ME02819B

ME02819B - Formulacije sa visokom koncentracijom antitijela

Info

Publication number: ME02819B
Application number: MEP-2017-147A
Authority: ME
Inventors: Timothy D Osslund
Original assignee: Amgen Inc
Priority date: 2010-05-14
Filing date: 2011-05-11
Publication date: 2018-01-20
Also published as: IL295275B2; PL2569010T3; CY1122669T1; HRP20250025T1; EA201291226A1; HUE047492T2; DK2569010T3; JP2016138110A; ZA201208543B; CO6640258A2; SMT201700252T1; CN102946903A; LT3195880T; WO2011143307A1; RS66360B1; TWI617570B; RS56210B1; JP2023182702A; HUE033315T2; ES2773031T3

Description

SEQUENCE LISTING 5 [0129] <110> Timothy Osslund 10 <120> High Concentration Antibody Formulations <130> 31173/45219A <140> US-61/334,986 15 <141> 2010-05-14 20 25 30 <160> 248 <170> Patentln version 3.5 <210> 1 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Ab-A & Ab-1 LCDR1 <400> 1 Gln Ser Ser Gln Ser Val Tyr Asp As n Asn Trp Leu Ala l 5 10 35 <210> 2 <211> 7 <212> PRT <213> Artificial Sequence 40 <220> <223> Ab-A and Ab-1 LCDR2 <400> 2 45 <210> 3 50 <211> 10 <212> PRT <213> Artificial Sequence <220> 55 <223> Ab-A and Ab-1 LCDR3 <400> 3 Asp Ala Ser Asp Leu Ala Ser l 5 20 EP 2 569 010 81 Gln Gly Ala Tyr Asn Asp Va l Il e Tyr Al a l 5 10 5 10 15 <210> 4 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Ab-A and Ab-1 HCDR1 <400> 4 20 <210> 5 <211> 16 <212> PRT <213> Artificial Sequence 25 <220> <223> Ab-1 and Ab-2 HCDR2 <400> 5 30 Ser Tyr Trp Met Asn l 5 Thr Ile Asp Ser Gly Gly Arg Thr Asp Tyr Ala Ser Trp Al a Lys Gly l 5 10 15 35 <210> 6 <211 > 4 <212> PRT <213> Artificial Sequence 40 <220> <223> Ab-A and Ab-1 HCDR3 <400> 6 45 <210> 7 50 <211> 654 <212> DNA <21 3> Artificial Sequence <220> 55 <223> Rabbit-Mouse Chimera <220> <221 > misc_feature Asn Trp Asn Leu l 21 i EP 2 569 010 81 <223> Ab-A light chain (no signal) <400> 7 5 gcgcaagtgc tgacccagac tccagcctcc gtgtctgcag ctgtgggagg cacagtcacc 60 atcaattgcc agtccagtca gagtgtttat gataacaact ggttagcctg gtttcagcag 120 10 aaaccagggc agcctcccaa gctcctgatt tatgatgcat ccgatctggc atctggggtc 180 ccatcgcggt tcagtggcag tggatctggg acacagttca ctctcaccat cagcggcgtg 240 15 cagtgtgccg atgctgccac ttactactgt caaggcgctt ataatgatgt tatttatgct 300 ttcggcggag ggaccgaggt ggtggtcaaa cgtacggatg ctgcaccaac tgtatccatc 360 ttcccaccat ccagtgagca gttaacatct ggaggtgcct cagtcgtgtg cttcttgaac 420 20 aacttctacc ccaaagacat caatgtcaag tggaagattg atggcagtga acgacaaaat 480 ggcgtcctga acagttggac tgatcaggac agcaaagaca gcacctacag catgagcagc 540 25 accctcacgt tgaccaagga cgagtatgaa cgacataaca gctatacctg tgaggccact 600 cacaagacat caacttcacc cattgtcaag agcttcaaca ggaatgagtg t tag 654 <210> 8 30 <211>217 <2 12> PRT <213> Artificial Sequence <220> 35 <223> Rabbit-Mouse Chimera <220> <221> MISC FEATURE - <223> Ab-A light chain (no signal) 40 <400> 8 45 50 55 22 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 Ala Gln Val Leu Thr Gln Thr Pro Ala Ser Va l Ser Ala Ala Va l Gly l 5 10 15 Gly Thr Val Thr Ile Asn Cys Gln Ser Ser Gln Ser Val Tyr Asp Asn 20 25 30 Asn Trp Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu 35 40 45 Leu Ile Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val 65 70 75 80 Gln Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Ala Tyr Asn Asp 85 90 95 Val Ile Tyr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Thr 100 105 110 Asp Ala Ala Pro Thr Val Ser Il e Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125 Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140 Lys Asp Ile Asn Val Lys Trp Ly s Ile Asp Gly Ser Glu Arg Gln Asn 145 150 155 160 Gly Val Leu Asn Se r Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg Hi s 180 185 190 Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205 Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 23 • EP 2 569 010 B1 <210> 9 <211> 1302 <212> DNA <213> Artificial Sequence 5 <220> <223> Humanized Antibody <220> 10 <221 > misc_feature <223> Ab-A heavy chain (no signal) <400> 9 15 60 cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc tgcacagcct ctggattctc cctcagtagt tattggatga actgggtccg ccaggctcca 120 20 ggggaggggc tggaatggat cggaaccatt gattctggtg gtaggacgga ctacgcgagc 180 tgggcaaaag gccgattcac catctccaga acctcgacta cgatggatct gaaaatgacc 240 agtctgacga ccggggacac ggcccgttat ttctgtgcca gaaattggaa cttgtggggc 300 25 caaggcaccc tcgtcaccgt ctcgagcgct tctacaaagg gcccatctgt ctatccactg 360 gcccctggat ctgctgccca aactaactcc atggtgaccc tgggatgcct ggtcaagggc 420 30 tatttccctg agccagtgac agtgacctgg aactctggat ccctgtccag cggtgtgcac 480 accttcccag ctgtcctgca gtctgacctc tacactctga gcagctcagt gactgtcccc 540 tccagcacct ggcccagcga gaccgtcacc tgcaacgttg cccacccggc cagcagcacc 600 35 40 45 50 55 24 ~ EP 2 569 010 81 aaggtggaca agaaaattgt gcccagggat tgt ggttgta agccttgcat atgtacagtc 660 ccagaagtat catctgtctt catcttcccc ccaaagccca aggatgtgct caccattact 720 5 ctgactccta aggt cacgtg tgt tgtggta gacatcagca aggatgatcc cgaggtccag 780 ttcagctggt ttgtagatga tgtggaggtg cacacagctc agacgcaacc ccgggaggag 840 10 cagttcaaca gcactttccg ctcagtcagt gaacttccca tcatgcacca ggactggctc 900 aatggcaagg agt t caaatg cagggtcaac agtgcagctt tccctgcccc catcgagaaa 960 accatctcca aaaccaaagg cagaccgaag gctccacagg tgtacaccat tccacctccc 1020 15 aaggagcaga tggccaagga taaagtcagt c t gacctgca tgataacaga cttcttccct 1080 gaagacatta ctgt ggagtg gcagtggaat gggcagccag cggagaacta caagaacact 1140 20 cagcccatca tggacacaga tggctcttac ttcgtctaca gcaagctcaa t gtgcagaag 1200 agcaactggg aggcaggaaa tactttcacc tgctctgtgt tacatgaggg cctgcacaac 1260 caccatactg agaagagcct ctcccactct cctggtaaat ga 1302 25 <210> 10 <211> 433 <2 12> PRT <213> Artificial Sequence 30 <220> <223> Humanized antibody <220> 35 <221> MISC FEATURE - <223> Ab-A heavy chain (no signal) <400> 10 40 45 50 55 25 EP 2 569 010 8 1 Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro l 5 10 15 5 Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr Tr p 20 25 30 10 Met Asn Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Ile Gly 35 40 45 Thr Ile Asp Ser Gly Gly Arg Thr Asp Tyr Ala Ser Trp Ala Lys Gly 15 50 55 60 Arg Phe Thr Ile Ser Arg Thr Ser Thr Thr Met Asp Leu Lys Met Thr 65 70 75 80 20 Ser Leu Thr Thr Gly Asp Thr Ala Arg Tyr Phe Cys Ala Arg Asn Trp 25 30 35 40 45 50 55 26 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 85 90 95 Asn Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 100 105 110 Lys Gly Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr 115 120 125 Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu 130 135 140 Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His 145 150 155 160 Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser 165 170 175 Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn 180 185 190 Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro 195 200 205 Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser 210 215 220 Ser Va l Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr 225 230 235 240 Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp 245 250 255 Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr 260 265 270 Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser 275 280 285 Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Gl u 290 295 300 Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys 305 310 315 320 Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr 27 5 10 15 20 25 30 35 EP 2 569 010 81 325 330 335 Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr 340 345 350 Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln 355 360 365 Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met 370 375 380 Asn Thr As n Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys 385 390 395 400 Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu 405 410 415 Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly 420 425 430 Lys <210> 11 <211> 390 <212> DNA <213> Artificial Sequence <220> <223> Humanized antibody <220> 40 <221 > mise_ feature <223> Ab-1 light variab le (with signal) 45 50 55 28 <400 > ll atggacacga 5 acatttgctc gtgactatta cagcaaaaac 10 ggtgtgccaa tctctccagc 15 tatgccttcg <210 > 12 20 <211> 133 <212> PRT gggcccccac aagttctgac cctgtcaatc cgggcaaagc gccgtttcag cggaagattt gtcagggcac <213> Artificial Sequence <220> 25 <223> Humanized antibody <220> <221> MISC_FEATURE EP 2 569 010 81 tcagctgctg gggctcctgc ccagagtcca agcagtctct tagtcagagc gtgtatgata cccgaagctg ctcatctatg tggcagtggc agcggtactg cgccacttac tattgtcaag taaagtagaa <223> Ab-1 light variable {with signal) 30 <400> 12 35 40 45 50 55 29 tgctctggct cccaggtgcc 60 ccgccagcgt aggcgatcgt 120 acaattggct ggcgtggtac 180 acgcgtccga tctggctagc 2 40 actttaccct cacaatttcg 3 00 gtgcttacaa cgatgtgatt 360 390 5 10 15 20 25 30 35 EP 2 569 010 81 Met Asp Thr Arg Ala Pro Thr Gln Leu Leu Gl y Leu Leu Leu Leu Trp l 5 10 15 Leu Pro Gl y Ala Thr Phe Ala Gln Val Leu Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Val Gl y Asp Arg Val Thr Ile Thr Cys Gln Ser Ser 35 40 45 Gln Ser Val Tyr Asp Asn Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro 50 55 60 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asp Leu Ala Ser 65 70 75 80 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Thr I l e Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 100 105 110 Gln Gly Al a Tyr Asn Asp Val Ile Tyr Ala Phe Gly Gln Gly Thr Lys 115 120 125 Val Glu Ile Lys Arg 130 <21 0> 13 <2 11> 393 <212> DNA 40 <213> Artificial Sequence <220> <223> Humanized antibody 45 <220> <221 > misc_feature <223> Ab-1 heavy variable (with signal) <400> 13 50 55 30 y EP 2 569 010 81 atggagactg ggctgcgctg gcttctcctg gtcgctgtgc tcaaaggtgt ccactgtgag 60 gtgcagctgt tggagtctgg aggcgggctt gtccagcctg gagggagcct gcgtctctct 120 5 tgtgcagcaa gcggcttcag ctt a t cctct tactggatga attgggtgcg gcaggcacct 180 gggaagggcc tggagtgggt gggcaccatt gattccggag gccgtacaga ctacgcgtct 2 40 10 tgggcaaagg gccgtttcac catt t cccgc gaca act cca aaaataccat gtacctccag 300 atgaactctc tccgcgcaga ggacacagca cgttattact gtgcacgcaa ctggaatctg 360 tggggt caag gtactcttg t aacagt ctcg age 393 15 <210> 14 <211> 131 <212> PRT <213> Artificial Sequence 20 <220> <223> Humanized antibody <400> 14 25 30 35 40 45 50 55 31 EP 2 569 010 B1 Met Glu Thr Gly Leu Arg Trp Leu Leu Leu Val Ala Val Leu Lys Gly l 5 10 15 5 Val His Cys Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 10 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gl y Phe Ser Leu 35 40 45 Ser Ser Tyr Trp Met Asn Trp Val Arg Gln Al a Pro Gly Lys Gly Leu 15 50 55 60 Glu Trp Val Gly Thr Ile Asp Ser Gly Gly Arg Thr Asp Tyr Ala Ser 65 70 75 80 20 Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 85 90 95 25 Met Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Arg Tyr 100 105 110 30 Tyr Cys Ala Arg Asn Trp Asn Leu Trp Gly Gln Gly Thr Leu Val Thr 115 120 125 Val Ser Ser 35 130 40 <210> 15 <211> 10 <212> PRT <213> Artificial Sequence 45 <220> <223> Ab-B LCDR1 <400> 15 50 Ser Ala Ser Ser Ser Val Ser Phe Val Asp l 5 10 <210> 16 55 <211>7 <212> PRT <213> Artificial Sequence 32 <220> <223> Ab-B LCDR2 <400> 16 5 10 <210> 17 <211> 9 <212> PRT <213> Artificial Sequence 15 <220> <223> LCDR3 <400> 17 20 <210> 18 25 <211> 7 <212> PRT <213> Artificial Sequence <220> 30 <223> Ab-B HCDR1 35 <400> 18 <210> 19 <211> 16 40 <212> PRT <213> Artificial Sequence <220> <223> Ab-B HCDR2 45 <400> 19 EP 2 569 010 81 Arg Thr Ser Asn Leu Gly Phe l 5 Gln Gl n Arg Ser Thr Tyr Pro Pro Thr l 5 Thr Ser Gly Met Gly Val Gly l 5 His Ile Trp Trp Asp Asp Val Lys Arg Tyr Asn Pro Val Leu Lys Ser 50 l 5 10 15 <210> 20 <211 > 14 <212> PRT 55 <21 3> Artificial Sequence <220> <223> Ab-B HCDR3 33 5 <400> 20 <210> 21 <211> 642 <212> DNA EP 2 569 010 B1 Glu Asp Phe Asp Tyr Asp Glu Glu Tyr Tyr Ala Met Asp Tyr l 5 10 10 <213> Mus musculus <220> <221 > misc_feature <223> Ab-B light chain (no signal) 15 <400> 21 caaattgttc tcacccagtc tccaacaatc gtgtctgcat ctccagggga gaaggtcacc 20 ctaatctgca gtgccagttc aagtgtaagt ttcgtggact ggttccagca gaagccaggc acttctccca aacgctggat ttacagaaca tccaacctgg gttttggagt ccctgctcgc 25 ttcagtggcg gtggatctgg gacctctcac tctctcacaa tcagccgaat ggaggctgaa gatgctgcca cttattactg ccagcaaagg agtacttacc cacccacgtt cggtgctggg accaagctgg aactgaaacg ggctgatgct gcaccaactg tatccatctt cccaccatcc 30 agtgagcagt taacatctgg aggtgcctca gtcgtgtgct tcttgaacaa cttctacccc aaagacatca atgtcaagtg gaagattgat ggcagtgaac gacaaaatgg cgtcctgaac 35 agttggactg atcaggacag caaagacagc acctacagca tgagcagcac cctcacgttg accaaggacg agtatgaacg acat aacagc tatacctgtg aggccactca caagacatca acttcaccca ttgtcaagag cttcaacagg aatgagtgtt ag 40 <21 0> 22 <2 11 > 213 <212> PRT <213> Mus musculus 45 <220> <221> MISC FEATURE - <223> Ab-B light chain (no signal) 50 <400> 22 55 34 60 120 180 240 300 360 420 480 540 600 642 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Gln Ile Val Leu Thr Gln Ser Pro Thr Ile Val Ser Ala Ser Pro Gly l 5 10 15 Glu Lys Val Thr Leu Ile Cys Ser Ala Ser Ser Ser Val Ser Phe Val 20 25 30 Asp Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Arg Thr Ser Asn Leu Gly Phe Gl y Val Pro Ala Arg Phe Ser Gly Gly 50 55 60 Gly Ser Gly Thr Ser His Ser Leu Thr Ile Ser Arg Met Glu Ala Glu 65 70 75 BO Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Thr Tyr Pro Pro Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro 100 105 110 Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly 115 120 125 Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn 130 135 140 Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn 145 150 155 160 Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 165 170 175 Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr 180 185 190 Cys Glu Al a Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe 195 Asn Arg Asn Glu Cys 210 35 200 205 • EP 2 569 010 8 1 <210> 23 <211> 1350 <212> DNA <213> Mus musculus 5 <220> <221> misc_feature <223> Ab-B heavy chain (no signal) 10 <400> 23 caggttactc tgaaagagtc tggccctggg atattgcagc cctcccagac cctcagtctg 60 acttgttctt tctctgggtt ttcactgagc acttctggta tgggtgtagg ctggattcgt 120 15 cacccatcag ggaagaatct ggagtggctg gcacacattt ggtgggatga tgtcaagcgc 180 tataacccag tcctgaagag ccgactgact atctccaagg atacctccaa cagccaggta 240 20 ttcctcaaga tcgccaatgt ggacactgca gatactgcca catactactg tgctcgaata 300 gaggactttg attacgacga ggagtattat gctatggact actggggtca aggaacctca 360 25 gtcatcgtct cctcagccaa aacgacaccc ccatctgtct atccactggc ccctggatct 420 gctgcccaaa ctaactccat ggt gaccctg ggatgcctgg tcaagggcta tttccctgag 480 ccagtgacag tgacctggaa ctctggatcc ctgtccagcg gtgtgcacac cttcccagct 540 30 gtcctgcagt ctgacctcta cactctgagc agctcagtga ctgtcccctc cagcacctgg 600 cccagcgaga ccgtcacctg caacgttgcc cacccggcca gcagcaccaa ggtggacaag 660 35 aaaattgtgc ccagggattg tggt tgtaag ccttgcatat gtacagtccc agaagtatca 720 tctgtcttca tcttcccccc aaagcccaag gatgt gctca ccattactct gactcctaag 780 gtcacgtgtg ttgtggtaga cat cagcaag gatgatcccg aggtccagtt cagctggttt 840 40 gtagatgatg tggaggtgca cacagctcag acgcaacccc gggaggagca gttcaacagc 900 actttccgct cagtcagtga acttcccatc atgcaccagg actggctcaa tggcaaggag 960 45 ttcaaatgca gggtcaacag tgcagctttc cctgccccca tcgagaaaac catctccaaa 1020 accaaaggca gaccgaaggc tccacaggtg t acaccattc cacctcccaa ggagcagatg 1080 gccaaggata aagtcagtct gacctgcatg ataacagact tcttccctga agacattact 1140 50 gtggagtggc agtggaatgg gcagccagcg gagaactaca agaacactca gcccatcatg 1200 gacacagatg gctcttactt cgtctacagc aagctcaatg tgcagaagag caactgggag 1260 55 gcaggaaata ctttcacctg ctct gtgtta catgagggcc tgcacaacca ccatactgag 1320 36 EP 2 569 010 81 aagagcctct cccact ctcc tggt aaatga 5 <210> 24 <211> 449 <212> PRT <213> Mus musculus 10 <220> <221> MISC_FEATURE <223> Ab-B heavy chain (no signal) <400> 24 15 20 25 30 35 40 45 50 55 37 1350 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln l 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Val Gly Trp Ile Arg His Pro Ser Gly Lys Asn Leu Glu 35 40 45 Trp Leu Ala His Ile Trp Trp Asp Asp Val Lys Arg Tyr Asn Pro Val 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn Ser Gln Val 65 70 75 80 Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Glu Asp Phe Asp Tyr Asp Glu Glu Tyr Tyr Ala Met 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Ser Val Ile Val Ser Ser Ala Lys Thr 115 120 125 Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr 130 135 140 Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser 38 ) 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 180 185 190 Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn 195 200 205 Val Ala His Pro Ala Ser Ser Thr Lys Va l Asp Lys Lys Ile Val Pro 210 215 220 Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Va l Pro Glu Va l Ser 225 230 235 240 Ser Va l Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr 245 250 255 Leu Thr Pro Lys Va l Thr Cys Va l Val Va l Asp Il e Ser Lys Asp As p 260 265 270 Pro Glu Va l Gln Phe Ser Trp Phe Val Asp Asp Va l Glu Va l His Thr 275 280 285 Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser 290 295 300 Val Ser Glu Leu Pro Il e Met His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Phe Lys Cys Arg Val As n Ser Ala Ala Phe Pro Ala Pro Il e Glu Lys 325 330 335 Thr Ile Ser Lys Thr Lys Gl y Arg Pro Lys Ala Pro Gln Va l Tyr Thr 340 345 350 Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Va l Ser Leu Thr 355 360 365 Cys Met Il e Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln 370 375 380 Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys As n Thr Gln Pro Ile Met 385 390 395 400 Asp Thr Asp Gl y Ser Tyr Phe Va l Tyr Ser Lys Leu Asn Va l Gln Lys 405 410 415 Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu 39 EP 2 569 010 81 420 425 430 5 Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly 435 440 445 10 15 20 Lys <210> 25 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Ab-C LCDR1 <400> 25 Lys Ala Ser Gln Ser Val Asp Tyr Asp Gl y Asp Ser Tyr Met Asn l 5 10 15 25 <210> 26 <211> 7 <212> PRT <213> Artificial Sequence 30 <220> <223> Ab-C LCDR2 <400> 26 35 <210> 27 40 <211> 9 <212> PRT <213> Artificial Sequence <220> 45 <223> Ab-C LCDR3 50 <400> 27 <210> 28 <211> 5 55 <212> PRT <213> Artificial Sequence <220> Al a Ala Ser Asn Leu Glu Ser l 5 Gln Gln Ser Asn Gl u Asp Pro Trp Thr l 5 40 <223> Ab-C HCDR1 <400> 28 5 <210> 29 10 <211> 17 <212> PRT <213> Artificial Sequence <220> 15 <223> Ab-C HCDR2 <400> 29 EP 2 569 010 81 Asp Cys Tyr Met Asn l 5 20 Asp Ile Asn Pro Phe Asn Gly Gl y Thr Thr Tyr Asn Gl n Lys Phe Lys l 5 10 15 25 30 35 Gly <210> 30 <211>16 <212> PRT <213> Artificial Sequence <220> <223> Ab-C HCDR3 <400> 30 Ser His Tyr Tyr Phe