO: 198, SEQ ID NO: 208, SEQ ID NO: 218, SEQ ID NO: 228, SEQ ID NO: 318, SEQ ID NO: 328, SEQ ID NO: 338, SEQ ID NO: 348, SEQ ID NO: 358, SEQ ID NO: 368, SEQ ID NO: 378, SEQ ID NO: 388, SEQ ID NO: 588, SEQ ID NO: 598, SEQ ID NO: 608, SEQ ID NO: 618, SEQ ID NO: 628, SEQ ID NO: 638, SEQ ID NO: 648, SEQ ID NO: 658, SEQ ID NO: 668, SEQ ID NO: 678, SEQ ID NO: 688, SEQ ID NO: 698, SEQ ID NO: 708, SEQ ID NO: 718, SEQ ID NO: 728, SEQ ID NO: 738, SEQ ID NO: 748, SEQ ID NO: 758, SEQ ID NO: 768, SEQ ID NO: 778, SEQ ID NO: 788, SEQ ID NO: 798, SEQ ID NO: 808, SEQ ID NO: 818, SEQ ID NO: 828, SEQ ID NO: 838, SEQ ID 123 1 35449Β1 NO: 968, NO: 998. طاق ربط الاول يضم كما هي VL منطقة كما هي VL منطقة كما هي VL منطقة كما هي VL منطقة منطقة اثما كما هي كما هي VL منطقة كما هي VL منطقة منطقة اثماكماهي كما هي VL و منطقة 177 و منطقة اثما: VI 187 و منطقة: VI 197 و منطقة: VL 207 و منطقة : SEQ ID NO: 978, SEQ ID NO: 988, jSEQ ID ها-جزيء الربط وفقأ لاي واحد ٠ن ءأعر اكلا الاع ‘ ب. ان ذ مخت١ل من مجموعة تتكون من : VL و منطقة VH منطقة كما هي ممورة في اس اب رض : 7 و VH (1)هذطقة مصورة في التسلسل المعريى رض:ج؛ كما هي مصورذ في ا- العبرف رض : 17 و VH 2)هذطقة) ;1مصورة في التسلسل المعرف رقم:ج كما هي مصورة في النعشل اب رض : 27 و VH 3)مذطقة) ;28: مصورة في النشل المعر ف رض كما هي مصورة عي التسلسل اكبرف رض : 37 و VH 4)مذطقة) ;38: مصورة فى التلسل المعرف رض كما هي مدززة في التسلسل المعرف رض : 47 و VH 5)مذطقة) ;48:مصورة ني التسلسل المعرف رقم كما هي مصورة في التسلسل المعرف رض : 57 و VH ج)هذطقة) ;58: مصورة فى التسلسل المعرف رض كما هي مصورة في التسلسل المعرف رض ' 7ج و VH 7)مذطقة) ;68: مصورة فى التسلسل المعرف رض كما هي مصورة في التسلسل المعرف رض. 77 و VH 8)مذحلقة) ;78: مصورة فى التسلسل المعرف رض ' 167 : كما هي مصورة في التسلسل المعرف رض VH 9)مذطقة) ;168: مصورذ ر التسلسل المعرف رض كعا ض مصورة فى التلل اب رض VH ٦٠) منطقة) ;178: كما هى مصورة فى التعلل التعرف رض كعا هي مصورة فى اسن الصف رض VH 11) منطقة) ;188: كما هى مصورة فى التد~.ل المعرف رض 12) ٠ذطقة كن هي مصورة في التدل اب رتم) ;198: كما هي مصورة في التسلسل المعرف رض كما هي مصورة في التسلسل ١لمعر' رض VH 13) منطقة) ;208: كما هي مصورة في الشفلل المعرف رض [cl/ 124 MK 35449Β1 (14) منطقة VH كما ه;ءا مصورة في التسلسل المعرف رقم :217 و منطقة VL كما هي مصورة في التسلسل المعرف رقم:218;(15) منطقة VH كما هي مصورة في التسلسل المعرف رقم : 227 و منطقة VL كما هي مصورة في التسلسل المعرف رقم:228 ؛ (جا) منطقة VH كما. هي مصورة في التسلسل المعرف رقم : 317 و منطقة VL كما هي مصورة في التسلسل المعرف رقم :318 ؛ (17) منعلقة VH كما هي مصورة في التسلسل المعرف رقم : 327 و منطقة VL كما هي مصورة في التستسف لععرف رقم :328 ;(18) منطقة VH كما هي مصورة في التسلسل المعرف رقم : 337 و منطقة VL كما هي مصورة في التسلعل المعرف رقم:338 ;(ج 1) منطقة VH كما هي مصورة في التسلسل المعرف رقم : 347 و منطقة VL كما هي مصورة في التسلسل المعوف رقم:348 ;(20) منطقة VH كما هي مصورة في التسلسل المعرف رقم : 357 و منطقة VL كما هي مصورة في الشف ل المعرف رقم :358 ؛ ( 21) منطقة VH كما هي مصورة في التسلسل المعرف رقم : 367 و منطقة VL كما هي مصورة في التسلسل المعرف رقم:368 ;(22) منطقة VH كما هي مصورة في الفسلسل المبرف رقم : 377 و منطقة VL كما هي مصو.ر.ة قي التكل الععرف رقم :378 ;(23) منطقة VH كما هي مصورة في النفلسل المعرف رقم : 387 و منطقة VL كما هي مصورة في التسلسل المعرف رقم :388 ;(24) منطقة VH كما هي دحور ذ في التسلفل المعرف رقم : 587 و منطقة VL كما هي مصورة في التسلسل المعرف رقم:588 ;(25) منطقة VH كما هي مصورة في التسلسل المبرف رقم : 597 و منطقة VL كما هي مصورة في التسلسل المعرف رقم:598 ;(26) منطقة VH كما هي مصورة في التسفل المعرف رقم : 607 و منطقة VL كما هي مصورة في التسلسل المعوفرقم:608 ;(27) منطقة VH كما ه.ي مصورة في التسلسل المعرف رقم : 617 و منطقة VL كما هي مصورة في التسلسل المعرف رقم:618 ;(28) منطقة VH كما هي مصورة في التسلسل المعرف رقم : 627 و منطقة VL كما هي مصورة في التسفل المعر ف رفم :628 ;(ج2) منطقة VH كما هي مصورة في التلل المعرف رقم : 637 و منطقة VL كما هي مصورة في التسلسل المعرف رقم :638 ;(30) منطقة VH كما هي مصورة في التسلسل المعرف رقم : 647 و منطقة.VL كما هي مصورة في التسلسل المعرف رقم :648 ;(31) منطقة VH كما هي مصورة في التسلسل المعرف رقم : 657 و منطقة VL كما هي مصورة في التسلسل المعرف رقم :658 ;125 MA 35449Β1 VL كما هي مصورة في الشلمل المعرف رقم : 667 و منطقة VH 32) منطقة) ;668: كما هي مصورة في التسلسل المعرف رقم VL كما هي مصورة في التسلسل المعرف رقم : 677 و منطقة VH 33) منطقة) ;678:كما هي مصورة في التسلسل انععرف رقم VL كما هي مصورة في التسلسل المعرف رقم : 687 و منطقة VH (34) منطقة كما هي مصورة في التسلسل المعرف رقم:688 ؛ VL كما هي مصورة في الندل العتوف رقم : 697 و منطقة VH 35) منطقة) ;698: كما هي مصورذ في الشلل المعوف رقم VL كعا هي مصورة في النشلسل المعرف رقم : 707 و منطقة VH (36) منطقة كما هي مصورذ في النط المعرف رقم :708 ؛ VL كما هي مصورة في التسلسل المعرف رقم :717 و منطقة VH 37) منطقة) ;718:كما هي مصورة في التسلسل المعرف رقم VL كما هي مصورة في التسلسل المعرف رقم : 727 و منطقة VH 38) منطقة) ;728: كما هي مصورة في التسلسل المعرف رقم VL كما هي مصورة في التسلسل المعرف رقم : 737 و منطقة VH ج3) منطقة) ;738: كما هي مصورة في التسلسل المعرف رقم VL كما هي دصوزة فى الشلسل المعرف رقم : 747 و منطقة VH 40) منطقة) ;748: كما هي مصورة في التسلسل المبرف رقم VL كما شي مصورة في الئلفل المعرف رقم : 757 و منطقه VH 41) منطقة ) ;758: كما هي مصورة في التدل المعرف رقم VL كما هي مصورة في التلل المعرف رقم : 767 و منطقة VH 42) منطقة) ;768: كما هي مصورة في التسلسل المعرف رقم VL كما هي مصورة في التسلسل المعرف رقم : 777 و منطقة VH 43) منطناذ) ;778: كما هي مصورة في التسلسل المعرف رقم VL كما هي مصورة في التسلسل المعرف رقم : 787 و منطقة VH 44) منطقة) ;788:كما هي مصورة ني التسلنسل المعرف رقم VL.كما هي مصورة في التسلسل المعرف رقم : 797 و منطقة VH 45) منطقة) ;798: كما هي مصورة ني التسلسل المعرف رقم VL كما هي مصورة فى النسلسل المعرف رقم : 807 و منطقة VH 46) منطقة) ;808:كما هي معورة في التسلسل لتعرف رقم VL.كما هي مصورة في التسلسل المعرف رقم : 817 و منطقة VH 47) منطقة) ;818: كما هي مصو ر ة في التسلدل ١ لشعرف رقم VL كما هي مصورة فى التسلذد المعرف رقم : 827 و منطقة VH 48) منطقة) : 828: كما هي مصورة في النشلسل المعرف رقم VL كما هي مصورة في التسلسل المعرف رقم : 837 و منطقة VH 49) منطقة) ;838: كما هي مصورة في التسلسل المعرف رقم 126 UK 35449Β1 (60) منطقة VH كما هي مصورة في التسلسل المعرف رهم : 967 و١٠ ٦ا٩ه VL كما هي مصورة في التسلل المعرف رقم:968 ;( 51) منطقه VH كها هي س٤ فى ١لمعرف رقم : 977 و منطقة VL كما هي مصورة في التسلسل المبرف رقم:978 ;(52) منطقة VH كما هي مصورة في التسلسل المعرف ز.قم : 987 و هذطقة VL كما هي مصورة في التسلسل المعرف رقم 988 ؛ (53) منطقة VH كما هي مصورة في التسلسل المرف رؤم : 997 و د ا٧ كما هي مصورة في التندل المعرف رقم :998 ;1 ا_ جزيء ربط وفقأ لعنحر الحماية 10 ، حيث از نطانى اربط الاول بضها تسلسل حمض الامينو المختار من مجموعة تتكون من SEQ ID NO: 9, SEQ ID NO: 19, SEQ ID NO: 29, SEQ ID NO: 39, SEQ ID NO: 49, SEQ ID NO: 59, SEQ ID NO: 69, SEQ ID NO: 79, SEQ ID NO: 169, SEQ ID NO: 179, SEQ ID NO: 189, SEQ ID NO: 199, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 319, SEQ ID NO: 329, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 359, SEQ ID NO: 369, SEQ ID NO: 379, SEQ ID NO: 389, SEQ ID NO: 589, SEQ ID NO: 599, SEQ ID NO: 609, SEQ ID NO: 619, SEQ ID NO: 629, SEQ ID NO: 639, SEQ ID NO: 649, SEQ ID NO: 659, SEQ ID NO: 669, SEQ ID NO: 679, SEQ ID NO: 689, SEQ ID NO: 699, SEQ ID NO: 709, SEQ ID NO: 719, SEQ ID NO: 729, SEQ ID NO: 739, SEQ ID NO: 749, SEQ ID NO: 759, SEQ ID NO: 769, SEQ ID NO: 779, SEQ ID NO: 789, SEQ ID NO: 799, SEQ ID NO: 809, SEQ ID NO: 819, SEQ ID NO: 829, SEQ ID NO: 839, SEQ ID NO: 969, SEQ ID NO: 979, SEQ ID NO: 989, jSEQ ID NO: 999. 2ا_ جزيء الربط وفقأ لاي واحد ...: عناصر الحماية 1-6 لديهم تسلسل حمحش الامينو المبين ني التسلسل المعرف رقم: 340 او التسلسل المعرف زقم : 980. 3ا-جزيء الربط وفقآ لاي واحد من عناصر الحماية انعابقة ، الموصوفة خلال EC50 (pg/ml) من 350 او اقل، يفخفل 320 او اقل. 127 MA 35449Β1 EC50 4ا-جزيء الربط وفقا لاي واحد من عناصر الحماية السابقة ، هوصوفة ذلآل يعادل (pg/ml) EC50 لاي واحد من عناصر الحدادة النابقة الموصوفة خلال (pg/ml) BC Ε5 33-Β11-Β8) BC 5G9 92-Ε10, BC لاي وك ض EC50 (pg/ml)في 5G9 91-D2-B10, BC Β12 33-Α4-Β2) BC 3Α4 37-A11-G1, BC Α7-27 C4-G7, BC C3 33-D7-B1, BC C3 33-F8-E6 Β1 15- تسلسل حمض النوو, ي يرمز ار جزيء ربط كما هو معرف في اي وك ض ءف١صر الحماية 1 ار 14. ج 1-ناقل يضم تسلسل حمض النووي كما عرف في ء('صر الحهاية.15 ر 1 -خلية مضيفة نقلت او تأثرت مع تسلسل حمض الروي كها رف ني - اا٩عاية 15 او مع ناقل كما عرف في عنصر الحماية.16 ح 1-عملية انتاج جزيء ربط وفقأ لاي واحد من ءذا٠ر الحماية 1 افي 14 ‘ العملية المنكورة نشم زراعة خلية مضيفة كما ءرف ني عنحر الحم-اية 17 د ادت المسموح لها بانتاج جزيء الربط كما عرف في اي راحش س لأص الحماية 1 افى 14 و كشف جزيء ربط منتج من الزراعة. 19- تركيبة صيذلانية شم جري... ربط وفقأ لاي و'حد ٠ذة ءذا٠در الحماية 1 ار 14 او منتج وفقأ اني عملية من عنصر الحماية 18 . 20- جزيء الربط وفقأ لاي واحد مر ءذاصر 'لحماية 1 ار 14‘او. ۶ وئ ار ء٠ليه عنصر ١لحعاية 18 للاستخدام في ١لمذع، علاج او. تحطن ض ارض لاو ض ٠جموءه تتكون من اهطراب خفية ١لبلازماء اضطر١ب خلية B اذي تر٧ ح ١ذتاج BCMA و امراض مناعية ذاتية. 21- طريقة ءلاج ١و تحسين من رض ء ض مجهوءة رل ، اضطرابات اخليه البلازما٤ ١ضطرابات خنية ح اضى الش دردط مع اذتاج BCMA و ارض الهذاءي ١لذاب الامراض ذهم حطوة اءهلاء 'ئمحضوخ الاي بحا’جة نيء اربط وئ لاي واد ض غاه٠ر الماية 1 الى 4!. ، ار متتح اش عملية سر أحم'ية 18. 128 MA 35449Β1 22-طريقة وفقأ لعنصر الحماية 21 ، حيث ان اضطراب خلية البلازما مختارة من مجموعة تنكون هن ورم نخاعي متعدد، بلاسماسيتوما، بلازما خلية ليوكيميا ، هأكروغلوبوكميا، املودوسيس، والدينسترومس ماكروغلوبولينيميا، عظم بلاسماسيتوما د، ايكستراميدولاري بلاسماسيتوما، ورم نخاعي اوستوسيليروتك، امراض سلسلة ثقيلة ؛ غاموب1ش من هام غير محدد و ورم نخاعي متعدد مشتعل. 23_طريقة وئ فر الحماية 21، حيث ان المرض المناعي الذاتي هو اردوس النئبة النظامي. 24-معدات تضم جزيء الربط كما عرف فى اي و١حد من ٠ظاصر الحماية 1 افى 14 ‘ جزيء حمض النووي كما عرف في عنصر الحماية 15ء ناقل معرف في ءذهبر اكايه ج 1 و/او خلية مضيفة كما عرف في عنصر الحم١ية 17 . ج2-كتلة ١لابيتوب الهستخدمة 3 من BCMA لتوليد جزيء الربط ء يهضل الج٠دم الا' ١لتي هي قادرة عر ربط ١فى BCMA‘ حيث١نكتلة الاببدوب 3 ٠ن BCMA لارب الى بقايا حمخى الامينو 24 ار 41 من تشل مصور في تسلسل هبرف رفى.1002 ج2-طريقة توليد الجسم المضاد، يفضل جزيء ربط ثناني ااا'حديد ‘ ١لش هي ' ر ءد٠ ربط الى BCMA، تضم (A) منعي ١لحيوان هع بولي بيبتيد تضم كتلة الابيتوب 3 من BCMA‘ ^ ان ^ الابيتوب 3 من BCMA يتقارب الى بقايا حمض الا٠يذو 24 ار 41 ٠ن لآلادل ى هو مصور في التسلسل المعرف رقم: 1002‘ (B) نتج الجسم المضاد المنكور، و (ح)اختإاريا'تعويل الج٠م الهغاد الهذكرر الىبزيء ربط ص ادد ار ٠يهدرء طى ربط BCMA بشري و يفضل الى T خية CD3 خلر د 129

108 paragraphs in 1 section, as filed

MA 35449Β1

Embryo The present invention in bilateral bind specific molecules which Ilv from the scope of primary and secondary linking, where he is the first to link capable domain to bind to one group of Apsob 3 Z BCMA, and the scope of secondary linking unable to bind to the T-cell independent compound CD3. Elaoh, the invention provides a nucleic acid sequence to symbolize Dzqe connectivity; snitch consists 0 Q sequence DNA and cell Almnkurh movable or hostess To; one of the bus to Tkor. Elaoh, the invention provides a process of producing Dzqe linkage Z invention, but-M1 to a medical molecule linking Almnkur and equipment consisting of & lt; link Almnkur esophagus. BCMA (MOQ Mkhadkhneh me, TNFRSF17; CD269) p 0 Ebalv En Ross Ouabr membrane belongs 1 Li ultra-receiver set BCMA. TNF Z is mentioned in one descriptive Kbrocan membrane mainly in equipment Golgi cells me one mature Vobh; & lt ;, Z Alhthal 'protein between cells (GR 1 on 1 v 1's., (1995) Ahazul Atrd'hwal 7 (7): 1093-1128) Ashe show that BCMA seem to have played an important role during the development of B cells, and balance the body. Can be linked to the discovery of Grass about each in the fact that Ross BCMA and Lalai was Om 0 Gh in the tractor about each, and because of the germination of chromosomes; is 0 Roche 1 Stmr hull BCMA and 2-AA - in Alok NVH BCMA, it is found to be the index. Cells 0 me and that is the basis of p Akhlmah - Yi and balance in Table 0 L (Shi 0 to 1 v 1's .e (2001) Elom 293 (5537): 2111-2114) and 3 Qa R TVA 4 1 Muftrechn the foundation with ties to BAFF (activate my) cell factor, as is the r Apr 1-TALL 1 and TNFSF13B, and APRIL (a proliferation - link incitement). The BCMA ^ defined in strain cell p and Rjd form ADAS 0 blast-plasma cells and T-1 Rat plasma and Avi somewhat cells my memory, but in the completed AVI not d Jt cells My Almahbtih and Statistics 0 are also produced BCMA on multiple Almiloma cells (MM ). Together with Hgael 1 Eghae Mjhuta cross-deceit 0 and Sichaelofelin reactor Link (TACI) and activating factor 0 except me Hustqubl Buah BAFF-R) TNF), aspects of the BCMA Alachtlgh organizations Almmaeh A-; z my cell and balance in the body. Production BCMA appears rather late in the different cell A_ Z and contributes to the long-term survival of plasma currents and cells 1 to Alaza in Zkh 1 GS 1 Zm. Alhanaf desired gene does not affect any BCMA Ald'n shower Tulip Khalaa 1:00; ; And the quality of the humoral immune responses - the formation of Aljvena center and generate. Qsberh AA plasma cells despite z I, that these mice had reduced its membranes Todlh Albr plasma cells;, ···, & gt; significantly for in the bone marrow, which refers to the importance of BCMA on survival (less the 0.4 Aod 2004). In line 0 p this research, BCMA also working to support the growth and survival of Mudba S cells: (MM) this one has 0 found Novak about each that beacons MM cell and Alaazzolh MM cells 35449Β1 promise Ntij BCMA and protein TACI are p hive and it produced Almtver of protein BAFF -R on the surface of the hive (Novak about each., (2004), we would like 103 (2): 689-694). Almiloma Akeddh '(MM) is c 1 Rh z second most malignant blood diseases constitute 2% are cancers. MM is a disease Z Htjas Lai. Z equ Navlat Alchorhusum Inter Walia (17) t (11; 14), t (4; 14), t (8; 14)) del (13), del (Dr'ch less the 0 '(1998), we would like 92 ( 3): 802-809; incited about each .e (2006) -2837 number: (8) 106 2840; Zkon 1 v 1's E (2001), Blood (1571 to 1566: (6) 97. be able to test more patients affected by many they are symptoms that relate Ppalarad Ua that 'Adaq Zkh 1 GS as' Tdher bones, kidney failure, immune deficiency E and 1 to Abye 1 Zgsa, socio-1 Apr -asertan. in 2006, the survival rate Altqrs to ditch 5. Sdhu 1 T. the MM r m 1 approximately 34%, which highlights all that MM is Ebarh Z trauma for treatment d Azh currently there is no treatment options exciting new Hlajat like Alkemiana treatment and SJ transplant Alkhalada Aljzeah p Mtohrh up survival rates improved, but often brings side effects goers Sgob out 'and b-1 to Tignes remains MM Z incurable (Lee s Al., (2004) J. r d as if you Nadu (383-379: (4) c) -hny now, is regarded as more treatment options Almsthdmh p anomaly; a land of Dalloum 1 1 slats is a combinations are Alstaryudat, thalidomide '' and Rrod or a thousand 'grate multiple toxicity, and for patients younger Jrtoua o ^ Ezosr Alag Adwi Ha Ganaah cells self-sow. more transplants Ne Ala'h E d d example' using patients who have the cells. 5 implant these operations E Z 1 g Although the mystery of therapeutic 0.1 Azhatahlely appeared to prolong the period of life when the disease was one Alanden well-being. Shower implemented when Danny Almrs who were Tchkad condition in a modern or Ni-Whyte Walles, Ezd Dy 1 1 Sen were selected, more than one transplant may be recommended financial framework; Alkahlh En & gt; 1 disease -anasser treatment Alkemiana used to treat one disease Ne Nichaelcgaabb E Duchorubisan 'vincristine y Mylvalan, treatments Aqird 0 p Elohr Alhmaeh one of the multiplicity of Hthel (®Thalomid®), lenalidomide (Revlimid®), bortezomib (Velcade) and Alchorticocd 1 T. (on Sepel'lmthel Ddson) 1 Dhirt Dr. August are options for treatment Almiloma, on both the disease who were - where del Valley 1 Sapf Dd Ne Hrtlh advanced when Olank two dunums Alag failure Sh 1 or 1 to plant Shall treatments used are 1 to Hana is a non-therapeutic. Kha said transplant cells 1 to n shower Jzeah not be an option baptized number of 1 to display the love lessons one sniff 'responded land other serious' 1 and 1 T. Tzid Verd Other. 1 it works to treat a ^ Tmoe Hatt & lt; & lt ;, Vea Alheiloma aluminum; 'and I Dara lead to full dilution. Thus, there is h 1 0 JH Weapons Lagat Hpetkrh fresh '

MA 35449Β1 Pelosi about each (Blood 2005; (10) 05 Aihdd Alajnaam specific Almkhadh BCMA in multi Almiloma after he is giving them leaks lymph donor (DLI) serum included those patients was capable of one pardoned Tobt Nhac cells specific BCMA Bo 1 Plan ADCC and CDC are disclosed only patients in the anti-tumor responses (4/9), but when patients who do not respond (0/6). the researchers Akhadd that induction of antibodies -BCMA contribute to the elimination of Almiloma cells and alleviate the long term, Ryan's data 1. (Mall . thier Cancer 2007; 6 (11) deny that Ganam Almkhad exact ...... which works to prevent the activation of NF-κΒ which is related in reference to maintain strong life in the natural and malignant B cells, path. in addition to that the antibody works granting antibody strong - strong cell - toxic intermediate cells (ADCC) to Khalaa 1 Almiloma tracks multiple in vitro and in which he had significantly improved design -Fc other approaches in the fight against tumors and blood -alazemih or disorders autoimmune focus on nutritional 1 z between BAFF and APRIL, For example links from a group TNF link, Hatqubladtha TACI, BAFF-R and BCMA, which are activated by BAFF and \ or APRIL. Z pesticide example; Bdehj Fc domain of human immunodeficiency Alawites to TACI, Zaimojinnitks, Azk 0, 0 t Qa Prlid Atassept (TACI-lg) to Thabayd both these links and prevents activation of the future. Is Atassept commonly in clinical trials for the treatment of Alnibh erythematosus (SLE, stage III), Multiple Sclerosis (MS, Phase II) and arthritis Aroaa J (RA; 1 phase II), both Z he Ne Phase I clinical trials for the treatment of lymphocytic leukemia malignant (CLL), for Amgooma non-Hodgkin (NHL) and MM. Studies in the pre-clinical work Atassept Whitney - Su's disease and primary MM cells and MM cell pathways in vitro (Morox about each, Blood, 2004.103), in the organism (Jacobi about each, leukemia 0.2008, from 22.13 to 406 ), two shows a relationship links TACI MM cells. P 1 in the defeated MM cells and Almstahedh of Madar't cell Ntak BCMA and TACI; Ahish that is 1 4 are not a T-nee, centering growth and the commencement -alrabott. These data suggest that antagonism of both TACI and BCMA can be useful without Ne treating plasma cell disorders. Besides RNA, Alhkhadat 1 -BCMA 1 specific T-optimistic about Ha TACI been Sgha (02/066516 WO), Qaht human Aljiveh Science and GlaxoSmithKline to develop an antibody targeting BAFF, which is called Bilmomab. Bilmomab works on inventory Ward R BAFF Azmazb Affi Massa: kisses BAFF-R, BCMA and TACI heavy Vlaya Ba.layahl Bilmomab to link my cells Hbeshr; 1 R. Looney connects BAFF 'Bdehl Bilmomab presented inhibition of survival of me, which include B cells, cells Aouturakatv, and it reduces the variation seen me Andaj Albulazha -asef immune cells. 3

MA 35449Β1 Moreover, in spite of the fact that the BCMA; BAFF-R and TACI, for example 'receptors my cell that belongs to the future group high-TNF, and Rabottha BAFF and APRIL are the subject of treatments in the fight against the cancer and \ or disorders autoimmune' there remains a need even contain other options for the treatment of medical conditions . According to it, the means and methods available for solutions to this problem in the form of connecting Dzqe which is on a bilateral scope and specify at least one of the cells of toxic linking, for example -asameeh T cells, however Ztaq second connecting to the BCMA. Thus, on the side of the first 0 n present invention connecting on a bilateral specifically least molecule available Atolov from the scope of linking the first and second, as the (9) Ztaq first binding is unable to bind to Alaeptob Group 3 Z BCMA (SEQ ID N0: G6) (CQLRCSSNTPPETCQRYC ); and (I) Ztaq second unable to bind to the T-cell compound linked to the future of CD3; and where Alajddob Group 3 0 1 n BCMA perimeter bugs Bakada A- Alahpve 24 1 41 Li Q sequences as Tsolr in 1002: SEQ ID NO. Me? AAA Necker as he as used here, the individual forms a, an and the; - Ely & gt; Signals pluralism is not content indicates otherwise. Thus, antiquated ways Alosal 0.1 Rbdja 1 R. & quot; Ml & quot; Includes one or more reactants are Almokhtlgh and reference to & quot; Way & quot; - Ouay reference to equivalent steps and methods known to a person skilled in the drawing can be modified or replaced by the ways described here. LED 1 Λ betrays Wallach 1 0 t Rh otherwise, the term & quot; At least a & quot; Follows are a series of elements Bashir to harm in this series. These practitioners will recognize, or be able to ascertain a Q-or not more than routine tests, many Almkavnat description to Debba instantiations of the invention. Through this Almkavnat it is covered by the invention Azar. 1- & quot; and \ or & quot; Urging used here includes the meaning of & quot; And & quot; , & Quot; Or & quot; , & Quot; all or any combinations of | Vsr that relate to the term user & quot; Sher 0 1 Stalh & quot; Approximately & quot; Or & quot; Almost '' is within ± 20% 'presented the best - ± 015 / H; & lt;) Thousands 0 0 y del over the art of ± 0% and & lt ;, better than ± 5% of the value of Alaadl given. During this 1 0 Sab passed Olney protection seen, what content otherwise requires, the term refers II Joel j; AA and variables such as & quot; Comprising & quot; And & quot; Which consists & quot; , R-integer Almnkur include or Khaoh Maine -m here the term & quot; Atolov of & quot; May be replaced in the term & quot; It consists & quot; Or & quot; Ensures & quot; Or at times when used herein the term & quot; Swe & quot; . 4 35449Β1 when used here, & quot; It consists Z & quot; - Er & gt; Any Ezsr 0, step or En β Mazd in an era Alhaaah. When used herein, the term does not include & quot; Mainly consists Z t materials or steps that do not significantly affect the basic features and Aljaddeddh -1 Mmadh Ne CKD step here any of the terms & quot; Consisting of & quot; , & Quot; mainly consists z ^ and fitting for the & quot; It can be replaced with any of the other terms. Chmd 1 Group 3 Aeptub outside the elite z BCMA. Athber'a BCMA scale Aj cell '' and 1 & quot; BCMA ECD & quot; Alyhkhin BCMA which R 1 S Sia Khar & lt ;, 1 x cellular and Alzhlaqat .lsitoblazmih Z BCMA. Z will be one of the SPS R1 Is Almhvq that Zhlaq 0 Alhishba membrane is one of the specified Affi BCMA Boulibptbb Z Ala'a 1 is currently number 1 ^ newcomer Goodyear Almatkhaddmh generally in the drawing to determine the scope of the type Alhaadroforbak. S d Akod walked one to stash the membrane is saturated, but most likely by no more than 5 Amilah acids or every END OF; mentioned here specifically. BCMA ECD Mgdil Ne SEQ ID shows 1007: NO. Marie future CD3 T cell is Ebarh Z 0 rode Roche and consists of one housewife distinct Tddlat when one of the mammals, irrigation Z IL CD37 consists of '0's Dallah CD35; and S Akhh (Laden) Z chains, related to these five sequences in Dzu knows that he let the future 0 (TCR) and a series ζ to generate a signal to activate the cells in one Foe. The decomposition is required to direct cells to β 0 Chief Khalaa 1 in Bo Plan 1 & lt; Liat 1 to bind Imaveh includes networked and connected to the cell 1 to Perfuren t Alr'remat formation. Cells in 1-Sale p capable seen Il serial cell, and do not affect the mechanics of the immune vein that interfere with the generator anti-Ptid in the presence of a valley, or a different one Slakh cleared him Ne; 1 Zer, .Je d Alhthal, 2007/042261 WO- refers Alhstalh '' Dzby linking & quot; But in Mahto.y 1 GS lar any & lt; esophagus der z ^ 1 in the duck (Presentation face pus) 1, .ltvaal 0 p 1 and one to know one Li Aldzemat 'required for the BCMA and CD3. Oaq 1 R-1, but the current GS, linking molecules are best Alboulibptidat. These could include Alboulibptidat on parts and Prussian Alaza Z Albrociveh (& lt ;, d example Arwad chemical or binding - elements such as transient 0 1 Sarneded). & Lt; esophagus 1 Rlna; seen counting the one to say, Yoo to Coffee ranges linking one or the most Almnkurh where 1 n i Azibt one of the flash can Trt 1 and interact Ha molecules required BCMA and CD3 seen slaves Alhthal E Nberh This is it routine er, most notably scale ANZ also (1 Verds ) E mmE7 | (Rotiat immunohistochemistry), ΒΡΤΙ / ΑΡΡΙ (ranges Kontez), protein