Asp Gly Ar g Val Pro Trp Asp Al a Met Asp Tyr l 5 10 15 40 <210> 31 <211> 657 <212> DNA <213> Mus musculus 45 <220> <221 > misc_feature <223> Ab-C light chain (no signal) <400> 31 50 55 41 • EP 2 569 010 81 # gacattgtgc tgacccaatc tccagcttct ttgactgtgt ctctaggcct gagggccacc 60 atctcctgca aggccagcca aagtgttgat tatgatggtg atagttatat gaactggtac 120 5 cagcagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa tctagaatct 180 gggatcccag ccaggtttag tggcaatggg tctgggacag acttcaccct caacatccat 240 10 cctgtggagg aggaggatgc tgt aacctat t actgtcaac aaagtaatga ggatccgtgg 300 acgttcggtg gaggcaccaa gct ggaaatc aaacgggctg atgctgcacc aactgtatcc 360 15 atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 420 aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 480 aatggcgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 540 20 agcaccctca cgtt gaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 600 actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgttag 657 25 <210> 32 <211> 218 <21 2> PRT <213> Mus musculus 30 <220> <221> MISC FEATURE <223> Ab-C light chain (no signal) <400> 32 35 40 45 50 55 42 EP 2 569 010 B1 Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Thr Val Ser Leu Gly l 5 10 15 5 Leu Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp 20 25 30 10 Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala 15 50 55 60 Arg Phe Ser Gly Asn Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 20 Pro Val Glu Glu Glu Asp Ala Val Thr Tyr Tyr Cys Gln Gln Ser Asn 85 90 95 25 Gl u Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 30 Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln 115 120 125 Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr 35 130 135 140 Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln 40 145 150 155 160 Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr 45 165 170 175 Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg 180 185 190 50 His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro 195 200 205 55 Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 43 EP 2 569 010 81 <2 10> 33 <2 11 > 1350 <212> DNA <2 13> Mus muscu lus 5 <220> <221> misc_feature <223> Ab-C heavy chain (no signal) 10 <400> 33 gaggtccagc tgcaacaatc tggacctgag ctggtgaagc ctgggacttc agtgaagatg 60 tcctgtaagg cttctggata cacattcact gactgctaca tgaactgggt gaagcagagc 120 15 catgggaaga gccttgaatg gattggagat attaatcctt tcaacggtgg tactacctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca aatcctccag cacagcctac 240 20 atgcagctca acagcctgac atctgacgac tctgcagtct attactgtgc aagatcccat 300 tattacttcg atggtagagt cccttgggat gctatggact actggggtca aggaacctca 360 25 gtcaccgtct cctcagccaa aacgacaccc ccatctgtct atccactggc ccctggatct 420 gctgcccaaa ctaactccat ggtgaccctg ggatgcctgg tcaagggcta tttccctgag 480 ccagtgacag tgacctggaa ctctggatcc ctgtccagcg gtgtgcacac cttcccagct 540 30 gtcctgcagt ctgacctcta cactctgagc agctcagtga ctgtcccctc cagcacctgg 600 cccagcgaga ccgtcacctg caacgttgcc cacccggcca gcagcaccaa ggtggacaag 660 35 aaaattgtgc ccagggattg tggttgtaag ccttgcatat gtacagtccc agaagtatca 720 tctgtcttca tcttcccccc aaagcccaag gatgtgctca ccattactct gactcctaag 780 gtcacgtgtg ttgtggtaga catcagcaag gatgatcccg aggtccagtt cagctggttt 840 40 gtagatgatg tggaggtgca cacagctcag acgcaacccc gggaggagca gttcaacagc 900 actttccgct cagtcagtga acttcccatc atgcaccagg actggctcaa tggcaaggag 960 45 ttcaaatgca gggtcaacag tgcagctttc cctgccccca tcgagaaaac catctccaaa 1020 accaaaggca gaccgaaggc tccacaggtg tacaccattc cacctcccaa ggagcagatg 1080 50 gccaaggata aagtcagtct gacctgcatg ataacagact tcttccctga agacattact 1140 gtggagtggc agtggaatgg gcagccagcg gagaactaca agaacactca gcccatcatg 1200 gacacagatg gctcttactt catctacagc aagctcaatg tgcagaagag caactgggag 1260 55 gcaggaaata ctttcacctg ctctgtgtta catgagggcc tgcacaacca ccatactgag 1320 aagagcctct cccactctcc tggtaaatga 1350 44 5 <210> 34 . <211> 449 <212> PRT <213> Mus musculus <220> <221> MISC_FEATURE <223> Ab-C heavy chain (no signal) EP 2 569 010 81 10 <400> 34 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Thr l 5 10 15 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Cys 20 25 30 20 Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 25 Gly Asp Ile Asn Pro Phe Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Ly s Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 30 65 70 75 80 Met Gln Leu Asn Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 85 90 95 35 Ala Arg Ser Hi s Tyr Tyr Phe Asp Gly Arg Val Pro Trp Asp Ala Met 100 10 5 110 40 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr 115 120 125 45 Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr 50 55 45 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 130 135 140 Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Gl u 145 150 155 160 Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His 165 170 175 Thr Phe Pro Al a Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser 180 185 190 Val Thr Val Pro Ser Ser Thr Trp Pro Ser Gl u Thr Val Thr Cys Asn 195 200 205 Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro 210 215 220 Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser 225 230 235 240 Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr 245 250 255 Leu Thr Pro Lys Val Thr Cys Va l Val Va l Asp Ile Ser Lys Asp Asp 260 265 270 Pro Gl u Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr 275 280 285 Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser 290 295 300 Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr 340 345 350 Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr 355 360 365 Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln 46 5 10 15 20 EP 2 569 010 81 370 375 380 Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met 385 390 395 400 Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys 405 410 415 Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu 420 425 430 Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys <210> 35 <211> 11 435 440 445 25 <212> PRT <213> Artificial Sequence <220> <223> Ab-D LCDR1 30 <400> 35 Gln Ala Ser Gln Gly Thr Ser Ile Asn Leu Asn 35 l 5 10 <21 0> 36 <211> 7 <212> PRT 40 <213> Artificial Sequence <220> <223> Ab-D LCDR2 45 <400> 36 50 55 <21 0> 37 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Ab-D LCDR3 Gly Ser Ser Asn Leu Glu Asp l 5 47 5 <400> 37 <210> 38 <211> 5 <212> PRT 10 <213> Artificial Sequence <220> <223> Ab-D HCDR1 15 <400> 38 20 25 30 <210> 39 <211>17 <212> PRT <213> Artificial Sequence <220> <223> Ab-D HCDR2 <400> 39 EP 2 569 010 B1 Leu Gln His Ser Tyr Leu Pro Tyr Thr l 5 Asp His Tyr Met Ser l 5 Asp Ile As n Pro Tyr Ser Gly Glu Thr Thr Tyr Asn Gln Lys Phe Lys l 5 10 15 35 Gly <210> 40 <211> 10 40 <212> PRT 45 50 <213> Artificial Sequence <220> <223> Ab-D HCDR3 <400> 40 <210> 41 <211> 645 <212> DNA 55 <213> Mus musculus <400> 41 Asp Asp Tyr Asp Ala Ser Pro Phe Ala Tyr l 5 10 48 . EP 2 569 010 B1 ) gatgtccaga tgattcagtc tccatcctcc ctgtctgcat ctttgggaga catagtcacc 60 atgact tgcc aggcaagtca gggcactagc attaatttaa actggtttca gcaaaaacca 120 5 gggaaggctc ctaagctcct gatctatggt tcaagcaact tggaagatgg ggtcccatca 180 aggttcagtg gcagtagata tgggacagat ttcactctca ccatcagcag cctggaggat 240 10 gaagatctgg caacttattt ctgtctacaa catagttatc tcccgtacac gttcggaggg 300 gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360 15 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540 20 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645 25 <210> 42 <211>214 <212> PRT <213> Mus musculus 30 <400> 42 35 40 45 50 55 49 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 Asp Val Gln Met Ile Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly l 5 10 15 Asp Ile Val Thr Met Thr Cys Gln Ala Ser Gln Gly Thr Ser Ile Asn 20 25 30 Leu Asn Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ser Ser Asn Leu Glu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Asp 65 70 75 80 Glu Asp Leu Ala Thr Tyr Phe Cys Leu Gln His Ser Tyr Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Ile Asp Gl y Ser Glu Arg Gln Asn Gly Val Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 50 EP 2 569 010 81 <210> 43 <211 > 1332 <212> DNA <21 3> Mus musculus 5 <400> 43 gaggtccagc tgcaacagtc tggacctgaa ctggtgacgc ctggggcttc agtgaagata 60 10 tcttgtaagg cttctggata cacattcact gaccactaca tgagctgggt gaagcagagt 120 catggaaaaa gccttgagtg gattggagat attaatccct attctggtga aactacctac 180 15 aaccagaagt tcaagggcac ggccacattg actgtagaca agtcttccag tatagcctac 2 40 atggagatcc gcggcctgac atct gaggac tctgcagtct attactgtgc aagagatgat 300 tacgacgcct ctccgtttgc ttactggggc caagggactc tggtcactgt ctctgcagcc 360 20 aaaacgacac ccccatctgt ctatccactg gcccctggat ctgctgccca aactaactcc 420 atggtgaccc tgggatgcct ggtcaagggc tatttccctg agccagtgac agtgacctgg 480 25 aactctggat ccctgtccag cggt gtgcac accttcccag ctgtcctgca gtctgacctc 540 tacactctga gcagctcagt gact gtcccc tccagcacct ggcccagcga gaccgtcacc 600 tgcaacgttg cccacccggc cagcagcacc aaggtggaca agaaaattgt gcccagggat 660 30 tgtggttgta agccttgcat atgtacagtc ccagaagtat catctgtctt catcttcccc 720 ccaaagccca aggatgtgct caccattact ctgactccta aggtcacgtg tgttgtggta 780 35 gaca t cagea aggatgatcc cgaggtccag ttcagctggt ttgtagatga tgtggaggtg 840 cacacagctc agacgcaacc ccgggaggag cagttcaaca gcact ttc c g c t cagtcagt 90 0 gaacttccca tcatgcacca ggactggctc aatggcaagg agttcaaatg cagggtcaac 960 40 agtccagctt tccctgcccc catcgagaaa accatctcca aaaccaaagg cagaccgaag 10 2 0 gctccacagg tgtacaccat tccacctccc aaggagcaga tggccaagga taaagtcagt 1080 45 ctgacctgca tgataacaga cttcttccct gaagacatta ctgtggagtg gcagtggaat 1140 gggcagccag cggagaacta caagaacact cagcccatca tggacacaga tggctcttac 1200 50 ttcatctaca gcaagctcaa tgtgcagaag agcaactggg aggcaggaaa tactttcacc 1260 tgctctgtgt tacatgaggg cctgcacaac caccatactg agaagagcct ctcccactct 1320 cctggtaaat ga 1332 55 <210> 44 <211> 443 <212> PRT 51 EP 2 569 010 81 <213> Mus musculus <400> 44 5 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Thr Pro Gly Ala l 5 10 15 10 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His 20 25 30 Tyr Met Ser Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 15 35 40 45 Gly Asp Ile Asn Pro Tyr Ser Gly Glu Thr Thr Tyr Asn Gln Lys Phe 50 55 60 20 Lys Gly Thr Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Ile Ala Tyr 65 70 75 80 25 Met Glu Ile Arg Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 30 Ala Arg Asp Asp Tyr Asp Ala Ser Pro Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser Val Tyr 35 115 120 125 Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu 130 135 140 40 Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp 45 50 55 52 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 145 150 155 160 Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser 180 185 190 Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser 195 200 205 Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys 210 215 220 Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr 245 250 255 Cys Va l Val Val Asp Ile Ser Lys Asp Asp Pro Glu Va l Gln Phe Ser 260 265 270 Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg 275 280 285 Glu Gl u Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile 290 295 300 Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn 305 310 315 320 Ser Pro Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys 325 330 335 Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu 340 345 350 Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe 355 360 365 Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala 370 375 380 Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr 53 EP 2 569 010 81 385 390 395 400 5 Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly 405 410 415 Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His 10 420 425 430 Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 15 <210> 45 <211> 11 <212> PRT 435 440 <213> Artificial Sequence 20 <220> <223> Ab-2 LCDR1 <400> 45 25 30 <210> 46 <211> 7 <212> PRT Arg Ala Ser Ser Ser Val Tyr Tyr Tyr Met Hi s l 5 10 <213> Artificial Sequence 35 <220> <223> Ab-2 LCDR2 <400> 46 40 <210> 47 45 <211> 9 <212> PRT <213> Artificial Sequence <220> 50 <223> Ab-3 LCDR3 <400> 47 55 <210> 48 Ala Thr Ser Asn Leu Ala Ser l 5 Gln Gln Trp Ser Ser Asp Pro Leu Thr l 5 54 <21 1>5 <212> PRT <213> Artificial Sequence 5 <220> <223> Ab-2 HCDR1 <400> 48 10 <210> 49 15 <211>17 <212> PRT <213> Artificial Sequence <220> 20 <223> Ab-2 HCDR2 <400> 49 EP 2 569 010 81 Asp Iyr Phe Ile His l 5 25 Arg Leu Asp Pro Glu Asp Gly Glu Ser Asp Iyr Ala Pro Lys Phe Gl n l 5 10 15 30 35 40 A sp <210> 50 <211>12 <212> PRT <213> Artificial Sequence <220> <223> Ab-2 HCDR3 <400> 50 Glu Asp Iyr Asp Gly Ihr Iyr Ihr Phe Phe Pro Iyr 45 <210> 51 <211> 642 <212> DNA <213> Mus musculus 50 <220> <221 > misc_feature l 5 10 <223> Ab-2 light chain (no signal) <400> 51 55 55 EP 2 569 010 B1 caaattgttc tctcccagtc tccagcaatc ctgtctacat ctccagggga gaaggtcaca 60 atgacttgca gggccagctc aagt gtatat tacatgcact ggtaccagca gaagccagga 120 5 tcctccccca aaccctggat t tatgccaca tccaacctgg ct t ctggagt ccctgttcgc 180 ttcagt ggca gt gggtctgg gacctcttac tctctcacaa tcaccagagt ggaggctgaa 240 10 gatgctgcca cttattactg ccagcagtgg agtagtgacc cactcacgtt cggtgctggg 300 accaagctgg agctgaaacg ggctgatgct gcaccaactg tatccatctt cccaccatcc 360 15 agtgagcagt taacat ctgg aggtgcctca gtcgtgtgct tcttgaacaa cttctacccc 420 aaagacatca a t gtcaagtg gaag attgat g gcagt gaac gacaaaatgg cgtcctgaac 480 agttggactg atcaggacag caaagacagc acctacagca tgagcagcac cctcacgttg 540 20 accaaggacg agtat gaacg acataacagc tatacctgtg aggccactca caagacatca 600 acttcaccca ttgtcaagag ct t caacagg aatgagtgtt ag 642 25 <210> 52 <211>213 <212> PRT <213> Mus musculus 30 <220> <221> MISC FEATURE - <223> Ab-2 light chain (no signal) <400> 52 35 40 45 50 55 56 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Thr Ser Pro Gly l 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Tyr Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Thr Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asp Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Gl u Leu Lys Arg Ala Asp Ala Ala Pro 100 105 110 Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly 115 120 125 Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn 130 135 140 Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn 145 150 155 160 Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 165 170 175 Thr Leu Thr Leu Thr Lys Asp Gl u Tyr Glu Arg His Asn Ser Tyr Thr 180 185 190 Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe 195 200 205 Asn Arg Asn Glu Cys 210 57 EP 2 569 010 B1 <210> 53 <211 > 1338 <212> DNA <213> Mus musculus 5 <220> <221 > mise_ feature <223> Ab-2 heavy chain (no signal) 10 <400> 53 gaggttcagg tgcagcagtc tgggccagaa cttgtgaagc caggggcctc agtcaagttg 60 tcctgcacag cttctggctt caacattaaa gactact tta tacactgggt gaagcagagg 120 15 cctgaacagg gcctggagtg gattggaagg cttgatcctg aggatggtga aagtgattat 180 gccccgaagt tccaggacaa ggccattatg acagcagaca catcatccaa cacagcctat 240 20 cttcagctca gaagcctgac atctgaggac actgccatct attattgtga gagagaggac 300 tacgatggta cctacacctt ttttccttac tggggccaag ggactctggt cactgtctct 360 25 gcagccaaaa cgacaccccc atctgtctat ccactggcc c ctggatctgc tgcccaaact 420 aactccatgg tgaccctggg atgcctggtc aagggctatt tccctgagcc agtgacagtg 480 acctggaact ctggatccct gtccagcggt gtgcacacct tcccagctgt cctgcagtct 540 30 gacctctaca ctctgagcag ctcagtgact gtcccctcca gcacctggcc cagcgagacc 600 gtcacctgca acgttgccca cccggccagc agcaccaagg tggacaagaa aattgtgccc 660 35 agggattgtg gttgtaagcc ttgcatatgt acagtcccag aagtatcatc tgtcttcatc 720 ttccccccaa agcccaagga tgtgctcacc attactctga ctcctaaggt cacgtgtgtt 780 gtggtagaca tcagcaagga tgatcccgag gtccagttca gctggtttgt agatgatgtg 840 40 gaggtgcaca cagctcagac gcaaccccgg gaggagcagt tcaacagcac tttccgctca 900 gtcagtgaac ttcccatcat gcaccaggac tggctcaatg gcaaggagtt caaatgcagg 960 45 gtcaacagtg cagctttccc tgcccccatc gagaaaacca tctccaaaac caaaggcaga 1020 ccgaaggctc cacaggtgta caccattcca cctcccaagg agcagatggc caaggataaa 1080 50 gtcagtctga cctgcatgat aacagacttc ttccctgaag acattactgt ggagtggcag 1140 tggaatgggc agccagcgga gaactacaag aacactcagc ccatcatgga cacagatggc 1 2 00 tcttacttca tctacagcaa gctcaatgtg cagaagagca actgggaggc aggaaatact 1 260 55 ttcacctgct ctgtgttaca tgagggcctg cacaaccacc atactgagaa gagcctctcc 13 20 cactctcctg gtaaatga 1338 58 5 <210> 54 <211> 445 <212> PRT <213> Mus musculus <220> <221 > MISC_FEATURE <223> Ab-2 heavy chain (no signal) EP 2 569 010 B1 10 <400> 54 Glu Val Gln Val Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala l 5 10 15 15 Ser Va l Lys Leu Ser Cys Thr Ala Ser Gl y Phe Asn Ile Lys Asp Tyr 20 25 30 20 Phe Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile 35 40 45 25 Gl y Arg Leu Asp Pro Glu Asp Gly Glu Ser Asp Tyr Al a Pro Lys Phe 50 55 60 Gln Asp Lys Ala Ile M et Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr 30 65 70 75 80 Leu Gln Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 35 Glu Arg Glu Asp Ty r Asp Gl y Thr Tyr Thr Phe Phe Pro Tyr Trp Gl y 100 105 110 40 Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser 45 50 55 59 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 8 1 115 120 125 Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro 180 185 190 Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro 195 200 205 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly 210 215 220 Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe I l e 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys 245 250 255 Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln 260 265 270 Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu 290 295 300 Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg 305 310 315 320 Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro 340 345 350 Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr 60 5 10 15 20 EP 2 569 010 B1 355 360 365 Asp Phe Phe Pr o Gl u Asp I le Thr Val Gl u Trp Gln Trp Asn Gly Gln 370 375 380 Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly 385 390 395 400 Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Va l Gl n Lys Ser Asn Trp Glu 405 410 415 Ala Gly Asn Thr Phe Thr Cys Ser Val Leu Hi s Glu Gly Le u His Asn 420 425 430 His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 445 <210> 55 25 <211> 12 <212> PRT <213> Artificial Sequence <220> 30 <223> Ab-3 and Ab-15 LCDR 1 <400> 55 35 Ser Val Ser Ser Thr I l e Ser Ser Asn His Leu His l 5 10 <210> 56 <211> 7 40 <212> PRT 45 50 <213> Artificial Sequence <220> <223> Ab-3 and Ab-15 LCDR2 <400> 56 <210> 57 <211> 9 <212> PRT 55 <213> Artificial Sequence <220> <223> Ab-3 and Ab-15 LCDR3 Gl y Thr Ser Asn Leu Al a Ser l 5 61 5 <400> 57 <210> 58 <211> 5 <212> PRT EP 2 569 010 81 Gln Gln Trp Ser Ser Tyr Pro Leu Thr l 5 10 <213> Artificial Sequence <220> <223> Ab-3 and Ab-15 HCDR1 15 <400> 58 20 25 30 35 <210> 59 <211 > 17 <212> PRT <213> Artificial Sequence <220> <223> Ab-3 and Ab-15 HCDR2 <400> 59 Asp Ph e Tyr Leu His l 5 Arg Ile Asp Pro Glu Asn Gly Asp Thr Leu Tyr Asp Pro Lys Phe Gln l 5 10 15 As p <210> 60 <211> 16 40 <212> PRT 45 50 <213> Artificial Sequence <220> <223> Ab-3 and Ab-15 HCDR3 <400> 60 Gl u Ala Asp Tyr Phe His Asp Gl y Thr Ser Tyr Trp Tyr Phe Asp Va l l 5 10 15 <210> 61 <211> 648 <212> DNA 55 <213> Mus musculus <220> <221 > mise_ feature 62 EP 2 569 010 81 <223> Ab-3 light chain <400> 61 5 60 gaaat t gtgc tcacccagtc tccagcactc atggctgcat c t ccggggga gaaggtcacc atcacctgca gtgtcagttc aactataagt tccaaccact tgcactggtt ccagcagaag 120 10 tcagacacct cccccaaacc ctggatttat ggcacatcca acctggcttc tggagtccct 180 gttcgcttca gtggcagtgg atctgggacc tet tat tete tcacaatcag cagcatggag 240 gctgaggat g ctgccactta t t actgtcaa cagtggagta gttacccact cacgttcggc 300 15 gctgggacca agctggagct gagacgggct gatgctgcac caactgtatc catct tccca 360 ccatccagt g agcagttaac atctggaggt gcctcagtcg tgtgcttctt gaacaacttc 420 20 taccccaaag acatcaatgt caagtggaag attgatggca g t gaacgaca aaat ggcgtc 480 ctgaacagtt ggactgatca ggacagcaaa gacagcacct acagcatgag cagcaccctc 540 acgttgacca aggacgagta tgaacgacat aacagctata cctgtgaggc cact cacaag 600 25 acatcaactt cacccattgt caagagcttc aacaggaatg agtgttag 648 <210> 62 <211>215 30 <212> PRT <213> Mus musculus <220> <221> MISC FEATURE - 35 <223> Ab-3 light chain (no signal) <400> 62 40 45 50 55 63 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Glu Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ala Ala Ser Pro Gly l 5 10 15 Gl u Lys Va l Thr Ile Thr Cys Ser Val Ser Ser Thr Ile Ser Ser Asn 20 25 30 His Leu His Trp Phe Gln Gln Lys Ser Asp Thr Ser Pro Lys Pro Trp 35 40 45 Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu 65 70 75 80 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro 85 90 95 Leu Thr Phe Gl y Ala Gly Thr Lys Leu Glu Leu Arg Arg Ala Asp Ala 100 105 110 Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser 115 120 125 Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp 130 135 140 Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val 145 150 155 160 Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met 165 170 175 Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser 180 185 190 Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys 195 200 205 Ser Phe Asn Arg Asn Glu Cys 210 215 64 EP 2 569 010 B1 <210> 63 <211> 1350 <212> DNA <213> Mus musculus 5 <220> <221 > mise_ feature <223> Ab-3 heavy chain 10 <400> 63 gaggttcagc tgcagcagtc tggggctgaa cttgtgaggc caggggcctt agtcaagttg 60 15 tcctgcacag ct t ctgactt caacattaaa gacttctatc t acactggat gaggcagcgg 120 cctgaacagg gcctggactg gattggaagg attgatcctg agaatggtga t act ttatat 180 gacccgaagt tccaggacaa ggccactctt acaacagaca catcctccaa cacagcctac 240 20 ctgcagctca gcggcctgac a t c t gagacc act gccgtct attactgttc tagagaggcg 300 gattatttcc acgatggtac c t cctactgg tacttcgatg t ctggggcgc agggaccac a 360 25 atcaccgtct cct cagccaa aacgacaccc ccat ctgtct a t ccactggc ccctggatct 420 gctgcccaaa ctaactccat ggt gaccctg g gatgcctgg tcaagggcta tttccctgag 480 ccagt gacag tga cctggaa c t c t ggat cc c t gtccagcg g t gtgcacac cttcccagct 540 30 gtcctgcagt ctgacctcta cact ctgagc agctcagtga c t gtcccctc cagcacctgg 600 cccagcgaga ccgt cacctg caacgttgcc cacccggcca gcagcaccaa ggtggacaag 660 35 aaaat t gtgc ccagggattg tggttgtaag cct tgcatat g t acagtccc agaagtatca 720 tctgtcttca tctt cccccc aaagcccaag gat gtgctca ccattactct gact cctaag 780 40 gtcacgtgtg ttgt ggtaga cat cagcaag gat gatcccg aggtccagtt cagctggtt t 840 gtagat gatg tggaggtgca cacagct cag acgcaacccc gggaggagca gttcaacagc 900 actttccgct cagt cagtga act tcccatc a t gcaccagg actggctcaa t ggcaaggag 960 45 ttcaaatgca gggtcaacag tgcagctttc cctgccccca tcgagaaaac catctccaaa 1020 accaaaggca gaccgaaggc tccacaggtg t acaccattc cacctcccaa ggagcagatg 1080 50 gccaaggata aagtcagtct gacctgcatg a t aacagact t cttccctga agacattact 1140 gtggagtggc agt ggaatgg gcagccagcg gagaactaca agaacactca gcccatcatg 1200 gacacagatg gctcttactt ca t ctacagc aagctcaatg tgcagaagag caactgggag 126 0 55 gcaggaaata ctt t cacctg ctct gtgtta catgagggcc tgcacaacca ccatactgag 132 0 aagagcctct cccactctcc tggtaaatga 1350 65 5 <210> 64 <211> 449 <212> PRT <213> Mus musculus <220> <221> MISC_FEATURE <223> Ab-3 heavy chain (no signal) EP 2 569 010 B1 10 <400> 64 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala l 5 10 15 15 Leu Val Lys Leu Ser Cys Thr Ala Ser Asp Phe Asn I l e Lys Asp Phe 20 25 30 20 Tyr Leu His Trp Met Arg Gln Arg Pro Glu Gln Gly Leu Asp Trp Ile 35 40 45 25 Gly Arg Ile Asp Pro Glu Asn Gly Asp Thr Leu Tyr Asp Pro Lys Phe 50 55 60 Gln Asp Lys Ala Thr Leu Thr Thr Asp Thr Ser Ser Asn Thr Ala Tyr 30 65 70 75 80 Leu Gln Leu Ser Gly Leu Thr Ser Glu Thr Thr Ala Val Tyr Tyr Cys 35 40 45 50 55 66 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 85 90 95 Ser Arg Glu Ala Asp Tyr Phe His Asp Gly Thr Ser Tyr Trp Tyr Phe 100 105 110 Asp Val Trp Gly Ala Gly Thr Thr Ile Thr Val Ser Ser Ala Lys Thr 115 120 125 Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr 130 135 140 Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His 165 170 175 Thr Phe Pro Ala Va l Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser 180 185 190 Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys As n 195 200 205 Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro 210 215 220 Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser 225 230 235 240 Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr 245 250 255 Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp 260 265 270 Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr 275 280 285 Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser 290 295 300 Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys 67 5 10 15 20 25 30 EP 2 569 010 B1 325 330 335 Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Al a Pro Gln Val Tyr Thr 340 345 350 Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr 355 360 365 Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln 370 375 380 Trp Asn Gl y Gln Pro Al a Glu Asn Tyr Lys As n Thr Gl n Pro Ile M e t 385 390 395 400 Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys 405 410 415 Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu 420 425 430 Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gl y 435 440 445 Lys 35 <210> 65 <211> 324 <212> DNA <213> Mus musculus 40 <220> 45 50 55 <221 > mise_ feature <223> Ab-15 light variable <400> 65 gacatccaga tgacccagtc ataacatgca gcgtatcatc cccggcaaag cacctaaatc tcaagatttt caggctctgg cccgaagact tcgcaaccta ggcggcacaa aagtagaaat tccatcctcc ctctcagcat ccgt aggcga tagagttaca aactatatca tcaaatcatc tt cattggtt ccaacagaaa acttatatac ggcacatcaa atctcgcatc aggcgttcct ctcaggcacc gactttactc ttacaatatc ctccctccaa ttactgtcaa caatggtcct cat atccact cacatttggc ta aa 68 60 120 180 240 300 324 5 <210> 66 <211> 108 <212> PRT <213> Mus musculus <220> <221> MISC_FEATURE <223> Ab-15 light variable EP 2 569 010 B1 10 <400> 66 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly l 5 10 15 15 Asp Arg Va l Thr Ile Thr Cys Ser Val Ser Ser Thr Il e Ser Ser Asn 20 25 30 20 His Leu His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu 35 40 45 25 Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 30 65 70 75 80 Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro 85 90 95 35 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 40 <210> 67 <211>375 <212> DNA <213> Mus musculus 45 <220> <221 > mise_ featu re <223> Ab-15 heavy variable <400> 67 50 55 69 EP 2 569 010 B1 gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctgactt caacattaaa gacttctatc tacactgggt gcgacaggcc 120 5 cctggacaag ggcttgagtg gattggaagg attgatcctg agaatggtga tactttatat 180 gacccgaagt tccaggacaa ggtcaccatg accacagaca cgtccaccag cacagcctac 240 10 atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagaggcg 300 gattatttcc acgatggtac ctcctactgg tact tcgatg tctggggccg tggcaccctg 360 15 gtcaccgt ct ctagt 375 <210> 68 20 <211> 125 <212> PRT <213> Mus musculus <220> 25 <221> MISC FEATURE - <223> Ab-15 heavy variable <400> 68 30 35 40 45 50 55 70 - , 5 10 15 20 25 30 EP 2 569 010 8 1 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala l 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Asp Phe Asn Ile Lys Asp Phe 20 25 30 Tyr Leu Hi s Trp Va l Arg Gln Al a Pro Gly Gln Gly Leu Glu Trp I l e 35 40 45 Gly Arg I l e Asp Pro Glu Asn Gl y Asp Thr Leu Tyr Asp Pro Lys Phe 50 55 60 Gln Asp Lys Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gl u Ala Asp Tyr Phe Hi s Asp Gly Thr Ser Tyr Trp Tyr Phe 100 105 11 0 Asp Val Trp Gly Arg Gly Thr Leu Val Thr Va l Ser Ser <210> 69 <211 > 645 115 120 125 35 <212> DNA 40 <213> Artificial Sequence <220> <223> Humanized antibody <220> <221 > mise_ feature <223> Ab-15 light chain 45 <400> 69 50 55 71 EP 2 569 010 81 gacatccaga tgacccagtc tccatcctcc ct ct cagea t ccgtaggcga t agagttaca 60 ataacatgca gcgtatcatc aactatatca tcaaatcatc t t cattggtt ccaacagaaa 120 5 cccggcaaag cacct aaatc act t atatac ggcacatcaa a t ctcgcatc aggcgttcct 180 tcaagatttt caggctctgg ctcaggcacc gactttactc t t acaatatc ctccctccaa 240 10 cccgaagact tcgcaaccta ttactgtcaa caatggtcct catatccact cacatttggc 300 ggcggcacaa aagtagaaat ta aacgtacg gtggctgcac catctgtctt catcttcccg 360 ccatctgatg agcagttgaa atct ggaact gcctctgttg tgtgcctgct gaataacttc 420 15 tatcc c agag aggc caaagt acagt ggaag gtggataacg ccctccaatc gggtaactcc 480 caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540 20 acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600 ggcctgagct cgcccgtcac aaagagcttc aacaggggag agt gt 645 <210> 70 25 <211>215 <212> PRT <213> Artificial Sequence <220> 30 <223> Humanized antibody sequence <220> <221> MISC FEATURE - <223> Ab-15 light chain 35 <400> 70 40 45 50 55 72 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly l 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Val Ser Ser Thr Il e Ser Ser Asn 20 25 30 His Leu His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu 35 40 45 Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Va l Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Al a Ser Val Va l Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Va l 180 185 190 Tyr Ala Cys Glu Val Thr His Gl n Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 73 5 <210>71 <211 > 1353 <212> DNA <213> Artificial Sequence <220> <223> Humanized antibody <220> 10 <221 > misc_feature <223> Ab-15 heavy chain <400> 71 15 gaggtgcagc tggtgcagtc tcctgc aagg cttctgactt 20 cctggacaag ggctt gagtg gacccgaagt tccaggacaa atggagctga ggagcctgag 25 gattat t tcc acgatggtac 30 35 40 45 50 55 EP 2 569 010 B1 tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 caacattaaa gacttctatc tacactgggt gcgacaggcc 12 0 gattggaagg attgatcctg agaatggtga tactttatat 180 ggtcaccatg accacagaca cgtccaccag cacagcctac 2 40 atctgacgac acggccgtgt attactgtgc gagagaggcg 300 ctcctactgg tacttcgatg tct ggggccg tggcaccctg 360 74 " EP 2 569 010 81 gtcaccgtct ctagtgcctc caccaagggc ccatcggtct tccccctggc gccctgctcc 42 0 aggagcacct ccgagagcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa 480 5 540 ccggtgacgg tgtcgtggaa ctcaggcgct ctgaccagcg gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc agcagcgtgg t gaccgtgcc ctccagcaac 600 10 ttcggcaccc agacctacac ctgcaacgta gat cacaagc ccagcaacac caaggtggac 660 aagacagttg agcgcaaatg ttgt gtcgag tgcccaccgt gcccagcacc acctgtggca 720 ggaccgtcag tct tcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780 15 cctgaggtca cgt gcgtggt ggt ggacgtg agccacgaag a ccccgaggt ccagttcaac 840 tggtacgt gg acggcgtgga ggtgcataat gccaagacaa agccacggga ggagcagttc 900 20 aacagcacgt tccgtgtggt cagcgtcctc accgttgtgc accaggactg gctgaacggc 960 aaggagtaca agtgcaaggt ctccaacaaa ggcctcccag cccccatcga gaaaaccatc 10 2 0 tccaaaacca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080 25 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta ccccagcgac 1140 atcgccgtgg agtgggagag caat gggcag ccggagaaca actacaagac cacacctccc 1200 30 atgctggact ccgacggctc ct t cttcctc tacagcaagc tcaccgtgga caagagcagg 1260 tggcagcagg ggaacgtctt ctcat gctcc g t gatgcatg aggctctgca caaccactac 1320 acgcagaaga gcctctccct gtct ccgggt a aa 1353 35 <210> 72 <211>451 <212> PRT <213> Artificial Sequence 40 <220> <223> Humanized antibody sequence <220> 45 <221> MISC FEATURE - <223> Ab-15 heavy chain <400> 72 50 55 75 EP 2 569 010 8 1 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala l 5 10 15 5 Ser Val Lys Val Ser Cys Lys Al a Ser Asp Phe Asn Ile Lys Asp Phe 20 25 30 10 Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 15 20 25 30 35 40 45 50 55 76 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 35 40 45 Gly Arg Ile Asp Pro Glu Asn Gl y Asp Thr Leu Tyr Asp Pro Lys Phe 50 55 60 Gln Asp Lys Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Gl u Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Va l Tyr Tyr Cys 85 90 95 Ala Arg Glu Ala Asp Tyr Phe His Asp Gly Thr Ser Tyr Trp Tyr Phe 100 105 110 Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Va l Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys 195 200 205 Asn Va l Asp His Lys Pro Ser Asn Thr Lys Va l Asp Lys Thr Val Gl u 210 215 220 Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Gl u Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gl y Val Glu Va l 77 5 10 15 20 25 30 35 40 45 EP 2 569 010 B1 275 280 285 His Asn Al a Lys Thr Lys Pro Arg Glu Glu Gl n Phe Asn Ser Thr Phe 290 295 300 Arg Val Val Ser Va l Leu Thr Val Val His Gl n Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gl y Leu Pro Ala Pro Ile 32 5 330 335 Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Gl u Glu Met Thr Lys Asn Gln Va l Ser 355 360 365 Leu Thr Cys Leu Val Lys Gl y Phe Tyr Pro Ser Asp I l e Ala Va l Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Al a Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 73 <211> 11 50 <212> PRT <213> Artificial Sequence <220> <223> Ab-4 and Ab-5 LCDR1 55 <400> 73 78 EP 2 569 010 81 Ar g Ala Ser Gl n Asp Il e Ser As n I yr Leu Asn l 5 10 5 <210> 74 <211> 7 <212> PRT <213> Artificial Sequence 10 <220> <223> Ab-4 and Ab-5 LCDR2 <400> 74 15 <210> 75 20 <211>9 <212> PRT <213> Artificial Sequence <220> 25 <223> Ab-4 and Ab-5 LCDR3 30 <400> 75 <210> 76 <211>5 35 <212> PRT 40 45 <213> Artificial Sequence <220> <223> Ab-4 and Ab-5 HCD R 1 <400> 76 <210> 77 <211> 17 <212> PRT 50 <213> Artificial Sequence <220> <223> Ab-4 and Ab-5 HCDR2 55 <400> 77 I y r Ihr Ser Arg Leu Leu Ser l 5 Gln Gln Gly Asp Ihr Leu Pr o Tyr Ihr l 5 Asp Iyr Asn Met Hi s l 5 79 5 EP 2 569 010 81 Glu Ile Asn Pro Asn Ser Gly Gly Ala Gl y Tyr Asn Gln Lys Phe Lys l 5 10 15 Gly <210> 78 <211>14 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 15 <400> 78 Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val 20 l 5 10 <210> 79 <211> 645 <212> DNA 25 <213> Mus musculus 30 35 40 45 50 55 <220> <221 > misc_feature <223> Ab-4 light chain <400> 79 gatatccaga tgacacagat atcagt tgca gggcaagtca gatggaactt t t aaactcct aggttcagtg gcagtgggtc gaagattttg ccact tactt gggaccaagc tggaaataaa tccagtgagc agttaacatc cccaaagaca tcaat gtcaa aacagttgga ctgat cagga ttgaccaagg acgagtatga tcaacttcac ccattgtcaa <210> 80 <211>214 <212> PRT tacatcctcc ctgtctgcct ctctgggaga agacattagc aattatttaa actggtatca tat cttctac acatcaagat tactctcagg tggaacagat tattctctca ccatttacaa ttgccaacag ggagatacgc ttccgtacac acgggctgat gctgcaccaa ctgtatccat tggaggtgcc tcagtcgtgt gcttcttgaa gtggaagatt gatggcagtg aacgacaaaa cagea a ag ac agcacctaca gcatgagcag acgacataac agct atacct gtgaggccac gagcttcaac aggaatgagt gttag 80 cagggtctcc gcagaaacca agtcccatca cctggagcaa t ttcggaggg cttcccacca caacttctac tggcgtcctg caccctcacg tcacaagaca 60 120 180 240 300 360 420 480 540 600 645 EP 2 569 010 81 <213> Mus musculus <220> <221> MISC_FEATURE 5 <223> Ab-4 light chain <400> 80 10 Asp Ile Gln Met Thr Gln Ile Thr Ser Ser Leu Ser Ala Ser Leu Gl y 15 20 25 30 35 40 45 50 55 81 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 l 5 lO 15 Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile 35 40 45 Phe Tyr Thr Ser Arg Leu Leu Ser Gly Va l Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr Asn Leu Glu Gln 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Va l Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Va l Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 <21 0> 81 <211> 1344 <212> DNA 82 EP 2 569 010 B1 <213> Mus musculus <220> <221> misc_feature 5 <223> Ab-4 heavy chain <400> 81 gaggtccaac tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60 10 tcctgcaagg cttct ggata tacat tcact gactacaaca t gcactgggt gaagcagaac 120 caaggaaaga ccctagagtg gataggagaa attaatccta acagtggtgg tgctggctac 180 15 aaccagaagt tcaagggcaa ggccacattg actgtagaca agt cctccac cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300 tacgatgata tctacgacga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360 20 gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420 caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480 25 acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agct gtcctg 540 cagtctgacc tcta cactct gagcagctca gtgactgtcc cct ccagcac ctggcccagc 600 30 gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660 gtgcccaggg attgt ggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720 ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780 35 tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtt tgtagat 840 gatgtggagg tgca cacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900 40 cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960 tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020 ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080 45 gataaagtca gtctgacctg cat gataaca gacttcttcc c t gaagacat tactgtggag 1140 tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200 50 gatggctctt acttcatcta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260 aatact ttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320 ctctcccact ctcctggtaa at ga 1344 55 <210> 82 <211> 447 <212> PRT 83 EP 2 569 010 81 <213> Mus musculus <220> <221> MISC_FEATURE 5 <223> Ab-4 heavy chain <400> 82 10 15 20 25 30 35 40 45 50 