MA 35449Β1 linking - 0.1 x 6-AF (Ztaqat PDZ), Thariddotokhs (they wanted tock 0 Den); -CTLA 4 '23-Min ( Kdhuch 1 v) E to Epokak 1 T. (Antekalinat), Nyukarzinostaten, the scope of Vaebrnictan, agree Ankirin or scope ( as upper' z 'Laos 'Baaotikul' 295 to 304.18; Mania 1 v 1's., protein 1 x PCI (2006) 27-14, 15; é s 1 for E protein Kass CIA (2004) from 1891 to 1882.13; sixth and Afairsd. -strak Laos Pajul (1997) 469-463 a 7)) part 1 to connect the A- de L Anti -os shor 1 n molecule Rass are produced by (or obtained by) display phage or ring the office Viewed 1 each Q rang CDR 0 n antibody found them before (mono antibodies) to the scaffold, for example; i j ^ 1 for stepped Ezho s -ichir Alhstalh & quot; Tmaia 'to determine a' are the one is this one Affi Lars part'lve Batalla 0 P & lt ;, Wallach u - scale first and second, as the scope of linking first p s 1 der folding linkage Affi .ol Mmad 1 z 0 Kha & quot; Rass molecule & quot; Are the invention on multiple identification linking molecules such as three specifically linking molecules - one of the intifada eg; no bands Rs - Kha Azh Z A-0.1 n VI part of the invention has, in addition to his job by linking to Almtalo.bh BCMA and CD3 E 1 Khry.elyama molecules , molecule Lars Z Brz 0 for Dzqe three - link or multi 1 Otef Ne required Aldadzt cells p Tighten r BCMA; effective Ni Ni Toss cell mechanism of cross - linked CD3 and provide other functionality such as Fc hard scale 1 to functional fully in response Alhsm counter - Lalai Iathd Suhah u 1 to cheek Ebr employ affecting cells such as NK cells, a sign (and moghdan-e bastak etc.) 'z 0 uniforms such as botulinum or Radioniochled and one or supported - this topic serum life; Affi -eetmaz term & quot; & lt; esophagus linkage & quot; Linking with the invention , one of the barefoot Ne Zhlaq Lado & lt ;, Lars Ed 0 specifically Affi \ interaction with a Alaeptob for a given or Ravi M. El- some give 5, the & lt; a Liat \ claim BCMA and CD3. Are inconceivable that the scope of the binding of sharers range of connectivity Almnkurh Salv'a would have been & lt; g Ne that & lt; E are these Almanhat Alasaolh the peg on the desired; for the student Z - blooded have removed part of the donor - wide connectivity, loses donor Almnkur its ability to bind. 'Loses it Ddna Azz 1 Z R c at least 0% of the ability to link compared Ha donor connectivity. Rack Hrq blood Hoaqa link in this drawing -baltana is within the knowledge of the profession to locate \ sketching patches 1 0 Azh not linked to the scope of connectivity and, therefore , & quot; Extraction & quot; Connectivity scope of Almnkur sharers Zhlaq Lars appetizers. The term & quot; Alaeptob & quot; Movie born to counter where it is linked to an antibody or an immune gloss or a derivative or portion of an antibody. & quot; Alaeptob & quot; Hoamadad Jenny and thus a-Alaeptob it is sometimes referred to here to & quot; Genetic makeup counter & quot; Or & quot; The opposite end 6 1 genetic 35449Β1 & quot; . Thus, the scope of linkage is & quot; Tvaal- site generator counter '· Kha Lifa 0 of Iel Linking Almnkur to identify & quot; Altaez exact & quot ;. In one example E is linked \ Zhlaq link mentioned reaction (z specifically) with Alaeptob required given or the site Almt 1 and B S shower Jerinat required BCMA and CD3 is an antibody or Glos Hmaea 'and Zhlaq 1 for connecting 0 and VH region and \ or VL of the antibody or immune globin. Ahecn όμ & quot; Alaeptob & quot; Balahaad 1 - standing Alehtsalh or amino acids is Alatsalh related by third weakness of protein. & quot; Alaeptob Ataiwla'a is Ebalh Z Aeptub V, the amino acid sequence consists of preliminary Alaepterp biting. Sz 1 Aaill fully usually at least 3 or 'at least four, and most familiar, at least a C or presented one of the less h or t least 7, for example, approximately 8 painful approximately 10 Z Allaghafoua Alamch 1 Kdlh individual & quot; Aldzvy configuration of A.bbtob & quot; , Presented contrary Aleijerb S E is Ebarh Z Alaeptob where Altzlslh 1 for an initial amino acids that make up 0 n 1 Aill 5 and leads the sole determinant S 0 n Alaeptob on (for example , 0.1 to Aaill Hut that 1 Study Op are amino acids is not necessarily known to the scope binding). Usually Yadav όΐβ 1 to Asub of a growing number 0 n amino acids soon to Alasub a ^ in. Trotted 1 R Alad 1 P Balaeputobat formed, binding domain consists Z wetted Dadash Aladd to hook one Phad; blast - 0 best peptide or protein or also a part (in the context of Lahraa Aszew; Hawk except for one Z connectivity ranges is covered within Jt protein. (BCMA for 1 Il '& lt ;, Duke & lt; esophagus Brocam to form a three - dimensional installation; become acids Ahiveh 0 set and \ or 1 SAS Boulibptih Lalai the formation Alaeptob neighboring allowing antibody 1 Aill. - Fly 3.19001 0.60 formation Alaeptob, but not limited to , Z cycles 1 to rays of any E nuclear magnetic land of two - dimensional (2 D-NMR), SS and spin sensation to the name and analysis 1 Latifi resonance 'site for Ktrona magnetized (EPR). Moreover u so' was 0 P examples provided another way to test if it was linked to the scope of post R and 1 extent or more 0 z 1 m Muat Alaeptob protein Almahr, presented most notably BCMA. at one side, Iatberntaq the first link of the invention pressed-R ^ der pardoned Ward R mg, Muh 1 Aeptub 3 of BCMA 1 to a human, the best BCMA presented human ECD - to Ehgha Affi that E until replaced by a group Alaeptob concerned Ne protein BCMA know in Ahjmuh Alajddob concerned of the generator Almkhozd gari BCMA (gross Ne S Lalai Dav BCMA 1 series' where 3 is replaced with human Alaeptob group set Aladob 1 Irah 3; Lader SEQ ID 1011: NO), it will happen a reduction in the connectivity of the scope of connectivity. Reduction Alhzkor 5 and & lt ;, best presented least H / H 0 C,. / 0.40, 30%,. / 0.20, 10%; Z Wallace more than 0.1 to less e / e 95 Ah / e of 90, 80%, 70%, 60% or folding ./.100 compared Ha Alaeptob group involved in protein JBCMA ^, where the link to Alaeptob group Almmah in Rosh 7

MA 35449Β1 human BCMA is 0 Ahha 1. 0 n inconceivable that human BCMA mentioned previously \ BCMA 'for Murine are produced in CHO cells. It is envisaged also BCMA urticaria BCMA1 1 Ira are built to the scope membrane polyunsaturated and \ or scope Saitoblazmik are Ross Rbahl -gshaia d like EpCAM; see Figure 2a. Way to test this loss to link according R exchanges with Ahjhuh 1 Aitob 1 Maveh R-born anti BCMA (Presentation For example murine) Allapshra are described in the examples are one thing; 0 u most notably Ne examples 3_ 1 is another way to determine the contribution of residue-specific antigen in question in the selection molecule linking given or binding domain is a Adh Alalas a ^ u (u Azhler example of Morrison K and Ass Blu. Cure Owen Shim Pajul .2001 John; 302-7: (3) 5) where all the remains that are biodegradable Mattabdlh Balalanin E For Lacalle .abbar Ace 1 T. Mohah R Alaouka. 'Is used because Al bulkiness alanine, lethargy 1 Kpmaany methyl group functional and that it is working with the presentation of synthetic simulation Heradja 1 to 1 Dadhuah u consumed by Aldd of amino Cadhan other. Sometimes it is used Cas amino huge like health or leucine in cases where they are asked Hgz size remains metamorphic. Dh is considered one brown one for Wallace important technique which is used for a long period of time. As used herein, the term denotes & quot; Alad group B & quot; Z Mjhoa 1 to 1 u Coatings received 5 AA Ni along the exact juxtaposition of the birth of an anti .taatolv Aeptub a set of one or wasn or Ashe Q Alaeptobat. It is described Alaeptob groups that have been identified-Ha - to sound the Aladzaa Adfy - in I'q x 1 0 n Shake cell BCMA above to proceed and be photographed in Figure 1.

Terms refer & quot; (Capable) link to & quot; ; & Quot; 0 Arov z o 1 under & quot ;; & quot; U 0 JH Affi and & quot; Reacts Ha'a according to this invention that sounded Hervé p Lader R. interaction Z will specifically 0 p and one or more, on! The best at least S E pardoned best Ashe Z Wallach Zlat 9 and most Nedeila Ne Wallach four amino acids in Aeptub. 1 km is used here, the terms indicate '' the specific interaction & quot; E '' Hervé exact & quot; Or a specific Aruay & quot; RNA binding domain shows affinity dos Ross specified or 0 born Hiaz Epeshklo E and E 1; 0 TVA does not show El Tahoz with Albrocivat 1 and 1 to 1 generators to counter other than BCMA R-CD3. - & Quot; 1 affinity for one of the concrete & quot; On 'to link in a ratio which approximately (1006Μ (KD R1 powers. In one of the best, is to link specific, while the ratio of 1 is to link her nearly 1210 to 10, 10 8 M 1 t M e -0 a '12 -10 1 t M Ha & quot; 0 A, 10.11 to M H & quot; 10, the best around 10:11 1 at 10-9 M. if the interaction domain linking specifically or was linked to Affi goal Ahecn Akhzbarh Bzholh, Antralaa, Bakarnh interaction of the scope of connectivity Almnkur 0 p 1 mite Alhtalob or Adok

MA 35449Β1 counter 0 p interaction scale 1 to connect with Almnkur Arullac or one of the generators of anti BCMA or CD3. At best, it is not linked to Zhaaq linkage z Alaouaa E additional or Azh Z unable to bind to proteins or generators Plain Bzlav BCMA or CD3 (& lt ;, for Adla Alhthal the scope of the first binding is unable pardoned 1 to connect the R-1 to probate Unlike BCMA and sound the one to connect the second is unable to connectivity R Alaotd't Bahlav CD3) The term & quot; No linking is Las & quot; 4 or & quot; non-s 1 t der linkage & quot; RNA Ztaq Rabtts Wallach 1 EF; a current not Tom linking protein 1 and Mok Hiad one another other than BCMA or CD3 'Presentation Speed 1 Tal Vaelah for more than 30%' z Wallace) not Dr. Z 20% 'z best does not appear no more than 10./0 , most notably seen Alafajl not Z p. 9% '8%, 5/57, 00 of 0.1 and 5 ha 0 with' proteins or Akok't Almkhadh Unlike BCMA or CD3; limited to binding to BCMA or CD3, on one of the Tawar E provided 100./ .- on the selected link to be effective catalysts specific Ne · IL A- Asny to Zhlaq 1 Rzd alternator counterattack. Thus, access to R-1 as a result of linking Ze fully 'Aryan and \ or S as well as the result of secondary modifications of rare combinations. Dzdj Altaal August interaction Houka-born counter 0 p birth counter exact Ne Art Ed Dr. Ader ¥ not -klah, the interaction specific to the interaction of Hota Ed counter 0 p birth counter exact shower that produces an alternative or an extra at the beginning of the excitement E d for Ed and Halyvd d-born anti, anti Olajomirzishn generator; BL. On one side, or macaca Vashikiolaras is linked to the scope of connectivity Earl Z Alatraa Wallach R-40 A bear three are BCMA human and capable are the last to link R Alaeptob Group 3 Z Alacak BCMA Hthel BCMA of 0 Akaka Mullaca (1017: SEQ ID ΝΟ) (1017: SEQ ID ΝΟ), of Ader said i 1 s Art Arbahl or not connecting to murine BCMA. According seen it, in the embodiment of one, the scope of linking, which connects to the BCMA 1 human E most notably R u Alaeptob Group 3 of the protein domain outside the cell of the BCMA Lalai blood LET.: ;; Λ10 Ne remnant Cas acids 24 to 41 of the human Altzlslh as the perception of the SEQ ID 1002: NO, connects to Macaca BCMA, most notably R Alaeptob group presented 03 Ntaz protein Khar h BCMA of the cell which was formed remnants of amino acids 24 R 41 are Hsalh BCMA Hakaka as conceived in 1006: SEQ ID NO. In the embodiment of one, the scope of linking the first & lt; esophagus linkage unable to bind to Alad B 3 0 n BCMA, where 1 n Alaeptob Group 3 0 n BCMA corresponds to the remnants of acids equ 24 to 41 are entertained as conceived in 1002: BCMA) SEQ ID NO Aryan d d s) r-1007: BCMA) SEQ ID NO Valley p Zt 1 s outside the: equ equ 1-64 z 1002: SEQ ID NO). 9 7a)

MA 35449Β1 attractive in one of the one of the invention S 'Zt 1 s Link are the first & lt; esophagus Rabhl capable d extra

Callithrix jacchus, Saguinus or Bdid seen linking Mojtuah but 0 Eptub 3 Z - Saimiri sciureus BCMA and \ or Oedipus that one of Brocivat (1 t include the presentation parts 1 Da 'meant equ but & lt; termination Aslat Bayou 0 loggia E and 1 peptides 0.1 t for 0 a pal 0 birth less z 30 Hed 0 o) Escherichia 0 n and 'wed or Akthb 0 n Aminth acids, which bounce off one another Li in part 1 Presentation Rabahl Syed Htrabott (DA in 4L p acids 1 to Amiveh) fulfilled Alhstalh & quot; Boulibptid & quot; RR 0 serve Ua Z Aldzeat 'up Taatolov Z and K 1 and 1 massively multiplayer p. 30 Z 0 to acids Alas.d said Dr. coral polyps 0 s d 1 Ex Al Hayrat Alehtazdh 0 Zhaiaalmir, Zs of 0 coals, Tlavyalmiro births of any Supreme', for example, one T-Taatolov are one massively multiplayer 0 n & lt; esophagus Wad one 'Ahecn that the fact Adzibat 1 Ptbptid 1 T-Nie Z the 0 hr E r S E Dlah Meer etc. E Z or Z 0' 1 Trquint Almhlapqh Supreme Marie Z Meer 1 T. Altddh is '-Je Alawar' Dloh Meer V Alehths, Tmave water Alehtjams K.kthaler Al Hayrat 1 slats Z Alehtjazsh 0 and & lt; Yep body Htad, y 1 the one who, in its wide-E Holov Q; Sens del Baud light sneezing 1 bug and .siv Z Albollieptid heavy chains of conformity. As a show-T & quot; D & quot; And & quot; Ross & quot; R Alboulibitidat \ Albotanat Alaadlh naturally where that amendment is affected by the 'B Jf example s after Ataatl such link Balgluckozhel E equ the E; and 0 August 1- & quot; Me & quot; A while back here can also be Manl Kimiyanja 0 such as Bijlatbd. This one knows for amendments in the drawing. In Jkb additional of the invention, the second link is capable scope pardoned one to link R Asselon CD3 - in Yep one another Z only 1 GS, the scope of the second link capable pardoned Link R-CD3 Valley and Macak CD3, presented one of the best 1 t CD3 Arra Asron and 1 m CAC-CD3 Adon's more or Id Bdid , Zt 1 1 s to tie for second one is able to connect Presentation 1 R Callithrix jacchus, Saguinus

Oedipus and \ or CD3 Adon. Light of births R ', or Wade

Acdermn Ztaqat binding of molecules are Arbahl allegation is in & lt ;, equ unconscious reciprocal specific Ttaah Mammal .ztaqat linking CD3 are species in the swap, Evysepel Ed E Tohv in 2008/119567 WO of 1. In Asos to Jrra linkage Z invention MSN scale Link opium capable of folding one for connecting to the compound's future CD3 cell in Atolov of Hztqh VI Ilav Z CDRLI, CDR-L2 and CDR-L3 Selected 0 Z: 10 ΜΑ 35449Β1 'wo 2008/119567 of SEQ ID NO: 27 p Ka in CDRLI (a) z SEQ ID NO: 28 Apr SEQ ID NO: 28 Kha images in the CDR-12, & gt; SEQ ID NO: 29 km 1 depicts the CDR-13 and wo 2008/119567; WO 2008/119567 4 WO 2008/119567 0 n SEQ ID NO: 117 as depicted in CDRLI (b) and WO 2008/119567 are SEQ ID NO: 118 as images of the CDR-E2; and WO 2008/119567 0 n SEQ ID NO: 119, as depicted in the CDR-L3 E WO 2008/119567 are SEQ ID NO: 153 Kha depicted in CDRLI (C) and WO 2008/119567 of SEQ ID NO : Kha 154 pictures in the CDR-E2. WO 2008/119567 are SEQ ID NO: 155, as depicted in the CDR-L3 in the embodiment of Mgdil Alternatively the & lt; esophagus linkage of the invention Alhani 'said Zhlaq Rabhal Olathe 1 Ni T cell Atolov Q Salève Region 0 n CD3 capable of binding to a compound selected future 0 n CDR -H3 CDR-Η 1, CDR-H2 E WO 2008/119567 0 n SEQ ID NO: 12 and b Khaasour in WO 2008/119567 of SEQ ID NO: 13 Kha images in CDR-H2 0 n 2008/119567; SEQ ID NO: 14, as depicted in the CDR-H3 'WO 2008/119567 0 n SEQ ID NO: 30 Kha depicted in CDR-H1 (b) Z SEQ ID NO: 31 in SEQ ID NO: 31 as images in CDR-H2 Z SEQ ID NO: 32 Kha depicted in CDR-H3 and wo 2008/119567; WO 2008/119567 'WO 2008/119567 of SEQ ID NO: 48 Kha depicted in CDR-H1 (c) and WO 2008/119567 of SEQ ID NO: 49 also depicts in CDR-H2; WO 2008/119567 are SEQ ID NO: 50 depicted in Î ^ CDR-H3 'WO 2008/119567 of SEQ ID NO: 66 to 1 km in the images and WO 2008/119567 are SEQ ID NO: 67 Kha Besol in CDR-H2; WO 2008/119567 are SEQ ID NO: 68 Z depicted in CDR-H3 'WO 2008/119567 0 n SEQ ID NO: 84 Kha persists in CDR-H1 (e) and WO 2008/119567 of SEQ ID NO : 85 Kha Besol in CDR-H2; WO 2008/119567 0 n SEQ ID NO: 86 Kha images in CDR-H3 'WO 2008/119567 Z SEQ ID NO: 102 Kha Besol in CDR-H1 (f) and WO 2008/119567 are SEQ ID NO: 103 Kha Asdol in CDR-H2; WO 2008/119567 of SEQ ID NO: 104 Kha depicted in CDR-H3 'WO 2008/119567 Z SEQ ID NO: 120 Kha persists in CDR-H1 (g) and WO 2008/119567 Z SEQ ID NO: 121 Kha depicted in CDR-H2; WO 2008/119567 Z SEQ ID NO: 122 Kha Seoul in CDR-H3 11

UK 35449Β1 'wo 2008/119567 of SEQ ID NO: 138 Kha depicted in CDR-H1 (h) and WO 2008/119567 are SEQ ID NO: 139 as depicted in CDR-H2; WO 2008/119567 0 n SEQ ID NO: 140 as depicted in the CDR-H3 E WO 2008/119567 are SEQ ID NO: 156 1 km portrayed in CDR-H1 (i) and WO 2008/119567 of SEQ ID NO: 157 Kha depicted in CDR-H2 and WO 2008/119567 are SEQ ID NO: 158, as depicted in the CDR-H3 'WO 2008/119567 Z SEQ ID NO: 174, as depicted in the CDR-H1 (j) and WO 2008/119567 of SEQ ID NO: 175 Kha depicted in CDR-H2. WO 2008/119567 Z SEQ ID NO: 176 Kha depicted in the CDR-H3 of Amodil is another Dzqe linkage of the present invention that Zhlaq 1 to connect the Alavi Kadl t Mokhtarg 0 are Almjmo.eh Ashe VL T cell consists of Mnhalqh CD3 binding to compound the future of 165 or SEQ ID NO: 35, 39, 125, 129, 161 Kha conceived in VL Taatonf are 2008/119567 -WO area of the cell CD3 of Amodil Alternatively the scope of the second link capable of Adrt Affi accept Ne consists Z Barr 7 area Sirh Z Almjmugh which consists from area a 1 as the perception in SEQ ID NO: 15, 19, 33, 37, 51, 55, 69, 73, 87, 91, 105, 109, 123,. WO 2008/119567 177, 163, 159, 145, 141, 127 1 and 181 are preferably more, that is characterized by Dzne linkage Z invention Aszewy Bzhlaq link Alavi Aladr VH T cell that the above-Z Mzhlqh a 7 and Mzhlqh CD3 Presentation link to a compound selected future the group consists of: WO 2008/119567 or 21 Z SEQ ID NO: 17 Kha conceived in VI (3) Hztqh or 19 are SEQID NO: 15 Kha depicting the VH and region; WO 2008/119567 WO 2008/119567 39 o j ' SEQ ID NO: 35 (I) Hishtqha 7 Kmatsorvi or 37 of SEQID NO: 33 4 depict the VH and region; WO 2008/119567 or 57 of SEQ ID NO: 53 4 portrayed in the VL (h) Hztqh or SEQ ID NO: 51 km 1 conceive in VH and WO 2008/119567 area; WO 2008/119567 55 or 75 of the Q SEQ ID NO: 71 Kha perception in the VL (l) Mztqh or SEQ ID NO: 69 Kha depicting the VH and WO 2008/119567 area; WO 2008 / n 119567 073 12 35449Β1 1 and 93 of SEQID NO: 89 as the perception of Ne VE c) Hztqh) SEQ ID NO: 87 as the perception of the VH and WO 2008/119567 area; WO 2008/119567 or 91 or z 111 are SEQID NO: 107 as in the resurrection VI 4) Hztqh) SEQ ID NO: 105 as the perception of the VH and WO 2008/119567 area; WO 2008/119567 or 109 or z 129 S. SEQ ID NO: 125 Kha conceived in VL 9) 0 Ztqh) SEQ ID NO : 123 Kmatsour in VH and the WO 2008/119567; WO 2008/119567 or 127 or z 129 pp SEQ ID NO: 125, as in the VI Tsol not) Mztqh) SEQ ID NO: 123 as the perception of the VH and 2008/119567 wo area; WO 2008/119567 or 127 u, & gt; 147 or SEQ ID NO: 143 as soon as the VI area (!) SEQ ID NO: 141 as the perception of the VH and WO 2008/119567 area; WO 2008/119567 or 145 or 165, p SEQ ID NO: 161 area of 7 Kha perception Ne (j) SEQ ID NO: 159 as the perception of the VH and WO 2008/119567 and area; WO 2008/119567 1 and 163, & gt; 183 or SEQ ID NO: 179 km 1 depicting the VL Ka) Mztqh) SEQ ID as the perception of the VH region and WO 2008/119567 .WO 2008/119567 181 of j1NO: 177 Alad link Je-scale 'according to the embodiment Amodil 0 n connectivity are Dzqe the present invention and regions VH- Ne cell E pairs Hmatq second CD3 capable of binding to a compound in the future of the VL and VH Pettm Nzib Hmatq. (SeFv) is in the form of the antibody chain Adfrdh VL- I Ν- at the end of the VH Amodil be put area, VL-VH or VH-VL Nrnab in Zhaah -0 sequence of the link. VL sequence link. Ong is Hntqh embodiment Mgdil p & lt; esophagus linkage 1 described Aelah are Alad'a Alavi; 4 & lt; In that Zt 0 0 Aq linking cell consists Ne 0 n wielded A- Alammivu CD3 second capable of linking independent I Mr.kp SEQ ID NOs: 23, 25, 41,43, 59, 61, 77, Hharhsasutalvitofmn 185, 169, 167 151 149 , 133 131 115, 113.97, 95.79 187 or z. WO 2008/119567 1 35449Β1 I Ztaq Rabhd first Affi BCMA Abannra MSAS equ 15 Nm; 't equ, Las Tevgela 5 ηΜ & gt; , Z 0 mother Eg night ηΜ Ah, Hvy motherland. Zdt 0 No 0.5 ηΜ E, Z needles I ηΜ A.hh 0 and ESL S 0.05 ηΜ him. Semi-caw of 0 i first ... BCMA .05 is the folding Alavdd 15 ηΜ;, and Alakatr ways ηΜ epiglottis, p Alair preferred 5 ηΜ y, z mother Thiala ηΜ uh 'z mother I 0.5 ηΜ;, Lahti mother μ; ηΜ a 0.0 H, and mezzanine ABS 0.05 ηΜ; or even 05ΐηΜ & gt; . No 4 N. Nias Sbntyseladthal, in Tejrebhbaaukdr or Tjobhskaahard, V AA; A_] example as described in Alahthelh. Alnrq between F-yen Lars Affi Macak BCMA 0 Qaal BCMA Aabthrey are folding the best [1: 5-1: 10] or [10: 1-5: 1] 'd Alakq M [1: 5-5: 1] E and A.lailrhdd [3: 1-1: 2] Ed crisp [3: 1-1: 1]. I do not see ways to determine Sbh is known to the people of Azmhzh.

Ahecn Yasin Seah medium cells by Anrt Ndaidh particles 1 under BCMA / CD3 ways Htuh 0 walked to Khalaa 6 1. Presentation for example, that T-positive cells are CD8 (Human) lighter 1 and Khalaa one blood peripheral (human) is catalyzed (PBMC). If the required cells, are [0 repel LACAC Osjaotzqlna BCMA -acak, the responsive cells that Chen Z 1, bless Macak 0 path such as T cells, for example Ta 4119LnPx. One must Ztaj [for cells to wanted (at least 1 s Zt V'rj A-) BCMA; hr for Almt 1 for BCMA 1 to Shri or Hacak. Ahecn 1 1 n be the cells required path. Cell (such as CHO 0) stable or Almzaolh Iddma BCMA, Elyobeilalhthal BCMA Alepeshah or Macak.epeshkl alternative, walked the path of the required cells are produced naturally positive cell BCMA 't like touching one of these Almiloma 1 multiple 1 to 363 A or human jL. NCI-H929 Khaddq Akloha keda 0 363 A or human NCI-H929. Usually EC50 is expected to be less than 1 line of t ^ DBP values that produce the highest levels of BCMA on the surfaces of the cell. Prose writer ratio of ^ 1 play (Ε: τ) is usually L Yerbe 10: 1 ', but also can be different. You can measure the effectiveness of toxic particles 1 to bind specifically bilateral BCMA / CD3 Ne launch chromium -51 (Zs incubation approximately 18 hours) or in the experience of the pardoned August -FACS (Zs 1 to Akhcan approximately 48 hours). Also, amendments to the Tger.bh incubation time (Antal August) IL. As you know other ways to measure the toxicity of the cells to the profession and consists of experiments MTT or MTS, experiences that overwhelmed m on the ATP, which include biological lighting experiments, b Slforhodamen B (SRB), the experience of WST, experience Alklenogenik and technical .ECIS as he is better measure the effectiveness of cytotoxic in Tnaah linking molecules specifically BCMA / CD3 present invention are the toxicity of experience based on the cell. They d in the value of EC50, which Nttabq focusing the middle of an effective Supreme (concentration tribute linkage which serves to induce toxic response between the base line and the upper limit). Presentation is better, the value of linking molecules Tnana specifically BCMAGD3 is 20.000 pg / ml of, the best 14

MA 35449Β1 5000 pg / ml & gt; E Z most Thiala 000 pg / ml AAC, p Wallach Thiala 00 pg / ml JH E meant the most preferred 350 pg / ml & gt; E even the most favorable pg / ml H 2 QC, Jun 1 more I 250 pg / ml of E p motherland agent 00 pg / ml AAC E Z 1 for more Tqdala 50 pg / ml & gt; Even one of the more favorable 10 pg / ml & gt; E and parent preference 5 pg / ml- -1 J ecso 1 of the given above you can see any h z baskets 1 values y1 escaped you? Rabbo Alsah which you turn over one of the cell. Pardoned for 1 for an example of trimming is Adam Khalaa 6 in positive CD8 (human) or Khalaa 1 T Macak Kkhalaaa Hustjabh, ECso z values & lt; Ivat link pubic S BCMA / CD3 is a folding one of the best 000 pg / ml AKA 'z 1 for the best one massively multiplayer pg / ml hee 5K' up 1 Lash Tvillla 250 pg / ml of E p Wallach NL 0 pg / ml Hack 'p Wallach Ts 1 y 50 pg / ml & gt; Until 1 Lash preferred 10 pg / ml K Ka E Wallach Sale 5 pg / ml Ka as one Khnnhzh Nmottagrbh 1 cells 1 ratio BCMA cells 1 to stun (1 drink or Macak) 0 such as cells CHO E p ECso to Dzra Rabttmaia threat BCMA / CD3 z Eating 0 pg / ml Gah, Folding values one of the best 1 st 100 pg / ml Ka E Z Wallach I 50 pg / ml-; Until 1 Lash preferred 30 pg / ml & gt; E p Wallach Melt 0 pg / ml AAC 'Wallach Hiala 5 pg / ml Ka. If Kazt cells 1 are required in Saar Alj BCMA positive cells Alabieih 'Hivha ύβ value ECso folding one to eat 350 pg / ml of, the best over 320 pg / ml' shower Wallach preferred 250 pg / ml & gt; , Even the most favorable 200 pg / ml K E R Wallach Heseatt 00 pg / ml Ah, so Walsh preferred 150 pg / ml Ka; p Wallach preferred pg / ml hee Ka 1 and most preferred 50 pg / ml or Ka Ashe. While in one fully PBMCs (human) Kkhalaaa responsive, ECso z values are Hervé Tmany A'kdid BCMA / CD3 Er part of the best 000 pg / ml AAC 'z 1 of the best Ashe 750 pg / ml of E folding one to eat the 1 st 500 pg / ml of, bowed Wallach preference 0 pg / ml of c 3 E 1 Ne Lash Thiala 320 pg / ml, even Wallach Esela 250 pg / ml of, even Wallach preferred 00 pg / ml Ah, Wallach preferred 50 pg / ml K or less. In - Mvdd folding the face of one of the _khasos, characterized Jrpennek 'to bind specifically Tmaveh BCMA / CD3 are Alachter 1 GS SV EC50 of 350 pg / ml or Ka Ashe E m 1 Afajl Ashe 320 pg / ml or less of. In this embodiment the required cells are 3 c 3 cells and the cells 7 skirt in PBMCs Albashrah is motivating. Skilled in the art knows how to measure the value of EC50 without Adu last. Moreover, the selection gives specific instructions on how to measure the value of EC50;, jerked, folding example example 8.3, below A protocol is appropriate agencies \ y me 15

MA 35449Β1 a) preparation of human peripheral blood mononuclear cells (PBMC) by Hiri Ki 1 FH gradual Phicol, the captain of the preparations of the preparations lymphocytes (printed 1 T. b 1). . b) Optional chapter in Dollbecko PBS (GEPCO) C) remove the remaining red blood cells from PBMC across Alachan overlooking d Haodah erythrocytes ((155 mM NHCI. 10 mM KHC.3, 100 μΜ EDTA (h) the removal of platelets, according to Ir what floats Sroe expulsion 1 0 n PBMC in lOOxg

(L) Astzgad cells + CD14 and NK cells (c) isolating CD14 / CD56 negative cells using columns LS (Myeltsl b \ Aotik -130 # 042-401). (F) Zrat cells + PBMC w / o CD14 + / CD56 'Z For Alhthal in Hhost shoulders RPMI For example RPMI1640 (Baaokrom FG1215' AG #) cough Ha 10% FBS (b 1 Rkrom 1X '(# S0115' AG Cahzn exponential Z basic (Baaokrom Κ0293, AG #), equivalent to the acidity of Hibs 10 mM (Boaokrom 'AG 13 c 1 a #), 1 mM sodium Aerfat (Baaokrom 0473, AG A #) and 100 U / mL penicillin \ Streptomitin (Baaokrom Α2213, AG #) 37 0 degree relatives Ne incubator until needed. (g) designation required cells (h) blending responsive cells required, the best in volumes equal, ie Levy N. him 0 of Nenabh Ε cell: τ z 10: 1); (Add molecule 0 connectivity, the better relieve sequential (n display for 48 hours in 7% 2.C of moist incubator (k) the safety of the required cell membrane control, for example the addition of iodide Albroodidom (ΡΙ) in Nahanni concentration of 1 pg / mL, for example by flow cell. (l) EC50 account, for example, according to the following formula;

Cytotoxicity [%] = 5 a dead target cells xioo target »; Ils 16

MK 35449Β1 using g Software 1 Badrizum c (Graf iPad software, Jan Igo), the toxicity ratio of planning versus antibody concentrations dual corresponding identification are analyzed -t 1 response dose Balimang four regression logistical border to assess the Sunni response bold-H curves in the slope of hard Hill and is EC50 values are calculated in the presentation of the Necker above to proceed, from Amodil that & lt; esophagus binding of invention Alhani enacted Ne pg / ml) EC50) Z 350 or E Ashe pardoned 320 or better Ashe. The present invention also regards molecules link described here and because I characterized in pg / ml) EC50) Walsh equivalent pg / ml) EC50) Z any are BCMA / CD3 & lt ;; ^ C bilateral specifically bind BCMA-83xCD3, BCMA-62 X CD3, BCMA- 5 X CD3) BCMA-, 98 X CD3, BCMA-71 X CD3, BCMA-34 X CD3, BCMA-74 X CD3 BCMA-20 X CD3 0 in order to determine whether the EC50 0 n Jfairs link as described this Aandl EC50 0 n 1 j are -BCMA-83 X CD3, BCMA-62 X CD3, BCMA, 5 X CD3, BCMA-98XCD3, BCMA-71 X CD3) BCMA-34 X CD3 BCMA-74 X CD3, BCMA-20 X CD3. They are thought to determine the value of EC50 in the same test is applied. The term includes & quot; Equivalent to & quot; Z deviation of 10% -ab; Avy best & gt; 7.5% + / -, the best over 5% + / -, even the most Thillla ./.2.5 - / + Z value of EC50 concerned. BCMA / CD3 Dzemat .rabt Tmaveh 'to determine -BCMA-83xCD3, BCMA, 62 X CD3, BCMA-5 X CD3, BCMA-98 X CD3, BCMA-71 X CD3 BCMA-34 X CD3, BCMA-74 X CD3, BCMA -20 X CD3 1 u Adam K'a reference & quot; Particles 1 to bind Apr 1 Kpbh Adudulo Aelah are Nenni equ Hztjh in Hlaa 1 CHO difference nee 'to the effectiveness of Alsuhah between the form of simple and binary Alaizulntrb Alamirak to Dzenat link Tmaveh 1 Kdiv BCMA / CD3 (Hthel one of the bodies of one delegation) returns Avi & quot; 1 of the strength in the gap 0 & quot; - This one madder in Otho n. It walked, for example, is calculated as a percentage of EC55 values of Z compound one molecule inst form Qz 1 Apr Alamirak. Gaps in force to molecules bind specifically bilateral BCMA / CD3 of the present invention is the best of five, and four more of the best, even for one more I 3 & gt; ; Even the most favorable 2 K and the most preferred Λ-. It 0 1 Aqdil; does not bind or Tmaiah Rabhd molecules interacting specifically BCMA / CD3 are the one to invent one for Hani 1 Li, Thez 1 and TVA 0 El Eobr with a human BAFF-R TACliy 1 to Shri. & Lt; s 1 Qtv 0 n Alel transit in the BAFF-human and \ or! Human TAC R is Alkiaf in Example 9. 17 1 35449Β1 of Amodil metabolize 0 of 1 N. molecule 1 v 1 to bind Ndandh one of Adad BCMA / CD3 z 1 for the invention of one of Hani in the transformation of Y, but ^ 1. After a number episodes of freezing \ melt. The best ratio Danané 1 0 Aber is a 50 & gt; Ni better uh 0 4 & gt; , Even the most favorable of 0 ° 3 & gt; Even the most intrinsic to 2.5% & gt; E bowed most preferred 0 Uh 2 & gt; , Even the most favorable% 1.5 & gt; E and parent preference e / a 0 & gt; ; Tine Speed example after three rings frozen \ thawed. Can Tngiv ring frozen \ thawed and determine the percentage of Tnaye Alaamr and Haa R example C1-show mow 1 s 1 to bind Tmaiah Humping (such as objects 1 delegation) Z 1 Akhcaa 1 to current blast-0 Alahil thermal resistance favorable varying 1 Vhar Ashe 0 N 60 ° b Specify the 1 Ziel externa 0 for connecting Tzoveh specifically molecules BCMAGD3 (such as Ashe 0 protracted) 0 p plasma proteins 1 to mankind; can Tngiv Akhanar reference (each year for & gt; example 'Alhthal 18) 0 Ne - Mgdil, there is a marked decline are linking the desired Z Tmaveh linking molecules 1 EZE BCMA / CD3 August Berutivat plasma. Fallacy opportunities Albulaz 0 of 1 SSH is the best 2 & gt; . Z Alhishor Bikd last 1 1 n molecules to bind specifically Tmaah BCMA / CD3 of Alachter'a Alavi is able to Hits! Tthbyzih for therapeutic or effective anti-Orme. Ahi Hveam so heavy the tribe 4 1 for example in the generation of 1 Study Kha has been one of the disclosed in one of the Mil 19 (^ Zj AAC 0 Nygravc to Amrhah Almto & lt; of Z 1 human tumor) 0 knows skilled in the art how to modify or adopt some of the parameters of this Alarralh 'such as the number of tumor cells 1 to Mhakozh, Houka 1 to Han, number of Helan in the & lt; Ruh Alarb 9 'b & lt; Ivat Albahl Tzoveh BCMA / CÜ3 to give, and timelines, the Alavgl in the eye of not 0.1's bench nee result y 1 t r meaning of Tucker 1 t, inhibition multiplexer Alzho [%] T / C is 70 1 and HJ 1 and 1 Say; it meant one of the best 50 or 40 or less, even the most favorable at least 30, 20 or one less and one of the most popular 10 or Ashe '5 or Ashe Ne 2.5 or Ashe -hvy Wallace 4 E Althdbb BCMAGD3 are present invention presented urged 1 Tzsat 0 Alttal or do not induce mainly 1 mediated decomposition of the BCMA of cells Lhasa Hthel HL60, MES-SA and 16-SNU. Ttaar terms & quot; Do not induce presented the decomposition of 'I do not pardoned 1 tirelessly Se essential & quot; , & Quot; Not mediated lysis & quot; & Quot; Not mediated lysis is based & quot; Affi RNAi molecule Z invention to surround one, do not induce or mediate the decomposition of more than 30 huh, pardoned best no more than 20% Z E Ni better than 0 Uh / e, more particularly at most 9%, 08 uh 0.7 ha. 0.6% 0.1 and 5% of Aceh BCMA cells, a love that p BCMA lar cell Hthel _ the positive, or 2-ΟΡΜ to be 00% of the DTM d not Ashkiv't molecule 18

MA 35449Β1 1 to bind to & lt ;, least 500 nM. Skilled in the art knows how to cell lysis without Addo measured one another Moreover, specifically gives specific instructions for how to measure decomposition Lhasa; Azhler & lt ;, however, 'for example, example 20 below. In one embodiment, the first binding domain or the second is the singer of the antibody. In another embodiment, Ka 1 energies linkage is derived from an antibody that includes the term & quot; antibody & quot definition; The instantiations such as monoclonal antibodies August, phantom, single chain, and human Almansnh. In addition to antibodies Kamilmh length, also it includes a definition of the antibody derivatives and parts of the antibody, Shell or automatically; parts Fab. Hoof parts of the antibody or derivatives in the last Z parts, 2 (F (ab Fv, scFv or monoclonal antibodies to the scope of a single such antibodies ranges or Agam Madhu 'Zt 1 s 1 t antibodies Mufdh changing or scope Alglobin immune singular Almtver which Q is just the scope of Mtver one, which can be a VHH, VH or VL, linking & lt specifically anti generator or Aeptub independently ;, all zones or ranges V Others; see Obaid example, Harlow and Wayne's nest (1988) and (1999), Locke. Kate; Contrman and Dobell '-aljsm anti ς Springer E 2010. 2nd ed and Little E antibodies isolation Amtlgh to Azenj 1 Mmas; Cambridge University Press, 2009, also includes the term Almnkur on objects Walsh 1 Veh or bitropic targeting - Rey (DART) antibody. conceive another is Father 13:00 anti single series (bilateral specify), binary objects Tandom (Tandab), objects acceded 1 Ende Statistics & quot;. actress in the installation of which is as follows: antibodies -VH-VL) "Fc DART" 1 02,, CH3) 2 and objects anti DART ",, IgG multiple antibodies, such as antibodies .taatolv ranges duck Alglobin immune to not only antibody-scale Boulibptid single isolated Mtver, Welch also Boulibb biggest ¥ comprising one or more of the unilateral Almirat to scale sequencing Boulibptid single Mtver.