55 84 > 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala l 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Thr Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val 100 105 110 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro 115 120 125 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 130 135 140 Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 180 185 190 Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala 195 200 205 His Pro Ala Ser Ser Thr Lys Va l Asp Lys Lys Ile Val Pro Arg Asp 210 215 220 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 85 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 225 230 235 240 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 245 250 255 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 260 265 270 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 290 29 5 300 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu .Phe Lys 305 310 315 320 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 340 345 350 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 355 360 365 Ile Thr Asp Phe Phe Pro Glu Asp Il e Thr Val Glu Trp Gln Trp Asn 370 375 380 Gly Gln Pro Ala Gl u Asn Tyr Lys Asn Thr Gln Pro I l e Met Asp Thr 385 390 395 400 Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 405 410 415 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 420 425 430 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys <2 10> 83 <2 11 >321 <212> DNA 435 440 445 86 EP 2 569 010 81 <213> Mus musculus <220> <221 > mise_ feature 5 <223> Ab-5 light variable <400> 83 10 gacatccaga tgacccagtc tccatcctcc ctctccgcat ataacatgta gagc atctca agat atttcc aactatttga ggcaaagcac ctaaactcct catt tactat acatcaagac 15 cgattctcag gctccggctc cggcacagat t t cacactca gaagattttg caacctatta ctgt caacaa ggcgatacac 20 ggcacaaaag ttgaaattaa a <210> 84 <211> 107 <212> PRT 25 <213> Mus musculus 30 35 40 45 50 55 <220> <221> MISC_FEATURE <223> Ab-5 light variable <400> 84 87 ccgtaggcga ccgcgtaacc 60 attggtacca acaaaaaccc 120 tcctctccgg cgttccatca 180 ctatt t cctc cct ccaacca 240 tcccatacac attcggcggc 300 321 EP 2 569 010 B1 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly l 5 10 15 5 Asp Arg Va l Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 10 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly 15 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 20 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Thr Leu Pro Tyr 85 90 95 25 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 85 30 <211> 369 <212> DNA <213> Mus musculus <220> 35 <221 > mise_ feature <223> Ab-5 heavy variable <400> 85 40 gaggtgcagc tggtgcagag cggcgccgag gtaaaaaaac caggagcaag cgttaaagtt tcttgtaaag caagcggata tacatttaca gattacaaca tgcattgggt aagacaagcg 45 ccaggacaag gattggaatg gatgggcgaa attaacccta atagtggagg agcaggctac aatcaaaaat tcaaagggag agttacaatg acaacagaca caagcacttc aacagcatat atggaactgc gatcacttag aagcgacgat acagctgtat actattgcgc acgacttggg 50 tatgatgata tatatgatga ctggtatttc gatgtttggg gccagggaac aacagttacc gtctctagt 55 <210> 86 <211> 123 <212> PRT <213> Mus musculus 88 60 120 180 240 300 360 369 <220> <221> MISC FEATURE <223> Ab-5 heavy variable EP 2 569 010 81 5 <400> 86 Glu Val Gln Leu Va l Gln Ser Gl y Ala Gl u Va l Lys Lys Pro Gl y Al a l 5 10 15 10 Ser Val Lys Val Ser Cys Lys Al a Ser Gl y Tyr Thr Phe Thr Asp Tyr 20 25 30 15 As n Met His Trp Val Arg Gln Al a Pr o Gl y Gl n Gly Leu Glu Trp Met 35 40 45 20 Gly Glu Il e Asn Pro Asn Ser Gl y Gly Ala Gly Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Ar g Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 25 65 70 75 80 Met Glu Le u Ar g Ser Le u Ar g Ser Asp Asp Thr Ala Va l Tyr Tyr Cys 85 90 95 30 Ala Arg Le u Gl y Tyr Asp Asp I l e Tyr Asp Asp Trp Tyr Ph e Asp Val 100 105 110 35 100 105 110 40 Trp Gl y Gln Gly Thr Thr Va l Thr Val Ser Ser 115 120 <210> 87 45 <211> 642 <212> DNA <213> Artificial Sequence <220> 50 <223> Humanized antibody 55 <220> <221 > misc_feature <223> Ab-5 light chain <400> 87 89 EP 2 569 010 B1 gacatccaga tgacccagtc tccatcctcc ctctccgcat ccgtaggcga ccgcgtaacc 60 ataacatgta gagcatctca agatatttcc aactatttga attggtacca acaaaaaccc 120 5 ggcaaagcac ctaaactcct catttactat acatcaagac tcctctccgg cgttccatca 180 cgattctcag gctccggctc cggcacagat ttcacactca ctatttcctc cctccaacca 240 10 gaagattttg caacctatta ctgtcaacaa ggcgatacac tcccatacac attcggcggc 300 ggcacaaaag ttgaaattaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420 15 cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540 20 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt g t 642 <210> 88 25 <211> 214 <212> PRT <213> Artificial Sequence <220> 30 <223> Humanized anti body <220> <221> MISC FEATURE - <223> Ab-5 light chain 35 <400> 88 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 40 45 50 55 90 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 l 5 lO 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu Leu Ser Gly Va l Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gl n Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr Hi s Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 89 <211> 1347 <212> DNA 91 .. EP 2 569 010 B1 <213> Artificial Sequence <220> <223> Humanized antibody 5 <220> <221 > misc_feature <223> Ab-5 heavy chain 10 <400> 89 gaggtgcagc tggtgcagag cggcgccgag gtaaaaaaac caggagcaag cgttaaagtt 60 tcttgtaaag caagcggata tacatttaca gattacaaca tgcattgggt aagacaagcg 120 15 ccaggacaag gattggaatg gatgggcgaa attaacccta atagtggagg agcaggctac 180 aatcaaaaat tcaaagggag agttacaatg acaacagaca caagcacttc aacagcatat 240 20 atggaactgc gatcacttag aagcgacgat acagctgtat actattgcgc acgacttggg 300 tatgatgata tatatgatga ctggtatttc gatgtttggg gccagggaac aacagttacc 360 gtctctagtg cctccaccaa gggcccatcg gtcttccccc tggcgccctg ctccaggagc 420 25 acctccgaga gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 480 acggtgtcgt ggaactcagg cgctctgacc agcggcgtgc acaccttccc agctgtccta 540 30 cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag caacttcggc 600 acccagacct acacctgcaa cgtagatcac aagcccagca acaccaaggt ggacaagaca 660 35 gttgagcgca aatgttgtgt cgagtgccca ccgtgcccag caccacctgt ggcaggaccg 720 tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780 gtcacgtgcg tggtggtgga cgtgagccac gaagaccccg aggtccagtt caactggtac 840 40 gtggacggcg tggaggtgca taatgccaag acaaagccac gggaggagca gttcaacagc 900 acgttccgtg tggtcagcgt cctcaccgtt gtgcaccagg actggctgaa cggcaaggag 960 45 tacaagtgca aggtctccaa caaaggcctc ccagccccca tcgagaaaac catctccaaa 1020 accaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140 50 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacacc tcccatgctg 1200 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260 55 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320 aagagcctct ccctgtctcc gggtaaa 1347 92 5 <210> 90 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Humanized antibody <220> 10 <221> MISC_FEATURE <223> Ab-5 heavy chain <400> 90 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 93 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala l 5 10 15 Ser Val Lys Val Ser Cys Lys Al a Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Va l 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly Ala Le u Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cy s Asn Val 195 200 205 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys 94 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 210 215 220 Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Gl u Gln Phe Asn Ser Thr Phe Arg Va l 290 295 300 Val Ser Va l Leu Thr Val Val Hi s Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Thr Lys Gly Gl n Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Gl u 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys 95 5 10 <210> 91 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Ab-6 LCDR1 <400> 91 EP 2 569 010 81 Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn l 5 10 15 <210> 92 <211> 7 <212> PRT <213> Artificial Sequence 20 <220> <223> Ab-6 LCDR2 <400> 92 25 <21 0> 93 30 <211> 9 <212> PRT <213> Artificial Sequence <220> 35 <223> Ab-6 LCDR3 40 <400> 93 <210> 94 <211>5 45 <212> PRT 50 55 <213> Artificial Sequence <220> <223> Ab-6 HCDR1 <400> 94 <210> 95 <211>17 Tyr Thr Ser Arg Leu His Ser l 5 Gln Gln Gly Asp Thr Leu Pro Tyr Thr l 5 Asp Tyr Asn Met His l 5 96 EP 2 569 010 81 <212> PRT <213> Artificial Sequence <220> 5 <223> Ab-6 HCDR2 <400> 95 10 Glu Ile Asn Pro Asn Ser Gly Gl y Ser Gly Tyr Asn Gln Lys Phe Lys l 5 10 15 15 20 25 Gly <210> 96 <211>14 <212> PRT <213> Artificial Sequence <220> <223> Ab-6 HCDR3 <400> 96 Leu Va l Tyr Asp Gl y Ser Tyr Glu Asp Trp Tyr Phe Asp Val l 5 10 30 <210> 97 <211> 645 <212> DNA <213> Mus musculus 35 <220> 40 45 50 55 <221 > misc_feature <223> Ab-6 light chain <400> 97 97 EP 2 569 010 81 gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga atcagttgca gggcaagtca ggacattagc aattatttaa actggtttca 5 gatggaactc ttaaactcct gatcttctac acatcaagat tacactcagg aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa 10 gaagatattg ccacttactt ttgccaacag ggtgatacgc t t ccgtacac gggaccaagc tggaaataag acgggctgat gctgcaccaa ctgtatccat tccagt gagc agttaacatc tggaggtgcc tcagtcgtgt gct tcttgaa 15 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag 20 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcaacttcac ccattgtcaa gagct tcaac aggaatgagt gttag 25 30 <210> 98 <211>214 <212> PRT <213> Mus musculus <220> <221 > MISC_FEATURE <223> Ab-6 light chain 35 <400> 98 40 45 50 55 98 ... cagagtcacc 60 gcagaaacca 120 agttccatca 180 cctggagcaa 240 gttcgggggg 300 c t tcccacca 360 caacttctac 420 t ggcgtcct g 480 c accctcacg 540 tcacaagaca 600 645 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly l 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Al a Ser Gln Asp Il e Ser As n Tyr 20 25 30 Leu Asn Trp Phe Gln Gln Lys Pr o Asp Gly Thr Leu Lys Leu Leu Ile 35 40 45 Phe Tyr Thr Ser Arg Leu His Ser Gl y Va l Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gl y Gly Thr Lys Leu Glu Ile Arg Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Le u Thr Ser Gly 115 120 125 Gly Ala Ser Val Va l Cys Phe Leu Asn Asn Phe Tyr Pr o Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Il e Asp Gly Ser Glu Arg Gln Asn Gly Va l Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 99 EP 2 569 010 81 <210> 99 <211> 1344 <212> DNA <213> Mus musculus 5 <220> <221> misc_feature <223> Ab-6 heavy chain 10 <400> 99 gaggtccagc tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60 15 tcctgcaagg cttctggata cacattcact gactacaaca tgcactgggt gaaacagaac 120 caaggaaaga gcctagagtg gataggagaa attaatccta acagtggtgg tagtggctac 180 aaccaaaagt tcaaaggcaa ggccacattg actgtagaca agtcttccag cacagcctac 240 20 atggagctcc gcagcctgac atctgaggac tctgcagtct att actgtgc aagattggtc 300 tacgatggca gctacgagga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360 25 gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420 caaactaact ccatggtgac cct gggatgc ctggtcaagg g ctatttccc tgagccagtg 480 acagtgacct ggaactctgg at ccctgtcc agcggtgtgc acaccttccc agctgtcctg 540 30 cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600 gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660 35 gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720 ttcat cttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc t aaggtcacg 780 tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg g t ttgtagat 840 40 gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900 cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960 45 tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020 ggcagaccga aggctccaca ggt gtacacc at t ccacctc ccaaggagca gatggccaag 1080 gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140 50 tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200 gatggctctt acttcatcta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260 55 aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320 ctctcccact ctcct ggtaa atga 1344 100 5 <210> 100 <211> 447 <212> PRT <213> Mus musculus <220> <221> MISC_FEATURE <223> Ab-6 heavy chain EP 2 569 010 B1 10 <400> 100 15 20 25 30 35 40 45 50 55 Glu Val Gln Leu Gln Gln Ser Gl y Pro Gl u Leu Met Lys Pro Gly Ala l 5 10 15 Ser Val Lys Met Ser Cys Lys Al a Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met His Trp Va l Lys Gln Asn Gln Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn Pro Asn Ser Gly Gly Ser Gly Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Al a Arg Leu Val Tyr Asp Gly Ser Tyr Gl u Asp Trp Tyr Phe Asp Va l 100 105 110 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro 115 120 125 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 130 135 140 Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Va l 145 150 155 160 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 101 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 165 170 175 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 180 185 190 Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala 195 200 205 His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 210 215 220 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 245 250 255 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 260 265 270 Val Gln Phe Ser Trp Phe Val Asp Asp Val Gl u Val His Thr Ala Gl n 275 280 285 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 290 295 300 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 305 310 315 320 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 340 345 350 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 355 360 365 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 370 375 380 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 385 390 395 400 Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 102 EP 2 569 010 B1 405 410 415 5 Trp Glu Al a Gly Asn Thr Phe Th r Cys Ser Val Leu His Glu Gly Leu 420 425 430 His Asn His His Thr Gl u Lys Ser Leu Ser Hi s Ser Pro Gly Lys 10 435 440 445 <210> 101 <211> 11 <212> PRT 15 <213> Artificial Sequence <220> <223> Ab-7 LCDR1 20 <400> 101 Arg Ala Ser Gln Val I le Thr Asn Tyr Leu Tyr l 5 10 25 30 35 <210> 102 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Ab-7 LCDR2 <400> 102 40 <210> 103 <211> 9 <212> PRT <213> Artificial Sequence 45 <220> <223> Ab-7 LCDR3 <400> 103 50 <210> 104 55 <211>5 <212> PRT <213> Artificial Sequence Tyr Thr Ser Arg Leu Hi s Ser l 5 Gln Gl n Gly Asp Thr Leu Pro Tyr Thr l 5 103 <220> <223> Ab-7 HCDR1 <400> 104 5 10 <210> 105 <211>17 <212> PRT <213> Artificial Sequence 15 <220> <223> Ab-7 HCDR2 <400> 105 20 EP 2 569 010 B1 Asp Tyr Asn Met His l 5 Glu Ile Asn Pro Asn Ser Gly Gl y Ala Gly Tyr Asn Gln Gln Ph e Lys l 5 10 15 25 Gl y <210> 106 <211>14 <212> PRT 30 <213> Artificial Sequence <220> <223> Ab-7 HCDR3 35 <400> 106 Leu Gl y Tyr Val Gl y Asn Tyr Glu Asp Trp Tyr Phe Asp Val l 5 1 0 40 45 <210> 107 <211> 642 <212> DNA <213> Mus musculus <220> <221 > misc_feature <223> Ab-7 light chain 50 <400> 107 55 104 EP 2 569 010 B1 gatat ccaga tgacacagac tacat cctcc ctgtctgcct ctctgggaga cagagtcacc 60 atctgttgca gggcaagtca ggtcattacc aattatttat actggtatca gcagaaacca 120 5 gatggaactt ttaaactcct gatctactac acatcaagat t acactcagg agtcccatca 180 aggttcagtg gcagtgggtc tggaacagat t attctctca ccattagcaa cctggaacag 240 10 gaagatattg ccactt actt t t gccaacag ggtgatacgc ttccgtacac gttcggaggg 300 gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360 15 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420 cccaaagaca tcaatgtcaa gtggaagatt gat ggcagtg aacgacaaaa tggcgtcctg 480 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540 20 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt g t 642 25 <210> 108 <211>21 4 <212> PRT <213> Mus musculus 30 <220> <221> MISC FEATURE - <223> Ab-7 light chain <400> 108 35 40 45 50 55 105 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly l 5 10 15 Asp Arg Val Thr Ile Cys Cys Arg Ala Ser Gln Val Ile Thr Asn Tyr 20 25 30 Leu Tyr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 106 EP 2 569 010 81 <210> 109 <211> 1341 <212> DNA <213> Mus musculus 5 <220> <221 > mise_ feature <223> Ab-7 heavy chain 10 <400> 109 gaggtccagc tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60 tcctgcaagg cttct ggata cacattcact gactacaaca tgcactggat gaagcagaac 120 15 caaggaaaga gcctagaatg gataggagaa attaatccta acagtggtgg tgctggctac 180 aaccagcagt tcaaaggcaa ggccacattg actgtagaca agtcctccag gacagcctac 240 20 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300 tacgttggta attacgagga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360 25 gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420 caaact aact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 48 0 acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540 30 cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600 gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660 35 gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720 ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780 tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840 40 gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900 cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960 45 tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020 ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080 50 gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140 tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1 200 gatggctctt act tea teta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1 260 55 aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320 ctctcccact ctcct ggtaa a 134 1 107 5 <210> 110 <211>447 <212> PRT <213> Mus musculus <220> <221> MISC_FEATURE <223> Ab-7 heavy chain EP 2 569 010 81 10 <400> 110 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala l 5 10 15 15 Ser Val Lys Met Ser Cys Lys Al a Ser Gl y Tyr Thr Ph e Thr Asp Tyr 20 25 30 20 Asn Met His Trp Met Lys Gln Asn Gln Gly Lys Ser Leu Glu Trp Ile 35 40 45 25 Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Gln Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Arg Thr Ala Tyr 30 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 35 Ala Arg Leu Gly Tyr Va l Gly Asn Tyr Gl u Asp Trp Tyr Phe Asp Val 100 105 110 40 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro 115 120 125 45 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 50 55 108 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 130 135 140 Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 180 185 190 Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala 195 200 205 His Pro Al a Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 210 215 220 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Va l 225 230 235 240 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 245 250 255 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 260 265 270 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gl n 275 280 285 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 290 295 300 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 305 310 315 320 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 340 345 350 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 355 360 365 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 109 EP 2 569 010 B1 370 375 380 5 Gl y Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 385 390 395 400 Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 10 405 410 415 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 420 425 430 15 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 20 <210> 111 <211> 11 <212> PRT 435 440 445 <213> Artificial Sequence 25 <220> <223> Ab-8 LCDR1 <400> 111 30 <210> 112 35 <211> 7 <212> PRT Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn l 5 10 <213> Artificial Sequence <220> 40 <223> Ab-8 LCDR2 45 <400> 112 <210> 113 <211> g 50 <212> PRT <213> Artificial Sequence <220> <223> Ab-8 LCDR3 55 <400> 113 Tyr Thr Ser Arg Leu Leu Ser l 5 110 5 <210> 114 <211> 5 <212> PRT <213> Artificial Sequence 10 <220> <223> Ab-8 HCDR1 <400> 114 15 <210> 115 20 <211>17 <212> PRT <213> Artificial Sequence <220> 25 <223> Ab-8 HCDR2 <400> 115 EP 2 569 010 81 Gln Gln Gly Asp Thr Leu Pr o Tyr Thr l 5 Asp Tyr Asn Met Hi s l 5 30 Glu Ile Asn Pro Asn Ser Gly Gl y Ala Gly Tyr Asn Gl n Lys Phe Lys l 5 10 15 35 40 45 Gly <210> 116 <211>14 <212> PRT <213> Artificial Sequence <220> <223> Ab-8 HCDR3 <400> 116 Leu Gl y Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Ph e Asp Va l l 5 10 50 <210> 117 <211> 645 <212> DNA <213> Mus musculus 55 <220> <221 > misc_feature <223> Ab-8 light chain 111 EP 2 569 010 81 <400> 117 gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 60 5 atcagttgca gggcaagtca agacattagc aattatttaa actggtatca gcagaaacca 120 gatggaactt ttaaactcct tatcttctac acatcaagat tactctcagg agtcccatca 180 10 aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 240 gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 300 15 gggaccaaac tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480 20 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600 25 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645 <210> 118 <211 > 214 <212> PRT 30 <213> Mus musculus <220> <221 > MISC FEATURE - <223> Ab-8 light chain 35 <400> 118 40 45 50 55 112 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 Asp Ile Gl n Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly l 5 10 15 Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp I l e Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile 35 40 45 Phe Tyr Thr Ser Arg Leu Leu Ser Gly Va l Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr Asn Leu Glu Gln 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 14 0 Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Va l Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Me t Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 <21 0> 11 9 <211 > 1344 113 EP 2 569 010 81 <212> DNA <2 13> Mus musculus <220> 5 <221 > mise_ feature <223> Ab-8 heavy chain <400> 119 10 60 gaggtccaac tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg tcctgcaagg cttctggata tacattcact gactacaaca tgcactgggt gaagcagaac 120 15 caaggaaaga ccctagactg gataggagaa attaatccta acagtggtgg tgctggctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agt cctccac cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300 20 tacgatgata tctacgacga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360 gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420 25 caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480 acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540 cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600 30 gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660 gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720 35 ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780 tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840 40 gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900 cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960 tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 10 2 0 45 ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080 gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140 50 tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200 gatggctctt act tea teta cagea a get e aatgtgcaga agagcaactg ggaggcagga 1260 aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320 55 ctctcccact ctcctggtaa at ga 1344 <210> 120 114 <211>447 <212> PRT <213> Mus musculus EP 2 569 010 81 5 <220> 10 15 20 25 30 35 40 45 50 55 <221> MISC_FEATURE <223> Ab-8 heavy chain <400> 120 Glu Val Gln Leu Gln Gln Ser Gl y Pro Glu Leu Met Lys Pro Gly Ala l 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Hi s Trp Val Lys Gln Asn Gl n Gly Lys Thr Le u Asp Trp I l e 35 40 45 Gly Glu Ile Asn Pro Asn Ser Gly Gl y Ala Gly Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Glu Le u Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Gl y Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val 115 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 100 105 110 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro 115 120 125 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 130 135 140 Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 180 185 190 Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala 195 200 205 His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 210 215 220 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 245 250 255 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 260 265 270 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 290 295 300 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 305 310 315 320 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 116 .. ' 5 10 15 20 25 EP 2 569 010 81 340 345 350 Pro Pr o Lys Gl u Gln Met Al a Lys Asp Lys Val Ser Leu Thr Cys Met 355 360 365 Ile Thr Asp Phe Ph e Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 370 375 380 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro I l e Met Asp Thr 385 390 395 400 Asp Gly Ser Tyr Phe I le Tyr Ser Lys Leu Asn Val Gl n Lys Ser Asn 405 410 415 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu Hi s Gl u Gly Leu 420 425 430 His Asn Hi s His Thr Gl u Lys Ser Leu Ser His Ser Pr o Gly Lys <210> 121 <211> 11 435 440 445 30 <212> PRT <213> Artificial Sequence 35 40 <220> <223> Ab-9 LCDR1 <400> 121 <210> 122 <211> 7 <212> PRT Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn l 5 10 45 <213> Artificial Sequence <220> <223> Ab-9 LCDR2 50 <400> 122 55 <210> 123 <211> 9 <212> PRT Tyr Thr Ser Arg Leu Ph e Ser l 5 117 5 10 <213> Artificial Sequence <220> <223> Ab-9 LCDR3 <400> 123 <210> 124 <211> 5 <212> PRT EP 2 569 010 B1 Gln Gln Gly Asp Thr Leu Pro Tyr Thr l 5 15 <213> Artificial Sequence <220> <223> Ab-9 HCDR1 20 <400> 124 25 30 35 40 <210> 125 <211>17 <212> PRT <213> Artificial Sequence <220> <223> Ab-9 HCDR2 <400> 125 Asp Tyr Asn Met His l 5 Gl u Ile As n Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gl n Lys Phe Lys l 5 10 15 Gly <210> 126 <211>14 45 <212> PRT 50 55 <213> Artificial Sequence <220> <223> Ab-9 HCDR3 <400> 126 Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Va l <210> 127 <211> 642 l 5 10 118 ' " ""' EP 2 569 010 B1 <212> DNA <2 13> Mus musculus <400> 127 5 gatatccaga tgacacagat tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 60 atcagttgca gggcaagtca agacattagc aattatttaa attggtatca gcagaaacca 120 10 gatggaactt ttaaactcct tatcttctac acatcaagat tattttcagg agtcccatca 180 aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 240 15 gaagattttg ccact t actt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 300 gggaccaagg tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420 20 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540 25 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt g t 642 <210> 128 30 <2 11 > 214 <212> PRT <213> Mus musculus <400> 128 35 40 45 50 55 119 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Asp Ile Gln Met Thr Gln Ile Thr Ser Ser Leu Ser Ala Ser Leu Gly l 5 10 15 Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile 35 40 45 Phe Tyr Thr Ser Arg Leu Phe Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr Asn Leu Glu Gln 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 <210> 129 <211> 1350 120 EP 2 569 010 81 <212> DNA <213> Mus musculus <400> 129 5 gaggtccaac tgcaacagtc tggacctgaa ctaatgaagc c t gggacttc agtgaagatg 60 tcctgcaagg ctt c t ggata tacattcact gactacaaca tgcactgggt gaagcagacc 120 10 caaggaaaga ccctagagtg gataggagaa attaatccta acagtggtgg tgctggct ac 180 aaccagaagt tcaagggcaa ggccacattg act gtagaca agt cctccac cacagcctac 240 15 atggagct cc gcagcctgac atctgaggac tctgcagtct attactgtgc aaaattgggc 300 tacgatgata tctacgacga c t ggt a t ttc gatgt ctggg g cgcagggac cacggtcacc 360 gtctcctcag ccaaaacaac agccccatcg gtctatccac t ggcccctgt gtgtggagat 420 20 acaactggct cctcggtgac tctaggatgc ctggtcaagg gt t atttccc tgagccagtg 480 accttgacct ggaactctgg atccctgtcc agtgatgtgc acaccttccc agctctcctg 540 25 cagtctggcc tctacaccct cagcagctca gtgactgtaa c cacctggcc cagccagacc 600 atca cctgca atgtggccca cccggcaagc agcaccaaag t g gacaagaa aattgagccc 660 agagggtccc caacacataa accctgtcct ccatgcccag c t cctaacct c t tgggtgga 720 30 ccatccgtct tcatcttccc tccaaagatc aaggatgtac tcat gatctc cctgagcccc 780 atggtcacgt gtgt ggtggt ggatgt gagc gaggatgacc cagatgtcca tgtcagctgg 840 35 ttcgt gaaca acgtggaagt acacacagct cagacacaaa ceca tag aga ggattacaac 900 agtactatcc gggtggtcag tgccct cccc a t ccagcacc aggactggat gagtggcaag 960 40 gagttcaaat gcaaggtcaa caacaaagcc ctcccagcgc ccatcgagag aaccatctca 1020 aaacccaaag ggccagtaag agctccacag gtatatgtct tgcctccacc agaagaagag 1080 atgactaaga aacaggtcac tctgacctgc atgatcacag acttcatgcc tgaagacatt 1140 45 tacgtggagt ggaccaacaa cgggcaaaca gagctaaact acaagaacac tgaaccagtc 1200 ctggactctg atggt tctta cttcatgtac agcaagctga gagtggaaaa gaagaactgg 1260 50 gtggaaagaa atagctactc ctgttcagtg gtccacgagg gtctgcacaa tcaccacacg 1320 actaagagct tctcccggac tccgggtaaa 1350 <210> 130 55 <211> 450 <212> PRT <213> Mus musculus 121 EP 2 569 010 B1 <400> 130 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Thr l 5 10 15 5 Ser Val Lys Met Ser Cys Lys Al a Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 JO 10 Asn Met His Trp Val Lys Gln Thr Gln Gly Lys Thr Leu Glu Trp Ile 35 40 45 15 Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe 50 55 60 20 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 25 85 90 95 Ala Lys Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val 100 105 110 30 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Ala 115 120 125 35 Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser 130 135 140 40 Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 45 50 55 122 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 145 150 15 5 160 Thr Le u Thr Trp Asn Ser Gl y Ser Leu Ser Ser Asp Val His Thr Phe 165 170 175 Pro Ala Le u Leu Gln Ser Gl y Leu Tyr Thr Leu Ser Ser Ser Va l Thr 180 185 190 Val Thr Thr Trp Pro Ser Gl n Thr Ile Thr Cys As n Val Al a His Pr o 195 200 205 Ala Ser Ser Thr Lys Va l As p Lys Lys I l e Glu Pro Arg Gl y Ser Pro 210 215 220 Thr Hi s Lys Pro Cys Pro Pro Cys Pro Ala Pro Asn Leu Leu Gl y Gl y 225 230 235 240 Pr o Ser Val Ph e Ile Phe Pro Pro Lys I l e Lys Asp Val Leu Met Il e 245 250 255 Ser Le u Ser Pro M et Val Thr Cys Val Va l Val Asp Va l Ser Gl u Asp 260 265 270 Asp Pro As p Val His Val Ser Trp Phe Va l Asn Asn Val Gl u Val His 275 280 285 Thr Al a Gl n Thr Gln Thr His Ar g Glu Asp Tyr Asn Ser Thr Ile Ar g 29 0 295 300 Val Va l Ser Ala Leu Pro I l e Gl n His Gl n Asp Trp Me t Ser Gl y Lys 305 310 315 320 Glu Ph e Lys Cys Lys Va l As n Asn Lys Al a Leu Pro Al a Pro Il e Gl u 325 330 335 Arg Thr Il e Ser Lys Pro Lys Gl y Pro Val Arg Al a Pro Gln Val Tyr 340 345 350 Val Le u Pr o Pro Pro Glu Gl u Gl u Met Thr Lys Lys Gln Va l Thr Le u 355 360 365 Thr Cys Me t I l e Thr Asp Phe Met Pro Glu Asp I le Tyr Val Gl u Tr p 370 375 380 Thr As n As n Gl y Gl n Thr Gl u Leu Asn Tyr Lys Asn Thr Glu Pro Va l 123 EP 2 569 010 81 385 390 395 400 5 Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu 405 41 0 415 Lys Lys Asn Trp Va l Gl u Arg Asn Ser Tyr Ser Cys Ser Val Val Hi s 10 420 425 430 Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pr o 15 Gly Lys 450 20 <210> 131 <211> 11 <212> PRT 435 440 445 <213> Artificial Sequence 25 <220> <223> Ab-10 LCDR1 <400> 131 30 <210> 132 35 <211> 7 <212> PRT Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn l 5 10 <213> Artificial Sequence <220> 40 <223> Ab-10 LCDR2 45 <400> 132 <210> 133 <211> 9 50 <212> PRT <213> Artificial Sequence <220> <223> Ab-10 LCDR3 55 <400> 133 Tyr Thr Ser Arg Leu Leu Ser l 5 124 5 <210> 134 <211> 5 <212> PRT <213> Artificial Sequence 10 <220> <223> Ab-10 HCDR1 <400> 134 15 <210> 135 20 <211 > 17 <212> PRT <213> Artificial Sequence <220> 25 <223> Ab-10 HCDR2 <400> 135 EP 2 569 010 B1 Gl n Gln Gly Asp Thr Leu Pro Tyr Thr l 5 Asp Tyr Asn Met His l 5 30 Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe Lys l 5 10 15 35 40 45 Gly <210> 136 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Ab-10 HCDR3 <400> 136 Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Va l 50 <210> 137 <21 1> 645 <212> DNA l 5 10 <213> Mus musculus 55 <400> 137 125 EP 2 569 010 B1 ". gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 60 atcagttgca gggcaagtca agacattagc aattatttaa actggtatca gcagaaacca 120 5 gatggaactt ttaaactcct tatcttctac acatcaagat tactctcagg agtcccat c a 180 aggt t cagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 240 10 gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 3 0 0 gggaccaaac tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacta 360 15 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540 20 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645 25 <210> 138 <211>214 <212> PRT <213> Mus musculus 30 <400> 138 35 40 45 50 55 126 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly l 5 10 15 Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile 35 40 45 Phe Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr Asn Leu Glu Gln 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Leu Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gl y Val Leu 145 150 155 160 As n Ser Trp Thr Asp Gln Asp Ser Ly s Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Ly s Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 127 EP 2 569 010 B1 <210> 139 <211> 1344 <212> DNA <213> Mus musculus 5 <400> 139 gaggtccaac tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60 10 tcctgcaagg cttctggata tacattcact gactacaaca tgcactgggt gaagcagaac 120 caaggaaaga ccctagaatg gataggagaa attaatccta acagtggtgg tgctggctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccac cacagcctac 240 15 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300 tacgatgata tctacgacga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360 20 gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420 caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480 25 acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540 cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600 gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660 30 gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720 ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780 35 tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840 gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900 cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960 40 tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020 ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080 45 gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140 tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200 50 gatggctctt act tea teta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260 aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320 ctctcccact ctcctggtaa at ga 1344 55 <21 0> 140 <211> 447 <212> PRT 128 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 <213> Mus musculus <400> 140 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala l 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Thr Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val 100 105 110 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro 115 120 125 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 130 135 140 Met Va l Thr Leu Gly Cys Leu Val Lys Gl y Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 129 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 180 185 190 Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Va l Ala 195 200 205 His Pro Ala Ser Ser Thr Lys Va l Asp Lys Lys Ile Val Pro Arg Asp 210 215 220 Cys Gly Cys Lys Pro Cys Ile Cys Thr Va l Pro Glu Val Ser Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Pro Lys Asp Va l Leu Thr Ile Thr Leu Thr 245 250 255 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 260 265 270 Val Gln Phe Ser Trp Phe Val Asp Asp Va l Glu Val His Thr Ala Gln 275 280 285 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 290 295 300 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 305 310 315 320 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 340 345 350 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 355 360 365 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp As n 370 375 380 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 385 390 395 400 Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 405 410 415 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 130 EP 2 569 010 B1 42 0 425 430 5 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 44 5 <210> 141 <211>10 10 <212> PRT <213> Artificial Sequence <220> <223> Ab-11 and Ab-16 LCDR1 15 20 <400> 141 <210> 142 <211> 7 <212> PRT 25 <213> Artificial Sequence <220> Arg Ala Ser Ser Ser I le Ser Tyr Ile His l 5 10 <223> Ab-11 and Ab-16 LCDR2 30 <400> 142 35 40 <210> 143 <211> g <212> PRT <213> Artificial Sequence <220> Al a Thr Ser Asn Leu