Know the diverse actions in the drawing and can be used to produce these antibodies and 5 \ or Aladza therefore, can produce derivatives (antibody) in Bptidommateix. In another; techniques God of 0 and Sdovh for the production of single-chain antibody (see, Antralaa, patent US 19

MA 35449Β1 4,946,778, Contrz and Dobell (2010). Luc 0.4 At, and Tel (2009), Locke, Kate,) can be adopted for the production of single-chain antibody specific for Boulibptidat selected. You can also use genetically modified animals to produce antibodies specific for Almansnh Boulibptidat compact and proteins of the present invention. To prepare monoclonal antibodies, any technique, it provides antibodies plantations that produce continuous cell path can be used. Examples of these five techniques on tumor hybrid technology include (Kohler and Milstein Nature, (1975) 256495-497). Pious Trioma, Heiberoduma technique for cell human BV (Kosber, Aminologi claim 4 (1983) 0.72) and technology Heiberoduma EBV for the production of monoclonal antibodies and human antibodies (Cole about each., Antibodies, monoclonal and Alah Alnartan, now seen. Not. You (1985) 0.77 to 96). Ringing Plasmon surface it is also used in Biakour system can Astkhm to increase the effectiveness of the bodies Vij antibodies that bind to the epitope for Boulibptid desired 4, such as epsilon CD3 (Taar. Monoclonal human anti Haeybodomasn (1996) 7. 105-97; Malmborj; Gee, Aminol. Methods 13 -7, (1995) 183). From Tsour also in the content of this invention, the term & quot; antibody & quot; Atolov of antibody combinations, produced as described U below, for example, the body anti formulations which can be transferred and one or Tenbg through 'Inter Walia, viruses or plasmid Alarh factors, the respect of the term' antibody & quot; As it used here in derivatives or Htgeralt of Asam anti described here which displays the same determination as antibodies -taatdmn describe examples of & quot; Antibody variants & quot; On Almansnh variables Ajdzisak Esad; non-human, monoclonal antibodies & quot; Mature ratio '' (see, for example Hawkins about each -ja. Maud, Pajul, (1992) 896 to 889.254 and Le Mans about each ,, Bayukihstre 30 '(1991), 10837-10832) and Tgrat antibody response to changing Bozanf (Bending 'folding P F' reading 5, 648, 260 US states and E (2010) 'to Ok.kit-and Joshua (2009), Locke, Kate). Terms refer & quot; The scope of linking -amold Aledad & quot; , & Quot; Linking Alhold counter-part & quot; And & quot; Hztqh duck antibody & quot; When it is used here to the part of the & lt; esophagus antibody which are Ahaalgy a 00 Saolh Study for the specific link between the antibody and the anti-born. Generator part Mahanaad Lalai 20 1 35449Β1 sweat t c 0 0 specifically linking antibody is referred to s: Aabitob & quot; As Dr. P Bolaiy as mentioned above to proceed, the scope of linking an anti generator usually consists presented Ztaaq I Khgevh the area: «; Anti (VL) and the scope of the area of heavy chain antibody (VH); shower 0's for you; thief has to contain both parts Fd E For does not fill the E contain Z Lassen Z regions of VH and often kept some of the Zigh duck -amold anti-scale linking Adaam born. Examples El Z 0 1 -amold linking members of the anti-antibody (1) Fab part; Part 1 Tda 1 Equal NH Zhlaqat VL, VH. CL and CHI; (2) Part 2 ( 'F (ab E & lt; E p 1 equal to 1 age of 1 penalty Fab linking to link Nthaia Asalafid in the joint area; (3) & lt; E Fd to Hatven 0 n i 1 s 1 t CHVH; (4) part Fv him ranges VL and VH arm apostasy Asm Hiad E (c) dAb part (and Ar.d about each., (1989) Naitre 546-544: 341), which has Zt 1 s VH; (6) the area to identify isolated in an integrated manner ( CDR); and (7) Fv series Mgrdh (gcFv); the latest being the favorite (for example, derived from scFV) group. despite the 1 n Ka-1 S-1 T. VI part, Fv and VH are color-coded discrete genes, can be linked, using combined methods , by compositional link that allows her to Taku, n Kbrocan solo where 1 n Woogie areas VI and VH to Chkpl molecules monovalent (Almaov individually as a string Fv (scFv); see, for example ,, Haston about each. (1988) Brooke. Natalie. Akad. S Aa 0 j 85: 5879-5883 USA). is to get these antibody using the techniques Adolovh known to a person skilled in drawing, and is evaluated parts of the job the same way Kalnna in antibodies sound the term & quot; antibody monoclonal & quot; is also used here the antibody is obtained Elb 9 of the amount of antibodies heterogeneous to some extent KPI, for example antibodies Azadi 2, which consists of that quantity are identical except for possible mutations that occur naturally and 1 or amendments after the transport (for Alaizumiazishnat example, amides) which can be found Vicmyat zero. Monoclonal antibodies are specific is a shame, being directed against the counter-site single gene. Furthermore the presentation, the opposite of the preparations of the antibody (multi monoclonal) fashionable and which usually include antibodies Almokhtlgh against endings Mahtlvh (Alaeptobat), heading this antibody monoclonal against the end of individual ills born anti plus R Thddia, considered antibodies monoclonal

21 1 35449Β1 useful where she composed cultivation Alheiberdema, Guy stocked immune Balglobainat. Dnddr specific monoclonal & quot; To the antibody advantage being obtained from scattering Antdd 1 Li J large antibody, nor Nzqb such as the production of antibody is required in any specific Tr.iqh. For example, monoclonal antibodies monoclonal antibody used according to Alachter 1 GS 1 for current Ahecn be manufactured by Heiberoduma way described first in Kohler about each.; Maadr '495: 256 (1975), or can be made in ways that DNA recombinant (see, pardoned for example E Select reading 1 GS No. 4,816,567). As can be isolated & quot; monoclonal antibodies basketball & quot; Mbmuat of Vij antibody using the techniques described in the Clarkson data.; Naddr; -624: 352 (1991) and 628 Harks 1 v 1's., Ja.hol .bveol., (1991) 597-581: 222 'For heavy Almtnl. We cover one of the bodies of one delegation Z Alakhozaa S Er face Althdbb & quot; D objects delegation 1 & quot; Phantom & quot; (Alglobainat immune) as part are heavy chain and \ or Alggegh 0 and i 1 bugs or Mottagazs sequences 1 to match Ne Glades Amoadh A-H are the species confirmed by 0 or 1 t r 1 in a given class are antibody or subclass, while the rubble Q Aldla ( c) de teacher 1 bugs 1 and harmonious sequences corresponding to the antibodies Alstdh Z Alaraa weapon to or that Che Avi class antibody last or sub-varieties, as well as Alavy'e Zhzh 1 Agam pumps 1 Ende, as long as it was offering biological Hits requested (Abah 1 invention. U. S RIP , 4816 567; s 1 Morrison's., Brock. Zatd 0.1 CAD 0.1 o C 1 j. 81: 6851-6855 'USA (1984)) 0 We cover Alasam phantom focus of attention here, & quot; Alasam newcomer 0 and d-Ashe Ttak are Chasslat Rdt d 1 Lerch 1 Dam Almtver Almstahedz & lt ;, Alehiomat Alrzise non-I (Dsthagaokord Hankiouab etc.). Hdlat ^ Achatas. Alazq Almansnh 1's & quot; They are antibodies Alapshrah (pardoned for example, one of the necktie) p Asubvlot the 0 supplementary food Alohaah, Chains 1 globin Alhmaea 1 and Aladz 1 E Ace 1 (eg, Fv, Fab, Fab 2 ( 'F (ab 1 and sequences linked to another generator counter of Alasam 1 delegation) from Ed Ed pustular E which comprise 0 n Altzlslh Alassary derived are Alalobin Rattler non pustular 'Ze 1 Ladd, objects 1 to counter Almansnh are Alglobainat' human immune (S-1 FD A-) where 1 n visor 1 are .lngar Allt region (also CDR) are Ambassy 5 j del I z

MA 35449Β1 Altver overgrowth of non-human species area (the donor antibody) such as mouse E 1 for a rat or rabbit that have the desired selection, affinity, and capacity. In some, Z Azlat, replacing the last ditch 1 Fly Fv residues (FR) are Alglobin 1 clove human remnants corresponding non-human. Moreover, consisting & quot; Aladjaam anti Almansnh & quot; Used herein are the remnants of the damage of one of the last one to find a god -2 not in future anti-body, not even in the donor antibody. * Walt Tmdna these modifications of the 31 A and improve the performance of the antibody. Body Almkhvad Atolov Almansn on 1-to-face optimal Z Wallach as part Ps Alglobin area of fixed platforms (Fc), usually that are Aws Almz one human apolipoprotein 0 Ntvesel 1 massively multiplayer 0.1 Zzer Jones 1 T. th., Maatr (1986) 525-522 .'321; Rischhan less the ' 332: 323-329 (1988) 'I; and bracket 1 4 Lior. Op. 4 t. Ba * 's., -593: 2 (1992) 596. The term includes & quot; Human antibody & quot; Antibody 1 for in b 0 Matq to change and constant corresponds to a large extent with the sequences Germlaan Alglobin 1 clove 1 to mankind Ashe Rana in the drawing, which include, for example, those described in Kabat about each. (Azzer Kabat 1 T. The (1991)) Locke. Kate). Monoclonal human Muf'dh of Alachter 1 GS 0 includes folding residues 1 amino Alahaad which not only symbolized in Hlslat Algirmlaan human Zawban 1 Foua (blast-to Addl example mutations displayed randomly or mutations Alhoqaah -mahddh in the laboratory or Boath Tgr 1 v 1 to Djaddah P 1 Kazn one neighborhood), the speed Alhthal in CDRs 'u Walles CDR3 .aekn to be the body of the human Aledad Wallach and k, H E Q, Larch' five, or nest more sites Chtbdl remnants acid Wahine is over & lt; g 0 v 0 cent Alglos 1 Sea Algirmlaan human as used here, refers & quot; Antibody was generated in 1 Zmokhtbraa Affi encourages 0 m Anti p that every 1 and part of one of the Mztqh 1 variable (Presentation Speed 1 for an example of folding one for less CDR Y) L Tolbbh in one evil non-immune cell (for example, in the presentation of Glen Ne Avvi; Rqatq Adros and j are Alhlerq as the one selected for the sequences can be tested at 1 N. Qdrnnha blast-0 linkage AVI Anti u) -baltana this | Almsllh best folding 0 No Eshmd sequences 1 Mukh Danzlab Algeevi Alzih in the immune system. 23

MA 35449Β1 antibody & quot; Binary specifically & quot; Or & quot; Dual-function & quot; Or immune Alglobin is an artificial hybrid antibody or immune globin him at least two pairs of heavy chain \ different Khviqh and two different binding sites. The production of antibodies specifically bilateral many ways in which to integrate Heiberodoms We cover or linking to parts' Fab. See, for example Sonevsivili and Lachmann Clin. Win. Aminol. (1990) 321-79: 315. The many ways known to a person skilled in the drawing are available for anti Alajnam or parts connecting -amold counter too. For example, you can Antah antibodies using methods of DNA Almatlgh (patent. US No. 4,816,567). As Aekn produce antibodies monoclonal generate Alheiberodumas (see Kohler and Malcetn (1975) Naitre 0.495 to 499: 256) according to known methods. The problem is examined Alheiberodumas in this way using standard tapping, using superseded absorption immune link enzymatic (ELISA) and analyze the resonance surface Albulasmon (™ BIACORE), to identify one or more are Alheiberodumasalta produces an antibody binds specifically birth Aledad Alahdd any form of birth counter set can be used Cglobin immunotherapy, for example, the birth of an anti Matlv, the shapes found naturally, any variables or parts too, as well as peptide-born counter also includes Tiqh representative and one on the antibody industry to examine protein production groups, for example groups View Glen ribosomes. Phage display is described, for example, one to want to sow seeds in the data.; Reading Annazza .US No. 5,223,409; (b 1985) Elom1317-228: 1315; 6 I n the data (1991). Maabr E 628-624: 352. For the Lad 1 feat R-use display groups, the generator is used to counter specific to immunize one animal for no mortal; for example, rodents, for example mouse, Alhast, or barn. In - 1 and end animal Allapshoa includes at least a portion of the gene Alglobin HIV. Presentation Sibley Olathe 1's, it is possible Vian strains deficient in the production of an antibody Vary in the design are great views of the human Ig loci. Alheiberoduma using the technique, monoclonal antibodies AVI 2 specific antigen derived from genes specifically desired can produce and choose Z MEED example '™ XENOMOUSE, Grease about each. (1994) Naitre Genetics 7: 13-21, 96/34096 2003-0070185, WO c 7 and W096 / 33735. The over-the antibody's unilateral antibodies from an animal not human, then amends, for one Nthal As; fortifies, placebo, can be produced using DNA Almatlgh known in Anrsam techniques described fulfilled many of the manufacturing methods Alajmaam anti phantom. See, for 24

MA 35449Β1 example of Morrison 1 T. 0 'Rock. Matl. Akad. SCL. 81: 6851 .USA E 1985; TICAD 1 1 T. of.; Maatr 1985.314: 452, K-1 Billy about each., Bur 1 cent Achter'a US RIP 4,816,567; Boss about each., Patent. US No. 4,816,397; Tanaguchi about each.; 0171496 EP; 2177096 EP 0173494, GB, is the production of antibodies Almansnh, for example, using the modified Algian genetically Ntij genes of heavy chain and light, but it is capable of producing heavy and light chain genes Zawban immune to rat homogeneous Winter describes a method of p -CDR Ashe said a representative Ahecn -m - one objects to anti Almazszh 1 described this (reading Akhozaa RIP US 5,225,539). CDRs are all human antibody specific Ahin that shows on Apr Wallach & lt; E Z CDR only for drying; or only a few of the CDRs can be evidenced in the CDRs proud. Vgahl of Anwari Adal number of CDRs required to bind the antibody Almansn Ashe born Mufkhad exact y. Also are generating antibodies Almansnh or parts to replace Alhllat 0 n Zt 1 s Fv Alehtgar which does not include a direct part in the anti-born, which connects the Tzlalat equivalent z ranges Fv Almngah human ways representative to generate antibodies Alma 0 Zszh or Alaza metabolize 0 of β (nee Morson (1985) Saivs 1207 -229: 1202; ne or about each. (1986) -1 is your opinion 4: 214; and in; 5,693,762 US 5,585,089; US 5,693,761; US 5,859,205 US and 6,407,213 US. Sun these methods on insulation, processing, and production of DNA sequences that symbolize on all or part of Q ranges Fv ace of Zawban immune from the Wallach is one of the heavy Allslh or light. DTM a-for I & lt ;, these nucleic acids from Heiberoduma which produces an antibody against a specific desired y 'how one described above. as well as other sources. the Astnfaj DNA 1 Lalai rice r Code molecule antibody Almansn to the carrier adequate production. is improving antibody humanized in the presentation Almstbdlat Alamaaohh a \ stoma; -lat a-compliant, genetic Almstbdlat and \ or mutations supportive. the r & lt; Liat F ^ Sa Avcm 4 changing any of these multiple techniques known in Ranam (the scion of one aluminum Ddnj about each.; Brooke. Matl. 1 CAD. 1 Q C-nee. 80: 7308-7312,. , USA; Zzrr 1 T. of, Ameonologi Tudi; 1983.7279: 4; Olson about each., Meth. Enzyme.;, 16.3 921 982), and can be manufactured and Faqaanehatm Ataih at 400 239 EP. Γ / 25

MA 35449Β1 also can be modified antibody or part deletion of the specified Aeptobac human T cells, or & quot; Immunization & quot; The ways described in the 98/52976 and WO 00/34317 WO. In short, the heavy and light variable ranges assholes analysis 0 n to Albptbdat antibody that binds to MHC Class AA, Tmthb these peptides Aeptobac potential of T cells (as specified in WO 98/52976 and 00/34317 WO). To detect Aeptobac bewitching 'T Mahthlh, a computerized approach is applied Nmang called & quot; Polypeptide Threydnh '', and add Uweewman MHC database class! I duck peptides can be searched for in the amendments to the existing VH and VL sequences, as described in the 98/52976 and WO 00/34317 WO .tmrthzh 1 Vfsat seen any are 18 major MHC class II DR for all species, thus forming Aeptobac potential of T cells is eliminated Aeptobac potential of T cells that have been detected by replacing A- figures are the remnants of amino acids in the variable domain, or at best, but the acid Bmstbdlat 0 D single. Usually, the resistance Almstbdlat manufacture of Tver. Often; but Lesser | Ouaili limited to, Ahana amino acid to the site of the Hlslat antibody bowed Shri J 00 Be be used. Is detected Hlslat genetic mankind; for example in Tuhedpson; the data (1992). s. Holl. B Jul 1. 798-227: 776; Cook, Ji .ba the data (1995) Aminol. Tudi delegations 242-237: (5) 16; Tomlivson data and the (1995) EMBO J. 12:14 14: 4628-4638. V BASE directly Dell provides a comprehensive 0 n sequences Alglobin region of human immunoglobulin variable (Group by Tomlinson; the LES. About each. MRC spray - La Roche; Bard c, Yukih). You can use these five sequences as a source of human sequence, for example, to areas of the tire and CDRs. As Imkz 0 0 Adam Matq human Tires compatible; Jt For example, as described in US patent No. 6,300,064. Form pairs VH and VL together Rbttsold Anti single site. CH is designed Alakta scale closer to 1 t VH in CHI. The chain link L R H series in binary Connector Htkavye one, t while he is linked to two of the H R chains - in the land of Rabahl Wade or more of the weight Q Atmad 1 meant pulling ISO Study H. Taatolov ranges VH and VI g August regions of one of the sequences' to HostGator relatively Olney p Ignored 1 Taq Aladarat (FRI, FR2, FR3 and FR4) and 1 st form a coughing for three zones of variable sequences excessively (specifically complementary areas E CDRs). Seduces CDRs Presentation majority remains responsible for specific interactions Njsm Alhiad Ha 1 of the birth of one of the counter. Back CDRs 1 t CDR 1, CDR2 and CDR3 - and Ehgha to that, Zhkellat CDR back on the chain basket R Η1, Η2 and Η3 'r formations in the CDR Alkhviqh series R2 back a AA 0 and 3 a. The term & quot; Mtver & quot; To parts ranges Asuc Acae Ashe Z Altver in u; A'a; one here, which we include in determining the quality and the PEG ratio of the body 1 FD Alfdd (eg. In & quot; Alq 1 T. changing & quot;). Are not distributed Altver evenly across the bands 1 Study of the bodies of one delegation 'ββ that U (// 1 35449Β1 in sub-bands for each of the heavy chain variable chain light areas; Sama these subdomains regions & quot; Haaparvariabl & quot; R & quot; specifically Integrative & regions quot; ( CDRs). 1 many parts negotiable Tver (for example, Alla- Heibervaribl) Almngah ranges called regions AA frame & quot; (FRM) both changing bands of heavy and light chains are composed naturally from the four regions of FRM, which rely heavily on the formation of Shit - β, visor I in three areas Heibervaribl, which form loops related, in some cases forming part of the installation chit _β are Hgz areas Heibervaribl in each series together on a dusty FRM; and with areas Heibervaribl other chain, contribute to the formation of Z-born anti - 0 occurred connectivity (see Kabat about each., Luc. Kate). fixed ranges are ^ not include der Ne connecting 0-born counter, but the functions of diverse response, like, me for example, show; Lalai Iathd the antibody, toxicity, which mediate cell and activation integrative. Amodil of the Dzfairs binding of invention that constitutes a first range and'tna & lt; esophagus Mokhtar 0 n Z group 2 (scFv), (mAb scale solo) scFv- mAb range of solo, duo or body Alaolajomirat too. Pierre d & quot; CDR & quot; And a total of & quot; CDRs & quot; , To identify complementary region (CDR) are the Tree-clearing, three of which made connectivity feature of the light chain variable region (, CDRLI CDRb2 and CDRL3) and three of them made connectivity feature of Stqh heavy chain variable (CDRHI) CDRH2 and CDRH3). CDRs contribute to the functional Aldhalah rewarded. The antibody Btzlslat separating the amino acid, which consists of the scaffolding or Aladarat areas. CDR limitless tariff and specific lengths are placed to different classification and Agherna systems. Balt 1 Ne back CDRs I Kabat, Kuthia, contact or any other specific definitions, include & lt ;, J 13:00 numbering described here. Although Almokhtlgh border, each of these systems Asbouk degree Akedaza Ne formulations which are called & quot; Heibervaribl regions & quot; Within the changing sequences. Thus Seche said - I Naravat CDR Rafka these regimes in length and border areas, according to one Affi area adjacent frame. See, for example Kabat, Kuthia, and \ or Makaleom (Kabat about each I RCA Kate; Cuthba about each. P Lord Pajul 901; 196.1987 and Hakaleom less the r b Hall 1 Jul 732; 262.1996). Although it, the numbering according to the so-called ^ m Kabat is problematic. Indicate the terms of a 'amino acid & quot; Or & quot; Lamcy acid residues & quot; ^ For the birth of R Hmkh 7 Ambz-Z These 0 Ely Wallach recognized definition such as Cas selected amino group that Taatolov & lt ;,: Wallach (Ala or A); Arjanin (Arg R-R), Aspargen (Asn or N); acid 1 to Adhartd Asp) or D); Saistin (Cys or C); glutamine (Gin or Q); Glutamak acid (Glu or E); glycine (Gly or G), Hstidin (His or H); ISO, Lucien (He or I): Los (Leu 1 and L) E Lassen (Lys or K); Mecioh (Met or M); Ffinelalad (Phe or F) 'walked Rowe (Pro or P); serine (Se2 or c); Tronen (Thr or T); Traytovun (Trp or W); 27

MK 35449Β1 Although the modified formulations, or acids, (V or Val); and valine (Y 1 and Tyr) Tairosen nation Avadrh can be used according to the desire, in general, can be collected acids dysentery Ala) Cys, He, leu. Met, presented it side chain non-polar (pardoned bubonulus example; series (Asp, Glu; side chain negatively charged (for example (Phe, Pro, Val or side chain polarity Guy, (Arg, His, side-lys charged positively (Presentation For example Asn, Cys, Gin, Gly, His, Met, Phe, Ser, Thr, charged (for Alhial. (TyrjTrp feel 1. AA Heibervaribl & quot area; (because I also know in the & quot; area determine complementary & quot; or CDRs) while -m here to the remnants of amino acids of an antibody which are (usually three or four short regions of Tver series Wallach) - Ndlaq area -V are not; that. & n S 1:00 and which is linked to -amold counter site and are endings basic generator counter. there are at least Z to determine residues 1 1): CDR) Hzahj Ahdhum & lt ;, s 1 Q Alaraa cross-changing (for example Kabamt about each., Luc. -); and (2) - Ahom blast-based Dramdat gelling compounds antibody - 1 antigen (Kot | 'daddy; 1 T. of Lage Maud, Biol. (1987) 917-901: 196). Although 0 n so, the extent to which the two devout identify the remains presented identify overlapping areas; but Lunds Hmatq stretch one bug, -L t A. to determine Hybrid CDR. On it, a ^ m, disparaging number of bugs 1 O CDR blast-Ala- Oukq 0 1 R so-called system (numbering) Kabat term & quot refers; Frame & quot area; R-known parts of the Erdem - 0 m m pilaster Z Z between CDRs Alakir variation (Presentation For Almth Heibervaribl). Dodd Mmat ^ a 1 to the framework of this usually 0 1.0 Matq frame 1 1 R. 4 (FRI, FR2, FR3 and FR4) and provide a scaffold to provide six CDRs (three from the heavy chain and three for Alkhnevh series) Apr Zath Ala-; P, the surface of the Pt antigen B-1 for the usually * - CDRs installation episode you can describe as installing unacceptable. The term & quot; Installing acceptable & quot; Home to the formation of the series, which was obtained herewith -t 0 for 1 with whether Mok counter (CDR), the compositional studies Alakarnh, found that pardoned Study x 0 or Z Habqat with whether the generator counter her only reference Mahdrd formations' for Mtofferz. Little & lt; Each Dr- Yale Balzo 1 O twisted Alboulibptid basis. Thus matching loops Ben Glades anti t installation of 1 L GF 1a trilogy is very small, although Tver sequence homocysteine shame in A- 1 penalty loops & lt; Kloulia and coining Ji Mall! Jul E 901: 196.1987; Kl.a 1 T. of 0.4 - E: 342.1989 877; Zrtn and Thorntyon, Ji Mall Pajul 0.800: 263.1996 'lasted all - your certificate included in the totals). Moreover, there Aladh Z Dr- A- I and one sweet to acid Alahivy that surround it. Dade is one Dash- Adash Seoul Alhhdd Bo'th the length of the loop and the remnants of homocysteine, which Tnh in re- sites - coordinated by E Hvla & lt ;, within the reserved frame (for Almial, outside Iqh 1). Short Nkod Htef Set 28 1 35449Β1 therefore, is based on the inventory of the remnants of these amino acids, can be - a composition-acceptable & quot; Considerations as in Altzlslh longitudinal 0 n antibody 'For example, as cataloged in Kabat (Kabat about each., Locke Kate..) Are adopted Nrd Kabat scheme (system) is widely numbering remnants of amino acids of the scope of the Tver antibody consistent and how one he Amodil Almtbol planned in the present invention is also mentioned here. Also, a «Rat synthetic extra can also be used to determine the composition acceptable to the antibody. For example, 'these differences that are not fully reflected numbered caps are described in the system argue Ku 0 Thea about each and \ or disclose techniques other, for example, gelling and Altmang the Λ' «his father has Inadih or Althelandh dimensions according to it, is placed sequence antibody is given in the category of acceptable where Ddh in determining the sequences of appropriate structures (for example, you are pardoned basis Tdb & lt ;; t 0 '& quot; 6 a 1 t Alded 0 n 1 Arkilat accepted in the group) 0 numbering Kabat sequences amino acid of the antibody and synthetic considerations as described in Kuthia about each; taste. Kei. And -t Akhartmd aspects Nczykab acceptable Tkib antibody, described Apr 1 Z landfill;: tags. CDR3 Padadh is the most important source of diversity Jizzi, within the connecting - the antibody site. Η3, "b; S's, it could be a limited two amino acid residues or more as of 26 from amino acid sub-unit and combinations of T-Lad-dimensional & lt ;, Aladt 1 P different from Alglobainat immune spared in the drawing. Krd uniforms ales 1 1 hands; Azz 0 Alajdz 13:00 anti: laboratory folder, Cold Spring H 1 rapper to Autuori, Adz. 199 Darz data -uahd skilled in the art will recognize that each installation and sub-unit, for example the installation of CH, VH, CL, VL, CDR, FR comprises 0 n effective parts E For Shall 'about VH, VL, or CDR subunit attached to having a generator counter, for example E Rbahl part -amold counter, or, the unit ground CH Ashe Trbahl part Affi and \ or fetch, shower Q 1 for an example of the future of the Fc and \ or Mkml.d CDRs Bela 1 de Affi Cap 1 T. CDRs' k 0 a Aohv in a -t Z Albrooaat immunity, U S. Department of health and human Services (1991) '1 DZ Cap 1 t 1 t of, additional bar to distinguish the anti-born, which connects the site is to refer to Habderf rings 1 Chubby Kha described in Kuthia. See, for example Kuthia about each (1987 G Mall Zayoud 817-227: 799); and the Tomiinson 1 T. (1995) 4638-4628: 14 SYP EMBO. Standard one another is Ib 1 Rh Add AbM software used in the modified Oxford Maklor AbM Jesse Hiad 0 0 1 Zzer; Epeshkd year, for example, and protein sequence analyzes the installation ranges AA? ":. Newcomer one household, in addition to Manuel designing an antibody (Ed: Djubl S and Konnenzzn; the I; Springer Dharlag Heldberj), instantiations described according Affi Kabat CDRs Ahguen that to that point led Bdid using Anwabt similar described according to Kotie rings Heibervaribl or rings AbM- specific. , T 0 Ttslo Jiv 1 T. reduce anti accumulated after the boom and physical are high, and estimates. This | to Jivat 1. Hnyhzafyha 10 of antibody molecules Alachtlvh (genes Alglobainat 29 i 35449Β1 immune, DJ f, Adz, Johnnyo about each. Academic Press; o \ n Ddloo; K'dfferslaa; 1995). According to this, the immune system provides a reference for Zawbanat Afbh. Athber term & quot; Reference & quot; To at least one sequence nucleotides derived wholly or partially Z for at least one sequence symbolizes the at least one immune globin. The Tweed sequences B1 to arrange in the organism 0 n segments V) D and for heavy chains, and segments V and for strings any Alternatively, is generated sequences for the cell to respond, where the order is happening; for example in the stimulation in vitro. Alternatively, part or all of the sequences can be obtained by linking DNA, the structures of nucleotides, mutagenesis, and other ways, see the Sepel_, Almial c 0.7 5,565,332 patent the invention. It includes a reference to the sequence and includes only one or many of the sequences, which include those that vary genetically. In the embodiment of one, the scope of the first binding of & lt; esophagus linkage of the invention consists of a VH region comprising 0 n CDR-H1, CDR-H2 and CDR-H3 and the region of 7 comprised 0 n, CDR-L1 CDR-L2 and CDR-L3 selected from the group composed as they are illustrated SEQ ID NO: 6, CDR-H2 is illustrated in ^ CDR-H1 (1) SEQ ID NO: 3, Z Dahsrh in SEQ ID NO: 2, CDR-H3 in as is illustrated SEQ ID NO: 4 a CDR-L-2 is illustrated in ^ CDRLI SEQ ID NO: 6: Z r sucking 0 Subject to fay CDR-L3 in 0: 5 ^ 0 £ is as is SEQ ID NO: 11, CDR-H2 is illustrated in ^ CDR-H1 ( 2) SEQ ID as is illustrated in SEQ ID NO: 12, CDR-H3 Kha illustrated in SEQ ID NO: 14, CDR-I2 is Msh- in ^ NO: 13, CDR-11 as is illustrated Ne CDR-I3 and SEQ ID NO: 15 are illustrated in SEQ ID NO: 16; As SEQ ID NO: 21, CDR-H2 is illustrated in ^ CDR-H1 (3) SEQ ID Kha p Hsourh in SEQ ID NO: 22, CDR-H3 Msolh in Kha SEQ ID NO: 24, CDR-12 is Hsourh in ^ NQ: 23, CDR-I1 as is illustrated in the CDR-13 and SEQ ID NO: 25 are illustrated in SEQIDNO: 26; 30