Al a Ser l 5 <223> Ab-11 and Ab-16 LCDR3 <400> 143 45 50 <210> 144 <211> 5 <212> PRT <213> Artificial Sequence 55 <220> Gl n Gln Trp Ser Ser Asp Pro Leu Thr l 5 <223> Ab-11 and Ab-16 HCDR1 <400> 144 131 5 <210> 145 <211>17 <212> PRT 10 <213> Artificial Sequence <220> <223> Ab-11 and Ab-16 HCDR2 15 <400> 145 EP 2 569 010 81 Asp Tyr Tyr Ile Hi s l 5 Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala Pro Lys Phe Pro l 5 10 15 20 Gly <210> 146 25 <211> 12 <212> PRT <213> Artificial Sequence <220> 30 <223> Ab-11 and Ab-16 HCDR3 <400> 146 35 Glu Asp Tyr Asp Gly Thr Tyr Thr Tr p Phe Pro Tyr <210> 147 <211> 642 40 <212> DNA <213> Mus musculus <400> 147 45 50 55 l 5 10 132 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 caaattgttc tctcccagtc tccagcattc ctgtctgtat ctccagggga atgacttgca gggccagctc aagtataagt tacatacact ggtttcagca tcctccccca gatcctggat ttatgccaca tccaacctgg ctt ctggagt ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagagt gatgctgcca cttattactg ccagcagtgg agtagtgacc cactcacgtt accaagctgg agctgaaacg ggctgatgct gcaccaactg tatccatctt agtgagcagt taacatctgg aggtgcctca gtcgtgtgct tcttgaacaa aaagacatca atgtcaagtg gaagattgat ggcagtgaac gacaaaatgg agttggactg atcaggacag caaagacagc acctacagca tgagcagcac accaaggacg agtatgaacg acataacagc tatacctgtg aggccactca acttcaccca ttgtcaagag cttcaacagg aatgagtgtt ag <210> 148 <211>213 <212> PRT <213> Mus musculus <400> 148 133 taaggtcaca 60 gaagccagga 120 ccctggtcgc 180 ggaggctgag 240 cggtgctggg 300 cccaccat cc 360 cttctacccc 420 cgtcctgaac 480 cctcacgttg 540 caagacatca 600 642 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 Gln Ile Val Leu Ser Gln Ser Pro Ala Phe Leu Ser Val Ser Pro Gly l 5 10 15 Asp Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Ile Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Arg Ser Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asp Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro 100 105 110 Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly 115 120 125 Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn 130 135 140 Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn 145 150 155 160 Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 165 170 175 Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr 180 185 190 Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe 195 Asn Arg Asn Glu Cys 210 134 200 205 EP 2 569 010 81 <210> 149 <211 > 1338 <21 2> DNA <213> Mus musculus 5 <400> 149 gaagttcagc tgcaacagtc tggggcagac cttgtgcagc caggggcctc agtcaaggtg 60 10 tcctgcacag cttctggctt cgacattaag gactactata tacactggat gaaacagagg 120 cctgaccagg gcctggagtg gattggaagg gttgatcctg acaatggtga gactgaattt 180 gccccgaagt tcccgggcaa ggccactttt acaacagaca cat cctccaa cacagcctac 240 15 ctacaactca gaggcctgac atctgaggac actgccatct attactgtgg gagagaagac 300 tacgatggta cctacacctg gttt ccttat tggggccaag ggactctggt cactgtctct 360 20 gcagccaaaa cgacaccccc atct gtctat ccactggccc c t ggatctgc tgcccaaact 420 aactccatgg tgaccctggg atgcctggtc aagggctatt tccctgagcc agt gacagtg 480 25 acctggaact ctggatccct g t ccagcggt gtgcacacct tcccagctgt cctgcagtct 540 gacctctaca ctctgagcag c t cagtgact gtcccctcca gcacctggcc cagcgagacc 600 gtcacct gca acgttgccca cccggccagc agcaccaagg tggacaagaa aattgtgccc 660 30 agggattgtg gttgtaagcc ttgcatatgt acagt cccag aagt atcatc tgtcttcatc 720 ttccccccaa agcccaagga tgtgctcacc attactctga ctcctaaggt cacgtgtgtt 780 35 gtggtagaca tcagcaagga t gatcccgag g t ccagttca gct ggtttgt agatgatgtg 840 gaggtgcaca cagctcagac gcaaccccgg gaggagcagt tcaacagcac t t tccgctca 90 0 gtcagtgaac ttcccatcat gcaccaggac tggctcaatg gcaaggagtt caaatgcagg 960 40 gtcaacagtg cagctttccc tgcccccatc gagaaaacca tctccaaaac caaaggcaga 1020 ccgaaggctc cacaggtgta caccattcca cctcccaagg agcagatggc caaggataaa 1080 45 gtcagtctga cctgca t gat aacagacttc ttccctgaag acattactgt ggagtggcag 1140 tggaatgggc agccagcgga gaactacaag aacactcagc ccatcatgga cacagatggc 1200 tcttacttca tctacagcaa gctcaatgtg cagaagagca actgggaggc aggaaatact 1260 50 ttcacctgct ctgtgt t aca tgagggcctg cacaaccacc atactgagaa gagcctctcc 1320 cact ctcctg gtaaatga 1338 55 <210> 150 <211> 445 <212> PRT <213> Mus musculus 135 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 <400> 150 Glu Val Gln Leu Gln Gln Ser Gly Ala Asp Leu Val Gln Pro Gly Ala l 5 10 15 Ser Val Lys Val Ser Cys Thr Al a Ser Gly Phe Asp Ile Lys Asp Tyr 20 25 30 Tyr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala Pro Lys Phe 50 55 60 Pro Gly Lys Ala Thr Phe Thr Thr Asp Thr Ser Ser Asn Thr Ala Tyr 65 70 75 80 Leu Gln Leu Arg Gly Leu Thr Ser Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Gly Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser 115 120 125 Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gl y Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro 180 185 190 Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Va l Ala His Pro 195 200 205 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly 210 215 220 136 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Val Leu Thr I l e Thr Leu Thr Pro Lys 245 250 255 Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln 260 265 270 Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu 290 295 300 Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg 305 310 315 320 Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro 340 345 350 Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr 355 360 365 Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln 370 375 380 Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly 385 390 395 400 Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu 405 410 415 Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn 420 425 430 His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys <210> 151 <211 > 318 435 440 445 137 EP 2 569 010 8 1 <212> DNA <213> Mus musculus <400> 151 5 gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc atcacttgca gggccagctc aagtataagt tacatacact ggtatcagca aaaaccaggg 10 aaagccccta agctcctgat ctatgccaca tccaacctgg cttctggggt cccatcaagg ttcagcggca gtggatctgg gacagaattc actctcacaa tcagcagcct gcagcctgaa 15 gattttgcaa cttattactg tcagcagtgg agtagtgacc cactcacgtt cggcggaggg accaaggtgg agatcaaa <210> 152 20 <211> 106 <212> PRT <213> Mus muscu lus <400> 152 25 Asp Ile Gln Le u Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly l 5 10 15 30 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Ile Ser Tyr Ile 20 25 30 35 His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu · Leu Ile Tyr 35 40 45 Al a Thr Ser Asn Leu Ala Ser Gl y Va l Pro Ser Arg Phe Ser Gly Ser 40 50 55 60 Gly Ser Gly Thr Glu Phe Thr Leu Tbr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 45 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asp Pr o Leu Thr 85 90 95 50 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 153 55 <211> 363 <212> DNA <213> Mus musculus 138 60 120 180 240 300 318 EP 2 569 010 81 <400> 153 gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 5 tcctgcaagg cttctggatt cgacattaag gactactata tacactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatcggaagg gttgatcctg acaatggtga gactgaattt 180 10 gccccgaagt tcccgggcaa ggtcaccatg accacagaca cgtccatcag cacagcctac 240 atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagaagac 300 15 tacgatggta cctacacctg gtttccttat tggggccaag ggactctggt caccgtctct 360 ag t 363 <210> 154 20 <211 > 121 <212> PRT <213> Mus musculus <400> 154 25 Glu Val Gl n Leu Val Gln Ser Gl y Ala Glu Va l Lys Lys Pro Gly Al a l 5 10 15 30 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Lys Asp Tyr 20 25 30 35 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala Pro Lys Phe 40 so 55 60 Pro Gly Lys Val Thr Met Thr Thr Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 45 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 50 Ala Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro Tyr Trp Gly 100 105 110 55 Gln Gly Thr Leu Va l Thr Val Ser Ser 115 120 <210> 155 139 EP 2 569 010 81 <211 > 639 <212> DNA <21 3> Artificial Sequence 5 <220> <223> Humanized antibody sequence <400> 155 10 gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgca gggccagctc aagt ataagt tacatacact ggtatcagca aaaaccaggg 120 15 aaagccccta agctcctgat ctatgccaca tccaacctgg cttctggggt cccatcaagg 180 ttcagcggca gtggatctgg gacagaattc actctcacaa tcagcagcct gcagcctgaa 240 gattttgcaa cttattactg tcagcagtgg agtagtgacc cactcacgtt cggcggaggg 300 20 accaaggtgg agatcaaacg tacggtggct gcaccatctg tcttcatctt cccgccatct 360 gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420 25 agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480 agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540 agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600 30 agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639 <210> 156 <211 > 213 35 <212> PRT <213> Artificial Sequence <220> <223> Humanized antibody sequence 40 <400> 156 45 50 55 140 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly l 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Ile Ser Tyr I l e 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 BO Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asp Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 141 EP 2 569 010 81 <210> 157 <211> 1341 <2 12> DNA <213> Artificial Sequence 5 <220> <223> Humanized antibody sequence <400> 157 10 gaggtgcagc tggt gcagtc t ggggctgag gtgaagaagc c t ggggcctc agt gaaggtc 60 tcctgcaagg cttctggatt cgacattaag gactactata tacactgggt gcgacaggcc 120 15 cctggacaag ggcttgagtg gatcggaagg gtt gatcctg acaatggtga gactgaattt 180 gccccgaagt tcc cgggcaa ggt caccatg accacagaca cgtccatcag cacagcctac 240 20 atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagaagac 300 tacgat ggta cctacacctg gtttccttat tggggccaag ggactctggt caccgtctct 360 agtgcctcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 420 25 gagagcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggt gacggtg 480 tcgtggaact caggcgctct gaccagcggc gtgcacacct tcccagctgt cctacagtcc 540 30 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcaactt cggcacccag 600 acctacacct gcaacgt aga tcacaagccc agcaacacca aggtggacaa gacagttgag 660 cgcaaatgtt gtgtcgagtg cccaccgtgc ccagcaccac ctgtggcagg accgtcagtc 720 35 ttcctcttcc ccccaaaacc caaggacacc ct catgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccacgaagac cccgaggtcc agttcaactg gtacgtggac 840 40 ggcgtggagg tgcataatgc caagacaaag ccacgggagg agcagttcaa cagcacgttc 900 cgtgtggtca gcgt cctcac cgttgtgcac caggactggc tgaacggcaa ggagtacaag 960 45 tgcaaggtct ccaacaaagg cctcccagcc cccatcgaga aaaccatctc caaaaccaaa 1020 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 50 tgggagagca atgggcagcc ggagaacaac tacaagacca cacctcccat gctggactcc 1200 gacggctcct tct tcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 55 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa a 1341 142 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 <210> 158 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Humanized antibody sequence <400> 158 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala l 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp I le Lys Asp Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Al a Pro Gl y Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala Pro Lys Phe 50 55 60 Pro Gly Lys Val Thr Met Thr Thr Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Va l Thr Val Ser Ser Ala Ser Thr Ly s Gly Pro Ser 143 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys 210 215 220 Val Gl u Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gl y Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 144 5 10 15 20 EP 2 569 010 B1 355 360 365 Va l Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gl y Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 159 25 <211 > 11 <212> PRT <213> Artificial Sequence <220> 30 <223> Ab-12 LCDR1 <400> 159 35 Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn l 5 10 <21 0> 160 <211> 7 40 <212> PRT 45 50 <213> Artificial Sequence <220> <223> Ab-12 LCDR2 <400> 160 <210> 161 <211> 9 <212> PRT 55 <213> Artificial Sequence <220> <223> Ab-12 LCDR3 Tyr Thr Ser Thr Leu Gln Ser l 5 145 5 <400> 161 <210> 162 <211> 5 <212> PRT 10 <213> Artificial Sequence <220> <223> Ab-12 HCDR1 15 <400> 162 20 25 30 <210> 163 <211>17 <212> PRT <213> Artificial Sequence <220> <223> Ab-12 HCDR2 <400> 163 EP 2 569 010 B1 Gln Gln Gly Asp Thr Leu Pro Tyr Thr l 5 Asp Tyr Asn Met His l 5 Glu Ile Asn Pro Asn Ser Gly Gly Ser Gly Tyr Asn Gln Lys Phe Lys 35 l 5 10 15 Gly <210> 164 <211>14 40 <212> PRT 45 50 <213> Artificial Sequence <220> <223> Ab-12 HCDR3 <400> 164 <210> 165 <211> 645 <212> DNA Leu Gly Tyr Tyr Gly Asn Tyr Glu Asp Trp Tyr Phe Asp Val l 5 10 55 <213> Mus musculus <400> 165 146 EP 2 569 010 81 gatctccaga tgacacagac tacttcctcc ctgtctgcct ctctgggaga cagagtcacc 60 atcagttgca gggcaagtca ggacattagc aattatttaa actggtatca gcagaaacca 120 5 gatggaactg ttaagctcct gatcttctac acatcaacat tacagtcagg agtcccatcg 180 aggttcagtg gcagtgggtc tggaacaaat tattctctca ccattaccaa cctggagcaa 240 10 gatgatgctg ccacttactt t t gccaacag ggtgatacgc ttccgtacac gttcggaggg 300 gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360 15 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540 20 ttgaccaagg acgagt atga acgacataac agctatacct gtgaggccac tcacaagaca 600 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645 25 <210> 166 <2 11 > 214 <212> PRT <213> Mus musculus 30 <400> 166 35 40 45 50 55 147 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Asp Leu Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly l 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Phe Tyr Thr Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asn Tyr Ser Leu Thr Ile Thr Asn Leu Glu Gln 65 70 75 80 Asp Asp Ala Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 148 EP 2 569 010 81 <21 0> 167 <211 > 1344 <212> DNA <213> Mus musculus 5 <400> 167 gaggtccagt tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60 10 tcctgcaagg cttctggata cacattcact gactacaaca tgcactggat 120 gaagcagaac caaggaaaga gcctagagtg gataggagag attaatccta acagtggtgg ttctggttac 180 aaccagaagt tcaaaggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240 15 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300 tactatggta actacgagga ctggtatttc gatgtctggg gcgcagggac cacggtcacc 360 20 gtctcctctg ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 42 0 caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480 25 acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540 cagtctgacc tctacactct gagcagctca gtgactgtcc cct ccagcac ctggcccagc 600 gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660 30 gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720 ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780 35 tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840 gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900 cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960 40 tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 10 2 0 ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080 45 gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140 tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200 50 gatggctctt act tea teta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260 aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 13 2 0 ctctcccact ctcctggtaa at ga 1344 55 <210> 168 <211>447 <2 12> PRT 149 EP 2 569 010 81 <213> Mus musculus <400> 168 5 Glu Val Gln Leu Gln Gln Ser Gl y Pro Glu Leu Met Lys Pro Gly Ala l 5 10 15 10 Ser Val Lys Met Ser Cys Ly s Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met His Trp Met Lys Gln Asn Gln Gly Lys Ser Leu Glu Trp Ile 15 35 40 45 Gly Glu Ile Asn Pro Asn Ser Gly Gly Ser Gly Tyr Asn Gln Lys Phe 50 55 60 20 Lys Gly Lys Ala Thr Leu Thr Val Asp Ly s Ser Ser Ser Thr Ala Tyr 65 70 75 80 25 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 30 Ala Arg Leu Gl y Tyr Tyr Gly Asn Tyr Glu Asp Trp Tyr Phe Asp Val 100 105 110 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro 35 115 120 125 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 130 135 140 40 Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 45 50 55 150 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 145 150 155 160 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 180 185 190 Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Va l Thr Cys Asn Val Ala 195 200 205 His Pro Al a Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 210 215 220 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 245 250 255 Pro Lys Va l Thr Cys Val Val Val Asp I l e Ser Lys Asp Asp Pro Glu 260 265 270 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 290 295 300 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 305 310 315 320 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 340 345 350 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 355 360 365 Ile Thr Asp Phe Phe Pro Gl u Asp Ile Thr Val Glu Trp Gln Trp Asn 370 375 380 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 151 EP 2 569 010 B1 385 390 395 400 5 Asp Gly Ser Tyr Phe Il e Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 10 15 20 25 405 41 0 415 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 420 425 430 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys <210> 169 <211>12 <212> PRT 435 440 445 <213> Artificial Sequence <220> <223> Ab-13 and Ab-14 LCDR1 <400> 169 Arg Ala Ser Ser Ser Val Thr Ser Ser Tyr Leu Asn l 5 10 30 <210> 170 <211> 7 <212> PRT <213> Artificial Sequence 35 <220> <223> Ab-13 and Ab-14 LCDR2 <400> 170 40 <210> 171 45 <211> 9 <212> PRT <213> Artificial Sequence <220> Ser Thr Ser Asn Leu Ala Ser l 5 50 <223> Ab-13 and Ab-14 LCDR3 <400> 171 55 Gln Gln Tyr Asp Phe Phe Pro Ser Thr l 5 <210> 172 152 <211> 5 <212> PRT <213> Artificial Sequence 5 <220> 10 <223> Ab-13 and Ab-14 HCDR1 <400> 172 <210> 173 <211> 17 15 <212> PRT <213> Artificial Sequence <220> <223> Ab-13 and Ab-14 HCDR2 20 <400> 173 EP 2 569 010 81 Asp Tyr Tyr Met Asn l 5 Asp I l e As n Pro Tyr Asn Asp Asp Thr Thr Tyr Asn His Lys Phe Lys 25 l 5 10 15 Gly 30 <210> 174 <211> 11 <212> PRT <213> Artificial Sequence 35 <220> <223> Ab-13 and Ab-14 HCDR3 <400> 174 40 <210> 175 45 <211> 645 <212> DNA <213> Mus musculus <400> 175 50 55 Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp l 5 10 153 EP 2 569 010 B1 cagattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60 atgacctgca gggccagctc aagtgtaact tccagttact tgaactggta ccagcagaag 120 5 ccaggatctt cccccaaact ctggatttat agcacatcca acctggcttc aggagtccca 180 gctcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagtgtggag 240 10 gctgaggatg ctgccactta ttactgccag cagtatgatt ttttcccatc gacgttcggt 300 ggaggcacca agctggaaat caagcgggct gatgctgcac caactgtatc catcttccca 360 15 ccatccagtg agcagttaac atctggaggt gcctcagtcg tgtgcttctt gaacaacttc 420 taccccaaag acatcaatgt caagtggaag attgatggca gtgaacgaca aaatggcgtc 480 ctgaacagtt ggactgatca ggacagcaaa gacagcacct acagcatgag cagcaccctc 540 20 acgttgacca aggacgagta tgaacgacat aacagctata cctgtgaggc cactcacaag 600 acatcaactt cacccatcgt caagagcttc aacaggaatg agtgt 645 25 <210> 176 <211>215 <212> PRT <2 13> Mus musculus 30 <400> 176 35 40 45 50 55 154 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly l 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Thr Ser Ser 20 25 30 Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp 35 40 45 I l e Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu 65 70 75 80 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Phe Phe Pro 85 90 95 Ser Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala 100 105 110 Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser 115 120 125 Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp 130 135 140 Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val 145 150 155 160 Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met 165 170 175 Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser 180 185 190 Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys 195 200 205 Ser Phe Asn Arg Asn Glu Cys 210 215 155 EP 2 569 010 81 <210> 177 <211> 1335 <212> DNA <213> Mus musculus 5 <400> 177 gaggtccagc tgcaacaatc tggacctgag ctggtgaagc ctggggcttc agtgaagatg 60 10 tcctgtaagg cttctggata cacattcact gactactaca tgaactgggt gaagcagagc 120 catggagaga gccttgagtg gattggagat attaatcctt acaacgatga tactacctac 180 aaccacaagt tcaagggcaa ggccacattg actgtagaca aatcctccaa cacagcctac 240 15 atgcagctca acagcctgac atctgaggac tctgcagtct attactgtgc aagagagacg 300 gccgttatta ctacgaatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360 20 tcagccaaaa cgacaccccc atctgtctat ccactggccc ctggatctgc tgcccaaact 420 aactccatgg tgaccctggg atgcctggtc aagggctatt tccctgagcc agtgacagtg 480 25 acctggaact ctggatccct gtccagcggt gtgcacacct tcccagctgt cctgcagtct 540 gacctctaca ctctgagcag ctcagtgact gtcccctcca gcacctggcc cagcgagacc 600 gtcacctgca acgttgccca cccggccagc agcaccaagg tggacaagaa aattgtgccc 660 30 agggattgtg gttgtaagcc ttgcatatgt acagtcccag aagtatcatc tgtcttcatc 720 ttccccccaa agcccaagga tgtgctcacc attactctga ctcctaaggt cacgtgtgtt 780 35 gtggtagaca tcagcaagga tgatcccgag gtccagttca gctggtttgt agatgatgtg 840 gaggtgcaca cagctcagac gcaaccccgg gaggagcagt tcaacagcac tttccgctca 900 gtcagtgaac ttcccatcat gcaccaggac tggctcaatg gcaaggagtt caaatgcagg 960 40 gtcaacagtg cagctttccc tgcccccatc gagaaaacca tctccaaaac caaaggcaga 1020 ccgaaggctc cacaggtgta caccattcca cctcccaagg agcagatggc caaggataaa 1080 45 gtcagtctga cctgcatgat aacagacttc ttccctgaag acattactgt ggagtggcag 1140 tggaatgggc agccagcgga gaactacaag aacactcagc ccatcatgga cacagatggc 1200 50 tcttacttca tctacagcaa gctcaatgtg cagaagagca actgggaggc aggaaatact 1260 ttcacctgct ctgtgttaca tgagggcctg cacaaccacc atactgagaa gagcctctcc 1320 cactctcctg gtaaa 1335 55 <210> 178 <211> 445 <212> PRT 156 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 <213> Mus musculus <400> 178 Glu Val Gln Leu Gln Gl n Ser Gly Pro Glu Leu Va l Lys Pro Gl y Al a l 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met As n Trp Va l Lys Gl n Ser His Gly Glu Ser Le u Glu Trp Ile 35 40 45 Gl y Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn His Lys Ph e 50 55 60 Lys Gly Lys Ala Thr Leu Thr Va l Asp Lys Ser Ser Asn Thr Al a Tyr 65 70 75 80 Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Va l Tyr Tyr Cys 85 90 95 Ala Arg Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp Tyr Trp Gl y 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser 115 120 125 Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gl n Thr Asn Ser Met Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pr o Glu Pro Val Thr Val 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gl n Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro 157 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 180 185 190 Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro 195 200 205 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly 210 215 220 Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys 245 250 255 Val Thr Cys Val Val Val Asp I l e Ser Lys Asp Asp Pro Glu Val Gln 260 265 270 Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu 290 295 300 Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg 305 310 315 320 Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro 340 345 350 Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr 355 360 365 Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln 370 375 380 Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly 385 390 395 400 Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu 405 410 415 Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn 158 .. EP 2 569 010 81 420 425 430 5 His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 445 <210> 179 <211>324 10 <212> DNA <213> Mus musculus 15 20 25 <400> 179 gacatccagc atcacatgcc ccaggaaaag tctcgatttt ccagaagact ggaggtacaa <210> 180 <211> 108 30 <212> PRT tgacccagag gcgcctcatc cacctaaact caggatctgg tcgccactta aagtagaaat <213> Mus musculus <400> 180 35 40 45 50 55 ccccagcttc ctttccgcat ccgt tggtga ccgagtaaca ttcagttaca tet tet tate ttaattggta tcaacaaaaa tcttatatac tctacatcta atct cgcatc aggagttccc atcaggcaca gaatttacac ttactatatc atcactccaa ttactgccaa caatacgatt tttttccaag cacattcgga ea ag 159 60 120 180 240 300 324 EP 2 569 010 B1 Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly l 5 10 15 5 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Thr Ser Ser 20 25 30 10 Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Va l Pro Ser Arg Phe Ser 15 50 55 60 Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 20 Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Phe Phe Pro 85 90 95 25 Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 181 30 <211> 363 <212> DNA 35 40 45 50 55 <213> Mus musculus <400> 181 gaggtgcagc agttgcaaag cctggacaaa aatcataaat atggaacttt gccgttatta ag t <210> 182 <211 > 121 <212> PRT tggtgcagag catctggata gacttgaatg ttaaaggaag cctcattgag ctactaacgc <213> Mus musculus <400> 182 cggcgccgag gtcaagaaac ctggagcaag cgtaaaggtt cacatttacc gactactaca tgaattgggt acgacaagcc gatgggagac attaaccctt ataacgacga cactacatac agttacaatt acaagagata catccgcatc aaccgcctat atct gaagac act gctgttt attactgtgc aagagaaact tatggattac tggggtcaag gaaccactgt taccgtctct 160 60 120 180 240 300 360 363 5 10 15 20 25 30 EP 2 569 010 B1 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala l 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn His Lys Phe 50 55 60 Lys Gly Arg Val Thr Il e Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Al a Arg Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser <21 0> 183 <211> 363 115 120 35 <212> DNA <2 13> Artificial Sequence <220> <223> Humanized antibody sequence 40 <400> 183 gaggtgcagc tggtgcagag cggcgccgag gtcaagaaac ctggagcaag cgtaaaggtt 45 agttgcaaag catctggata cacatttacc gactactaca tgaattgggt acgacaagcc cctggacaaa gacttgaatg gat gggagac attaaccctt ataacgacga cactacatac 50 aatcataaat ttaaaggaag agttacaatt acaagagata catccgcatc aaccgcctat atggaacttt cctcattgag atctgaagac actgctgttt attactgtgc aagagaaact gccgttatta ctactaacgc tatggattac tggggtcaag gaaccactgt taccgtctct 55 ag t <2 10> 184 161 60 120 180 240 300 360 363 <211>215 <212> PRT <213> Artificial Sequence EP 2 569 010 B1 5 <220> <223> Humanized antibody sequence <400> 184 10 Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly l 5 10 15 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Thr Ser Ser 20 25 30 Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 20 35 40 45 Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60 25 Gly Ser Gly Ser Gly Thr Glu Ph e Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 30 Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Phe Phe Pro 85 90 95 35 Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 40 45 50 55 162 5 10 15 20 25 EP 2 569 010 81 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Va l Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Va l Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys <210> 185 <211> 1341 210 215 30 <212> DNA <213> Artificial Sequence <220> <223> Humanized antibody sequence 35 <400> 185 40 45 50 55 163 EP 2 569 010 81 gaggtgcagc tggtgcagag cggcgccgag gtcaagaaac ctggagcaag cgtaaaggtt 60 agttgcaaag catctggata cacatttacc gactactaca tgaattgggt acgacaagcc 120 5 cctggacaaa gacttgaatg gatgggagac attaaccctt ataacgacga cactacatac 180 aatcataaat ttaaaggaag agttacaatt acaagagata catccgcatc aaccgcctat 240 10 atggaacttt cctcattgag atctgaagac actgctgttt attactgtgc aagagaaact 300 gccgttatta ctactaacgc tatggattac tggggtcaag gaaccactgt taccgtctct 360 agtgcctcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 420 15 gagagcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgctct gaccagcggc gtgcacacct tcccagctgt cctacagtcc 540 20 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcaactt cggcacccag 600 acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gacagttgag 660 cgcaaatgtt gtgtcgagtg cccaccgtgc ccagcaccac ctgtggcagg accgtcagtc 720 25 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccacgaagac cccgaggtcc agttcaactg gtacgtggac 840 30 ggcgtggagg tgcataatgc caagacaaag ccacgggagg agcagttcaa cagcacgttc 900 cgtgtggtca gcgtcctcac cgttgtgcac caggactggc tgaacggcaa ggagtacaag 960 35 tgcaaggtct ccaacaaagg cctcccagcc cccatcgaga aaaccatctc caaaaccaaa 1020 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 40 tgggagagca atgggcagcc ggagaacaac tacaagacca cacctcccat gctggactcc 1200 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 45 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa a 1341 <210> 186 50 <211> 447 <212> PRT <213> Artificial Sequence <220> 55 <223> Humanized antibody sequence <400> 186 164 EP 2 569 010 81 Glu Val Gl n Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala l 5 10 15 5 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 10 Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn His Lys Phe 15 50 55 60 Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 20 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Va l Tyr Tyr Cys 85 90 95 25 Ala Arg Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp Tyr Trp Gly 100 10 5 110 30 Gln Gly Thr Tbr Val Tbr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 35 40 45 50 55 165 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Va l 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Al a Pro Pro Val Ala Gly Pro Ser Va l 225 230 235 24 0 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu G1u Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 166 r 5 10 15 20 EP 2 569 010 81 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gl n Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 187 25 <211> 12 <212> PRT <213> Artificial Sequence <220> 30 <223> Ab-17 and Ab-18 LCDR1 <400> 187 35 Ser Val Ser Ser Ser I l e Ser Ser Ser Asn Leu His l 5 10 <210> 188 <211 > 7 40 <212> PRT 45 50 <213> Artificial Sequence <220> <223> Ab-17 and Ab-18 LCDR2 <400> 188 <210> 189 <211 > 8 <212> PRT 55 <213> Artificial Sequence <220> <223> LCDR3 Gl y Thr Ser Asn Leu Al a Ser l 5 167 5 <400> 189 <210> 190 <211> 5 <212> PRT 10 <213> Artificial Sequence <220> <223> Ab-17 and Ab-18 HCDR1 15 <400> 190 20 25 30 <210> 191 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Ab-17 and Ab-18 HCDR2 <400> 191 EP 2 569 010 81 Gln Gln Trp Thr Thr Thr Tyr Thr l 5 Asp Tyr Tyr Ile Hi s l 5 Arg Ile Asp Pro Asp Asn Gly Glu Ser Thr Tyr Val Pro Lys Phe Gln 35 l 5 10 15 Gly <210> 192 <211> 13 40 <212> PRT 45 50 <213> Artificial Sequence <220> <223> Synthetic peptide <400> 192 <210> 193 <211> 390 <212> DNA Gl u Gly Le u Asp Tyr Gly Asp Tyr Tyr Ala Val Asp Tyr l 5 10 55 <213> Mus musculus <400> 193 168 5 10 15 EP 2 569 010 81 atggattttc aggtgcagat tttcagcttc atgctaatca gtgtcacagt catattgtcc 60 agtggagaaa ttgtgctcac ccagtctcca gcactcatgg ctgcatctcc aggggagaag 120 gtcaccatca cctgcagtgt cagc t cgagt ataagttcca gcaacttaca ctggtcccag 180 cagaagtcag gaacctcccc caaactctgg atttatggca catccaacct tgcttctgga 240 gtccc t gttc gcttcagtgg cagtggatct gggacctctt attctctcac aatcagcagc 300 atggaggctg aagatgctgc cacttattac tgtcaacagt ggactactac g t atacgt t c 36 0 ggatcgggga ccaagctgga gctgaaacgt <210> 194 <21 1> 130 <212> PRT 390 20 <2 13> Mus muscu lus 25 30 35 40 45 50 55 <400> 194 Met Asp Phe Gln Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr l 5 10 15 Val Ile Leu Ser Ser Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Leu 20 25 30 Met Ala Ala Ser Pro Gl y Glu Lys Val Thr Ile Thr Cys Ser Val Ser 35 40 45 Ser Ser Ile Ser Ser Ser Asn Leu His Trp Ser Gln Gl n Lys Ser Gly 50 55 60 Thr Ser Pro Lys Leu Trp Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly 65 70 75 80 Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu 85 90 95 Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln 100 105 110 Gl n Trp Thr Thr Thr Tyr Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys Arg 130 115 120 125 169 EP 2 569 010 81 <210> 195 <211 > 423 <21 2> DNA <21 3> Mus musculus 5 <400> 195 atgggatgga actggatcat cttcttcctg atggcagtgg ttacaggggt caattcagag 60 10 gtgcagttgc ggcagtctgg ggcagacctt gtgaagccag gggcctcagt caagttgtcc 120 tgcacagctt ctggcttcaa cattaaagac tactatatac actgggtgaa gcagaggcct 180 15 gaacagggcc tggagtggat tggaaggatt gatcctgata atggtgaaag tacatatgtc 240 ccgaagttcc agggcaaggc cactataaca gcagacacat catccaacac agcctaccta 300 caactcagaa gcctgacatc tgaggacact gccatctatt attgtgggag agaggggctc 360 20 gactatggtg actactatgc tgtggactac tggggtcaag gaacctcggt cacagtctcg 420 age 423 25 <210> 196 <211 > 141 <212> PRT <213> Mus musculus 30 <400> 196 35 40 45 50 55 170 5 10 15 20 25 30 35 EP 2 569 010 81 Met Gly Trp Asn Trp Ile Ile Phe Phe Leu Met Ala Val Val Thr Gly l 5 10 15 Val Asn Ser Glu Val Gln Leu Arg Gln Ser Gl y Ala Asp Leu Val Lys 20 25 30 Pro Gly Ala Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile 35 40 45 Lys Asp Tyr Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gl y Leu 50 55 60 Glu Trp Ile Gly Arg Ile Asp Pro Asp Asn Gly Glu Ser Thr Tyr Val 65 70 75 80 Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn 85 90 95 Thr Ala Tyr Leu Gln Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Gly Arg Glu Gly Leu Asp Tyr Gly Asp Tyr Tyr Ala Val 115 120 125 Asp Tyr Trp Gly Gln Gl y Thr Ser Val Thr Val Ser Ser <210> 197 <2 11 > 390 <212> DNA 130 135 140 40 <213> Artificial Sequence <220> <223> Humanized antibody sequence 45 <400> 197 50 55 171 5 10 15 20 25 30 35 40 45 50 55 atggatatgc cgctgcgata gtgaccatta cagaaaccgg gtgccgagcc ctgcagccgg ggccagggca <210> 198 <211> 130 <212> PRT gcgtgccggc ttcagctgac cctgcagcgt gcaaagcgcc gctttagcgg aagattttgc ccaaactgga EP 2 569 010 81 gcagctgctg ggcctgctgc tgctgtggct gccgggcgcg ccagagcccg agctttctga gcgcgagcgt gggcgatcgc gagcagcagc attagcagca gcaacctgca ttggtatcag gaaactgctg atttatggca ccagcaacct ggcgagcggc cagcggcagc ggcaccgaat ttaccctgac cattagcagc gacctattat tgccagcagt ggaccaccac eta tacet tt aattaaacgt <213> Artificial Sequence <220> <223> Humanized antibody sequence <400> 198 Met Asp Met Arg Val Pro Ala Gl n Leu Leu Gly Leu Leu Leu Leu Trp l 5 10 15 Leu Pro Gly Ala Arg Cys Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Val Ser 35 40 45 Ser Ser Ile Ser Ser Ser Asn Leu His Trp Tyr Gln Gln Lys Pro Gly 50 55 60 Lys Ala Pro Lys Leu Leu Ile Tyr , Gly Thr Ser Asn Leu Ala Ser Gly 65 70 75 80 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu 85 90 95 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 100 105 110 Gln Trp Thr Thr Thr Tyr Thr Ph e Gly Gln Gly Thr Lys Leu Glu Ile 172 ( 60 120 180 240 300 360 390 EP 2 569 010 B1 115 120 125 5 Lys Arg 13 0 <210> 199 <211> 423 10 <212> DNA <213> Artificial Sequence <220> <223> Humanized antibody sequence 15 <400> 199 atggattgga cctggagcat tctgtttctg gtggcggcgc cgac cggcgc gcatagcgaa 60 20 gtgcagctgg tgcagagcgg cgcggaagtg aaaaaaccgg gcgcgagcgt gaaagtgagc 120 tgcaaagcga gcggctttaa cattaaagat tattatattc attgggtgcg ccaggcgccg 180 25 ggccagggcc tggaatggat gggccgcatt gatccggata a cggcgaaag cacctatgtg 240 ccgaaatttc agggc cgcgt gaccatgacc accgatacca gcaccagcac cgcgtat atg 3 00 gaactgcgca gcctgcgcag cgat gatacc gcggtgtatt attgcgcgcg cgaaggcctg 360 30 gattatggcg attattatgc ggtggattat tggggccagg gcaccctggt gaccgtctcg 420 age 423 35 <210> 200 <211> 141 <212> PRT <213> Artificial Sequence 40 <220> <223> Humanized antibody sequence <400> 200 45 50 55 173 EP 2 569 010 81 Met Asp Trp Thr Trp Ser Ile Leu Phe Leu Val Ala Ala Pro Thr Gly l 5 10 15 5 Al a His Ser Glu Val Gl n Leu Va l Gln Ser Gl y Ala Glu Val Lys Lys 20 25 30 10 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile 35 40 45 Lys Asp Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 15 50 55 60 Glu Trp Met Gly Arg I l e Asp Pro Asp Asn Gly Glu Ser Thr Tyr Val 20 65 70 75 80 Pro Lys Phe Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser 25 85 90 95 Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val 100 105 110 30 Tyr Tyr Cys Ala Arg Glu Gly Leu Asp Tyr Gly Asp Tyr Tyr Ala Val 115 120 125 35 Asp Tyr Trp Gly Gln Gl y Thr Leu Val Thr Val Ser Ser 130 135 140 <210> 201 40 <211> 11 <212> PRT <213> Artificial Sequence <220> 45 <223> Ab-19, Ab-20 and Ab-23 LCDR1 <400> 201 50 Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn <210> 202 <211> 7 55 <212> PRT l 5 10 <213> Artificial Sequence <220> 174 EP 2 569 010 81 <223> Ab-19, Ab-20 and Ab-23 LCDR2 <400> 202 5 Ser Thr Ser Arg Leu Asn Ser <210> 203 10 <211> 8 <212> PRT <213> Artificial Sequence <220> l 15 <223> Ab-19, Ab-20 and Ab-23 LCDR3 <400> 203 5 20 Gln Gln Asp Ile Lys His Pro Thr l 5 <210> 204 <211> 5 25 <212> PRT 30 35 <213> Artificial Sequence <220> <223> Ab-19, Ab-20 and Ab-23 HCDR1 <400> 204 <210> 205 <211>17 <212> PRT 40 <213> Artificial Sequence <220> <223> Ab-19, Ab-20 and Ab-23 HCDR2 45 <400> 205 Asp Tyr Il e Met His l 5 Tyr Ile Asn Pro Ty r Asn Asp Asp Thr Glu Tyr As n Glu Lys Phe Lys l 5 10 15 so Gly <210> 206 55 <211> 11 <212> PRT <213> Artificial Sequence 175 EP 2 569 010 81 <220> <223> Ab-19, Ab-20 and Ab-23 HCDR3 <400> 206 5 Ser Ile Ty r Tyr Tyr Asp Ala Pro