MK 35449Β1 Kha is SEQ ID NO: 31, CDR-H2 in 0 picture in ^ CDR-H1 (4) SEQ ID as is illustrated in SEQ ID NO: 32, CDR-H3 illustrated in Kaaa SEQ ID NO: 34, CDR-12 Kaaa is illustrated in NO: 33, CDRLI as is illustrated in the CDR-13 and SEQ ID NO: 35 are illustrated in SEQIDNO: 36; Kaaa is SEQ ID NO: 41, CDR-H2 in pictorial Ne Î ^ CDR-HI (5) SEQ ID Kha in Rh in SEQ ID NO: 42, CDR-H3 0 picture in Kha SEQ ID NO: 44, CDR-12 43 : 0 to 0 in the picture in, CDRLI as is illustrated in the CDR-E3 and SEQ ID NO: 45 are illustrated in SEQIDNO: 46; Z in SEQ ID NO: 51, CDR-H2 at p 0 of the ^ CDR-H1 (6) SEQ ID Kha in Hsourh in SEQ ID NO: 52, CDR-H3 Msourg 0 in the Z SEQ ID NO: 54, CDR-12 in Hsourh in NO: 53, CDR-L1 Z in Q6 him in the CDR-L3 and SEQ ID NO: 55 in -rz in SEQIDNO: 56; Z in SEQ ID NO: 61, CDR-H2 at p; in ^ CDR-H1 (7) SEQ ID as is illustrated in SEQ ID NO: 62, CDR-H3 illustrated in my SEQ ID NO: 64, CDR-12 63 : 0 SA in Hsourh in, CDR-L1 in Kha cameraman 0 CDR-13 and SEQ ID NO: 65 in Surat 'Ne SEQIDNO: 66; Kaaa is SEQ ID NO: 71, CDR-H2 is illustrated in ^ CDR-H1 (8) SEQ ID Z in Msolh in SEQ ID NO: 72, CDR-H3 Msourz 0 k 0 of SEQ ID NO: 74, CDR-L2 as they are illustrated in NO: 73, CDR-L1 Kha in Y; in CDR-L3 and SEQ ID NO: 75 are illustrated in SEQIDNO: 76;

Ik / 31 1 35449Β1 Kha p SEQ ID NO: 161, CDR-H2 p Hmurh Ne ^ CDR-H1 (9) SEQ ID as is illustrated in SEQ ID NO: 162, CDR-H3 illustrated in SEQ ID NO: 164, CDR -12 163: 410 is a pictorial in, CDRLI as is illustrated in the CDR-13 and SEQ ID NO: 166 as is illustrated in SEQIDNO: 166; Z r SEQ ID NO: 171, CDR-H2 Z Image 0 ^ CDR-H1 (10) SEQ ID also pp; in SEQ ID NO: 172, CDR-H3 Hsolh in SEQ ID NO: 174, CDR-I2 p Hsourh in L54NO: 173, CDR-11 as is illustrated in the CDR-I3 and SEQ ID NO: 175 as is illustrated in SEQIDNO: 176; Z Q SEQ ID NO: 181, CDR-H2 AM 0 picture in ^ CDR-H1 (11) SEQ ID Z p 0 picture in SEQ ID NO: 182, CDR-H3 cameraman · in SEQ ID NO: 184, CDR-E2 183: 0 C for 1 Rh ne, CDR-L1 as is illustrated in the CDR-13 and SEQ ID NO: 185 as is illustrated in SEQIDNO: 186; As SEQ ID NO: 191, CDR-H2 is illustrated in ^ CDR-H1 (12) SEQ ID Kha de Habbarrh in SEQ ID NO: 192, CDR-H3 Hsourh in SEQIDNO: 194, CDRL2 is 0 0 picture in Ι ^ ΝΟ: 193, CDR-L1 as is illustrated in the CDR-L3 and SEQ ID NO: 195 as is illustrated in SEQIDNO: 196; Z r SEQ ID NO: 201, CDR-H2 1 is illustrated Ne ^ CDR-H1 (13) SEQ ID Kha p Asolh in SEQ ID NO: 202, CDR-H3 Hsourh in SEQ ID NO: 204, CDR-I2 pp. ; in ^ NO: 203, CDR-11 Kha p Hsourh Ne CDR-E3 and SEQ ID NO: 205 4 what are the -rz in SEQIDNO: 206; 32

IK 35449Β1 as SEQ ID NO: 211, CDR-H2 Ne 0 Photo Ne ÜCDR-H1 (14) SEQ ID as is illustrated in SEQ ID NO: 212, CDR-H3 illustrated in SEQ ID ΝΟ: 214, CDR-E2 213: 410 a ne r; ne, CDRLI Kha is Hmurh in the CDR-13 and SEQ ID NO: 215 Kha Ne Q 0 Subject to the SEQ ID NO: 216; as Ne SEQ ID NO: 221, CDR-H2 Ne Study 0 ^ CDR-H1 (15 ) SEQ ID Kha is Msolh in SEQ ID NO: 222, CDR-H3 p; ne SEQ ID NO: 224, CDR-I2 223: 0 what is Y; in, CDR-11 as is illustrated in the CDR-E3 and SEQ ID NO 225 as is illustrated in SEQIDNO: 226; Z SEQ ID NO: 311, CDR-H2 p libra ni ^ CDR-H1 (16) SEQ ID as is illustrated in SEQ ID NO: 312, CDR-H3 illustrated in SEQ ID NO: 314, CDR-E2 313: 0 to Atma p. AL · in, CDRLI as is illustrated in CDRL3 and SEQ ID NO: 315 as is illustrated in SEQIDNO: 316; Z r SEQ ID NO: 321, CDR-H2 XY; in ^ CDR-H1 (17) SEQ ID as is illustrated in SEQ ID NO: 322, CDR-H3 illustrated in SEQ ID NO: 324, CDR-12 323: 410 is a Msolh in, CDRLI as is illustrated in the CDR-13 and SEQ ID NO: 325 as is illustrated in SEQIDNO: 326; Z Ne SEQ ID NO: 331, CDR-H2 nee Q 1 of the ^ CDR-H1 (18) SEQ ID as is illustrated in SEQ ID NO: 332, CDR-H3 illustrated in SEQ ID NO: 334, CDR-L2 333: 10 What p Surat, CDR-L1 Kha Ne Ne 0 cameraman CDR-L3 and SEQ ID NO: 335 as Ne -r; Ne SEQIDNO: 336; 33

MK 35449Β1 Z r SEQ ID NO: 341, CDR-H2 1 p Mhorh in ^ CDR-H1 (19) SEQ; in her F Kaa 1 Aa SEQ ID NO: 342. CDR-H3 0 Szl; in SEQ ID NO: 344. CDR- 0:00 S0-in ^ NO: 343, CDR-11 as is illustrated in the CDR-L3 and SEQ ID NO: 345 as is illustrated in SEQIDNO: 346: as SEQ ID NO: 351, CDR-H2 is illustrated in Î ^ CDR-HI (20) SEQ ID Kha is Y; in SEQ ID NO: 352, CDR-H3 0 image Apr SEQ ID NO: 354, CDR-E2 353: 0 for any p Hsourh in, CDR-I1 as is illustrated in the CDR-13 and SEQ ID NO: 355 as is illustrated in SEQIDNO: 356; Kha p 0 SEQ ID NO: 361, CDR-H2 p Rh in ^ CDR-H1 (21) SEQ ID Kha Z Hsourh in SEQ ID NO: 362, CDR-H3 p; in SEQ ID NO: 364, CDR-12 363: 0 Lay Online are in, CDR-L1 km 1:00 cameraman 'in the CDR-L3 and SEQ ID NO: 365 Kha Hmurh neighborhood in SEQIDNO: 366; Z Q SEQ ID NO: 371, CDR-H2 in bad 0 ^ CDR-H1 (22) SEQ ID as in Hsourh in SEQ ID NO: 372, CDR-H3 0 passed in SEQ ID NO: 374, CDR-L2 373: Hlay is illustrated in, CDR-1 Kha in a Y; in CDR-L3 and SEQ ID NO: 375 Ka is -rz in SEQIDNO: 376; Ka in SEQ ID NO: 381, CDR-H2 14 is Srrh in CDR-H1 (23) SEQ ID Kha in 0 picture in SEQ ID NO: 382, CDR-H3 Msolh in SEQ ID NO: 384, CDR-L2, as is illustrated in NO : 383, CDR-1 as a 5A my Msourg 0 in the CDR-L3 and SEQ ID NO: 385 as -rz in SEQIDNO: 386; / ,,; 34 1 35449Β1 Z Z SEQ ID NO: 581, CDR-H2 pp; in L ;; 0CDR-H1 (24) SEQ ID Kaaa is the fence; in SEQ ID NO: 582, CDR-H3 Surat in SEQ ID NO: 584, CDR-L2 583: Hearings p o! In, CDR-L1 is 1 km cameraman 0 Ne CDR-L3 and SEQ ID NO: 585 km 1 in Sozh 'in SEQIDNO: 586; As SEQ ID NO: 591, CDR-H2 is illustrated Ne ^ CDR-H6 (25) SEQ ID Kha is Y; in SEQ ID NO: 592, CDR-H3 Msourg 0 in SEQ ID NO: 594, CDR-I2 in 0 Photo in ^ NO: 593, CDR-I1 as is illustrated in the CDR-13 and SEQ ID NO: 595 as is illustrated in SEQIDNO: 596; Z in SEQ ID NO: 601, CDR-H2 at p; ne ^ CDR-H1 (26) SEQ ID as is illustrated in SEQ ID NO: 602, CDR-H3 illustrated in SEQ ID NO: 604, CDR-I2 in pictorial in LSNO: 603, CDRLI as is illustrated in the CDR-L-3 and SEQ ID NO: 605 as is illustrated in SEQIDNO: 606; Z in SEQ ID NO: 611CDR-H2 in Msh'vi ^ CDR-H1 (27) SEQ ID as 0 in a Dorz Ne SEQ ID NO: 612, CDR-H3 t; Ni SEQ ID NO: 614, CDR-12 613: 0 him in .sourh in, CDR-I1 as is illustrated in the CDR-13 and SEQ ID NO: 615 as is illustrated in SEQIDNO: 616; As in SEQ ID NO: 621, CDR-H2 in cameraman Ne Î ^ CDR-HI (28) SEQ ID Kha in the sacrament; of Ne SEQ ID NO: 622, CDR-H3 illustrated in SEQ ID NO: 624, CDR-I2 623: 0 SA is illustrated in, CDR-I1 km 1 in Sioux (of the CDR-L3 and SEQ ID NO: 625, as in the illustrated in SEQ ID NO: 626; A / 35 1 35449Β1 Z are 0 SEQ ID NO: 631, CDR- H2 Q Surat Ne ^ CDR-H1 (29) SEQID Z Z 0 picture of me SEQ ID NO: 632, CDR-H3 Q; in SEQ ID NO: 634, CDR-L2 in Surat in the 'NO: 633, CDR-11 as it is illustrated in the CDR-L3 and SEQ ID NO: 635 as is illustrated in SEQIDNO: 636; as SEQ ID NO: 641, CDR-H2 is illustrated in L ^ CDR-ΗΙ (30) SEQ ID km 1 Apr -rz Ne SEQ ID NO: 642, CDR-H3 cameraman 'in SEQ ID NO: 644, CDR-12 643: 1410 in Ne Sorh-, CDRLI as is illustrated in CDR- and 3 of SEQ ID NO: 645 as is illustrated in SEQIDNO: 646: Z Ne SEQ ID NO: 651, CDR-H2 Ne Y; in ^ CDR-H1 (31) SEQ ID as in Hsourh in SEQ ID NO: 652, CDR-H3 pictorial 0 Ne SEQ ID NO: 654, CDR-L2 as in Surat · in NO: 653, CDR-I1 as is illustrated in the CDR-L3 and SEQ ID NO: 655 as is illustrated in SEQIDNO: 656; Z in SEQ ID NO: 661, CDR-H2 at p; in ^ CDR-H1 (32 ) SEQ ID Kha in pictorial in SEQ ID NO: 662, CDR-H3 Mehrrh in SEQ ID NO: 664, CDR-E2 663: 410 in 0 picture in, CDR-11 Kha in cameraman 0 in the CDR-E3 and SEQ ID NO: 665 Ka p; ne SEQIDNO: 666; Z in SEQ ID NO: 671, CDR-H2 43 in Y; in DR-H1 (33) SEQ ID Kha in cameraman · Apr SEQ ID NO: 672, CDR-H3 0 picture in SEQ ID NO: 674, CDR-I2 673: 0 in any couches 4, CDR-E1 as the cameraman in the CDR-13 and SEQ ID NO: 675 in Hsourh Ka Ne SEQIDNO: 676; 3δ hi 1 35449Β1 as SEQ ID NO: 681, CDR-H2 is illustrated in Î ^ CDR-HI (34) SEQID as .sourh in SEQ ID NO: 820 c CDR-H3 illustrated in SEQ ID NO: 684, CDR- I2; r in r ^ NO: 683, CDRLI as is illustrated in CDRL3 and SEQ ID NO: 685 as is illustrated in SEQIDNO: 686; Ka Q SEQ ID NO: 691, CDR-H2 R She in ^ CDR-H1 (35) SEQ ID Kha AM 0 picture in SEQ ID NO: 692, CDR-H3 0 picture in SEQ ID NO: 694, CDR-L2 693: 0 loyalty is Sh- in, CDRLI Kha de Surat 0 Ne CDRL3 and SEQ ID NO: 695 Ka is Q 0 Subject to the SEQIDNO: 696: Z r SEQ ID NO: 701, CDR-H2 pp; in ^ CDR-H1 (36) SEQ ID Kha 5 j Hsourh in SEQ ID NO: 702, CDR-H3 Hsourh in SEQ ID NO: 704, CDR-L2 703: 0 for any p Hsourh in, CDRLI as is illustrated in the CDR-L3 and SEQ ID NO: 705 as is illustrated in SEQIDNO: 706; Z SEQ ID NO: 711, CDR-H2 Q Libra 0 Ne ^ CDR-H1 (37) as is illustrated in SEQ ID NO: 712, CDR-H3 are illustrated in SEQ ID p Hsourh in ^ SEQ ID NO: 713, CDR- 11 and SEQ ID NO: 715 714: 0 SA is illustrated in, CDR-L2 SEQ ID NO: 716; Is Surat ^ CDRL3 Z r SEQ ID NO: 721, CDR-H2 Q Study 0 ^ CDR-H1 (38) SEQ ID of 0 A is 0 libra ni SEQ ID NO: 722, CDR-H3 illustrated in SEQ ID NO: 724, CDR -12 p Hsourh in L ^ NO: 723, CDRLI km 1 4 is a photographer in the CDR-13 and SEQ ID NO: 725 Kaaa my -r; Ne SEQIDNO: 726: 37

MK 35449Β1 as SEQ ID NO: 731, CDR-H2 is the sura in the NDR-ΗΙ (39) SEQ ID; in Jf Ka is SEQ ID NO: 732) CDR-H3 p; in SEQ ID NO: 734, CDR-L2 p. e 0 image in the 'NO: 733, CDR-11 as is illustrated in the CDR-E3 and SEQ ID NO: 735 as is illustrated in SEQIDNIO: 736; As SEQ ID NO: 741, CDR-H2 is Msooh in the NDR-H1 (40) SEQ ID Kha is -rz Ne SEQ ID NO: 742, CDR-H3 0 picture in SEQ ID NO: 744, CDR-12 as is illustrated in NO: 743, CDRLI Ka is Srrh 'Ne CDR-L3 and SEQ ID NO: 745 km 1 is 0 Hsourh in SEQIDNO: 746; As SEQ ID NIO: 751, CDR-H2 is illustrated in the NDR-H1 (41) SEQ ID km 1 p; in SEQ ID NO: 752, CDR-H3 p; in SEQ ID NO: 754, CDR-L2 p 0 Photo in NO: 753, CDR-11 Ka is illustrated in the CDR-L3 and SEQ ID NO: 755 Kha in Y; in SEQIDNO: 756; As in SEQ ID NO: 761, CDR-H2 in a pictorial in the NDR-H1 (42) SEQ ID Kha in Srrh in SEQ ID NO: 762, CDR-H3 0 picture in SEQ ID NO: 764, CDR-L2 in a pictorial in NO : 763, CDR-11 Ka is illustrated in the CDR-13 and SEQ ID NO: 765 Ka in -r; in SEQIDNO: 766; Ka Z SEQ ID NO: 771, CDR-H2 in Mhsrh in the NDR-H1 (43) SEQ ID 1 km in -rz in SEQ ID NO: 772, CDR-H3 t; in- SEQ ID NO: 774, CDR-L2 as is illustrated in NO: 773, CDR-I1 4 is a pictorial in the CDR-I3 and SEQ ID NO: 775 Ka in -r; Ne SEQIDNO: 776; 38

MA 35449Β1 Ka Q SEQ ID NO: 781, CDR- H2 at p; in ^ CDR-H1 (44) SEQ ID as Y; in SEQ ID NO: 782, CDR- H3 Hsourh in SEQ ID NO: 784, CDR- 12 as is illustrated in NO: 783, CDR-L1 as is illustrated in the CDR-I3 and SEQ ID NO: 785 as is illustrated in SEQIDNO: 786; Ka in SEQ ID NO: 791, CDR- H2 r Se 'in ^ CDR-H1 (45) SEQ ID Kha in Surat in SEQ ID NO: 792) CDR- H3 0 image Apr SEQ ID NO: 794, CDR- 12 as it is illustrated in NO: 793, CDR-L1 as is illustrated in the CDR-13 and SEQ ID NO: 795 as is illustrated in SEQIDNO: 796; As in SEQ ID NO: 801, CDR- H2 in m picture in Î ^ CDR-HI (46) SEQ ID Kha in m 5 justified by the SEQ ID NO: 802, CDR- H3 Msourh- in SEQ ID NO: 804, CDR- E2 as it is illustrated in NO: 803, CDR-L1 as is illustrated in the CDR-L3 and SEQ ID NO: 805 as is illustrated in SEQIDNO: 806: Sha in SEQ ID NO: 811, CDR- H2 in the Rh in ^ CDR-H1 ( 47) SEQ ID Kha in Y; in SEQ ID NO: 812, CDR- H3 Hsourh in SEQ ID NO: 814, CDR- L2 813: 1 m 'in Sorh- in, CDRLI as is illustrated in the CDR-I3 and SEQ ID NO : 815 as is illustrated in SEQIDNO: 816; Z in SEQ ID NO: 821, CDR- H2 in the bad in ^ CDR-H1 (48) SEQ ID Kaaa are illustrated in SEQ ID NO: 822, CDR- H3 illustrated in SEQ ID NO: 824, CDR- 12 in a pictorial in ^ NO: 823, CDRLI as is illustrated in the CDR-I3 and SEQ ID NO: 825 as is illustrated in SEQIDNO: 826; 39

MK 35449Β1 1 km are SEQ ID NO: 831, CDR-H2 is illustrated in ^ CDR-H1 (49) SEQ ID Kha is illustrated in SEQ ID NO: 832, CDR-H3 x 4 in SEQ ID NO: 834, CDR-L2 as Hsourh are in NO: 833, CDRLI as is illustrated in the CDR-I3 and SEQ ID NO: 835 in Kha cameraman 0 in SEQIDNO: 836; Ka in SEQ ID NO: 961, CDR-H2 in SSH 0 ^ CDR-H1 (50) SEQ ID as in pictorial in SEQ ID NO: 962, CDR-H3 p; ne SEQ ID NO: 964, CDR-12 Kaaa are illustrated in NO: 963, CDRLI Ka in Q; in CDR- and 3 of SEQ ID NO: 965 Kha in Y; Ne SEQIDNO: 966; As in SEQ ID NO: 971, CDR-H2 in a pictorial in the Î ^ CDR-HI (51) SEQ ID Kha in Hsourh in SEQ ID NO: 972, CDR-H3 0 picture in SEQ ID NO: 974, CDR-L2 is illustrated Ne LSNO: 973, CDRLI Kha in Srrh 'in the CDR-I3 and SEQ ID NO: 975 as a 0 in -r; in SEQIDNO: 976; As in SEQ ID NO: 981, CDR-H2 in a pictorial in the ^ CDR-ΗΙ (52) SEQ ID Kha in pictorial in SEQ ID NO: 982, CDR-H3 Sdorh Ne SEQ ID NO: 984, CDR-12 in Hsourh in ^ NO: 983, CDR-11 as is illustrated in the CDR-E3 and SEQ ID NO: 985 as is illustrated in jSEQIDNO: 986; Kaaa in SEQ ID NO: 991, CDR-H2 in a pictorial in the ^ CDR-H1 (53) SEQ ID Kaaa in pictorial in SEQ ID NO: 992, CDR-H3 illustrated in SEQ ID NO: 994, CDR-12 in Surat L54NO: 993, CDR-L1 as is illustrated in the CDR-L3 and SEQ ID NO: 995 as is illustrated in SEQIDNO: 996. 40

MK 35449Β1

Selected VH in - additional Mgdil, consists Zt 1 s Tighten the first of lawn 0 esophagus binding of SEQ region ID NO: 7, as is illustrated in VH from the group consisting of SEQ region ID NO: 17, SEQ ID NO: 27, SEQ ID NO: 37 , SEQ ID NO: 47, SEQ ID NO: 57, SEQ ID NO: 67, SEQ ID NO: 77, SEQ ID NO: 167, SEQ ID NO: 177, SEQ ID NO: 187, SEQ ID NO: 197, SEQ ID NO: 207, SEQ ID NO: 217, SEQ ID NO: 227, SEQ ID NO: 317, SEQ ID NO: 327, SEQ ID NO: 337, SEQ ID NO: 347, SEQ ID NO: 357, SEQ ID NO : 367, SEQ ID NO: 377, SEQ ID No: 387, SEQ ID NO: 587, SEQ ID NO: 597, SEQ ID NO: 607, SEQ ID NO: 617, SEQ ID NO: 627, SEQ ID NO: 637 , SEQ ID NO: 647, SEQ ID NO: 657, SEQ ID NO: 667, SEQ ID NO: 677, SEQ ID NO: 687, SEQ ID NO: 697, SEQ ID NO: 707, SEQ ID No: 717, SEQ ID NO: 727, SEQ ID NO: 737, SEQ ID NO: 747, SEQ ID NO: 757, SEQ ID NO: 767, SEQ ID NO: 777, SEQ ID ^ 0: 787, SEQ ID NO: 797, SEQ ID NO: 807, SEQ ID NO: 817, SEqid NO: 827, SEQ ID NO: 837, SEQ ID NO: 967, SEQ ID SEQ ID NO: 997 and NO: 977, SEQ ID NO: 987: Mokhtalh VL in the embodiment of one another ; Zv the scope of the first binding Z & lt; esophagus Rabhl Q Hzzh; Eq id in SEQ ID Z p illustrated in VL 0, which Taatov from area c: 0 A \; - SEQ ID NO: 18, SEQ ID NO: 28, SEQ ID NO: 38, SeG ID 48: 0 ;, SEQ ID nO: 58. SEQ ID nO: 68, SEQ ID no ': S'. SEG ID 0: 168 ;, SEQID NO: 178, SEqid NO: 188, SEQID NOia Haheh NO: 208, SEQID NO: 218, SEQID NO: 228, SEQ her lyf 41

MK 35449Β1 NO: 318, SEQID SEQID NO: 358, NO: 388, SEQID SEQID NO: 618, NO: 648, SEQID SEQID NO: 688, NO: 718, SEQID SEQID NO: 758, NO: 788, SEQID SEQID NO: 828, NO: 328, SEQID SEQID NO: 368, NO: 588, SEQID SEQID NO: 628, NO: 658, SEQID SEQID NO: 698, NO: 728, SEQID SEQID NO: 768, NO: 798, SEQID SEQID NO: 838, SEQ ID NO: 998 NO: 338, SEQ ID NO: 348, SEQID NO: 378, SEQ! D NO: 598, SEQ ID NO: 608, SEQID NO: 638, SEQID NO: 668, SEQID NO: 678, SEQID NO: 708, SEQID NO: 738, SEQID NO: 748, SEQID NO: 778, SEQID NO: 808, SEQID NO: 818, SEQID NO: 968, SEQID and NO: 978, SEQ ID NO: 988 in the embodiment of one, the scope of the first link of the & lt; esophagus link consists of a VH-and VL region selected from the group consisting of; (1) Mztqh VH Kmahe illustrated in 7: SEQ ID NO, and the area of 7 Kmana Surat in 8: SEQIDNO;

(2) Mztqh VH Kaaa is illustrated in 17: SEQ ID NO, and VL region as Y; Apr 18: SEQ ID NO (3) Mztqh VH as is illustrated in 27: SEQ ID NO 'and VL region as Q Hsourh Apr 28 : SEQ ID NO; (4) Hztqh VH Kaaa is illustrated in 37: SEQ ID NO, and VL region as 5 j illustrated in 38: SEQ ID NO; (5) Mztqh VH as is illustrated in 47: SEQ ID NO, and. VL area Kha Ne illustrated in 48: SEQ ID NO; (h) Mztqh VH as is illustrated in 57: SEQ ID NO; and VL region as my Mehrrh in 58: SEQ ID NO; r / 42 35449Β1

MK (7) Mztqh VH as is illustrated in 7 h Surat 0 Apr 68: SEQ ID NO; (8) Mztqh VH as is illustrated in the 77 pictorial Apr 78: SEQ ID NO; (9) Mztqh VH as is illustrated in the 167 illustrated in 168 : SEQ ID NO; (10) VH region as is illustrated in the catalog are the 178: SEQ ID NO; (11) VH region as is illustrated in the -r; in 188: SEQ ID NO; (12) VH region as it is illustrated in the -r; in 198: SEQ ID NO; (13) VH region as is illustrated in the graphic at 208: SEQ ID NO; (14) VH region as is illustrated in the ^ Rh in 218: SEQ ID NO; (ja) VH region as is illustrated in the p; in 228: SEQ ID NO; (pw) VH region as is illustrated in the graphic at 318: SEQ ID NO; (17) VH region as is illustrated in the graphic at 328: SEQ ID NO; (18) VH region as is illustrated in the graphic at 338: SEQ ID NO; 43 SEQ ID, and a district 7 as SEQ ID, and VL region as SEQ ID, and VL region as they are: SEQ ID NO, and VL region as: SEQ ID NO, and VL region as: SEQ ID NO, and VL region as: SEQ ID NO, and VL region as: SEQ ID NO, and VL region as: SEQ ID NO, and VL region also: SEQ ID NO, and VL region as: SEQ ID NO, and the district 7 as: SEQ ID NO, and VL region as 35449Β1 1 (19) VH region as is illustrated ni cameraman 0 to 348: SEQ ID NO; (20 ) VH region as is illustrated in Ne Msourg 0 Apr 358: SEQ ID NO; (21) VH region as is illustrated in Ne cameraman in 368: SEQ ID NO; (22) VH region as is illustrated in Ne cameraman in 378: SEQ ID NO; (23) VH region as is illustrated in the graphic at 388: SEQ ID NO; (24) VH region as is illustrated in the cameraman Ne 588: SEQ ID NO; (25) VH region as is illustrated in the Hamburrh Ne 598: SEQ ID NO; (26) VH region as is illustrated in Surat 'nee 608: SEQ ID NO; (27) VH region as is illustrated in the Hsourh in 618: SEQ ID NO; (28) VH region as is illustrated in the p; ne 628: SEQ ID NO; (29) VH region as is illustrated in the graphic at 638: SEQ ID NO; (30) VH region as is illustrated in the graphic at 648: SEQ ID NO; 44: SEQ ID NO, and a 7 area as: SEQ ID NO, and VE Kaaa area: SEQ ID NO, and VL region as Z VL and d 'SEQ ID NO:: SEQ ID NO, and. VL region as: SEQ ID NO, and VL region as: SEQ ID NO, and VL region as Z VL and d 'SEQ ID NO:: SEQ ID NO, and VI area as: SEQ ID NO, and VL region as: SEQ ID NO, and VL Kaaa area: SEQ ID NO, and VL region as

MK 35449Β1 (31) Mzhlah VH Z RR; at 7 Gigi: SEQ ID NO, and VL region as p Msourg 0 to 658: SEQ ID NO; (32) VH region as is illustrated in 667: SEQ ID NO, and Hzh VL Ki Leahy issuance of 4 in 668: SEQ ID NO; (33) d VH Kt is Msooh in 677: SEQ ID NO, and the area of 7 Kha 5 j cameraman 0 to 678: SEQ ID NO; (34) Hztah VH k 0 a p Hsourh in 687: SEQ ID NO, and VL region as is illustrated in 688: SEQ ID NO; (35) VH region as Al Iba at 697: SEQ ID NO, and VI Z Hme Sr'rh area in 698: SEQ ID NO; (36) Mi VH Khaha Surat at 707: SEQ ID NO, and Mttqh a 7 as Hme -r; in 708: SEQ ID NO; (37) d VH Kt is illustrated in 717: SEQ ID NO, and VL region as Hmemsourg 0 to 718: SEQ ID NO; (38) area VH as is illustrated in 727: SEQ ID NO, and VL region as they are 4 cameraman in 728: SEQ ID NO; (39) VH region as is illustrated in 737: SEQ ID NO, and VL region as they are 4 cameraman 'in 738: SEQ ID NO; (40) VH region as is illustrated in 747: SEQ ID NO, and VL region as they are 4 -rz Ne 748: SEQ ID NO; (41) VH region as is illustrated in 757: SEQ ID NO, and VL region as Hme Q; in 758: SEQ ID NO; (42) VH region as is illustrated in 767: SEQ ID NO, and VL region as they are 0 cameraman 'in 768: SEQ ID NO; 45

U

1 35449Β1 (43) Mntth VH which is Surat 777: SEQ ID NO 'and Dz a 7 Z is 0 yolk 0 Subject to Ne 778: SEQ ID NO; (44) VH region as Y; in 787: SEQ ID NO, and VI area Kaaa It is illustrated in 788: SEQ ID NO; (45) VH region as is illustrated in 797: SEQ ID NO 'and Hzh VE Z Z 3 force in 798: SEQ ID NO; (46) VH region Kmahe illustrated in 807: SEQ ID NO and Shalla a 7 Z mettle cameraman 0 Apr 808: SEQ ID NO; (47) VH region as is illustrated in 867: SEQ ID NO, and cent VL 1 st Weserrhvi 818: SEQ ID NO; (48) VH region as is illustrated in 827: SEQ ID NO, and VI area as in the yolk 6 Rh in 828: SEQ ID NO; (49) VH region illustrated Kmahe in 837: SEQ ID NO, and the area of 7 Kaaa is illustrated in 838: SEQ ID NO; (50) VH region as is illustrated at 967: SEQ ID NO, and VL region as 5 j 0 image Apr 968: SEQ ID NO; (51) VH region Kaaa is illustrated in 977: SEQ ID NO, and VL region as is illustrated in 978: SEQ ID NO; (52 ) VH region as is illustrated in 987: SEQ ID NO, and VL region as -r; in 988: SEQ ID NO; and (53) VH region as is illustrated in 997: SEQ ID NO, and VL region as is illustrated at 998: SEQ ID NO; 46 i 35449Β1 Ne example of Waco; strand consists of the first binding sequence Hmgy amino selected from the group consisting SEQID NO: 9, SEQ ID NO: 19. SEQ ID NO: 29, SEQ ID Z NO: 39, SEQ ID NO: 49, SEQ ID NO: 59, SEQ ID NO: 69, SEQ ID NO: 79, SEQID NO: 169, SEQID NO: 179, SEQID NO.- 139, SEQID NO: 199, SEQID NO: 209, SEQID NO: 219, SEQID NO: 229, SEQID NO: 319, SEQID NO: 329, SEQID NO: 339, SEQID NO: 349, SEQID NO: 359, SEQID NO: 369, SEQID NO: 379, SEQID NO: 389, SEQID NO: 589, SEQID NO: 599, SEQID NO: 609, SEQID NO: 619, SEQID NO: 629, SEQID NO: 639, SEQID NO: 649, SEQID NO: 659, SEQID NO: 669, SEQID NO: 679, SEQID NO: 689, SEQID NO: 699, SEQID NO: 709, SEQID NO: 719, SEQID NO: 729, SEQID NO: 739, SEQID NO: 749, SEQID NO: 759, SEQID NO: 769, SEQID NO: 779, SEQID NO: 789, SEQID NO: 799, SEQID NO: 809, SEQID NO: 819, SEQID NO: 829, SEQID NO: 839, SEQID SEQ ID NO: 999 and NO: 969, SEQ ID NO: 979, SEQ ID NO : 989 of 12 amino acid CDR-H3 of Alhzdil 1 n Rabhl part of the present invention has CDR- region is present in position 4,3 and 12. Shows (Y) in Alahloul, where 1 n remnants of tyrosine 973 or SEQ ID NOs: 43, 193, 333, 613, 703, 733, 823 0 Gdil in Η3 appears in the CDR-H3 and Qqa 1 Li reminded; molecule t ^ of the present invention has Nee Mgdil embodiment,. 973 or SEQ ID NOs: 43, 193, 333, 613, 703, 733, 823. SEQ ID NO: 340 from 1-1 n part 'to link one the one who has a sequence acid Ahive appears in - SEQ ID NO: 980 Amodil also Rt these Hsalh part - Ahive j 0 Her in & lt; esophagus only 1 GS 1 current sowed is the best Dzqe linking & quot; Isolated & quot; . & Quot; Isolated & quot; ANZ appointed Dzue 1 Lrt here, I am referring ablation 1 Alrt esophagus that is defined. Separate and \ or 47 i 35449Β1 processor consists of the production environment. At best, & lt; 1 esophagus to link the God of Dol is 0 0 x 1 1 Z me to install p 0 Other components are the production environment. Contaminated Aekonat evidence produced E b that Akatj En-borne cells combined, are materials that interfere in God uses A- or therapeutic Boulibptid, and include enzymes, hormones, for one of the materials removed Laos ^ or Do mainland-and Tiveh in the embodiment of Mgdil, the purification rewarded E linkage ( 1) R-degree enough-H for & lt ;, Wallach & lt ;, of 1 0 n remnants Net end N or sequence homocysteine Akad 0 to Hdam Z 1 Core - 'or (2) to homogeneity by SDS-PAGE in Gore downward conditions or - using Kombasi Group or, at the best spot Vgbh. Regular E and so on; the blood - p Anti isolated in the Wallach in at least one step SSH. Sequence modifications Alhed amino from Elmo linking molecules 4 FH here r included - & lt ;,; * Jf, example, for example, required Tsien ratio of 1 to connect and \ or Akhhilalm {_, Beyoğlu 0 Wagih a & lt; Z of the antibody is prepared sequence variants Ahamkhy brother z Dzenat Rabhl Aaarany changes nucleotides appropriate to link the DNA molecules Azhoy 4 or amputation 1 1 Yep Dam. These include 0 amendments, for example; the Atthal Alhanaf, and \ or 1 Adzl 'and \ or replacement, remains within the DNA sequences for Azhoy & lt; 0 Liat connectivity. An outfit Z Alhanaf 'input, and tyranny is made to get into the building congratulations, on condition that my !, an efficient one for Zhaia Almtalobh.'nverat DNA features could change 0 Apt B 0 d transportation Z & lt; Liat Allbahl, such Altver in the number or the position of the link Algluckozhel sites . At best 0.5 a 4, 1,2,3 9.8, 7 (c or 10 amino acids are Aekn to replace the CDR, while 0.4, 1,2,3 20.19, 18.17, 16.15, 14.13, 12.11, 10, 9.8, 7 and 6.5 or 25 x amino acids can Tstbdlt in areas framework (FRs). Almstbdlat R & lt ;, shrugged substituents Mahvunlh as described here. additional or more allowance the Ed F1's or tasted any, 4.3, 2.1 c or h of amino acids in each case of the CDRs (Btaia, Tadhd Tuellaha) 'in the p 1 n, 19.18, 17.16, 15.14, 13.12 0.11, 10, 9.8, 7 and 6.5, 4, 3, 2, 1 20 or 25 0 n amino acids can enter or Thanaf in all FRs. method used to identify some of the remains or are areas Dzezat 1 t Pt 1 t z Ravi Mgdilh for Tefat called & quot; Tgrat survey alanine & quot; as at Ne Kazivgram and Wayne Ne Science;; 244 48 1 35449Β1 (1989) 1081-1085. here 0.0 s z remains Attloppe p & lt is determined residue or Mjmu; esophagus! to link (for example 1 residue honed such as arg, asp, his, lys, and aa 9) and LDL at Hed Wahine charged negatively or neutral (for the better over Walles or to influence Z interaction of amino acids within Alaeptob BPM Iah acid sites dysentery this aa Wendell pardoned functional sensitivity to Almstbdlat Apply each broadcast 0 1 Z 1 and assumptions of & lt; Z, or, not-for Doda. Thus, while the sequence is determined site Arkhan Mtver Hed Amini, you do not need the nature of the boom Bhd Mavy Affi 1 under Alhsbak. Z r example, όμ Tgrh perform on-site Ackley, is a survey or not mutations in Alaashoaiah Coupon required or region and is checked Almztjh Alrt molecules Ρ Tlmoph. At best, inputs include sequencing DNA 1 Shui and \ or Hedmjat in 1 Ah- Cabo-mighty in - of 9, 8.7 h 0.5, 4.3 A 2 0 whoa 0 Ahn remnants Aloulibptid consisting of a hundred or Aktar Z 1 residue E arrived p arrived are one baskets Dave Altzlslh the remnants of the amino acid, single or multiple. Input Mtver to Dzu linkage & lt ;, DA includes these one Yat -Ν or -C z AA & lt; & quot; Cm one fad to the enzyme or merge Boulibptid which increases with serum Mentges life Q palpation 1A Eyed The type another Almtver is a substituent Mtver A- Ala- . This 5 1 0 Tirat its blast-eating 4 Wallach 9.8, 7.6 to 5.4, 3, 2.1 or 10 are the amino acid residues in the & lt; link esophagus is replaced in a different residue. Mutations of sites-him - CDRs are heavy and one light or A-, most notably areas Alhaaparvarabl; -at Welch FR Ne Coterie light or heavy and 1 are also included Bmtdmnh For example, as the one included Tablh 6, & gt; CDR are one of Ahad Ala- 'J 4 Wen are inconceivable that one, two or three of these five amino Ala-, Lee replaced. It is; if CDR sequence included a 15 amino Hhi be conceivable that Z and K Aah'thelalo 'Araah, five or six of the amino acids are Hmtbdlh. 49

MA 35449Β1 In general, if the substituted amino acids in the 0.1 limit R \ β & lt ;, as 1 FH CDRs Z Light and 1 or light, Alhgdil that Andlh & quot; substituent & quot; That has been obtained is Z 1 Lash 0 JH / 0 E t better than 65%, most preferred 70 bowed huh, Amodil in Al_khaso 5 Z 75./0, Folding much better 1 80% 1 externa bugs R series CDR & quot; Aslmah & quot; . R. I ran it pulls along the folding CDR R b class be Mnnabth Altzlslh R & quot; Substituent. ' , HR Sbad Anmthal CDR Lalai's 0 5 Z Alaiad acids is preferably 80% corresponding to the corresponding order Tzlselth to have replacing acid Aheffi one - light of R I E CDRs Z Dzqe connectivity have Mokhtlgh degrees of Altathl R v 0 Dladtha late '\. him; Z Speed principles 1's, CDRLI him 80% while 3.CDRI Bzn these goods 9% D 0 Hlat 0 Gvloz (1 and is Ib 1 No. Z Sgdlat reserved. so, any substituent (categorized heavy DDD is Hzzaouahdao more 0 n '' Almstbdlat representative & quot; Almnkurh in the table 1 below) is conceivable as long as the & lt; esophagus link eroding 0 J Derna Z linkage r BCMA across Ztaq 1 the first duck and Asron CD3 Y fitting for Ward 1 bend and \ or CDRs Walles ^ of which 1.1 Study 1 paillasse then (z 1 to less than 60 huh, preferably 65%, even 0 for more Tvddr 70 e / e, presented one of the Geld folding one of the best 75% '0 Ely' for best Akir Hee% Alhtabqh 1 Li Tablh CDR '' August & quot;). substituents reserved appear in table 1 in M & quot; for the applicat preferring 0 of 0 if b this Alhustbdlat Vitagerfi Alvyalah biological e then the DTM View the changes in eating and light E 0 1 Mtomh & quot; Mudallaabdlat representative & quot; in table 9, or as u ^ BL form below Rah R-1 targets to Las Hed 1, are checked products required features. Table 1; Substituents homocysteine original Almstbdlat representative Almstldlat favorite Ala (A) val, leu, ile val Arg (R) lys, gin, asn to lys Asn (N) gin, his, asp, lys, a2g - E Asp (D) glu, asn glu 0 50 1 35449Β1 ser) ala ser asn, glu asn asp, gin asp ala ala asn, gin, lys, arg arg leu, val, met, ala, phe leu norleucine, ile, val, met, ala ile arg, gin, asn arg leu, phe, ile leu leu, val, ile, ala, tyr tyr ala ala thr thr ser ser tyr, phe tyr trp, phe, thr, ser phe ile, leu, met, phe, ala leu

Cys (c) Gin (Q) Glu (E) Gly (G) His (H) lie (1) leu (L) Lys (K) Met (M) Phe (F) Ρ2ο (P) Ser (S) Thr ( T) Trp (w) Tyr (Y) Val (V) substituted modifications in biological Khais of Dzqe binding of 1 km Aladzaa S. de T. 13:00 selected Palmstbdlat that significantly differ in their effectiveness Ji) to maintain & lt; & gt; (A) Ruba Alboulibptid basis in the replacement area, for example, Kcecchel and RNAi or Znona '(b) the consignment or Alhaadrofubista from one molecule as a location is required, or (c) side-chain size. Residues that occur naturally are divided into groups based on _khasaihn side chain: (1) Alhaidovubik: Aldhurlosen 'met, ala, val, leu, ile; (2) Alhaholk Neutrals:, cys thr, se2; (3) acid: asp , glu; (4) swivel j: asn, gin, his, lys; (5) residues that Tah on the direction of Allslh; and (c) Otari. trp, tyr, phe 51 1 35449Β1 consequent Almstbdlat non Mahvunlh to exchange one member or these items for additional items. Dadam replace any residue Spptin not included in the maintenance of proper installation Z & lt; esophagus Ward 'generally with serine, to improve Althiat oxidized from one molecule and prevents one of Tthabk Alhzhrv and vice versa, not added Astbn links to the antibody to improve its stability (pardoned 1 Geld 11..a' E, the antibody is an antibody such as Fv) pane. Mgdil type in particular Almtver replaced Bhta g replaced CCCP or a 4 Thayer 0 n remnants Heibervaribl region of the antibody origin (eg 1 Tmdm one must Alhasn or human) In general, the variables selected due to the development in the last betray him one Khmdaihr, improved biological close to the body anti original AVI lasted generated 0 these. Fly; Ah Ladd tulle; b replaced these variables include the Tgrh literature b 1 Stkhcam RIP Zj. (B), the T * Goodyear Edh areas Heibervaribl (eg 6-7 site) just ^ FH substituents AA 1 H 6 & lt; 7 Alahina at each site 0 thus are presented antibody variants in a unilateral way parity 0 n particle 1 T. Glen filamentous Kmadmjat product Jane III z Ahjmuh Μ13 Dahn each Jsaha. Has been charged with insulting the Vhs display Khj variables then Lga-7: $ a Avalogih (Zh example d 1 linking) Kha was 1- é this 0 of 0 in order to determine the specific amendment Heibervaribl area sites; be enacted SJ Alac DAT to identify the remains of Heibervaribl region, which contributes Big. Re-born in the counterattack. B, * & gt; alternative Ouao extra for, it is useful Do not install the crystalline compound of the antibody _afeld counter to determine the points of communication because Zt 1 s and Hervé, T avenue example BCMA know analysis. Residues 1 Altwahtm these and Ed rare is a filters to replace, according to the detailed techniques congratulated, while the Tulip these variables, Pettm Place the plate variables examined as described here is Ed Alajtm Q 1 de supreme characteristics in one or more of the tests for the development of a last is the text of the amendments 1 other for Jne 'response here. For example, is linked to Dzqe linking one in and one end or one massively multiplayer Z the Z Apolimrat non-protein, for example Bolyaethelen Gelesol 'Povirobien Paul; Reselelkinat, or polymers Almhnnrkh of Boljbuthailin Gelesol and Bolebrbbaan Paul, are engaging Dzne link in the preparation of microcapsules, For Alhthal, Im p or polymerization interfaces (for example, 52 or Hidroxmethylsellaloz

MA 35449Β1 gelatin -kabsolat very kind and poly (Methylmethylaceli) capsules 1 to Rqlaqh grandfather 1, & lt ;, respectively), the drug delivery systems colloid (for example, to Ibusomat, two days Maekerosgeirat, micro, nano and molecules emulsions Kpaaullac Nano), or emulsions Macro the disclosure of these techniques in Raanveton pharmaceutical Sciences, 16th edition, Oslo, A., Ed, (1980). As it can be formed by linking molecules that have been detected here immuno liposomes. & Quot; To Ibusom & quot; It is a minute vesicle composed of various types of lipids, phospholipids and 1 fat or surface materials useful for delivery of a drug in mammals. Allibusum components are arranged Butekl common in bilayer formation, similar to the lipid arrangement of biological Agiaah. Allibusomat is prepared, which consists of an antibody methods known in the drawing, such as those described Ne Aeptan the data (1986) 3688: 82, Prcc. Natl. Acad. Sci. , USA; Hoazg 0 Aq the .Proc (1980) 4030: 77, Natl Acad. Sci. USA; 4,485,045 .US Pat. And Nos 4,544,545 and WO 97/38731 Alhzchorh in 'and Oct. 1997.23. DTM detection Z Allibusomat in improved recycling h time of 7 reading one invention RIP 556, 5013. Zh Alad can generate useful Allibusomat way Ddndr Herhalh A- Barre Lenny consists Z Vosgotadcolin cholesterol and PEG- Almh 0 Tq Z Vosgotalpaithadhulamin (PEG-ΡΕ) DTM pull Allibusomat through revisions as defined size for permission c Allibusum 1 T in the LED 1 in Alttr required. It is linked parts' Fab Z poison, but are one of a land. Akharaa R Alibuso 0 0 data as described in the Martin 1 v 1's. Biol. Portal Chem. (1982) 288-286: 257 Ebertvaeltbadl Tmaia 1 sulfide. Elaj element adultery is Wasa Created in Alkusumat. 1 Fly Wen ^ 1 v 1's. Ji. Mat 0 and Y Kemer Chan. (1989) 1484 (19) 81. In one use Altaaat Alhatlgh, is one Ztaj & lt; esophagus Rabhi inside B 'in one of the area in August dinner Alherne E 1 and 1 to Mczh are .beshr to Alatost. Is one Ztak Alrt within one there 'Kahtoh 1 Looney 4 Sh.ldzebah part, either Alkhalaz Alhievh or parts August E is laze' z Speed Alhthal, expulsion or Alhrkra 1 Chbh 1 Arkz. Z Carter Aq Al.e B1 Bo \ Zhe: 10 (1992) 163-167 wage of E 1 to isolate one of the bodies that secrete Almkhadh R-space in August to one membrane Alheiopimenaah.kor. S3 1 35449Β1 purification installation is rewarded. Link that has been prepared from cells using, for example, Hyderoksilabbatet, chemotherapy, electric deportation gel, decomposition duo, and the proportion of Alakh Alkemiana, the fact Nenaih chemical purification Alalah favorite technique. On the other side, attachment to the present invention in Hsalh Aldhu.oa acid that symbolizes Dzqe binding of invention. The term & quot known; DNA & quot; To the people of the profession and consists of DNA (such as cDNA) and RNA (such as mRNA). It could be limited to DNA and Mzdokh a single, linear and circular. DNA consists Almnkur the best in the carrier Amodil author in the host cell. Alamadagh cell Almnkurh are, for example, after the shift or transport Btzlslh DNA of the invention, capable of producing Dzu connectivity. To this end Dzqe DNA is connecting in a practical setting Btzlslh carrier is rewarded. Nucleic acid used as a tool for the transfer of genetic Almazh (exotic) to the cell. Comprises the term & quot; Critic '-olkn not to prevent - a virus plasmids, Alkuzmidat and industrial chromosomes. In general, it consists of industrial carrier of the replication origin, multi-site Alachakh and index 0 to choose the carrier itself is in general sequence Nyukloitid; a Taaia sequence DNA; atopic consists of entrance (Jane transformative) and large sequence serving & quot; basis & quot; 1, say. Modern vector of extra _khasans composed along with the introduction of gene transfer and the basis of: a catalyst, the Gini index, resistance to the antibiotic, Jane mentioned, sequence Talo ^, to purify one Brlten mark. Ashe 1 Say Ashe C Rush 1 Ij (builders Atak) is precisely to produce the gene transfer in the desired cell, and in general the sequences settings such as Hsalh Dt and mother, we get one of the results of Affi Z bull 0 called introduction 1 for y 1 u desired cell is Dlaazh blind & quot; Transformation & quot; Bacterial cells, & quot; Transport & quot; The fact the nucleus of cells, although Q Adf'l viral vector is IMD 1 - in Nranadkhn ''. As used here, it means a & quot; Hievh cell & quot; R-blooded thrills Zh enter -roa symbolizes 1 R & lt; esophagus Avybahl Q invention in a manner which, Altravdkaahn and the like. Must be understood that this is not one of Mstaltt Tupper rude R A- 1 Rdt assigned Od R strain or potential strain of this cell. Because Bah 0 for Altos-scourge Yeh 0 Be that occur with 1 to Tollidat 54 1 35449Β1 | for sequential according to either boom or Alaatherat interfaces, this strain can match not be to one Study of evidence, but the rest are included within the scope of the term as used here Kha is used here, includes the term & quot; Production & quot; Included on any step in the production of post rewarded 0 Z invention which include, but Lear limited to, copying, modification after copying, Algtl, the amendment after the transport and secretion. Camel & quot; Control sequences & quot; To DNA sequences necessary for the production to Alhsalh that Terphz form of practical most especially to the organism's cell. Ntzlslh appropriate adjustment of eukaryotes; .Je) For the student, including the catalyst, optionally sequencing process, and ribosomes linking site. Known eukaryotic cell nucleus to the use of incentives; Bulad 0 Zlashen signals, and-T. A- nuclear program is & quot; It connects practically & quot; When placed in it has been associated with functional Btzlslh another amino acid. For example, DNA to the pre-sequence or performer secretory β seen? I form Ehli 1 Li DNA to if it was produced prior Kbrocan who is involved in the secretion of Albolbyptid, Catalyst BL Optimizer is linking practically to Hsalh code if influenced the piss Alchlh; or site sprinkle ribosomes connects practically to Hsalh code if given birth to reach aluminum. Heavily in 'evil Brat practically & quot; To DNA sequences are tethered on neighboring, and in his 1 h 1 Kada Pots, contiguous and in reading phase. On it, upgraders Yasin Elah 1 to be contiguous. Short and Mall 1 Li connectivity linking Hoaqa 1 to determine appropriate. If these sites do not exist, the use of a few synthetic oligonucleotide adapters or connectors in accordance with the opinions R-AZ. Sit terms & quot; Desired cell & quot; , & Quot; Aledeivh cell & quot; Or & quot; He Alah'a Ltd 0 to n any individual cell or cell planted, which have receptors for vectors or the introduction of & lt; Liat A- Azhoy interlocutor, Bolinyuklutidat and \ the proteins. As one means that the T & quot; within the Ely & gt; Strain Khaldah single, and the strain that it is not necessary to be M.kalqh full form (in Altzql or in genomic or total DNA integration) the original of the College, according to one of Tgrh S; E Kadth or deliberate cell can be a single core or the fact Alrah; and the year Woods Khmh Sep; limited to the bacterial cell's, fermented cells, Aklei 1 Laker brother's one of the cells of the instrument 'Ely & gt; For example mouse, barn, or human Macak 55

MA 35449Β1 appropriate host cells containing the host cells and a single pond and Ahakiqh Aldhulah - yeast cells, fungi, insects and cells Idbeh. Rewarded linkage is produced by bacteria in the invention. After one of the results; & lt; E Anrt & lt ;, invention 4 at best are isolated & lt; esophagus binding of E. coli cell Bassett Ne & lt; E Mazb u can shower through, for example, the proportion of chemotherapy and \ or exclusion size. Short for Thiv Altzqah Alzhaveh similarly to Tantih antibody-producing processes for aluminum in Khalaa 1 CHO. In addition to the fact that the nucleus of microbes, such as the single-core a fungus \ x; Fold or cheek 1 0 Dhar is suitable for Astsak or production cells to Dzqe binding of Alakharaa. Saccharomyces cerevisiae or Dhadhir b 1 Wicker Ahanah, are the most commonly used among Adeghiqh objects to the host cells at least. Therefore, are a number of other genes, species; and Allalat just Frz Tj-Larrea and useful here, such as Schizosaccharomyces pombe, Kluyveromyces \ Hdgkhz'mlq, K cells. fragiUs, K. lactis 1242411 Έ \ 7, K. bulgancus 11 & lt;? K. w.ickeramii, λ ^ TCC2A16 \ Kjltïh7 (56500 'K. drosophilarum (JH 9 c 3 K. thermotolerans' (ATCC t marxianus; EP 402 226) yarrowia); EP Pichia pastoris) (070 183; Alambdat; (234 244 Trichoderma reesia (EP ; Neurospora crassa; Schwanniomyces medal Schwanniomyces occidentalis and filamentous fungi such as, Neurospora, Pénicillium Tolypocladium and Lada Aspe2gillus A- like. A. nigerjA. nidulans derive appropriate host cells to produce Dzfairs link Algluzkozhel of the invention, the best antibody derived from linking molecules of the mechanics multiple cell examples of invertebrate cells include plant cells and insects. many Blalat viral Bakulo and variables and host cells that Nttabq with optional cells of the host cells such as Spodoptera frugiperda (Rev Alfr'hh); Aedes aegypti (Mosquito), Aedes albopictus (Hosquito) , Drosophila melanogaster (Melt 1 by 1 thousand Khh) and Bombyx mori have been defined. many of viral strains for transport are commercially available, for example from 1-1 Mtver NPV Autographa californica strain and 5-Bm are 56 1 35449Β1

Bombyx mori NPV, and these viruses can Stkhaddm Kdharos here and Fa to Aladaa warm, Z Alad Lal Khalaiaa. Spodoptera frugiperda cell cultivation of cotton, corn; Sealahy; Petunia tomatoes, Arabidobss and tobacco can also be used Kkhalaaa hostess. Cloning vectors and useful in the production of protein production in plant Kah Do you know the profession in the drawing. See, for example Hiatt about each, Naitre 76-78: 342 (1989), the online data (1992) \ Babu 10: 794-790 E Arcko data for one (1995). Blunt Ji 760-745: 8, and Wacker, the data (1996) Plant Mall Pajul 32: 979-986, it was the most important is the highest in the vertebrate animal cells, and the proliferation of vertebrate cells in what has been planted (1 Zsaj transplanted) has become a routine. Examples presented Almillgh cells of mammals are the kidneys' monkeys CV1 Alehthol path in (1651 of SV40 (COS-7, ATCC CR 0 marched human Aljziveh kidney (cells 293 or 293 Almcentschh sub for growth in suspension cultivation, Gore 1 Han s LG. Jane, Vairol (1977) 59: 36); cells Klay whistling hamster (10 BHK, ATCC CCI); ovary Hahstr Chinese CHO) / -DHFR, Orlab s 1 cells, (1980) 4216: 77 Proc. Natl. Acad. Sci. USA) Sertuvi 1 gars cells (ΤΜ4, Heather, 251-243: 23 .Biol. Reprod (1980)), Carr monkey cells (70 CVI ATCC CCL); Z Allard Alavriqiuren cells (VERO-76) ATCC CRH587); human cervical cancer cells (2 HELA , ATCC CCI) 4 Khalaa 1 kidney 1 for dogs (34 MDCK, ATCC CCI); kidneys liver cells of rat Buffalo (1442 BRU 3Α, ATCC CRI) 'Khalaa 1 Rlh squadron 9 (75 W138, ATCC CCI); liver cells of a human (8065 2.1413. hep) of the Rmvora (1 MMT060562, ATCC CCL5); Hlaa 1 TRI (Heather 1 T. The first E .N (1982) 44-68: 383 .Y Acad. Sci); through 5 MRC; Khalaa \ FS4, to mushy Alachan (hep G2 ). When using recombinant techniques, the production of & lt; esophagus binding of equ preparation AA 1 A '.. Its dinner in the surrounding cytoplasm area 0.1 and detachment directly seen the 0 mediate. If blood Asag & lt; 1 of the esophagus Ravi inside the cell, one step over, Aldzitat, either 'Guide A- or Ala'e Almttalh Wall E' 57

MA 35449Β1 For example, expulsion or Adkza nomination Algaiq. Carter about each technique E \ Bayou: 10 (1992) 163-167 describes a procedure for isolating antibodies Alaffersh to dinner Almaahh surrounding cytoplasm from any Cooley. In short,) For nearly 30 minutes it is melting Sanl cell in the presence of sodium acetate (3.5 EDTA, (pH, and Ffinelmethysalafonalglorid (PMSF. The removal of the wreckage of the cell centrifuged. While the antibody secretion into the Mediterranean, is Tzkiz materials that float Systems production is generally first using the concentration of Rs Tj 1 Leah; pardoned for example, the unit Ameco or Milbur Pisin ultra-filtration. includes inhibitor protein, such as PMSF in any of the following steps to inhibit proteolysis and antibiotics can be included to prevent the occasional inhibitions growth is purifying & lt; Youalrt of the invention is prepared from the host cells using, for example, Hyderoksilaptit, chemotherapy, Alter.ahil 4 Hrbana Alhlahi 0.1 to prolong Iz 1 u; and Zsph chemical Alalah, the fact that the proportion of Alkemiana treatment A- 1 Mghidlh. Almsdgovh \ *: ί that bind Tjh Achabt is most likely Agarws, but other matrices are also available. permit matrices A-, E m (, Kavek "a like or ^ c Alhsama a-i Ahumicadd (Sterendaffinel) gasoline at higher flow and times of the process shorter and YMCA y1 access Ha production 1 Ross. House & lt; esophagus 1 layer ducks are the invention consists of a range of CH3, is Baekerbund ABXMresin (G 0 Tibaikr Dearerg, iNG) is beneficial to the pious. Other purification techniques Albrocr Hthel Altdznh or Z Ehod Ed ion deposition ethanol, phase reverse the HPLC, chemotherapy on silica 'treatment Alkemiana Z wasn ™ SEPHAROSE treatment Alkemiana presented one of the Adhan or b 1 dl as 1 Tern Alratfj (Hthel betrayed Hhi Bolesbartek), Kromato - Vukaaaj E SDS -PAGE, and Toseb Salfit ammonium are also available on the adoption of the antibody erosion 5A Aa 1 committees. Ne attracts a & lt; , Aalalaat available-term binding molecules 0 n invention, Almnkurh operations Jj Z Zray 0 Khiat Hialh Dddz in conditions allow Bantak & lt; link esophagus and address what has been produced rewarded 0 linking what has been planted. / ;;;, / 58

MK 35449Β1 change 1- & quot; Q 1 has been Zrah'a I befell one word, the difference, Alnho, Altkacr and \ or the proliferation of cells in vitro in a suitable Ne conditions 0 mediate - Nea embodiment Bdid, Ntoffer 1 for combinations of any consist & lt ;, & lt; esophagus 1 to bind Z 1 Aaa 'or Almztjh light of the invention operations . The best Oualtra Lader 5 and 6 saw him r me druggist 'Kha is the blood, U E DOCUMENTS 1- & quot; Pharmaceutical composition & quot; In the installation of giving a patient the best E Z 1 in one human to MATH. Pharmaceutical composition comprising Amodil specified this Alad 1 GS Z & lt; 1 esophagus linking of only 0 p. At best, the pharmaceutical composition comprises 0 n 0 n formations Hmastm Auriga 1 Say 'stabilizers and 1 or excipients. In the embodiment Mgdil, consisting of configuration for.; \ / \ Ne t Ri of Ahlae Bin, across Aljk 'intraluminal' arterial 'intrathecal and \ or d 1 vinegar 1 Azv 1 and I Alhbeshr Ne Ed - are perceived specifically the installation Alazkor is Annie RIP via infusion or injection. Give appropriate formulations Behnrq Hchtlgh affected, Z gone off 1 for example, in the vein 'intraperitoneal' under Aljk 'In intramuscular Emods 1 and into the skin 0 On the motherland E provides the present invention continued to give to the installation of S 0 Khthal expose Hhdd' 1 Mtmasal ', for example, the continuous administration can achieve a suitable pump system, which alerts the Albraid to measure Aehg 1 fled the Valley r p 1 Karb. Dunums Atae «.-& Gt's; for, a. 1 to 1 Dlana one who is familiar with Dzfairs linkage of the invention using pumping systems Almnkurh. Some pumping systems are known in the d 1 to draw; and Iathd usually Z 0 1 Kdl periodic coil consisting z z galore Valley Ashe. Commencement of the DTM exchange 1 Agev in p pumping system, the temporary interruption of the flow of the continuous one evil therapeutic R-Ed Mud p Achtb b - case 'locality Alate Say replace the rabble and the stage of administration that follow replace the rabble built under! To be regarded as part and Sall and & lt; s Mdddlandh Z Alavr 1 GS Haa Z 1 Li & quot; Give continuous & quot; This element of one of the therapeutic. Continuous administration or sustained are & lt; Ivat Adt these are one of the sowed Ahecn that my 4 Wen inside one of the vein or under the skin in a way connected Nanl tool or Nzlam Ed Lafer, one me Ss Z 1 Mechanism Tohdel host to connect supporter of Dan and mechanism Alchgl to run August Alabl - - Azzmh pumping to give under the skin It can include folding Arz or Azpop to Ad'q Aljk Dd and Todal proper installation inside the patient's body. Can p Zmh Ed rare d 0 commenced or 59 [1 ///

MA 35449Β1 bind to the skin of the patient during the form z 1 to E vein or artery blood Op 'thus Adzh B-1 connection between Alhbeshr Zam Pump and the skin of the patient. Pump system is linked to skin Adrd 24 Saah R Alded are the days. Pumping system could be whistling sized tank with 1 Ag 13:00 0 Khthal small Veer specified, the size of the reservoir for Installation pharmacist appropriate for giving can be between 0.1 and 50 each. Ahin 1 n be continuous administration through the skin in a way Alentbah correction on the skin and replaces the time Fberat 0 Ashe profession conscious to track systems to deliver the right drug for this purpose. From Adlahz that Alate JJC skin is most especially Negotiable continued to give E as an exchange path - Aekn be useful done in one to replace the new secondary course of time; for Almial on the adjacent surface of the skin is Hbeshr 7 t ed I and A- d Hbeshr to have removed the track first Depleted . Path shower interrupted or made ready Rh Aa'khal? E. Dnda not. Invention combinations consist additional Z carrier drums Shehadlab 1. Ahthelh rack appropriate pharmaceutical Azah We cover as well, and the E Alhhalal the scion of one Phil E solutions g ^ v ^ Del Fashion de 'water, emulsions, such as oil \ water emulsions, multi-species Vsr 1 Steeb, sterile solutions, etc. Alibosumaat. Formulations comprising 0 n Azah Ahecn be formed by one common known claw. Can form a squad Alcarbohyder data; lotions equation of acidity, Cady acids and \ or Alhoad A-. YMCA (n The T4 Wen Alcalbohybl 1 T. sugars is downward, the better Atrawazz, effects in animals' 1 Kasalt; S.ordil or Akcelil 0 In general, as used here, & quot; carrier acceptable pharmaceutically & quot; plotting one me any and all Almnibat, the average dispersion, the elements of coverage , anti-bacterial elements 1 and 1 Ddhadh the instinctive 1 T. elements delay Aazotonak and absorption, appropriate Ha pharmaceutical composition. Baraf use this medium and the elements of effective components of a pharmacist in the drawing. Alracl 1 to acceptable 'excipients', or stabilizers are non-toxic to recipients at the concentrations used and Tdd & doses lt ;,: Zamr 0 equivalent extra acidity; preservatives, common solvents; antioxidants; - acid Aschorbak u and methionine; Chilatng elements such as EDTA; Hrkbat metal (Je Ddddl example protein compounds -Zn); polymers biodegradable, such as Alboljsrat; Annat 1 u E salt, such as sodium, sugar alcohols Alboulihaidik; amino acids; Til Alac; Aagal '' n '/ AAC / 60

MA 35449Β1 Alaspargen 0.2-Ivilalalaven, and thyronine; sugars or alcohols Q 4 confidentiality; 0 Similarly, Alatrawazz 'sucrose, Octasalafit, sorbitol or Xintol, Stacheloz, Hadhuz' o? G; J-for \ g 'Ribot g, Meoncem, galactose, to Aktatol , Reptull, Minciol; Glaktatol; -ol 'Saklitol (eg Anesitol), Bolyaethelen glycol; Z Atkla 0 n 0's n to that point-insisted reduction, such as glutathione, Theoktek acid, sodium' u-wall Tioglichaelat '[alpha]' s unilateral Taocaleerool, and Theo sodium sulphite; Breaulbbalt proteins - the weight of one molecule '0 such as human serum days, serum Puffin days, gelatin, or Alglobainat Alhmaeah Others; Haadrofubik and polymers, such as Banillepiieruledon. These can be used a T-constant give and which can be intravenously or subcutaneously with and \ or without pumping systems. Lash Shipping Cady amino amino acids, the better Allaasn; Ouay to Adddn; acetate 'Ardhan, glutamate and 1 or Hstidin. Surface materials can be lotions; En Alavsal weight ablation 0 esophagus from 1.2 KD & lt; And \ or Boljther, the best weight molecule 3 KD & lt; . Ahthelh Z specific lotions favorite 0 is Dwoi 20; Dwos 40; 60 Edwos 0.8 twos' or Noodn 85. Ahthelh is circumscribed to Boljther 1 T. Amodilh p. 4000 PEG 3000, PEG 3350, PEG or 5000 PEG 0 equivalent to the acidity of the systems used in the present invention 4 that Leko 0 n a 1 pH of preferred 9-5 and can consist are citrate, Soksenat 4 Alffersvat E loyalty R. acetate is give formulations 0 n present invention to the situation in an appropriate dose and that - identified b. Z example studies increasing the dose by giving increasing doses of 1 to Bolstep are Wallach 1 GS visor Tz 0 hr Kdid across -alanwaa described here to expectant mothers non Chambanza, for example Maxx 0 as shown Balaash; & lt; esophagus Rabhl Q A-sector Ashe - - r Ala'a described here can be used - 0 Gadvickl - in the A- Z Dardari in Aouk 1 Lalla Chambzza and a medicament in humans. As these constructs can be given to one for the installation of survey Aboppe Roy nor any protein. Are giving these drugs one time installation Lalai Rey Q 1 Bwlestah are Alad 1 GS as defined here or. Separately asset or after giving Ava- Alhzkor FSH Apr 1 T. Joe Tat specific timetable is specified dose regimen 0 n by the doctor and the factors Rirah. P Mbroq in medical fees, Almarb.aluahd doses depend according Awafi promise; Isaiah 61

MA 35449Β1 - r Jr Rabd, body surface area, age, the boat set for giving, sex, Alizen and route of administration, public health; and other medicines 1 0 t u Whyte O'z. Assan -at Alate intravenous solutions on Manet or not Manet, commentators' and-s. Examples Z solvents are not Manet propylene Gelesol, Bolyaethelen Gelesol, vegetable oils such as olive oil, and esters b goers are subject to the right, such as 7 Ischl 1 and lattes. Taathtts Dhu'ql m 1 a 0 e Jt Adne; hypothalamic alcoholic solutions, emulsions or suspensions, including saline and Mtuwayt the equivalent of acidity. Lassen tools include a lengthy ^ Reid sodium 'd-g response; DD and sodium colored, for Aktated Ranger, or fixed oils. Injection tools include Rapellntar Sanl and nutritious, Rablnscher electric (like I Walsh strengthened 1 Jt 1 Mas emergence replies) 's like. Preservatives and additives Aekn be found, for example, Amadanat Afabkrob 1 T., anti Alakendh, Chilanng elements, inert gases and the like. Besides; Zthalv Turkbat present invention of the vector protein, like, two days, or serum Asossa | to Mmaea, Er 0 best of human origin. It is envisaged that the installation of Alachtera.a Atalav Q 'R Alboulibptid addition of the specified invention here, is additional pardoned Alaz 1 grate effective d d', depending on the intended use Z installation. Avsr but & lt; Z Ahecn that Taku! N Adudh interact on the digestive system, medicines interact like Saitostateka, drugs that prevent Heiberyorikemia 'Aladodh Olney working on the inhibition of immune reactions (Presentation example Adharscudod't)' Aladodh that modulate the inflammatory response, drugs that interact on Ntam Adorh AAC priority 0 and 1 or 1 Ed passed Hthel Saetukenat known in the drawing. Alatsour Dzqe from the 1 to tie invention Z 1 walked blooded Ne common treatment, for example installation with the anticancer drug last. Biological Effectiveness of the pharmaceutical composition defined here are Tdidha Z Alhthal gone off the trail toxicity Allaaa, Kmatucefvi the following examples, in WO 99/54440, or in the less Hleyrt (Cancer of 0 Ivol, Ahivodhir (2005) 20) '12-1) & quot; 'FBI & quot; Or that a Heho Avdi 11 Z used here refers to Cjabh pharmaceutical composition for the treatment are Alachterakh E to use one example, the standard against NCI standard response. Success or valet in Alcann Ed therapy using the pharmaceutical composition of the invention n 0 indicates Affi events Turkibadavh unintended E Er 0 d example the compound's ability to cause the desired effect, for example) the -

K / 62 35449Β1 sick, for example Anorm cells. The Vhan 1 Fillet Ne Alkazn Valley B1 ways to gut one Les Show Alani, which include, but not limited to Az 'differences white blood cells, fluorescence activated cell sorting, Vqot bone marrow. Besides Affi 'Alasad Altddh the parameters set by the Clinical 0 Alkemianah and other ways can be used as a standard. Moreover, CT Alaktaah computer-aided rays 1 pussy '1 to portray Alehgtaa Dadhirzv S nuclear (eg Masaah cancer Alo ^ - Avas Ashe Nduom folding A'sas Adam response [Hpson my me, Horsj SGS, Cofer me, Shipp MA Fisher seen any 'course Ji 13:00; d ETA, Voss AG, Grillo-Hajzbak er, Cabanillas F' Kalpensenneptn me 'Heidemann W., Castellino R' e 1 Zisc that the 'R 0 Btajo Jq 0, or' ^ sprayed Deddew a R Kanillos JP 0 report of the international workshop to standardize response criteria for Amgoomat Agonczykv -mjmuah clunk Aalal inferiority Buraadh that Q any - tmp Z Aozkol -99 Ja ([1244: (4) 17; Ap2, computed tomography emissions positron 'in Sa Edd cells and blood; Alarouk survey, Sort activate the fluorescence cells, the fall of the bone marrow E Khzouat \ Atsjh 1 as having Alaamfawih; clinical Alkimpayh multiple Amgooma standards (eg Ua ^ Drojs Allaht 1 v) and other standard methods can be used. a major challenge last in Aladola like one of aluminous Alsddlavi Z Alaouaa P Aseel evolution Allaja Z Avzhy pharmacokinetic. Affi this end, the features of pharmaceutical 0 n Aladlo 'Ebeid St. 1 of example 1 n walked the features of the motor pharmaceutical .mwalimat affecting blast-0 of 7 Alawae exact given him. ! Pharmacokinetic parameters of the drugs, which are published on the Ara 1 to medicines to BTS Elah specific disease included Je, E Walsh is not presented for Ads: - life, size Sosea E Addie literature first and Prvi Ravi entertaining one blood. Ahguen that u & quot; Grate 1 1 ironer Afty Vykhin Almnkurh parameters above to proceed. Indicates & quot; Mid-grate '0 mortgage saluting 0 to 0% of the c Ako'e Tyeetmaltzsalzhebr 1 operations 1 for biological E pardoned Sddl example only ^ B and Alavr'z' AVI '

I 35449Β1 Athber & quot; But 0 Taatlab hepatic first & quot; Mile for General father PHP »Aladwi 0 p any 'Presentation for example; during Subject to the first 0 Presentation any' change 0 A mg Atuszaa" 1 t 1 degree to Ahgthat in medicine across multiple body closets, such as Presentation Speed Alhthal Alhsahat 1 breached and outside the E Father and Aladhae E 1 Lech ' and Nozda Ako'e across these five closets indicates & quot; The degree of linking blood Hsal & quot; 1 t-mile medication Z Athael Meh link Affi Brovemat d 1 km, such as albumin, which leads R lowering or loss of one biological Silaya for this one drug. As one pharmaceutical N. kinetic parameters Taatds Z fled Walsh 1 1 4 Shoji is no difference Aod; Thad, but Hadlat 0 Thas, many Daya 1 and \ or 0 o b Zd that; for the diseases of Almahvy 'Yesh seen 0 & quot; 1 to availability Albiologi'a one ever Kaaah medicine at Adam compartment. Ahbr & quot; 1 Elzimve teams & quot; Larg R & lt; Zs Z give medication and detection and standard capacity in one or blood plasm 1 - & quot; Temaks & quot; It is a time after it is to reach 1 1 Li R.kz. 1 km Wallach 'and & quot; Sim pussy 1 & quot; Heber Rkebz Wallach Lalai obtained medication Alaatty. Laos Aot affected Affi spray 1 km or R for drug and 1 Lay D 7 Biological Mechanism Bamuallat. Aflmat pharmacokinetic series! Objects Almkhadh bilateral single Cdan Ashe suffered z E 1 righteousness Adhu 1 GS, Lalai Dd selected in! To test the animal before Ghurairy Ne Alaort non Zori Z p - to Olad, is Aahma indicating meant for Alhthal publishing in chilblain that the. (Amivol Ambbodhir 20 1-12 ((2005)) - the term & quot; tonalities & quot; as used this Affi Alohrat b Cua 0 z S'dt Hecsah or Hawwadt counterproductive serious 0 can these side effects indicate the weakness of Ne carry Alawae are z and 1 or weakness Ne endurance topical after administration. toxicity Ahecn 1 Adha that - u effects distorted or carcinogenic Q .. ',; of the Alawae- determines Alstalh 0 of prevention & quot;; & quot; prevention in the neighborhood & quot object; or & quot; stress & quot; Kha de Seche; blood I a. fl Ur 1 ironer without one induce serious adverse incidents u are Mbatr must Alate (August brachytherapy) and during a longer period of Aod Z Thelmbaiq the diseases. & quot; Hamada & quot; protection in Alkazn Alehi'a or & quot; Althal & quot; can be evaluated, for example, in periods during the regular time 0.1 to treat and 64 i 35449Β1 seventh period include standards on the clinical evaluation, for example organic manifestations, screening laboratory abnormalities. It can Tngiv clinical evaluation and derivations natural results Msjrh \ color-coded Rafka to NCI-CTC, 11 and MedDRA standards. Organic appearances include parameters such as sensitivity 1 Almmaeh, bone marrow \ blood, irregular heartbeat, blood clotting and the like, as shown for example in Amaaber terms Althaia adverse incidents (ν3.0 (CTCAE. Laboratory parameters that can be tested include For the student on hematology, clinical chemistry, features Altjlad and polyurethane decomposition and a blood test liquids such as 1-, plasma, lymph or spinal, getter and the like. thus can be assessed 1 Kabbah, for example, physical examination, visualization techniques (for example ultrasound Ocoee 5, X-rays, Altso.ar magnetic resonance imaging (MRI), and other measures of technology tools (U eg electrocardiogram), vital signs, Bkiesr parameters a-la and recording adverse events. for example, adverse events in Protozoa non Chambanza in the uses and methods according to the invention can be examined histological means or Anesih, ^ d sucking 0 clustered & quot; effective dose & quot; or & quot; dose effective & quot; fixed quantity to reach, or at least one Hsal Aldzh to influence desired defines the term & quot; Quantity Alfalo therapeutically & quot; Quantity sufficient to cure or & lt; 0 least ease Almrs and its complications among Amartis who suffers from Almrkhr. Ace ^ v ^ Lzz AAC for this use depends on the severity of the injury and the general condition of the patient's immune system. The term includes & quot; Patient & quot; On humans and other mammals that are given a preventive or therapeutic treatment. Harm A- & quot; Anti-Semitism and effective dose & quot; As used here, the potential dose to 1 molecule is sufficient to bind the Hbb suffered in the pathological cells exhaustion, get rid of the disease, Azam 1 st tumor or the stability of the situation without major toxic effects. This is determined effective doses of 5 and non-toxicity of free example Tsaal tumor studies described in the drawing and must be less than a [Jrah which urges the adverse effects serious side (Thanid toxic dose,

. (DLT did not, / 65

MA 35449Β1 back to the terminology above, for example protection evaluation of pre-clinical pharmaceutical materials derived from biotechnology S6; ICH guideline triple coordinator; Ajtaaa ICH Steering Committee on July 16, 1997. The appropriate dosage, or therapeutically effective amount of a part of the linkage of the invention depends on the state that is being treated, the seriousness of the case, the pre-Alalah, and the history of the patient's clinical response and therapeutic element. It is modifying the appropriate dosage according to the doctor Nthreyr Mutaim where it can be given to a patient once or over several times. It is to give the pharmaceutical composition as monotherapy or installation with additional treatments such as anti-diabetic treatments as needed to Turkbbbat Abbnlanah of this invention are useful particularly at giving injections, for example, subcutaneous, intramuscular, Ni Ruwaid, intra-articular, and 1 or within synovitis . It can be administration by injection or infusion Boluses Almnashr. If a pharmaceutical composition freeze drying, are re-forming material A- (b) in a liquid filled before Walles ^ termination Reconstituting freeze dried substance, for example Elmejrtm water for injection (BWFI), physiological salt, equivalent acidity di-phosphate (PBS) ' or Z configuration is protein already drying freeze at best, Dzne linkage of the invention, which has been Anzjh -t Alannazza is -m Ne ban, cure or mitigate disease Alhkhtar are disease feast; t E Mod ALWIL 0 j 'or Alglobin immune disorder embodiment are alternative invention provides a method for 0 Za; cure or relaxation Z RIP Hkhtar 0 0 n 0 proliferatve trauma, disease and throw, or disorder Zs 0 Alimentarius Ailov Z step Atae opportunities Bhaj 0 connecting part invention or product in the process of & lt ;; invention. Configurations described herein are useful in pharmaceutical Kintrkib Elaj 0 E - and \ or Almza 0 n T'lh medical satisfying as described here has Mrahish need. Mention A- 1 for the treatment I as 1 y remedial actions and prevention or urgent. - Alalah against or Ata profile seen the body, texture insulated, or cell of Egypt Aaovi Z Rs \ Aznaab; Zd Z RIP \ disorder, or a tendency toward the disease, one literature, the aim of treatment 'Alhghae' 'A- 4 / Ng / 66 1 35449Β1 Altver, Alah, improve, relieve or mitigate disease, Projector Q Herd 'or the tendency toward the disease. Includes & quot; In need of treatment & quot; Olank injured on turbulent 'Hvla Z is Hza turmoil them. The term & quot; Disease & quot; Is any case need to form a 1 Sdech Droddn described here. This includes disturbances or chronic diseases and the situation Ashe - & lt ;, pathological conditions that predispose mammals to Awad concerned. Examples are unspecified disturbance 1 v 1 treated diseases here include proliferative diseases, oncology; or the immune-August. At best, Dzfairs linkage of the invention is for use in the prevention & lt ;,; or treatment of disorders-B cell, which are connected in Antak BCMA (excessive) such Alazt cell disorders; and \ or autoimmune diseases. Autoimmune disease is, for example, Alzzbh Alhmaheh Lhasa 1 uniform and rheumatoid arthritis. It is also available for the present invention a way to cure or improve de Ashe Tertbahl cell disorders in the BCMA production (excessive) such as plasma cell disorders, and \ or immune diseases Alz'zvi 0.1 him who include a step to give the case that need to & lt; esophagus linkage Z invention . RIP is an autoimmune For example Alnibh erythematosus or rheumatoid arthritis Alrlmatidi. Ne plasma cell disorders, cell reproduced one or Blazlama not multiply j 0 Be it control. As a result, this reproduction produces large quantities of the antibody F ^ d (1 monoclonal my) known protein or. Sometimes, such as Jamobatas, antibody Asc is incomplete, only Atolov of heavy chains Rsansl Khgevh. This Albulazt I. seen in August cells Antibodies produced which are usually specific to one type. The Leading Sire 'lasted 1 meet the plasma cell of the group that Taatolov multi Almiloma, Albulazemaobac' and plasma cell leukemia, presence of IgM Kabroa blood, amyloidosis, Valdnstrohm Jo.d Alglu.paulin Kabroa blood, Alingrada plasmacytoma bone marrow plasmacytoma outside 'August blowing bones , heavy chain disease, a Atadl Gamaia single nucleus of Pollack pain 61 d 1 and attention to inflammation multiple Almiloma ί 67 i 35449Β1 on the other side, Madat that Taatolov of rewarded 0 linking are invention 'molecule da Dhuoihn invention available E y 1 st of the invention, or a host cell They are the invention. Tzolov equipment loans and one or more bottles of Taatdhun Dzqe connectivity and usage instructions - all the 0 Ahecn that are comprised of Madat give rewarded 0 linkage of the invention, such as the syringe; A- '1 to 0 lead Ely decomposition or emboldened it. It means reshaping rewarded 0 linkage from the other sector and \ or Til 0) Dissolve Dzne binding of Alakhdhiraa.

Moreover, the present invention is related to the use of Alalarb Group 3 Q BCMA 'the best of the human BCMA, to generate Jr.ye Link E on the best antibody' & lt ;, capable of binding to BCMA, the best BCMA. ^. Match 3 Mjmuh Father Z BCMA Cadhan amino residues 24 to 41 0 n sequences Kha p 0 AL in SEQ ID. NO: 1002 in addition to the gas hot invention provides a method for generating an antibody, the Alavddl ablation 1 esophagus Rbahl generator Mkhad, capable of binding to BCMA, the best BCMA Abannra; Lalai Italov are (c) vaccinated animal in Bolbyptid composed of Aabitob Group 3 0 n Ji ' BCMA) better human BCMA, where Alaeptob Group 3 of the BCMA Taathlapq with Alaminba acid residues 24 R 41 Altafilh as -rz Ne SEQ ID 1002: NO E (I) get presented antibody Almnkur, and (h) optionally converting body anti Almnkur to link Ntaia rewarded 0 1 Alnhalid dirty t bind to the human BCMA and the best R T cell compound Melcl CD3.

Jr better, include step (b) the presentation that he is getting what was obtained by agencies one to me, when are exchanged Alaeptob group on the protein human BCMA group Alaeptob the meaning of the Anti generator BCMA murine (output in construction which consists are BCMA humans, J, Tree-clearing as 0 e human 3 is replaced Alaeptob group in Alaeptob gari Group 3; see 68 1 35449Β1 happen reduction in antibody binding. reduction Almnkur is, (SEQ ID NO: 1011 60%, on a one to eat him / her 50 a 0 / e 40,. / 0.30 ,. / 0.20, 10%; the better over at least 95, e / e 90 805/5705/5 ou even e / e 100, compared with Alaeptob group concerned% BCMA human, as the linkage to Alaeptob group concerned protein BCMA protein 1 Gary Z Hztjh in ΒΟΜΑ mortal 1 'BCMA .lepeshrah is 0 of 0 hee 1. from the liberal to the fiery Amj in ΒΟΜΑ Avery 1 BCMA are conceivable also Thsrat. CHO cells, endothelial Garemcba scale and \ or Saitoblazmik scale protein binds in -gsha different like

. 2a; see Figure EpCAM way Lapan this loss, according to the exchange with Alaeptob group concerned of an anti BCMA Alaz wells (Presentation example murine) is described in the examples attached 'pardoned particularly in Examples 1-3. Method involves Zh tested if either the antibody binds to Adbnob Group 3 are human BCMA and in another form capable of binding to Alaeptob Group 3 of the BCMA Macak Hthel BCMA of Macaca Mullaca (1017: SEQ ID ΝΟ) or Macaca Vasekolaras (SEQ 1017: IDNO). The present invention also comes in a dual-specifically linking element consists of at least two Q connectivity ranges; Ashe consists of a range of connecting the first and the scope of the second connecting where it is linked to the scope of the first binding Almnkur connects to the generator Anti spurt cell My BCMA and where it is linked to the scope of one to connect Aliava 1 in CD3 (Akeda 9, which also includes the presentation following the pendulum: 1 P-2; harm dual link selection from item 1, where the scope of linking the first Almnkur Arbahl RSS 1 s t 1 Rah cell of the BCMA and the scope of the second link Almnkur connects to a series & lt ;, CD3 -albzd 3; element dual specifically linked to the item 1 or 2 which is in Nmong body i shoulders of one shell or antibody portion 0.1 P 4; molecule dual specifically linking of item 3 in Nmong antibody full-length, Ddt that Zt 1 s linking BCMA first Almnkur is derived of the mouse Almnkur and where the scope of linking the second CD3 Almnkur is 0 - & lt ;, 1 for a rat - 69 1 35449Β1 item h; second one linking element to determine the z F-3; and Lalai is Sozj & lt; E c 0 mother counter in the form of & gt; Tnana body Italov of Zt 1 s H '¥ *' Htgar Dos [Ni Zhlaq IL - 0 change t Z-series Alboulibptid as the ace z ranges do not Nddrn 1 Bzd c; dual specifically linking of item 6 or 2 element which is in Nmong antibody series of individual bilateral specifically Ashe Ntalv Z Essen are Dzbmat scFv Ashe convey p rack β in serum rewarded 0 days Bhr.a -

1 P-7; Grate bind specifically deny 0 n item 6, Eetmnzatab Ssalhthagalh regions (VH) and Khgevh chain variable regions are identical (a 7), are Zhaa 1 T. Ν- Affi Zhaa 1 v C & quot; In Rrb (BCMA) -VH (CD3) -VL (CD3) _VH (BCMA) -V0 'VH (CD3) -VL (CD3) -VH (BCMA) -VL (BCMA) or (VH CD3) -VL (CD3 ) -VL (BCMA) -VH (BCMA item 8; second pointedness Z F-1 or 2 binding element; and Lalai is Ihozj Ztaq 1 mite immune single domain selected VHHs or VHs. item c: dual linking element 'to select from item 1 or 2 E and Lalai de ne b x & lt; esophagus Fv's Wharf antibody ranges Mtver 0 p at least an ace 0 n ranges Wharf 'Dave said shower 1 to less Zhlaq linking one specified R BCMA human and scope of the rack and one Zh Wallach fun LDL R-human CD3. item 10: binary specifically linked to the item 1 or 2 E and Lalai du ^ Zkh & lt element; esophagus rack Single consists Z scale connecting first defined in the BCMA series, Hztqh fled 0 Ah Thabthh) Evyzhaah C to a range of connectivity Alao.l Almnkur, Scorpene spots link in C R predatory coordinated by Althabnh rush, and the scope of linking the one specified in a CD3, and let .aki in size C Affi coordinated by rush Adapth 70

MA 35449Β1 1 x 11 Tel linking p Allied r F-1 or 2 and Lalai Du ^ Zj & lt element; esophagus Capers 0 B Hiad Arabhz R BCMA PO Aibn Z heavy dying \ Alkhvagh chain Fv are antibody or part mm L 1 and the one who Arbahl R-CD3 ACROSS linking is designed in rings not CDR Z heavy chain and light chain are p Hiad Er or & lt; p E counterattack. F-12; Element linking Tnana specifically r F 9:00 in B C & lt; E Aouadh Azkiran p Altdid Item 13: Dual specifically Z F-1 connecting element 4b that Zhlaq 1 first to connect Lader Laa Nmong selected Alnmang Maddh in any of the 1 FD 3 avi 12 and 0 as the Zt 1 s 1 rack Lalani Almnkur him Nmong various Mokhtar Z 1 Vzj specified in any z 1 FD 3 R-12. Item 14: Linking dual Alnded Z element F 1 and Lalai de Syed BC 1 Apr Adad Aq c 1: Installation of pharmaceutical consists of at least a dual-specifically bind any z items 1 to 14.1 to 1 c Bzd element; Ezt 0 der Rbz Tnana selection from any of the items 1 or R-14 installation of a pharmaceutical item 14 Sdj plasma cell disorders or other disorders Khadaa my link in the production of BCMA and for the treatment of autoimmune diseases. 1 P 17: 0 Zsr linking Shani specifically are any items from 1 to 14 or druggist from one installation to Bzd Ja Seng e-Apt plasma selected cell plasmacytoma, plasma leukemia cell, multiple myeloma, presence of IgM Kabroa blood, amyloidosis, Valdnstrohm having 1 to IgM Kabroa blood, bones Alingrada plasmacytoma, plasmacytoma outside the core, applied myeloma bone, heavy chain diseases, ill Gamana monoclonal Unknown Alosh, inflammation myeloma Almtadenh items variables above are Mhnth from 418.2 191 10 EP included here as well. It is noted that the discoveries here are not specific to Menhh Anmdd, protocols, or reagents, as they can vary are providing discussion and examples provided here to target specific instantiations described is not intended that it defines the scope of the present invention, only the specified elements of protection. I am 71

MK 35449Β1 0 Assor 1 T and 1 categories 1 to sowed Almnkurh Eraksnhma selection (which includes the K 1 Ge behind one T1 to Akhcaa E Application 1 t behind the 1 T. invention, scientific publications, selections Alasnah E Name 1 v E 1 Lech) aware Balaely or ^ to lowest are listed here Repertory Bmjamiaha There are no reserve what is here Aekn interpreted recognition that only 1 GS z den wanted this one discovery spirit Wallach 1 GS Alhsbak 0.1 Li Huda Akadh listed by reference contradicts or is inconsistent with this selection of specifically replace any other Mazh show formats; Figure 1: Mhanah Altzlslh domain of Khar h cell (ECD) & lt; a BCMA Alpes, wealthy (Baoaa - flashing 4 54-1 Z protein as 1 ml length) and BCMA gari (residues amino acid 1-49 are protein Ka 0 1 Q). 1 m was Araz 5:00 regions (domains or amino acid residues) that are exchanged Ne builders commandment); as it is designed for groups Alaeptob. Sixties pictorial black funds. The excitement to the second sulfide. Figure 2: Draw Alaeptob the builders BCMA. BCMA human or murine (Fig. 2a) as well as seven builders human BCMA -algare placebo (bereavement 2b) that has been produced on the surface of CHO cells Kaaa appear to flow cytometry. Production of human BCMA on CHO has been disclosed in a counter -BCMA human antibody. Is detected in the production of gari BCMA quizzes monoclonal anti -BCMA gari - antibody. The detection of antibody monoclonal in a counter -IgG-Fc mouse - gamma - an antibody specifically binds to phycoerythrin Figure 3: Examples of linking Ze set for the group Alaeptob Ε3 has also been detected in drawing Alaeptob of builders BCMA phantom (landscapes Example 3) . Figure 4: Determine connectivity components for Dzenat link Tnanah update (anti BCMA X, anti-CD3) Presentation BCMA Abriv and Macak using Zam Bayekor. The freeze-born counter 72

MA 35449Β1 intermediate density (100 RU) to CM5 chip. Dilutions links flowing on the surface of the wafer and. BiaEval determines connectivity using the software. Rates are concerned and build linkage (KD) of links concerned illustrated below in every form scheme 5: Hits toxicity of BCMA antibodies bilateral specifically as size in launching 18 Chromium- hour experience. Almostagabah cells: CD8 T cells fertilized human pluripotent. The required cells: CHO cells Alazqo.lh human BCMA (Ashkl left) and BCMA CHO cells Macak movable (Figure right). Affected. In a cell are required ratio (Ε: τ): 10: 1. Figure 6: Determine the builders binding of antibodies specifically bilateral BCMA / CD3 of Alaeptob group Ε3 the BCMA Macak and the human and the human CD3 Macak and using Baaokor system. The immunization is born anti - density composite Alloa * «for i (100-200 RU) sticking Chip CM5 flow dilutions of antibodies bilateral specifically on the surface of the wafer is determined by using the link BiaEval software. Alhaveh rates and an efficient output of Art (KD) z antibodies specifically bilateral Alafeeh is illustrated below in each scheme. Figure 7: Analysis 0 F ACS antibodies bilateral specifically BCMAGD3 are Alaeptob group Ε3 folding Hsarat 1 cell Alhishar one of her guardian: 1) distraught CHO cells BCMA 1 show him E 2) Hsar Zih Apr 3, HBP-ALL Alad Asheri BCMA (3 CD3 Macak are CHO cells 1 to Mzcolh , 4) jLt cell Apr 4119 LnPx 1 m AAC E c) JL cell NCI-H929 Millom 1 Alehtaddh 1 to secrecy positive BCMA and 6) Ahlaya CHO Gore Alhzcolh. A 1 ^ armpit salivary [1) I c);: detecting objects stile without BCMAGD3 dual antibody specifically Mspy. 73

MA 35449Β1 Figure 8; Skachard objects are analyzing bilateral Almkhadh pointedness BCMA / CD3 presented production BCMA 0 cells are embracing Metzadh cells at concentrations of antibody unilateral Almirak until saturation is detected antibodies to flow cytometry. Triple measurements are plotted as curves copies Heiberboleik values and curves ray even indicate Trkizsaleh user rate. Connectivity is determined using valuation Supreme Skatthard and KD values are concerned account. Figure 9: Hits toxicity of 1BCMA / CD3 ^ anti bilateral selection from a group Alaeptob Ε3 as size in launching 18 Chromium- hour experiment to 0 , the cells Z transmitted with human BCMA. Responsive cells: human CD8 T cells pluripotent fertilized. Unmoved in the required cells (Ε: τ) ratio: 10: 1 Figure 10: Hits toxicity of 1BCMA / CD3 ^ anti bilateral selection from Alaeptob Ε3 group size as in the experience of the toxicity of the cells which are based on Ayas - FACS in 48 hours. Cells 1-: PBMC human is motivating. The required cells: Khadaa 0 Brahalmzcolh in human BCMA. Affected in the desired cell (Ε: Τ) alum: 10: 1. Figure 11 FACS analysis of the antibodies less transient; BCMAGD3 of I-Alalaab Ε3 Z BAFF-R and movable CHO cells TACI. Cell: 1 tracks) movable CHO cells BAFF-R 'for mankind, 2) movable CHO cells and human TACI 3) multi - path Khalihhaloma 1363; negative controls; Detection of antibodies by John antibody specifically dual 74 1 35449Β1 BCMA / CD3 advance. Positive controls: Detection of BAFF-R: Goat against the R & amp; D AF1162; 1:20) hu BAFF-R) , which has been disclosed in the antibody anti - PE (Jackson 1:50; 147-116-705) revealed TACI: rabbit antibody anti TACI (Abacam 1: 100; 79023 AB) was Alktaf him in a counter - goat rabbit antibody PE (Sigma 1:20; Ρ9757). Figure 12: 1 Fbh toxicity of j4 & quot; ^ BCMAGD3 anti bilateral specifically as size in the experience of one divorce Aj- chromium 18 hours. Almostagabah cells: human CD8 T cells 1. stimulating. Cell needed: the path of a human cell 363 multi positive Miloma -BCMA (for example natural product). Which affects the required cells (Ε: τ) ratio: 10: 1. Figure 13: 1 effective Mechanism of Toxicity 1BCMA / CD3 ^ anti bilateral selection from a group Alaeptob Ε3 Kha is the size of the toxicity of the cells that are based on - FACS in the 48 - hour experience. Cells 1-: PBMC human is motivating. The required cells: the path Miloma multi - cell Labrie 363 A (^ BCMA Tabbiei). . Affected in the desired cell (Ε: Τ) alum: 10: 1. Figure 14: 1 faithful Mieh are MBCMA / CD3,1 anti bilateral specifically as size of the toxicity of the cells that are based on - FACS in 48 0 abuse experience. A- cells: PBMC humans 0 Ye Fair 1 to Mahgzh cells Z path Bh human multi Miloma 4929 A - 1 h. 'Unmoved to the monitor in the trap (Ε: Τ) b: 10: 1. 75 i 35449Β1 Figure 15: Hits toxicity of BCMA / CD3 Adjaam anti Tnanah size is defined as the toxicity of the cells which are based on experiment basis - FACS in 48 hours. Responsive cells: T - cell path Macak 4119LnPx. The required cells: cells 0 Z movable in .BCMA.Ë. Affected in the desired cell (Ε: τ) alum: 10: 1. Figure 16: Hits anti-tumor BCMA / CD3 antibodies bilateral selection from a group Alaeptob Ε3 at an advanced stage of the NCI-H929 Nmong Axinguat (see example 16). Figure 17: toxicity of cells that are based on FACS using beacons multiple human cell Miloma experience. 3 C 3-A and 2-ΟΡΜ Kkhalaaa required Kkhalaaa responsive and PBMC (10: 1 = 48h; Ε : τ). Visualize the shapes cytokine levels [pg / ml] that was selected to, 10-IL, a C-1, 2-11 TNF and IFN -gama in an increasingly Nczykizzat are BCMA / CD3 antibodies bilateral selection from a group Alaeptob Ε3 (see example 22) . Examples: The following Alashlh invention. 5 these examples do not restrict the scope of this invention. Alashlh my goals , including the invention, and the present invention is defined only elements of protection. Example 1 generating CHO cells that produce BCMA placebo 76 1 35449Β1 vomiting c ^ Joel T. 1 1 Asub drawn phantom, amino acid sequence change from bands Alaeptob Abthrey R Altzlslh 1 to expensive. B last BCMA or on the remains of a single amino acid z these molecules; (SEQ ID NO: 1009) 0 murine outside the human cell where the BCMA group: Out of the placebo cell BCMA scope or 1007 Hbdl Ne SEQ ID NO: 1002 1 to Aeptub 1 (tactful 1 O 1 acid 1 to Ammivu 1-7 Z (1008 or SEQ ID NO: 1004 4 -1 Lamine I Almjmuh antral 1 Maveh (residues 1 to acid 1007 or SEQ ID NO: 1002 E. G6Q a clubfoot remnants of one of the acid Alahive 1-3 and Tgrh (SEQ ID NO: 1010) 1 Gary Ε2 \ broadcast 0 Ri BCMA ECD 0 outside the human cell where the BCMA group outside placebo cell: Zt 1 s BCMA Zt 1 Qar 1007 Chtbdo in SEQ ID NO: 1002 1 to Aeptub 2 (residues Alhhi Alahive 8-21 0 n (1008 or SEQ ID NO: 1004 18-5 1 to Mjmuh Typhimurium Almaveh (residues 1 to acid 'to my regret in 1007 or SEQ ID NO: 1002 Tgrk in NI IS and S9F) QIOH in SEQ ID NO: 1011) mild Ε3 1 to Shri 1 BCMA ECD 0 Khark human cell where the BCMA extracellular Ersba: scope BCMA scale or SEQ ID NO: 1002 Group 1 Aeptub 3 (residues 1 to Hed Alavi 24 -041 n SEQ 36-21 007 Achtdl Apr 1 Mjmuh Azv'rah 1 Maveh (residues 1 to acid Eladie (1008 or ID NO: 1004 R39P and Q25H, S30N, Β35Α b clubfoot Pattaya one of Hed Alahive 31, 32 and Tgr 1 T. 1007 or in SEQ ID NO: 1002 Apr 77

MK 35449Β1 (SEQ ID NO: 1012) Aryan Ε4 Labrie 1 BCMA ECD 0 that, V outside the human cell BCMA outside placebo cell: the scope of BCMA scale or SEQ ID NO: 1002 Group 1 Aeptub 4 (residues 1 to acid Alahive 42-54 0 n SEQ 49 - 371 007 Tstbdd in 1 Mjmo Ah 1 Gharreh 1 Maveh (Bkaba 1 acid Wallace (1008 or ID NO: 1004 or SEQ ID NO: 1002 and A854tgrat in N42D, Α43Ρ, N47S, Ν53Υ to 1007 (SEQ ID NO: 1013) 1 Ira Ε5 \ 1 Shi BCMA ECD 0 outside the human cell where the remnants of BCMA trait Ashhaa Q: BCMA Taq Taq or 1007 (Aazolusen) SEQ ID NO: 1002 Alhaash Alahive in Mo'qa 22 or 1008 (E Las SEQ ID NO: 1004 Tstbdd the remnants Alhas 1 Las murine Z (19 Alhoqa 1007 or SEQ ID NO: 1002 in Ι22Κ b 1 Tora (SEQ ID NO: 1014) Ellery Ε8 1 mortal 1 BCMA ECD 0 outside the human cell where the remnants of BCMA outside placebo cell: the scope of BCMA scope or 1007 (Dtamny) will look SEQ ID NO : 1002 DNA Alahive in Elmo 1 Qa 25 0 n or 1008 (six-one days' site SEQ ID NO: 1004 Vibak 1 O Alhhi Alahive 1 to Murine are (221 007 or SEQ ID NO: 1002 in Q25H b Alhlgrh la / 78 1 35449Β1 BCMA ECD Lasry 1 17 Lee 1014: NO Here SEQ)) BCMA outside the scope of the imaginary cell: the scope of BCMA Khark cell Albashra where Alahina acid residues at positions 39 of 1002: SEQ ID NO or 1007 (arginine) replaced in Bakaya'lhamad 'Lamine Aryan are 1004: SEQ ID NO or 1008 ( Rollin; site 34) Tgrha R39P in 1002: SEQ ID NO or 1007 A) are cloned in the vector constructs Cdna production Daaat pEF-DHFR and the movement steadily to Khalaa 1 CHO. Be sure to produce human BCMA on CHO cells in an experiment FACS using anti-human monoclonal antibody BCMA. Production of murine BCMA appears in monoclonal anti - murine BCMA - antibody. Concentration of 0 to serve AGEs 13:00 anti BCMA p 10 pg / rnl in PBS / 2 ./. FCS. Short detection 1 Alamadadh'hadah monoclonal antibodies Ne Mkhad rat 1: 100) lgG-Fcy-ΡΕ in PBS / 2 ./. FCS; Jackson - enol Reric # 071-116-112). U'ü negative, is one Anadan cells in o FCS / PBS / 25 instead of the antibody one of the first, disparage measure Alaidt Bcdvq cell on FACSCanto 1 instrument 2 (Becton Dickinson) and analyzed with software Flojo (version 7.6) is the analysis of surface output to Himrat BCMA 1 Irbh - Human , transferred to CHO cells and cellular stresses in the stream experience in antibodies for anti Mokhtlgh -BCMA. (Figure 2) B) Dhuad Khalaa 1 CHO, which produces the human BCMA, Macak, gari and human 1 murine guardian of the membrane is saturated, the sequences encoded by BCMA 1 to Pfia; Macak 0.1 Ira and thier 1 T. human BCMA -alvora (sequences BCMA as Montaourh in Jivblazk 0.1 would launch Mahebr 001192-ΝΜ for human]; 011608-ΝΜ and Aryan and 001106892_ΧΜ [Macak] obtained formulators gene according to protocol recognized. site 0 Zam net 1e are buildings that are designed parts installed WAH SHIN shower first Z and sequence the symbol of the 19 amino globin acid 79

MA 35449Β1 peptide immunotherapy, followed in the framework of Btzlslh symbol of the BCMA, respectively, in the case of Hemrat with ranges of Alaeptob on Alhvlh Alps-Harih Almtbad 0 him Balt 11 of Typhimurium. Here Ed 1 BCMA ECD wild \ Ε4 Akari and BCMA adopt a sequence symbol of the band outside the cell are proteins BCMA followed by part of the sequence of rice are -Gly4-Ser9 Seri - industrial link followed in the range inside the cell g EpCAM 1 mortal (Aladad acids 314-226; Altzlslh as published in Jabblanc Wendell Hzzm 002354 _. (ΝΜ all sequences code tracking codon stop. as is Tassaam about Ri gene lattes 1 c Hoaf 1 to restrict Almmasph. is Achakh 1 spot installation of one gene in one Blazt pEF & quot;) pEF-DHFR DHFR described in Reims about each . Cancer Aminol Aminodhir 150-141 (2001) 50) all prior actions are Tngiv according to protocols standard (Saouk 'malware Klohj; for Abrocora Manuel, third Edition, Cold Spring Harbor to Arrdora Byrds 0.4 and k for chronicled zapper, Ziuyolk (2001)), each 0 Mo 0 LED Z is transferred dynasty in sequences Nyukloitid verification Z 1-1 Li DHFR Nleia CHO weak Aztaj Algalaya fact that the nucleus of the squad. The Tnqan production Bootan .lkhalaaa fact one of Zuh in Chania DHFR CHO A- Kha described in Kaufman RG (1990) enzyme ways. 566 to 537.185. Z r additional buildings are urging concentrations Almetz 1 mane of methotrexate (MTX) R spray Avi Ashe R & lt;, 20 ηΜ ΜΤΧ. Shall 22:11 to Azmaj S Ne 293 ΗΕΚ cells 1 strains from plasmids produced Pfaellat Nyuklutid Alsagqh of A- Lal and Aztaj protein in the production of 293 system Freestyle ( 'Nfeinzojin, z or r Ashe E Carverlh' Germany) according to Alasna protocol. What floats which consists Z 1 Zoat A- DTM assets it, is the removal of the cells are centrifuged and Hgz what floats at -20 generating u - '

MA 35449Β1

2.2 output, a constant in CHO cells are cell strains from plasmids produced in Alnyuklutid sequences generated from Ntzlslh 1 Li weak DHFR CHO cells to produce eukaryotic cells of constructions. Tngiv cell production is the fact that the nucleus Ne DHFR Khalaa 1 CHO A- km 10 connector is 0 ^ P Q R Kovhann Lage (1990) Methods of enzyme. 566 to 537.185. The induction at the genetic inflation for builders to focus one of T. Alehtzaidh 'to Mathoturksna (MTX) to a final concentration 0 n 20 nM MTX. 0 n must be two sections of fixed agriculture grow the cells in a circular bottles in Nyuklaoseid - 1 x Ne HyQ PF CHO average Sanl soy (in a 4.0 mM glutamine 0.1./. Florenak 68 - F; Heikklon) for 7 days before production. The removal of cells centrifuged in Aceh Alhoad atopic Tankon protein product kept at -20 ° Mtoah. 2.3 Nthagah protein purification are Tngiv BCMA proteins Almanbh as follows: Explorer ®GE system) Akta Healthcare) and ®Unicorn software used Radiology color. The proportion Tngiv scan color metallic Mahmnh IMAC ")") using ®Fractogel EMD chelate which is loaded Apr 2nCI2 light of Affi Protocol Lalai are supplied by the manufacturer. The calibration of the box in the equivalent acidity of 20) A mM Z equivalent acidic sodium phosphate, pH 7.2, 0.1 M NaCI) and are Ttabbh (0,2 μ2η) of cultivation of floating cells to block (0 for 10) in the flow of 3 ml \ min. Alkhalo are washed in an equivalent A Haodh to have removed Alaivh is Almertbth.dtm A'khkhraj protein by using a two-step trainees h equivalent acidity of 20 Mm) B equivalent acidity Vosgk 'Nsodiom pH 7.2, 0.1 M NaCI, 0.5 M Ahedlazul) and 0 Ta Affi wage' E 1 snooze 00 a-H 1: 0 of 0 uh Z equivalent Hammou, Dh Β PHP sizes box six thousand; 2: 0100 uh are equivalent acidity Β in sizes box 6 is p 1 penalty 1 protein derived from step 2 to purify other myth. All materials Alkihialah z score Aaban and ^ Hranha of Alaijma (Disnhovin) R Merck (Darmstadt) · (/ '{/ 81

MA 35449Β1 are Tngiv scan color gel filtration on Helrd 16/60 Sobrdicks 200 Hishrj Lord of the box (LG A1 Amersham) calibrated in equivalent acidity equal (citrate 10 Mm; 26 mM lysine pH 7.2, -HCI for your protein Alhztjh in Hlaya HEK and 7.4 PBS pH for Brovemat produced in CHO) cells. Protein samples are extracted mode (flow 1 ml \ Iqiqh rate) to standard SDS-PAGE and Western blot to detect. LaRouche pylons is determined using OD280 nm. Proteins, which was obtained through hard production Ne HEK 293 cells and the blood of one harmony vaccinations. Proteins that have been obtained through hard Attaj in CHO cells -m for selecting links and to measure linkage Example 3 Alaeptob kit of parts -scFv gari are staining cells 1 t of movement in the human BCMA or Alira E or & lt; Ivat BCMA convergence in the crude extracted from the cytoplasm membrane is diluted Lalai Lalai 0 formation scFv binds 0 u I BCMA human one Macak. ScFv is detected in one Hikrowerem \ ml are Hiad I Hiad body FLAG (Safma F1804) and R-PE labeled anti-murine Fc -gama - antibody. Dianov # 071-116-115). Are all easing antibodies in PBS in% 2 FCS. Khiabott captivity, are Ahthman cells in% 2 / FCS PBS rather ZZ 1 Kitabalgsha 1 to cytoplasmic. The Kiea Kaavo 'samples to flow cytometry on FACSCanto tool II (Becton Nekshgon) and analyzes in Rmjat FlowJo (Akaahh 7.6) / P Figure 3. Example 4 Fra 6 Ace 1 1 Almokhtlgh to Moltlqh of human BCMA and Macak MP A) sequences symbol & lt ;, BCMA human and one of the mite (Kha Dzzh in Gilpank 'Rafah 1 join Z Alaohi Albashra, Fc71 pustular and two days murine used to build Hlslat Cdna Rattler atopic seen & lt; I brooch 'v August Alz'h & lt; a human BCMA and Macak on Altoave and two days urticaria; IgGI Fc know and Larch S2 1 human 35449Β1 respectively as well as Alberutinat MP which is composed of all the bands outside the AA; \ him from the BCMA. to generate profiles for the production of proteins BCMA 1 to Bthbera and Macak 1 Aaloh, Adz'e cDNA is! to get Aiana Bo 1 middle Tgr 1 T. PCR Q BCMA cDNAs full-length described above and 1 molecule which Astsch and Fa R1 to Berltoclat standard. to Mdmjat of human two albums, the design of parts modified cDNA bowed en Presentation Houka Kozak first no 6 Ztaj cells fact that the nucleus of the squad followed by Btzlslh 1 symbol Z Droddnat human BCMA and rhesus (or Mokaka Mullaca) respectively, which Ttav Q amino acids 1 to 54 and 9 Affi 53 corresponding to R-ranging Khark cell of the BCMA Arra and rhesus, respectively, followed by in part they relish the symbol of Se21-Gly4-industrial Se21 link, followed in the framework of the code sequence of human serum days' 0 Keep in Ahlar Z symbol sequence of FLAG tag, followed in the framework of the Z sequence Waller & lt; (SGHHGGHHGGHH) and stop codon & lt ;; A-Lalai it was t * Delh. To Mdmjat of human two albums, the design of parts modified cDNA Ani 0 of Zaw'n & lt ;, Houka Kozak first to produce fact cell nucleus of the squad Alehtbuh - 1 rice z Berltbmat human BCMA and Macak respectively, which are composed acids Alamindh 1 R-54 and 1 to 53 corresponding to the scale outside the cell are BCMA Larry and 1 Rsus, HR Arava E followed in the framework are the sequence code of Ser1-Gly4-Ser6 Afoua 'Itm 4 in 1 link flew are Hsalh Alr.hz are serum days murine, followed by the R-Z dragged land of Elao FLAG, followed in the framework of Hsalh symbol of Alhscdv Lalai amended (SGHHGGHHGGHH) and Rdon Ragaf. Formations scale extracellular Almazb E is circulating a cDNA 1 Klh rr Z site Kozak first to produce Alhadia fact the nucleus of one Fezblatt 1 Quh - Arhz & lt ;; human BCMA and Macak proteins respectively, which Love Z Alahaad one touched one R 54 and one R 3 c Attabakh to scale extracellular 0 n BCMA Larry and Arders' & lt ;, respectively, Htbuaviatarmen sequence 1 to wormer from 0.1 ducks Se21-Gly4-Ser6 Alsz 1 apolipoprotein E Hia huj 83 1 35449Β1 as part of the sequence symbol Z Flag mark, followed by a part of the sequence code of Alhsaitidin which (amended SGHHGGHHGGHH) and stop codon, as is the design of parts cDNA even had the construction sites at the beginning and end parts. Restriction sites produced, is used EcoRI at the end of '5 and in all predatory' 3, in the following cloning procedures .eetm Astzsak parts cDNA via EcoRI and Sail 1 Li plasma designed pEF-DHFR (is described pEF-DHFR in Rerum about each. Cancer Aminol Aminodhir -141 (2001) 50 150 are Tngiv all measures described in advance, according to the protocols standard (Sambrook Melclor Klunung; BAA to Aportora Manuel; August third, Cook not-Brzg e-Arbor to Arrdora Press. Cook Spring Harbor Enyoryuk (2001)) B) sequence the symbol of the human BCMA and Macak as described above and the series symbol of the human two albums, human Fc71 'Fc71 1 Ira' Fc72a FAO my E Albohen murine, Albohen the font, Fc71 the font 'and Fc72b to Ajerz ^ category sequences industrial Cdna that trauma R Zotb 1 T. Akej Hersh BCMA 1 are mortal and Hacak on one of succession and Lars repeat my 'IgGI Fc human IgGI Fc 1 E Ira E gG2a Fc | Mouse, me, my days the mouse, IgGI Fc rat, 0gG2b rat and Albohbn Tjrn Presentation 1 Tawar Vhlla for Albroort Almannbh Ashe Ilv Z Ztaq one outside the Study 0 n BCMA. Just a not-T & amp; C Rort BCMA m 1 and CAC

1 to 1 of mortal dissolved penalty CDNA obtained in frameworks 1 T. PCR are BCMA cDNAs Kahla 1 Moumovh length and above. A_i_akh Aldzfairs according R protocols standard Hedmjat 0 n Alpohivat, are designed to hold CDNA Alaadelh Z hr Houke Komak first to Aztaj 1 is composed of cells of the fact Auriga one of Z 1 Hkellat and Hdlo 1 of the Code of 9 a Haash Amity are Alglubit the 5-security one Lenny lead one to Bptd, Alehtbuh t part - Rice Den Alttaq outside are protein ' BCMA followed meaning in Ahlar 0 0 No n lift 0.0 g z decision Gly4-Se21 a 2 Jeh Alhmaea followed in 1 flew Chih Waller 0 g of specific land one technician 'Mtbo 4-year framework for 1:00; Lest the symbol p 0 Ida y, z dilatable Ne lar rather land Z 1 Pugh (SGHHGGHHGGHH) and stopped 84 Rdon

IK 35449Β1 to Mdmjat of IgG Fes is designed parts CDNA MSAS District amended Houkh Koz'k 1 well to produce fact cell nucleus of the squad and the sequence code of 19 Hed Amdna Z Alglubit Alhmaea that lead to Albptd, followed by part of sequencing the symbol of the band x 1 Shake A- Z BCMA protein 'for meaning followed in 1 flew 0 n sequence Waller & lt; Of Rani Se21-Gly4-Se21 Alhmaea 0 of Ed 1 igGI Fc S where Rani Serl-Glyl Afhe Blood 'followed in the framework of Tzlsh symbol from one part link and J 0 of Fc Z IgG on' 0 Thelokh part are the sequence code of Filag sign E Mutaira in 1 flew Z 0 Dallah Anrz are one Snai Alfdl (SGHHGGHHGGHH) and Rdon Dhuhv. Formations range of extracellular deputy are designed parts of the modified cDNA Denny Tldon 0 Ouay Moo-Qa Kozak first to produce fact cell nucleus of the squad and the sequence Arms in 19 Aa0-6na 1 What Q immune Alglobin that lead to Albpt, followed by part sequence 1 to RNAi Z Alzh 7 GS 1 committees cell protein BCMA Alani followed as part of the sequence 1 to wormer Z Rani -Seri Gly4-industrial Ser1, followed as part of the sequence symbol Z marker 1 to Gallag 'Htbua part are Hsalh 1 of the code of Alhsaitidin' rate (SGHHGGHHGGHH) and codon d. Astdhakh displayed to the appropriate restriction sites. The cDNA clone parts Affi plasma -pEF pEF-DHFR) DHFR is described in the 2001 Roman s) Almsassah. Lam Nenni Almnkurh measures in advance according to standard protocols (Sambrook; 2001). The following formulations designed to allow for direct separation of the distinctive Alaeputobat. Oni sequence Z Himrat BCMA murine - human and Himuat BCMA Macak _aira (BCMA sequences for murine, human and Macak as Muhov above) and sequences symbol & lt ;, Albohbn murine and murine Fcyl used to build industrial cDNA sequences that Trevi Affi Bro.jat Hamad remote BCMA -alepeshra of murine and murine Himrat Macak respectively IgGI Fc murine and mouse me two days, respectively. To generate constructs for the production of Himrat BCMA murine - human and murine Macak Almanbh are presented Alhhol parts BCMA cDNA in mouse J (amino acid 1-49) with ranges Alaeptob on mature R Ngllh Butr.ah and Macak respectively are obtained genetic compositions according to the action 1 v 1 small intestine confidential. DTM 85 1 35449Β1 Tngiv clone compositions as described above, according to standard protocols (Sambrook E 2001). The construction of the following particulars: 0 Ahamkhy human amino 1-4, IgGI Fc gari 0 homocysteine human 1-4, two days murine 0 homocysteine 1-4 Reswe, IgGI Fc gari 0 Ahamkhr amino Reswe 1-4, two days gari 0 homocysteine 5-18 rhesus, IgGI Fc Aryan 0 homocysteine c humans 18-j, Albu. Maine Alfaz, J 0 homocysteine 5-18 rhesus, IgGI Fc murine 0 homocysteine 5-18 and rot; gari days 0 'acid' Lamine 37-49 'mortal, IgGI Fc 1 0 Ira homocysteine human 37-49, two days gari 0 1 acid Alahive 37-49 Ranaos, IgGI Fc Aryan 0 homocysteine 37-49 rhesus, two days Aryan Alosadj 1 5 Baaokor - which is based on determining the antibody dual-ratio limitation 0 Affi BCMA and human CD3 and Macak are Tnnin decomposition experiments Baaokor using pre and proteins integration of BCMA 1 to Hzvh in the serum of human Albu 0 yen (ABB) reason BCMA 1 is required to connect. Measurements proportion of CD3, mergers Almatlgh proteins that have a 27 amino acid & lt ;, end -N & lt ;, ie: Ceylon CD3 86 i 35449Β1 (© CD3) Built to an antibody Fc portion is used. Tu 4 Albrocivat Alchtfah hoarseness in 2-human CD3e1 and in version 27-CD3e1 1 in atomic and I CD3e monkey Lord 1 h, both of which carry Alaeptob of CD3 monoclonal Ne link one hand Tnaiah Aqahdid. Detail, are vaccinated Rqang sensitive CM5 (J. Ashe Hels including ^ Lord 655 R Ru approaches 6 are born anti-recombinant on B-1 to Takt'm equivalent Lf acetate ρΗ4.5 according to one of Asg guide. Is loaded antibody samples of dual-specificity in Meh concentration: 50 ηΜ, 25 ηΜ, 12.5 ηΜ, 6.25 Nm and L · 3.13 ηΜ * in HBSEP equivalent fast acidity (G spread of Healthcare). rate of 1 case was 30 AVI c 3 microliter for 3 a prevention, and then are placed equivalent Haodh Darda, HBS-EP for 8 Dave 1 DOCUMENTS rubbed · 1 other Ne drawing the inauguration p. 30 '0.35 Makrlitr 1 ml. is Tnfein renewal of one of the hall using 10 mM Nien 2.45 0.5 M NaCI pH. the data analysis is it's 0 Tdam recent BiaEval (see Figure 4). in general the two are Tngiv are experiments . 5.2 ratio of 1 to bind to the human BCMA and Macak is determined ratios one to connect from one to Ajhdam 1 to counter Tmaveh specifically BCMA / CD3 Affi BCMA human and Macak analysis Baiakour using Rozt Dehaj BCMA Alhav in two days gari (. (ALB detail, are vaccinated CM5 sensor chips (r additional * for \ H.l) in 1 m Teach 1501 R. 200 RU z Hawk 1 FD recombinant on the use of equivalent oxyphil acetate ρΗ4.5 according to the factory guide. is loaded samples & lt; esophagus Arz Qaveh Aq ^ d Ne five concentration: 50 ηΜ, 25 ηΜ , 12.5 ηΜ, 6.25 ηΜ and 3.13 ηΜ 1- in Haazl Amodh fast ΗΒδ-ΕΡ (H Healthcare) neighborhood. Ratio selections BCMA flow rate was 35 microliter 1 minute Z 3 minutes; blood Dadam use ^ Del fast acidity HBS-EP for 10.30 or 60 minutes Ne rate TDs are 35 microliter \ 0 for 0 is ito renew Take 1 Qzz using the equivalent acidity consists of a mixture 1; 1 S7

MA 35449Β1 are 10 mM glycine 1.5 0.5 M NaCI pH and M c Ganaedin chloride solution, the data is analyzed using BiaEval software (see Figure C). It is generally Tngiv two experiments. Tngiv be sure of connecting the human CD3 epsilon and Macak in individual experiments using the same concentrations as used to connect the BCMA; be conducted to determine the rate for 10 Dqang are time decomposition. Dual-antibodies show specifically BcMA / CD3 of Alaeptob group Ε3 descent to the human BCMA in sub Nanomolar rate less than the rate of Bekomolar No. -1 .eetm linkage equilibrium to Macak BCMA, as percentages appear in Nanomolar No. _1 Nanomolar less than a sub-set rate. Alfb and gaps biz ratios are Aladjaaam anti show bilateral specifically BCMAGD3 in Table 2. Table 2: antibodies bilateral proportions' to determine the BCMA / CD3 of m-Jmuh Alaeptob Ε3 to the human BCMA and Macak also defines analysis Baiakour; variance ratios Den Alhhassobh (ma BCMA: hu BCMA). Antibody - Dual specifically hu BCMA [nM] ma BCMA [nM] the difference between insults ma BCMA: hu BCMA BCMA-33 0.031 0.077 2.5 BCMA-98 0.025 0.087 3.5 ϋ-11 0.60 2.2!. & Lt ;? BCMA-34 0.051 0.047 1: 1.1 BCMA-74 L 0.088 .. 0.12 1.4 88

MA 35449Β1 BCMA-20 0.0085 0.016 1.9 5.3 Baiakour - which is based on antibody dual ratio Ataathdid Affi human BCMA and Macak are re BCMA / CD3 levels of antibodies bilateral specifically R BCMA recombinant Almanb on Rqang CM5 in Biakour gauges to confirm KDs and on Alad rates S using intervals biggest decomposition (Hh minutes instead of 5 1 Dqang also used in one of Djerba ales 1 Bah). All which was tested BCMA / CD3 antibodies bilateral convexity to put Affi 1 O & lt ;, ratios scales independently knockdown concentrations Mokhtngh. Objects ratios 1 Mkhadh Tmaveh Aletbid BCMA / CD3 z Mjhuh only one Abdhub μ as Ε3, clear sub Nanomolar less than the Akos Laz RIP -1; Ashe equ in Aa1'1 & quot; Lotta 3 '1 to Table 3: b (KD) 0 n bi-linking molecules specifically BCMA / CD3 & lt ;, 0 Jhot Alaeptob Ε3 of Babakur experiments with 1 Stkhtham 1 Wet Ashe less; (Isaiah Z 1 prep independent). Body such as 1 d ^ E BC1 / CD3 [| a KD ΒΟΜΑ; Μ & lt; ^ KD [nM] macaque BCMA BCMA-83 566 5 ± 0.053 0.062 ± 0.011 BCMA-98 0.025 ± 0.003 0.060 ± 0.001 BCMA-71 7 of 0.0 ± 0.242 0.720 ± 0.028 BCMA-34 0.089 ± 0.019 0.056 ± 0.003 BCMA-74 0.076 ± 0.002 0.134 ± 0.010 BCMA-20 0.0095 ± 0.0050 0.0060 ± 0.0038 example 6 7 AAA \ 89

MA 35449Β1 binary specifically bind and interactive cross between species to make sure they link to the BCMA and the human CD3 and Macak, the test objects gang Tnanah specifically cellular flow using Khalaa; CHO Almniconh in human BCMA and Macak, respectively, track cell Haloma human Alataddh NCI- H929, which produces the human BCMA original, CD3- which produces marched T cell leukemia DSMZ) ΗΡΒ-ΑΙΙ 'Brauzchgdg E, - which produces Manar cell Macak T 4119LPX (father and his father, about each 0.4 I 0.3261 to 3256.95, 2000a ) .elaohrzk.eetm 1 Tam CHO Z cells transmitted as an officer negative for cellular flow are embracing 200,000 cells from Alhaveh cell paths to ditch 30 v 0 Qiqh heavy snow in the Hh microliter of antibody dual pure concentration Z 5 micrograms \ Ml.eetm specifically HSL cells sprayed in PBS / 2% FCS and connectivity 0 n configurations are disclosed in the antibody PentaHis gari (the Qiagen; diluted 1:20 in 50 0 Bklozam PBS / 2. /. FCS), after chapter, is detected Alajiaam anti PentaHis in g Hiad specific Fc gamma ( Divova) connects one Li Vnsorthren 0.1 Mkhgv to 1: 100 Ne% 2 / PBS FCS. Is measured 'samples adoptive Me FACSCanto tool II and J in Birhejaat FACSDIva (both of which are Picton Ddn). Antibodies bilateral Altdid BCMA / CD3 are Su, a equ Ε3 A- d CHO Ancolh in BCMA Anbharih and Macak, human BCMA - Olney produces walked multi Miloma cell NCI-H929 as well Enkhalaa \ ne 1 to mankind and Haik - Elaoh heavy so, ü4 there no staining of the CHO Gore cells Alhzaolh (Azzer bereavement 7) example 7 _kachard - which is based on Ddddd Study Ed Land Adani 1 may Affi human BCMA and Macak to analyze Skachard, are Tngiv Rlt one experiences rumored Basila-M Zam p unilateral Altkaagaf Hthlor in Maakromat ( Mkhad -488 His Fab / Alexa) Zlkha 0 d specified only one XI Altkavv are antibodies bilateral specifically Z lar Alglah S -inm 1 Hchan cells * 10 2 X are walked Alani cell (human recombinant BCMA - my father Dzdj Hsar Zih CHO; Alaatlv Macak BCMA - Lalai Azzj walked Khaya CHO) z approaches in every microliter of easing Thelandh series (and one Veh Mkhhvat in 1: 2) are Ed termination for in Aqaibd BCMA Lucky beginning in 100 Nanomic followed by incubation at 16 of tuberculosis in 4 90

YAK 35449Β1 ° C with stirring and washing step of Kaya one. Then, the embrace of the cells for 30 minutes in a 30 microliter are anti - Fab lotion / Alexa488 - His (Maakromat 0.30 micrograms 1 ml). After the wash step one, tolerate cells in Fab / Alexa488 equivalent acidity consists of 3.5% Formalhaad, embraces c for 1 minute are re, it expels centrally be unbearable in the FACS equivalent acidity and analyzes using the machine Kantol jFACS software Deva FACS. It is giving data from the two sites of the experiment. Annm values as curves linking compared to the collection. The Skachard on account Qahoy to extrapolate the value of linking (Bmax). Dadam repel concentrations Asam anti bilateral selection from linking mid-Aqsa, which affects the KDs are collected on the values of metrics triple copies curves compared blood Thd 3 0 \ '1 Dhirbt Wallach using valuation Skachard and are KDs values are calculated. Is determined objects pumps ratios 1 de Tmaiah 1 to benefit the BCMA / CD3 R Akhlaya CHO Alhzaolh in the BCMA Albashra or Macak analysis Skatthard way most easily measured because Algjoin 1 PHP probability between human BCMA and Macak. The embrace of the cells that Ning generator Tadan BCMA amputation 4 Izzat Tz 1 z 1 de Tda Almirak BCMA / CD3 antibody dual Althddd blood Z 1 if the asset R1 to Asaa (16 x 1 cent). DTM detection antibody Hertbt flow cytometry. Short-Turkish DD (lattes between Alajdz 13:00 1 delegation bilateral specifically BCMA / CD3 in Rabtmztcef b Alad Maha Iserh KDs 1 In -eetm collect values of metrics Triple Akkh Kmenhndhat Ehgharzh and Mnhndhat against S rain in Ely 0 Hadlat Almlazm focus Z 1 for connecting at least R-Amish. The threat Ardt Wallach (Bmax) (1 of Figure 8) Bastkhadd 13:00 Rating Alskachard loom Hlaab KDs August. Ashe Ashe was Bnlo in table 4 betrays Astahedadi 1 near one of Stqlhbajsm Alhkhad Tmada 'to determine the BCMA / CD3. analysis Skachard the Presentation 1 SAS and travail pardoned the objects Av'dh Dnandh 1 under BCMA / CD3 of Alaepvyb group Ε3 are Nodomolar in sub b R BCMA and there because Alaraa Elsafarh BCMA 0 n ratio z Alasgl 4.91

MA 35449Β1 Table 4: ratios (KD) of Alajtam anti bilateral specifically BCMA / CD3 of Alaeptob group Ε3 of the cell that is based on the analysis of Skachard (0 n two independent experiments) Ed 1 Cobh KD KD Macak a BCMA Obhari BCMA. BCMA / CD3 KD [nM] KD [nM] JUx-foldKD human antibody Tnac BCI macaque KD ma vs. hu specifically BCMA BCMA BCMA-83 0.40 ± 0.13 1.22 ± 0.25 3.1 BCMA-98 0.74 ± 0.02 1.15 ± 0.64 1.6 Bcm 0.78 ± 0.07 3.12 ± 0.26 4.0 BCMA-34 0.77 ± 0.11 0.97 ± 0.33 1.3 BCMA-74 0.67 ± 0.03 0.95 ± 0.06 1.4 BCMA-20 0.78 ± 0.10 ± 0.01 0.85 1.1 for example 8 Hits toxic 6 c ^ Tj Bakz launch Ankromaom human T-cells are pluripotent get T cells to pluripotent cells, CD8 + T as described Dlasgl. (Petri dish is covered Ir 145 millimeter, Greiner Bio-Wan neighborhood or Bhd; Kracr) Apr body Mkhozd Mahdn Mkhad -CD3 commercially available (0ΚΤ3 'Orden) in Nrvy r b. Agencies at 37 ° Miobh. Elbrus is the removal of the associated guide

Btoh laundering and one in the 3 - 5 X 10 ?. PBS human PBMC Sadv Affi cattle ace advance in 120 Is RPMI 1640 Ha glutamine fixed \ 0% of the 2-AA FCS l / Li / f 92 1 35449Β1

Proleukin®) 20 u / iïil, Chiron) and stimulates for 2 days. On the third day, the cells are collected and washed 1 once in 1640 RPMI. Not added a 2-1 final concentration of 20 do not \ ^ Al and Zrat Alnleia again for a day and tamp the same as the average cell above. 1 cells are fertilized for Amgaoih Ne toxic Khalaa 1 CTLs) CDS) depletion are Khalaa 1 3 + CD4 cells and CD56 + NK using granules according Dayal R Rotokol 1 Mahda. BCMA is washed Macak urticaria or movable Almtalwabh Hrtiv CHO cells in PBS will in two pilgrims MBq A.aavi 1 to the size of Azz.aavy z 100 μΙ RPMI in 50 AH / AH FCS for 60 minutes at 37 ° sperm. Respectively 0.3 Rat Ne is washed desired cells called 5 mL of RPMI and then used in cell toxicity test. The experiments Tngiv Apr 96. ./'10015a shower in the volume of 200 microliter Zhave Astkmad in RPMI with Ε rate: τ Q 10: 1 - 1 Draiz Aptd nee Q Q.Q1 _a ug \ ml of antibody specifically Intna and is used thinners trilogy Dilution 0 incubation time for this experiment was 18 hours. Is determined toxicity of the cells as values relative to the launch of chromium in the percentage of what floats to the difference pail Alaafy (Add Nsbdhun 1 case) and random decomposition (without responsive cells). Tngiv are all scales. Tngiv are measured Faddh Alkroheeom in what floats in & quot; The Lizard 3 & quot; Gamma counter (Bear. Be the presentation of the uncertainty of Science, Cologne, Germany) is Tngiv analysis of the results in Brizum 5 of Windows (5.0 dirty; Z received FZE, Ed 0 San Diego of California, U Ashe Labbe). AVI is A'iam EC50 values of the blood by the sense of one of the curves indicates Bermaahj-ray dose-response to compare the effectiveness of toxicity (Azzdr Figure 5). 2 g force guiding human T cells responsive pluripotent human BCMA cells CHO cells transmitted are gimmick Hits 1 to the toxicity of one of the bodies of one of the anti Tnaiah'rabt BCMA / CD3 experience Ahllaq age-Kroheeom (56 Cr) for Suhah AVI cells using CHO Osceola cells h BCMA Avyr'bh Kkhalaa 1 Hallobh, and CD8 cells in the human fertilized motivational Kkhalaaa Msthibh. The Tngiv experience as described in Alhthal 8.1 show Aladjaam Almmadh 1 st Veh specifically BCMA / CD3 of Alaeptob group Ε3 very strong toxicity effective against BCMA movable CHO cells with EC50 in rum for Abe rate r 1 values Is 93 1 35449Β1 or even less (Figure 9, table 5). Where one group of Aaphipp Ε3 overlook in a very convenient Op - effective link supports an antibody Tnana very strong Althdbbn the Shatt Hits toxic Aljdo.l A: values pg / ml] EC50] antibodies Tnanah Althdbtd BCMAGD3 of Mjhuh Alaadereb E3analyzed nee the Open & lt; 0 by 1 Tdq 51. Kro.maom population of 1 Meh Khalaa 1 (2 Haj) using CHO cells that carry the human BCMA Kkhalaaa Hallobh E and CD8 cells Ne stimulating unfertilized human Kkhalaaa responsive. B0MA / CD3 antibody dual Althddd 0 ΕΟδΟ Îpg / ml] R value BCMA-square 83 0.38 0.79 BCMA-98 0.27 0,85 BCMA-71 3.2 0.85 BCMA-34 3.4 0.81 BCMA-74 0.73 0.80 BCMA-20 0.83 0.82 8.3 FACS - Iquma'ly the basis of toxicity cells Ne PBMC Abira Z Mahgz experience isolate responsive cells is prepared single cells 1 T. Alzzy surrounding blood Alepeshrdh (PBMC) to expel the Therj 1 Z of preparation 0 v 1 Amgaoih Almkhhbh (Tabnf DVI) Hztj ZZ accumulations bloody 0 Zjma 1 blood for transfusion. The supply of blankets in the Bash. Unrighteousness bloody Mohdei and blood - PBMC today are to collect the blood. Badtrdekzvh Phicol, the captain and Grlat B1 DOCUMENTS 0 p Dollbecko PBS (Taoa, Iqa 1 Zazh pellets Ahamr'e in PBMC via the 'Ladd in Lash Kiryat fought one of Hmmae e 0 just Sodh (155 mM NH4CI, 10 mM KHCO3, 100 μM EDTA). The BL 1 has Alsgazh Aldhoah through U floats - Alarz Al.rkza Z PBMC in 9 100 X: Ntonfn Asefomatalehtiqivepeshkl to Asmonlamgoomatbyosh, NK cells and monocytes [u / 94 1 35449Β1. PBMC saves in the button, efficiency at 37 ° C \ 50 e / e 2.C average in RPMI medium (GEPCO ) with 0 of 0 Ahjehm (GEPCO). Asentvad cells + CD14 and + CD56 depletion cells + CD14, CD14 Albashrah Maekerobidz (Milletna Biotech, MACS, # 130-050-201) are used. to Astzvad any CD56 of NK cells 1 Krobidz (, MACS # 130-050- 401.) are counted and the expulsion of PBMC for 10 Dakka'iq at room temperature at 300 X g. LaSalle is what floats in Witten re-suspend the cell plate to isolate the MACS equivalent acidity [lettuce? 10 80 μ7; PBS (Asros' 043-20012 #) '(0.5% (ν / ν FBS (d' 106-10270 #) '2 mM EDTA (Z _akerc E 511 c-p #). The addition CD14 Maekerobidz and CD56 Maekerobidz (106/20 μΙ cells) and embraces 30 minutes at 4-8 ° C. wash the cells are in an equivalent Khmudh isolate MACS (107 / 1-2 mL cells), after centrifugation (see above), is neglecting what floats and, re-suspended in Allaaa equivalent acidity isolate MACS (Hlaya 108 / _500 μΙ). Then isolate the CD14 / CD56 negative cells using Ahabat c; (Milletna Biotech, # 401-042-130). The cultivation of cells + PBMC w / o CD14 + / CD56 in complete RPMI medium, for one lethal RPMI1640 (Baaokrom FG1215 'AG #) A- in 10./. FBS (Baaokrom lx, (# S0115, AG of amino acids non-essential (Baaokrom AG, Κ0293 #) E medal District 10 mM Hepes (b 1 Aokrom 1613 'AG a #) E 1 mM sodium Berfat (Baaokrom 0473, AG A #) and 100 U / mL Bcelin \ Strepettmesen (Baaokrom Α2213, AG #) at 37 ° Hioahvi incubator as needed. naming cell Almtlouet to analyze the cell Ne flow cytometry experiments, Hbgh membrane fluorescence DiO) DiOCis) (Makilor Probus, V22886 #) used in human BCMA - or Macak BCMA -almnicol CHO cells Kkhalaaa Mtaloah and distinguish them from the responding cells. Briefly, the collection of one of the cells, prefer to Moh one in PBS and adjusted R H cell 10 \ ml in PBS consisting 0 n 02 / e v / v) FBS) and membrane 5 dye) DiO microliter of 1 c 10 pixels). After incubation for 3 minutes at 37 ° C, the cells are washed twice Ne complete RPMI medium and cell number is adjusted to C 10 1.25 X cell \ ml. It is determined vital cells using% 0.5 (ν / ν) EosinG isotonic solution (Roth 45 380 #). Analysis which is based on flow cytometry are designed this experiment to determine the decomposition Almacak or BCMA human - transmitted CHO cells in the presence of diluents sequential antibodies BCMA bilateral specifically b; 95 1 35449Β1 sizes Mnawah required DjQ cells Almnamah cells Almostagdah (eg Khalaa 1 + PBMC w / o CD14) blends, resulting in cell Ε rate: Τ of 10: 1 .eetm NFL 160 microliter of this suspension to each and d are 96. - Lowell. 40 microliter thinners are Altzlslh antibodies Tnaa ;: specifically BCMA officer and proud people may Tzolah 1 (anCD3 - Alzs is based on a dual antibody selection that barf Hold Anti required offline) or medium RPMI complete officer added an additional negative. Name one of the anti-I specifically - the interaction of cytotoxic average for 48 shiny is 7% 2.C of Handh Rhellbh & quot; DTM blood cells Nash 1 1 Li 96_ new plate and Dr. Ferran Mlahh cell membrane required is scanned to add Albroodiom iodide (PI) at a concentration of 1 Zh'h Sus'm \ ml. PI Z Eb'rh & lt ;, Hblo Hveah - naturally Klaya'akabl of the application, where the dead cells graduated Y Ahecn identified from fluorescent emission. It is measured 1 to Aivat Bakevq S on FACSCanto harming II and D with software FACSDiva (Klahmad Dddon). It is determined by the desired cells Kalkhalaaa positive -DiO. Short - Alkhalada S -PI Kkhalaaa required alive. The proportion of Ace cellular account light of Affi SS: ÜjËLÜxIOO, cells Aeloaaola η = number of events π = number of accidents by using Graf Bad Rizum Software (c Jr'v Daz software 'F Diego), the DTM Jha b toxicity 1A; [gg with concentrations Aljtm anti bilateral corresponding selection. The analysis of the dose response in Tviac Obah Nman c D'dja parameters tuck my Mzhveat p Wallace Hill constant slope and EC50 values blooded Hs'bha. 8.4 human PBMC is the catalyst against the required human BCMA cells Alhzcolh are analyzed Hits toxicity of Glades anti Tnandh Althdbb BCMA / CD3 in p Nduom Presentation 1 SAS 1 Gaalah 1 toxicity FACS Pat 13:00 Q CHO S in the cells of the human BCMA Kkhalabo Talobh PBMC the I human is motivating Kkhalaaa responsive. Tngiv experience is as described above to proceed (Adnal 8.3). (Ίό / 96 1 35449Β1 Ntanj toxicity cell experiments Nthom on the basis of FACS in human PBMC is jLJx Kalkhalaaa responsive and human BCMA, who transferred Chania CHO Kkhalaaa required as Z in Figure 0 height. Table: pg / ml values] EC50] Z antibodies bilateral specifically BCMA / CD3 Q Alaeptob group Ε3 as measured at 48. the hours of experience that are the basis of the toxicity of the cells 1 FACS in human PBMC is motivating Kkhalaaa responsive cells CHO is transmitted in human BCMA Kkhalaaa required. BCI / CD3 Jays 0 of Mud 0 Ed r s 0 Ed EC50 [pg / ml] R terrible value BCMA-83 212 0.97 BCMA-7 102 j 0.97 BCMA-5 58.4 0.94 BCMA-98 53.4 0.95 BCMA-71 208 0.94 BCMA-34 149 0.94 BCMA-74 125 0.97 BCMA-20 176 0.98 example 9

9.1 interactive Asentvad cross in Sthay BAFF cellular flow, are embracing .200,00 Z Z cells Hsar a ^ Alshve for 30 Apr Althelh in Hbkrawlinr approaches are linking molecules Ntanah selection in a concentration of c ug \ ml. GSD is one of the cells Hertyn in PBS 2% FCS and in the detection of Z-t ne c 0 L Hiad PentaHis 1 to Ira (Qiagen; diluted in 1:20 in a 50 microliter PBS in 2% 97 Ave.

MA 35449Β1

FCS). Figure E must be one whole Z antibodies PentaHis with the Fc gamma-specific antibody (Dianov) the one who Arat 1 1 0 t Fbacqua Aritren, 'to dilute in 1: 100 Ne PBS with 2% FCS. Samples are flow cytometry on FACSCanto tool II and degrades Ne FACSDiva Software (as if they are the Picton Dakinsoz). Links Tnanah show specifically so as not to be interactive with -aabrh future. BAFF

9.2 Asttvad antibody specifically Tnana BCMAGD3 _ebrh Ne BAFF -stqubl interactive (BAFF-R) and the exhaustion of TACI binds to the human BAFF-R, TACI, antibodies specifically Dolly BCMAGD3 are tested cell flow cytometry using .baltdvq Almentolh CHO cells in BAFF-R human and TACI, respectively. Moreover, what is the use of multiple 363 Almiloma a positive Kdhabhd to link Affi human BCMA. Be sure of one crown BAFF-R and TACI-born counter on CHO cells Pashin from Glades anti positive tuning is Tngiv flow cytometry as described Ne Alosal former cellular flow stresses' to analyze 1 n Alag 0 or Almkhozdh Tnanah specifically BCMA / CD3 & lt ;; Mjhuh Alabitob Ε3 for Nthaal transit in the human BAFF-R or TACI Albashrah (see Figure 1 6). 0 example of the interaction of toxic cells are monoclonal antibodies specifically analyze the strength of bilateral BCMA like -alepeshrah in a T-cells are produced against -alta required cells Ne five of the toxicity of the cells in the laboratory experiments additional six. The measure antibodies stronger bilateral specifically BCMA in directing the T-cells are pluripotent human BCMA -alaijaa against tumor cells (human) in the experience of one divorce chromium production. 98 35449Β1 2. The measure antibodies stronger bilateral specifically BCMA Ne redirect T cells in human PBMC is the catalyst against human BCMA CHO cells Ancolh office experience is based on measuring the toxicity of Ashe 1 Vdia -. FACS 03 are valuable 1 x force antibodies bilateral specifically BCMA to direct T cells in human PBMC is the catalyst against cells BCMA tumor -alaijaah - (human) in an experiment based on the toxicity of the cells 1 -FACS 4, to confirm Presentation 1 n objects Anamadadh BCMA interaction transit is able Ne Mac to direct cells as against 1. - Movable CHO cells, are Tngiv experience based on the S-1 Suhah Aklei 1 -FACS in Checked Macak cell Kalkhalaaa responsive. H is determined force 1 Dh between the composite shapes failure, secondary antibodies bilateral specifically BCMA in the experience of one divorce, one lacrosse -51 Batdam BCMA Folding - Khalaa 1 CHO A \, Aahoa.h Kallaaa required and stimulating T cells and human Kalkhalaaa example 11 Khalaa 1 Ne 0 for mankind 1 Dah against BCMA - track multiple human positive Almiloma cell 363 of the analysis of the effectiveness of the toxic cells from objects one delegation Ndantm 1 may BCMA / CD3 in the release of toxic chromium cells 0 Thaaq experience) -51 Bastkhcam BCMA- Ba'r Khch Arloha 1 human Dtidh 1 Amz 363 a (DSMZ No. ACC49) Kaamadr required for the cells, and fascinating Ne Adndrtm Mahgzh A- Kkhalaa 1 -. A blood test as described in Example 1 C. According to Ntanj Tjar.b Ahllaq 1 Krusum -51 in Amvooaat Ne CD8 1 drink of Mahgz 0 1 A_khasbh Kkhalaaa responsive and BCMA Arrtm Khalaa 1 CHO Ekhalaya would have been; 0 to Ajtm anti bilateral specifically BCMA / CD3 of Jhuh Alaladob Ε3 Z Dhutm grandfather 1 in August August (Figure 2 Awatmdol 7). 99

'VIA 35449Β1

Another group of antibodies identified through Mjhuat ops (Azhler Hthal 1 and 3); that is Ghader.h of R.bt 1 Li Mjhuat 1 Ops 1 and 4 of Ε1 / Ε4 ") BCMA & quot;). Lar 'to be expected, one of the objects 1 to counter Tmaiah specifically BCMAGD3 are Kdlh Alabitob Ε1 / Ε4- any Despite the strength Activity poison toward CHO cell transferred with the BCMA to ie, Q SMN Zho 0 cell line tumor medulloblastoma human Tdd 3 c 3 a production BCMA continued on the intensity less in the cell surface ( Figure 12 and table 7) 0 without connecting through Alzzerah, said inventors that epitope Ε1 / Ε4 of human BCMA walked to p any access to in productions BCMA August, which are 0 on Nql- cells. BCMA table 7: EC50 Rate [pg / ml] 0 n BCMA / CD3 monoclonal stile bilateral specifically are blocks Alabitob Ε1 / Ε4 (rows 1 and 2) and Ε3 (Hfov 3 R 8) decomposition Apr 18 hour 51-chromium (02 less) Sam examination divorced with a line BCMA -or cell, m medulloblastoma multi mortal positive 3 c 3 is a source Kkhalaaa purposeful, and Hgzat preached a CD8 cells Kkhalaaa splash. Antibody Tnana BCMA / 0D3 specifically EC50 lpg / m.1 R value box 9 BCMA-54 685 0.84 2 BCMA-53 1107 0.82 3 BCMA-83 28 0.83 4 BCMA.98 10 0.81 5 BCMA-71 125 0.86 6 BCMA-34 42 0.81 6 BCMA-74 73 0.79 8 BCMA-20 049 0.85 12 such as for human PBMC is a catalyst towards BCMA- multi medulloblastoma cell line human tumor a positive 363

100

MA 35449Β1 toxic activity of the BCMA / CD3 Glades Alamadadh'tnaiah are specifically analyst at 5VFACS, Sam examined using BCMA - medulloblastoma cell line Tdd Ddra a ^ P 3 c 3 a tumor (DSMZ, ACC49). 1 shows data c 1 to the surface of the weakest are the BCMA original goals for all tested T cell lines - Kmmadr of the cells and the mystery is aimed Mhaz PBMC Kkhalaaa impressive. Ngz examination as described in the Supreme (eg 8.3). It also achieved in 51. chromium divorced examination Ha strong humans catalyst CD8 T to Amhositat ho 0 J cell tumor medulloblastoma multi-mortal 363 A; antibodies bilateral AAC ^ d Z k; his Alabitob Ε1 / Ε4 compared actively powerful Sam about CHO cell transfer with BCMA Bthreyl yolk & lt ;, less powerful in the re-orientation of the toxic activity PBMC catalyst E Landau these line Hishdd flow tumor 3 c 3 1 Ij a continued BCMA less density on the cell surface. This is in line with the available theory here at the top. For Lacalle Ε1 / Ε4 Alabitob Z BCMA human can be lower and 4-in-1 Hrla Ztajat BCMA 1 Kaaah p BCMA- Akhlaya excited. Glades Alhiadh BCMA / CD3 of the cut; its Alaso.b Ε3 found Ha No. -3 pg hope Hbam EC50 in this assay (see Figure 13 and Table 8) Table 8: EC50 Rate [cWpg] of the BCMA / CD3 antibodies bilateral Specifically 0 n coated 1 Aviob 4 Hrah (array 1 and 2) and Ε3 (rows 3 R-8) as litas in 48 hours or FACS assay based p 0 preached non-catalyst PBMC Kkhalaaa poignant and tumor medulloblastoma cell line multi-mortal 363 a Kmmadr targeted cells. BCMÂ / CD3 body of 1 d Zmazy specifically EC50 lpg / m1] R value box 9 BCMA-54 3162 0.99 2 BCMA-53 2284 0.98 3 BCMA-83 241 0.99 4 BCMA-98 311 0.99 5 BCMA-71 284 0.99

101

MA 35449Β1 6 BCMA-34 194 and 9 of 7 BCMA-74 185 0.99 δ BCMA-20 191 0.99 expected, Guibm EC50 tests are toxic with high PBMC is stimulating Kkhalaaa influential Kha Ne Vhosk toxic using a powerful stimulating CD8 cells mankind. Shawl 13 human PBMC catalyst towards BCMA- cell line multi-Ds tumor z 1 Ijaa -NCI Η929 Walsh 1 i 1 long & lt ;, BCMA / CÜ3 antibodies bilateral specifically analyzed in FACS- examination Sam built using BCMA cell line tumor Las Tdd knows Adwi ATCC NCI-H929 ) (CRL9068 Kmmadr are cells 1 to Hadgh and seen z 0 Tz PBMC Kkhalaaa and Zh- fled examination as described in the buzzing (eg 8.3). the results of this examination 0 GS cell line tumor Alzkha 0 E multiple (0 Ely for a ^ NCI-H929) for Aztaj continued BCMA in the cell surface of these Wallace Ndua r J g confirmed tumor Nnas Tdd Zee 3 c 3 a 0.0 Rh Ady BCMAGD3 antibodies Tnanah Althdbd Z epitope mass Ε1 / Ε4- compared strongly Overall activity Landau CHO d cell Ha denied BCMA- proved Guo 0 Ashe in redirecting Alnnthat poison are BL 1 size PBMC Landau Khalaa \ g uniforms Aak tumor 0 theory 1 n 1 epitope Ε1 / Ε4 from 1 to Thor BCMA Ss Ashe nature of the hanging BCMA Z cells 1 ^ BCMA-l. such activity gap age BCMA - Zh cells 1 Viadvh and Hztjan Kha Ne Ε1 / Ε4 links not There's Ε3. the BCMA / CD3 Tnandh Ozddd m 3 Alazib bitten at -2 -3 No. pg / D Rate EC50 and BL g PBMC seen NCI-H929 cells aimed Ha values 50 Heh good well (BL form 14 and table 9). Grandparents 9: EC50 Iyim [Wpg,] are BCMA / CD3 antibodies second selection from the blocks epitope Ε1 / Ε4 (Hgov 1 and 2) and Ε3 (rows 3 R-8) in the Z das 48 0 FACS- its container examination Sam'ha humans is Mzer PBMC Kkhalaaa Donbrdh and J g tumor Zkh 1 E. multi human NCI-H929 Kmmadr 0 n 1 Vvea aimed R value box [D \ / ecsq Ipg Aljsmalamshad Tnana 1 pus B0MA / CD3 AVI 102 35449Β1 1 BCMA-54 26.4 0.99 2 BCMA-53 2474 0.99 3 BCMA -83 154 0.93 4 BCMA-98 67.6 0.87 c BCMA-71 50.7 0.96 6 BCMA-34 227 0.99 6 BCMA-74 103 0.97 8 BCMA.20 123 0.97 as expected, Rate EC50 less with medulloblastoma tumor cell line human Tdd NCI- H929 'by SJ Htwe 1 v E 1 tags of BCMA on the cell surface compared to 363 a shawl 14 cells a Mkak Iho BCMA Mkak - 1 Ztaj Linda meaningful in the end, the activity of poison & lt ;, objects one delegation Tnanah s cJL BCMA / CD3 in Vhan Q 13:00 -FACS Bsdenm building Hlaya CHO Zqlma 0 CAC BCMA Kkhalada Idvh, and 0 Kak T cell Kmahdr Hlayatkirh 0 Zih 2 line Mkak 0 41191ηΡχ (ie with a bouncing the. blood 95: 3256-61 (2000)) Astkhaddmo 1 Kmadr are Toiarah cells. Tmanev designed cell 0 n Hiak - Khala'a CHO not and tuck Edd cells building Presentation silat are activity poison Ngz as described in Wallach-Khalaa 1 T Hecak of J Zbh 4119L21Px Ashidtt Affi efficiency 0:00 Thak BCMA- Hlaa 1 .CH Alhzcol through one of the objects 1 to counter Tnandh 1 to determine BCMA / CD3 are I-, epitope Ε3. One of the objects appeared Alhiadh 1 1 power variation with Rana -1 -2 No. 1 R. Ashe pg / Is my 50 1 1 Hash this examination, confirms that this topic Alajz 0-long anti 'Zhhlh in Azzam Skat. I in the other 'objects 103 2 \ 1 U / 1 35449Β1 anti bilateral specifically BCMAGD3 blocks epitope Ε1 / Ε4 showed great strength with the weaker Rate EC50 in the No. 2 and No. -3 Wpg-, (see Figure 15 and Jdodh 6). The specific antibody Ε3 is approximately 3 to 55 times more powerful one in Mkak system. Table 10: EC50 Rate for JVpg,] of the BCMA / CD3 Aladjaam anti bilateral specifically blocks epitope Ε1 / Ε4 (rows 1 and 2) and Ε3 (rows 3 to 8) as measured in the 48 hours FACS- Sam Ha Mkak examination landed cell 41191ηΡχ Τ Kkhalaaa poignant and CHO cells Zqk 0 p Mkak BCMA Kkhalaaa purposeful. .lajdzisam .lamadadh Duet - - - specifically EC50Îpg /, H value Araba R 9 BCMA-54 78.5 0.98 2 BCMA-53 183 0.96 3 BCMA-83 1..9 0.97 4 BCMA-98 2.5 0.89 5 BCMA-71 3.2 0.97 6 BCMA.34 2.1 0.95 6 BCMA-74 2.0 0.95 8 BCMA-20 26 0.98 example 15 Guo Alijo 0 between the BCMA / CD3 antibody dual Cdad Modhuhr and Aldaamr Kadid different Alzh 1 i year between unilateral Hodhumbarak and 1 Zoform d 0 Lusk Z & lt; i BCMA / CD3 1 for bodies anti mischief such as 0 Althdbb (R indicates a gap Foe), production & quot; Hhs 0 Love

104 1 35449Β1 chromium as described in this 1 to Ar (eg 8.1) Tven with BCMA / CD3 filter 1 to 7 Jaddedm binary specifically monomer and dimer. Calculated as a power gap between the deaf EC50 Z for a binary counter Aajam iron monomer and Dayar ,. Strong gaps are objects briefing Zdaveh 1 CKD BCMA / CD3 tested Z Alasub blocks Ε3 is between 0.03 and 1.2 Hmak Das P activity compared to the monomer inert him. Shawl 16 monomer conversion dimer after three Doash glass / Frosty 5 1 n Thav specifically BCMA / CD3 monomer antibody aimed at three-d'Oise Mkhabh / Emtemjdh folded Nvann High SEC to determine antibody ratio Moumnomirk Mbdna '1 T-G6 late to dimer antibody. Jahalamn antibody unilateral Merck adjusted to a concentration of 250 Mg / Is 0 p Ouazl harmony and it requires froze the sperm -80 degrees 30 minutes followed by a 30-Abah Dqgah Je Dora 6 saw him in August. After three de-thawing Dhar 1 / icy. Tastiest content 1 Limo Hzd during ΗΡ-SEC. These Alzhaah, 15 Mg Hadzh are Aezovorm unilateral Merck antibodies deputized and equal Affi Allkiz & lt ;, 250 pg / ml in the insulator SEC Ahli (10 Mm Ahamad acetic - 75 mM to Aspf HCI -4% Trewazz - 7.2 pH) de 1 to embrace Z 37 0 degree of priority to Hdq 7 days. DIS SEC to box TSK Gel G3000 SWXE (Toso-Tokyo of Japan has) been associated Wara 8 10 GE) FPIC to Evicinsat filter) equipped Ha Α905 automatic. Moarlo instances and Ouazl one of the plays, consists of 100 Na2S04 mM 200 -ΚΗ2Ρ04 mM Ed 0 R 6.6 pH winding 7 1 William are A'loandhav, the antibody solution (15 pg Brod) Tak R Khala calibration and have removed y 0 Zt t alum shower are 0.75 Are / min Presentation Datt maximum are 7 MPa. 0 watched the blast-0280 '254 and 210 nm optical absorption. Analyses performed by the emergence of integration z 210 nm single log in Aoicorn Akta programs Taqbim page. Ald's Zlal content by splitting the emergence of dimer area during Alahjmua Region 0 n Hodhumar plus R Rose Daihr. N objects Almkhadh Tnabh specifically BCMA / CD3 & lt ;, 'blocks .labitob Ε3 appeared Meh bear Celsius d 1 are seen 0.7 R 1.1 H / H after three Downer thawing a strain, which is good. Although t 0.105

MK 35449Β1 ratios are turning Aldaamr, objects bilateral gang identification of epitope block E1 / Ε4 up Guibm Mgdilh is high, exceeding the beginning Rate Aldaamr Alpher appropriate from 0 a 2.50 & lt; (4.7% and 3.8% 'on Altoar) See Table 1 6. Table 11: Alum percentage of unilateral viruses Merck Daemrk BCMA / CD3 monoclonal Almkhadh Tnaiah'lthdid blocks Alabitob Ε1 / Ε4 (Sgovo 9 and 2) and Ε3 (m 0 Writer 3 R-8) after three Downer Tdjan / thawing as Hzz 010: Ahl size Ngaz shame Dhuna - (ΗΡ-SEC). BC1 / CD3 antibodies bilateral Althdld monomer 01.0; Dayaro 0/0 of 9 BCMA-54 95.3 4.7 2 BCMA-53 96.2 3.8 3 BCMA-83 99.1 0.9 4 BCMA-98 99.1 0.9 5 BCMA-71 99.1 0.9 c BCMA-34 98.9 1.1 BCMA -74 99.3 0.7 8 BCMA-20 99.2 0.8 17 shawl thermal stability Hzhveat 1 degree temperature determined by examining the various Looney (DSC) to determine the protein constants evil physicist from real I3CMA / CD3 anti Aladjaam second selection. This Altjar.b 106

MA 35449Β1 Ngzt Bastkhadd 13:00 Northampton, MA, USA) MicroCal LLC) Adaz VP-DSC. 1 0 n been taken energy sample containing BCMA / CD3 Aajsm but Althdbb r 0 e z 20 to 90 degrees compared to the sperm sample containing insulator Dov objects one delegation. Detail, BCMA / CD3 1 to 1 Ajtm young pad specifically modified Affi Nahanni concentration of 250 μg / Are in Ouazl storage. 300 μΙ of insulting Bruce prepared d 1 b light of Li 1 E Aaiqh and placed in a rack Hecan Aodhuheteki listed z Adaz DSC- or by any Colette Ha E 1 Zell lighting SEC habit of reference measurements. Process Jerusalem Hhlol Eros Zh Del I in self, for my hair. ! Hairline Walles Eba with Arl lighting SEC Z - Assen and Akjl Z Energy «; · ·;, g r Ka 1 1 thieves pardoned equal degree temperatures are 20 to 90 different degrees seminal worked for all samples. To register for the curve Alaz 1 by Kahn him, Dred 6 saw him Alaivat - increased step Z each grade Hr.arh Hlqh T 1 Take 1 to Aivh and Rah insulator configuration register 0 difference in energy taking 0C) Cp / kca! / Mole) of the sample minus 'due sort Zho degree of righteousness' Rh 1 alfalfa by 0 drawer 0 of Hrarh'lamabh known following their free 1 Rh AAC ashé the Euro-1 energy 1 Idzh 'All objects of 0 antagonist Tmaveh Altdd BCMA / CÜ3 detective are blocks Asub 3 woman's period starts Asthr 1 t thermal fun with degrees free 1 Rh-thawing Valley 0 c kicked 6 by 4 eating Z does not specifically between 2 c. 61 degrees Xue and 63.03 0 degree relatives shawl 18 dimensions of the plasma entering through flow cytometry Kdid 0 optimism for a strong Z BCMA / CD3 Alajdam 0 delegation to eat Aladdd He righteousness and Tivat Blaz 0 of mankind, a reference laboratory Albularha families. This topic Anrkl 10 R 9 each eating all of Alfdz 0 BCMA / CD3 bilateral Cdad own, embraced births hour 37 Je Drickl ventilation in 90./Ο Blazha one for humans. After Blake 0.1 to connect humans R BCMA Ataj Khazia Zlal me CHO cell flow. 107 1 35449Β1 flow cytometry, cells 200,000 Ende special cell lines hugged for 30 Dqqh Ne snow Ha approaches 0 of the antibody Mansh presented concentration of c JQ; W-. Gnanlt Hertyn cells in PBS / 2% FCS and response are 1 Lhasa revealed Ha Anjsm anti Pintahz Murine (Gaijin; 1:20 eased in 50 PBS / 2% FCS μΙ). After Jasmine, Alajdzm gang Penthaz revealed p 0 Deaf counter-link number Fc gamma (Danavoa) linked to Hissourran, softened 1: 100 in PBS / 2% FCS. Samples were measured by flow cytometry in Adaz FACSCanto II and Dtdl during Brz 1 mg FACSDiva (both z Lennon d-n). The resulting data are compared with screening using PBS disciple of soul with a bond rather Q 1 Waller. Ward Alehtmasp by as follows: (reference PBS sample a signal w / o detection element) / (sample 1 badge Albulazt a Z signal detection w / o) in this experiment became are clear that there is no Takhad Kber in to reply only, fasted acclaim bCmA / cD3 Menna dual specifically 0 of mass-mediated Ε3 block of Brocivat plasma Ngan entered Alba 9 LZMA like the value of any Z b 2 in Q Aslat / Walker Dgahedraouh between 0.25 ± 1.29 and 1.70 ± 0.26 (with a value of & quot; 2 & quot; in Atabar.h minimum indicated 1 T. overlap). Shawl 19 Algaolah 1 for therapeutic BCMA / CÛ3 Glades Alhishalh dolly ne r Zraasinoorm human in AST Akrash 0 was injected sic Chania ®.5x1 & lt; for because I 0 for data Albtherl H929-NCI Alhherah in the NOD SCID Alaran.

Hlm 0 Elaj body in August 0 0 n Z seemed IOM 3; 'Edm 1: M Alou arrived L Lord Heq 2A; m; S [All Mthoah lest 0 c valuable scheduled to open one seemed to treat any NIST Study z e 5 allegiance to see '108

MA 35449Β1 Alztdladt of the damage). Treated Grand with 0.5 Hlg / Kh IOM Z BCMA / CD3 monoclonal Asih s 1 Veh specifically BCMA-98xCD3 (Ahjmuh 3, 7 = Ν) or -BCMA 3 H 0 34 X (group 4, 6 = Ν) by injection into a vein for several 17 days. - Tumors through the caliper through the study of the evaluation process by comparing the range of sizes Orrm (TV). Inhibition of tumor growth [%] T / C identified during Haab TV like ./.X 100 + T / C (Mtoshl TV from the analysis set) / (average TV from setting group 2). Results Apr 1, Paul 12 and 16. Figure 1 Jdodh appeared; Average tumor size (TV) and inhibition of tumor growth (T / C) in today's 13 to 30 Mahmoah dose Data d13 dl4 d15 die d18 d19 d21 d23 d26 d Adjust the vehicle w / o Akhalaaa average TV. [Mm3] 238 288 395 425 543 632 863 1067 1116 13 T / C [0/0] 120 123 126 118 104 114 122 113 87 2 means the average TV. [Mm3] 193 235 310 361 525 553 706 942 1290 16 T / C [0/0] 100 100 100 100 100 100 100 100 100 1 3 BCMA- 98 Average TV. [Mm3] 207 243 248 235 164 137 93.5 46.2 21.2 (T / C [0/0] 105 104 79.7 65.0 31.2 24.7 13.2 4.9 1.6 (4 BCMA- average 0τν [mm3] 206 233 212 189 154 119 56.5 17.4 0.0 (/ than 1109

MA 35449Β1 34 T / C [0/0] 104 68.2 E 99.2 52.3 29.4 21.5 8.0 1.8 0.0 20 dimensions shawl decomposition aimed negative cells in laboratory tests biodegradable consumed using BCMA- medulloblastoma tumor cell line human Ige Tdd 1B NCI-H929 and T cells purified the effective rate of cell certificate of 5: 1, with a time of 1 Ahin Q 24 hours. Antibodies specifically bilateral 3.BCMA / C 0 n Alabitob BCMA- mass) Ε3 34 and 98-BCMA) high strength and efficiency shown in the decomposition are NCI-H929. Although 'is not biodegradable overdraft in the BCMA negative cell lines AML) HL60 / Arumah Aourcoljia), MEB-SA (Sazkuma and Neros, Rfologi fibroblasts), and 16-SNU (Srt 1 N. stomach; Morvolgaa epithelial) for more than 500 Nm for the body Almsvad. Shawl 21 extrapolate from Nchit cell of the sub-groups PBMC Mokhtlgh 1 n FACS based assay year (10: 1 = 4Sh; Ε: τ) consumed using tumor cell lines Alzhaj human Alehtadd 3 C 3-A, NCI-H929 and 2-ΟΡΜ Kkhalaaa purposeful and Mjmuat age of CDS a + PBMC (CD4 (+ CD25 + / CD69 human Kkhalaaa impressive (see table 13) shows the degree of activity E km 1:00 Nlal EC50 values, is the basis of Nagar size Haoat PBMC overlooking nations 3A: EC50 Rate [ng / ml] of BCMA / CD3 Aladjaam anti bilateral selection from p Alaitob Ε3 as measured Apr 48 hours FACS assay Sam built -FACS with professions of righteousness PBMC Kkhalaa Groups 1 influential cell lines and tumor spinal multi mortal Kkhalaaa purposeful 0.50 Heh [ng / ml] a, a ' y PBMC BCMA-98 X CD3 1 ------- a BCMA-34-

110

MA 35449Β1 Γ CD4 + / CD25 + 1.46 0.53 A 1.20 NCI- CD8 + / CD25 + 0.49 Η929 CD4 + t CD69 + 0.59 0.47 ^ CD69,; CD8 0.21 ü1 CD4 +, CD25 * 2.52 4.88 ΟΡΜ-2 CD80, CD250 1-00 1.20 CD4./CD69. 1.65 2.27 CD8 + t CD69 * 0.48 0.42 CD4 + / CD25 + 0.54 0.62 363-a CD8 + / CD25 + 0.24 0.28 CD4./CD69" 0.35 0.34 CD8./CD69. 0.12 0.11 22 Hal extrapolate from the open Alcetkon that FACS Anfhhr ostrich building (0: 1; = 48h; Ε: Τ) Tven using cell lines medullary multiple human 363-1, NCI-H929 and 2-ΟΡΜ Ekhalaya purposeful and human PBMC Kkhalaaa splash . Open Alwejtkon levels [pg / ml] identified high concentrations of BCMA / CD3 monoclonal Alamadadn second specifically Psalm Alabitob mass Ε3. Analyzed Alcetkonat Almtalah: A10 TNF-AA A6-A and 1 .2-11 Gama- IFN, the results appeared in Table 14 and Figure 17. U-Îf 111 1 35449Β1 μ9 2.5 d [pg / ml] Z c IFN-AA 0.2 A. | And, IL-10, TNF 0 lol 14: Lehrer Z and BCMA-S8) Ε3 Alag 0 M helm of the p Aa'gla BCMA / CD3 / HD r Henri Kyve 1 0 & lt; Rh PBMC examination Sam 0 D Meh FACS me 48 molest (BCMA-34. (Ε: Τ = 10: 1) cell lines and medulloblastoma multi mortal Kkhalaaa targeted tumor ml / No 3 Eeadstoyat Alcetkon NCH929 \\ _- 2 6-A1 10-a 1 TNF IFN & quot; gamma BCMA-98 1357 699 2798 10828 73910 BCMA-34 1327 631 3439 6675 77042 .ΡΜ-2 IL-2 6-a 1 IL-10 TNF IFN- gamma BCMA-98 41 118 990 5793 33302 BCMA-34 28 109 801 4913 23214 363-a 11-7 II-Κ 10-A1 TNF IFN- gamma BCMA-98 97 314 2433 5397 64981 BCMA-34 168 347 2080 5930 75681 Η 112

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201161560144	United States of America	P	2011-11-15
201161560149	United States of America	P	2011-11-15
201161560162	United States of America	P	2011-11-15
201161560178	United States of America	P	2011-11-15
201161560183	United States of America	P	2011-11-15
201261651486	United States of America	P	2012-05-24
201261651474	United States of America	P	2012-05-24
2012072699	European Patent Office (EPO)	W	2012-11-15

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Binding molecules for bcma and cd3

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