Phe Ala Tyr l 5 10 10 <210> 207 <211> 107 <212> PRT <213> Mus musculus 15 <400> 207 20 25 30 35 40 45 Asp Ile Gln Met Th r Gl n Thr Thr Ser Ser Le u Ser Al a Ser Leu Gly l 5 10 15 Asp Arg Val Asn I l e Ser Cys Ar g Ala Ser Gln Asp I le Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pr o As p Gly Thr Val Lys Leu Leu I l e 35 40 45 Tyr Ser Thr Ser Arg Leu Asn Ser Gly Va l Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gl y Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Ala Gl n 65 70 75 80 Glu Asp I le Ala Th r Tyr Phe Cys Gln Gln Asp Ile Lys His Pro Thr 85 90 95 Phe Gl y Gl y Gly Thr Ly s Leu Glu Leu Lys Arg <210> 208 <211> 120 <212> PRT 100 105 50 <213> Mus musculus <400> 208 55 176 5 10 15 20 25 30 EP 2 569 010 81 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala l 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gl y Phe Thr Phe Thr Asp Tyr 20 25 30 Ile Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr I l e Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe 50 55 6 0 Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Ser Ser Leu Thr Ser Glu Gly Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gl n 100 105 110 Gly Thr Leu Val Thr Val Ser Ser <210> 209 <211> 381 115 120 35 <212> DNA <213> Mus musculus <400> 209 40 atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcaac 45 atcagctgca gggcaagtca ggacattagc agttatttaa actggtatca gcagaaacca gatggaactg ttaaactcct gatctactcc acatcaagat taaactcagg agtcccatca aggttcagtg gcagtgggtc tgggacagat tattctctca ctattagcaa cctggcacaa 50 gaagatattg ccacttactt ttgccaacag gatattaagc atccgacgtt cggtggaggc accaagttgg agctgaaacg t 55 <210> 210 <211> 127 <2 12> PRT <213> Mus musculus 177 60 120 180 240 300 360 381 EP 2 569 010 81 <400> 210 Met Met Ser Ser Ala Gl n Ph e Leu Gly Leu Leu Leu Leu Cys Phe Gl n l 5 10 15 5 Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser 20 25 30 10 Ala Ser Leu Gly Asp Arg Val Asn Ile Ser Cys Arg Ala Ser Gln Asp 35 40 45 15 I le Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val 50 55 60 20 Lys Leu Leu Ile Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Gl y Ser Gl y Thr Asp Tyr Ser Leu Thr Ile Ser 25 85 90 95 Asn Leu Ala Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Ile 100 105 110 30 Lys His Pro Thr Phe Gl y Gly Gl y Thr Lys Leu Glu Leu Lys Arg 115 120 125 35 <210> 211 <211> 417 <212> DNA <21 3> Mus musculus 40 <400> 211 atggaatgga tctggatatt tctcttcctc ctgtcaggaa ctgcaggtgt ccactctgag 45 gtccagctgc agcagtctgg acctgagctg gtaaagcctg gggcttcagt gaagatgtcc tgcaaggctt ctgggttcac attcactgac tacattatgc actgggtgaa gcagaagcct gggcagggcc ttgagtggat tggatatatt aatccttaca atgatgatac tgaatacaat 50 gagaagttca aaggcaaggc cacactgact tcagacaaat cctccagcac agcctacatg ga tet cagea gtctgacctc tgagggctct gcggtctatt actgtgcaag atcgatttat 55 tactacgatg ccccgtttgc ttactggggc caagggactc tggtcacagt ctcgagc <210> 212 <211 > 139 178 60 120 180 240 300 360 417 5 10 15 20 25 30 35 40 EP 2 569 010 81 <212> PRT <213> Mus musculus <400> 212 Met Glu Trp Ile Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly l 5 10 15 Val His Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys 20 25 30 Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Phe Thr Phe 35 40 45 Thr Asp Tyr Ile Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn 65 70 75 80 Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Asp Leu Ser Ser Leu Thr Ser Glu Gly Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser <210> 213 <211> 381 <212> DNA 130 135 45 <213> Artificial Sequence <220> <223> Humanized antibody sequence 50 <400> 213 55 179 5 10 15 20 25 30 35 40 45 50 55 atgatgtcct gatatccaga atcacttgcc gggaaagccc cgcttcagtg gaagattttg accaaggtgg <210> 214 <211> 127 <212> PRT ctgctcagtt tgacccagtc gcgcaagtca ctaagctcct gcagtggctc caacttacta agatcaaacg EP 2 569 010 B1 ccttggtctc ctgttgctct gttttcaagg taccagatgt tccatcctcc ctgtctgcat ctgtaggtga ccgtgtcacc ggatattagc agctatttaa attggtatca gcagaaacca gatctattct acttcccgtt tgaatagtgg ggtcccatca tgggacagat ttcactctca ccatcagcag tctgcaacct ctgtcaacag gatattaaac accctacgtt cggtcaaggc t <213> Artificial Sequence <220> <223> Humanized antibody sequence <400> 214 Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln l 5 10 15 Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp 35 40 45 Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 50 55 60 Lys Leu Leu Ile Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gl y Ser Gly Ser Gl y Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Ile 100 105 110 Lys His Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 115 120 125 180 .. 60 120 180 240 300 360 381 5 10 15 20 <210> 215 <211> 417 <212> DNA <213> Mus musculus <400> 215 atggaatgga gtgcagctgg tgcaaggctt ggtcaagggc gagaagttca gagctgagca tactacgatg <210> 216 <211> 139 tctggatatt tgcagtctgg ctggttttac ttgagtggat agggccgtgt gcctgcgctc ccccgtttgc EP 2 569 010 81 tctcttcctc ctgtcaggaa ctgcaggtgt ccactctgag ggctgaggtg aagaagcctg ggtcctcggt gaaggtctcc cttcaccgac tatattatgc actgggtgcg tcaggcccct gggctatatc aacccttata atgatgacac cgaatacaac cacgattacc gcggacaaat ccacgagcac agcctacatg tgaggacacg gccgtgtatt actgtgcgcg ttcgatttat ttactggggc caagggactc tggtcacagt ctcgagc 25 <212> PRT <213> Artificial Sequence <220> <223> Humanized antibody sequence 30 <400> 216 Met Glu Trp Ile Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly 35 l 5 10 15 Val His Ser Glu Va l Gln Leu Va l Gln Ser Gl y Ala Glu Val Lys Lys 20 25 30 40 Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe 35 40 45 45 Thr Asp Tyr Ile Met His Trp Val Arg Gln Al a Pro Gly Gln Gly Leu 50 55 60 50 Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn 65 70 75 80 Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser 55 85 90 95 181 60 120 180 240 300 360 417 5 10 EP 2 569 010 81 Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Al a Tyr 11 5 120 125 Trp Gly Gln Gly Th r Leu Val Thr Va l Ser Ser <210> 217 <211> 318 130 135 15 <212> DNA 20 25 30 <213> Mus musculus <400> 217 gacatccaga atcacttgcc gggaaagccc cgcttcagtg gaagat tttg accaaggtgg <210> 218 <211> 106 tgacccagtc g cgcaagtca ctaagctcct g cagtggctc caacttacta agatcaaa 35 <212> PRT <213> Mus musculus <400> 218 40 45 50 55 tccatcctcc ctgtctgcat ctgtaggtga ccgtgtcacc ggat attagc agctatttaa a t tggtatca gcagaaacca gatctattct acttcccgtt tgaatagtgg ggtcccatca tgggacagat ttcactctca c c atcagcag tctgcaacct ctgtcaacag gatattaaac accctacgt t cggtcaaggc 182 60 120 180 240 300 318 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 Asp Ile Gln Met Thr Gl n Ser Pro Ser Ser Leu Ser Ala Ser Val Gly l 5 10 15 Asp Arg Va l Thr Ile Thr Cys Arg Ala Ser Gl n Asp Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gl n Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Thr Ser Arg Leu Asn Ser Gly Va l Pro Ser Arg Phe Ser Gl y 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Il e Ser Ser Leu Gl n Pr o 65 70 75 80 Gl u Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Ile Lys His Pro Thr 85 90 Phe Gly Gln Gly Thr Lys Val Gl u I l e Lys 100 105 <21 0> 219 <2 11 > 360 <212> DNA <213> Mus musculus <400> 219 gaggtgcagc tggtgcagtc tcctgcaagg cttctggttt cctggtcaag ggcttgagtg aacgagaagt tcaagggccg atggagctga gcagcctgcg tattact acg atgccccgtt <21 0> 220 <2 11 > 120 <212> PRT <213> Mus musculus <400> 220 tggggctgag gtgaagaagc tacet t cace gactatatta gatgggctat atcaaccctt tgtcacgatt accgcggaca ctct gaggac acggccgtgt tgcttactgg ggccaaggga 183 c t gggtcctc tgcactgggt ataatgatga aatccacgag att actgtgc ctct ggtcac 95 ggtgaaggtc gcgtcaggcc caccgaatac cacagcctac gcgttcgatt cgtctctagt 60 120 180 240 300 360 EP 2 569 010 81 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser l 5 10 15 5 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 10 Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe 15 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 20 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 25 Ala Arg Ser Il e Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln 100 105 110 30 Gly Thr Leu Val Thr Val Ser Ser 115 120 35 <210> 221 <211> 639 <212> DNA <213> Mus musculus 40 <400> 221 45 50 55 184 • ... EP 2 569 010 B1 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggtga ccgtgtcacc 60 atcacttgcc gcgcaagtca ggatattagc agctatttaa attggtatca gcagaaacca 120 5 gggaaagccc ctaagctcct gatctattct acttcccgtt tgaatagtgg ggtcccatca 180 cgcttcagtg gcagtggctc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 10 gaagattttg caacttacta ctgtcaacag gatattaaac accctacgtt cggtcaaggc 300 accaaggtgg agatcaaacg tacggtggct gcaccatctg tcttcatctt cccgccatct 360 gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420 15 agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480 agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540 20 agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600 agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639 <210> 222 25 <211> 213 <212> PRT <213> Mus musculus <400> 222 30 As p Ile Gln Met T hr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly l 5 lO 15 35 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp I l e Ser Ser Tyr 20 25 30 40 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val Pro Ser Arg Phe Ser Gly 45 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 50 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Ile Lys His Pro Thr 55 185 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 85 90 95 Phe Gly Gl n Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Va l Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 223 <211> 1338 <212> DNA <213> Mus musculus <400> 223 186 EP 2 569 010 81 gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggttt taccttcacc gactatatta tgcactgggt gcgtcaggcc 120 5 cctggtcaag ggcttgagtg gatgggctat atcaaccctt ataatgatga caccgaatac 180 aacgagaagt tcaagggccg tgtcacgatt accgcggaca aat ccacgag cacagcctac 240 10 atggagctga gcagcctgcg ctctgaggac acggccgtgt attactgtgc gcgttcgatt 300 tattactacg atgccccgtt tgcttactgg ggccaaggga ctctggtcac cgtctctagt 360 gcctccacca agggcccatc ggtcttcccc ctggcgccct gct ccaggag cacctccgag 420 15 agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgctct gac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 540 20 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 660 aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 720 25 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggt cacgtgc 780 gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 840 30 gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 900 gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 960 35 aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1020 cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1080 caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1140 40 gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1200 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260 45 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320 tccctgtctc cgggtaaa 1338 <210> 224 50 <211> 446 <212> PRT <213> Mus musculus <400> 224 55 187 EP 2 569 010 B1 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser l 5 10 15 5 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 10 Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe 15 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 20 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 25 Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln 30 35 40 45 50 55 188 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Va l 11 5 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Va l Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Va l 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys 19 5 200 205 Pro Ser Asn Thr Lys Val Asp Lys Thr Va l Gl u Arg Lys Cys Cys Va l 210 215 220 Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Va l Val Val Asp Val Ser His Glu Asp Pro Glu Va l 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val 290 295 300 Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 189 5 10 15 20 25 EP 2 569 010 81 340 345 350 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Th r Cys Leu Val 355 36 0 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Tr p 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Va l Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys <210> 225 <211> 11 435 440 445 30 <212> PRT <213> Artificial Sequence <220> <223> Ab-21 and Ab-22 LCDR1 35 <400> 225 Lys Ala Ser Gln Asp Val Phe Thr Ala Va l Ala 40 l 5 10 <210> 226 <211>7 <212> PRT 45 <213> Artificial Sequence <220> <223> Ab-21 and Ab-22 LCDR2 50 <400> 226 55 <210> 227 <211 > 9 <212> PRT Trp Ala Ser Thr Arg Hi s Thr l 5 190 5 10 EP 2 569 010 81 <213> Artificial Sequence <220> <223> Ab-21 and Ab-22 LCDR3 <400> 227 <210> 228 <211 > 5 <212> PRT Gln Gln Tyr Ser Ser Tyr Pro Leu Thr l 5 15 <213> Artificial Sequence <220> <223> Ab-21 and Ab-22 HCDR1 20 <400> 228 25 30 35 40 <210> 229 <211>17 <212> PRT <213> Artificial Sequence <220> <223> Ab-21 and Ab-22 HCDR2 <400> 229 Asp Tyr Tyr Met His l 5 Arg Ile Asp Pro Glu Asn Gly Asp Ile Ile Tyr Asp Pro Lys Phe Gln l 5 10 15 Gly <210> 230 <211 > 10 45 <212> PRT 50 55 <213> Artificial Sequence <220> <223> Ab-21 and Ab-22 HCDR3 <400> 230 <210> 231 <211 > 381 Asp Ala Gl y Asp Pro Ala Trp Phe Thr Tyr l 5 10 191 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 81 <212> DNA <213> Mus musculus <400> 231 atgaagtcac gacattgtga atcacctgca ggacaatctc cgcttcacag gaagacttgg gggaccaagt <210> 232 <211> 128 <212> PRT agacccaggt ctttgtatac tgacccagtc tcacaaattc aggccagtca ggatgtcttt ctaaactact gatttactgg gcagtggatc tgggacagat cagattattt ctgtcaacaa tggagctgaa a atgttgctgt ggttgtctgg tgttgaagga atgtccacgt cagtaggaga cagggtcacc actgctgtag cctggtatca acagaaacca gcatccaccc ggcacactgg agtccctgat ttcactctca ccattagcaa tgtgcagtct tatagcagct atcctctcac gttcggtgct <213> Mus musculus <400> 232 Met Lys Ser Gln Thr Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser l 5 10 15 Gly Val Glu Gly Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser 20 25 30 Thr Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp 35 40 45 Val Phe Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro 50 55 60 Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp 65 70 75 80 Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95 Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser 100 105 110 Ser Tyr Pro Leu Thr Phe Gly Al a Gly Thr Lys Leu Glu Leu Lys Arg 115 120 125 192 . . 60 120 180 240 300 360 381 .. EP 2 569 010 81 <210> 233 <211 > 41 1 <212> DNA <213> Mus musculus 5 <400> 233 atgggat gga actggatcat cttcttcctg atggcagtgg ttacaggggt caattcagag 60 10 gttcagctgc agcagtctgg ggct gagctt gtgaggccag gggccttagt caagttgtcc 120 tgcaaagctt ctggcttcaa tattaaagac tactatatgc actgggtgaa gcagaggcct 180 15 gaacagggcc tggagtggat tggaaggatt gatcctgaga atggtgatat tatatatgac 240 ccgaagttcc agggcaaggc cagtataaca acagacacat cctccaacac agcctacctg 300 cagctcagca gcctgacgtc tgaggacact gccgtctatt actgtgctta cgatgctggt 360 20 gaccccgcct ggtttactta ctggggccaa gggactctgg tcaccgtctc g 411 <210> 234 <2 11 > 138 25 <212> PRT <213> Mus musculus <400> 234 30 35 40 45 50 55 193 5 10 15 20 25 30 35 EP 2 569 010 81 Met Gly Trp Asn Trp Ile Ile Phe Phe Leu Met Ala Val Val Thr Gly l 5 10 15 Val Asn Ser Glu Va l Gln Leu Gln Gln Ser Gly Ala Gl u Leu Va l Ar g 20 25 30 Pro Gly Ala Leu Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Asn Ile 35 40 45 Lys Asp Tyr Tyr Met His Trp Va l Lys Gln Arg Pro Glu Gln Gly Leu 50 55 60 Glu Trp Ile Gly Arg Ile Asp Pro Glu Asn Gly Asp Ile Ile Tyr Asp 65 70 75 80 Pro Lys Phe Gln Gly Lys Ala Ser Ile Thr Thr Asp Thr Ser Ser Asn 85 90 95 Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Va l 100 105 110 Tyr Tyr Cys Ala Tyr Asp Ala Gly Asp Pro Ala Trp Phe Thr Tyr Trp 115 12 0 125 Gly Gln Gly Thr Leu Val Thr Va l Ser Ser <210> 235 <211>324 <212> DNA 130 135 40 <213> Mus musculus <400> 235 45 gatatccaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc attacctgca aagcgagcca ggat gtgttt accgcggtgg cgtggtatca gcagaaaccg ggcaaagcgc cgaaactgct gatttattgg gcgagcaccc gccataccgg cgtgccgagt 50 cgctttagcg gcagcggcag cggcaccgat tttaccctga ccattagcag cctgcagccg gaagattttg cgacctatta ttgccagcag tatagcagct atccgctgac ctttggcggc 55 ggcaccaaag tggaaattaa acgt <210> 236 <211 > 108 194 60 120 180 240 300 324 EP 2 569 010 81 <212> PRT <213> Mus musculus <400> 236 5 Asp Ile Gl n Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly l 5 10 15 10 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Phe Thr Ala 20 25 30 15 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly 20 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 25 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Leu 85 90 95 30 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <2 10> 237 35 <211> 357 <212> DNA <213> Mus musculus <400> 237 40 gaagtgcagc tggtgcagag cggcgcggaa gtgaaaaaac cgggcgcgag cgtgaaagtg 60 agctgcaaag cgagcggctt taacattaaa gattattata tgcattgggt gcgccaggcg 120 45 ccgggccagg gcctggaatg gatcggccgc attgatccgg aaaacggcga t attatttat 180 gatccgaaat ttcagggccg cgtgaccatg accaccgata ccagcaccag caccgcgtat 240 50 atggaactgc gcagcctgcg cagcgatgat accgcggtgt attattgcgc gtatgatgcg 300 ggcgatccgg cgtggtttac ctattggggc cagggcaccc tggtgaccgt ctcgagc 357 55 <210> 238 <211> 119 <212> PRT <213> Mus musculus 195 5 10 15 20 25 30 EP 2 569 010 81 <400> 238 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala l 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Asp Pro Glu Asn Gly Asp Ile Ile Tyr Asp Pro Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Tyr Asp Ala Gly Asp Pro Ala Trp Phe Thr Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Va l Ser Ser 115 35 <210> 239 <211> 15 <212> PRT <213> Artificial Sequence 40 <220> <223> Synthetic peptide <400> 239 45 Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Thr Ser Tyr Met Asn 50 l 5 lO 15 <210> 240 <211> 7 55 <212> PRT <213> Artificial Sequence <220> 196 <223> Synthetic peptide <400> 240 5 <210> 241 10 <211>9 <212> PRT <213> Artificial Sequence <220> 15 <223> Synthetic peptide 20 <400> 241 <210> 242 <211> 5 25 <212> PRT 30 35 <213> Artificial Sequence <220> <223> Synthetic peptide <400> 242 <210> 243 <211> 17 <212> PRT 40 <213> Artificial Sequence <220> <223> Synthetic peptide 45 <400> 243 EP 2 569 010 81 Ala Al a Ser Asn Le u Glu Ser l 5 Gln Gl n Ser Asn Gl u Asp Pro Phe Thr l 5 Thr Tyr Trp Met Asn l 5 Met Ile Hi s Pro Ser Ala Ser Gl u Ile Arg Leu Asp Gln Ly s Phe Lys l 5 10 15 50 As p <210> 244 55 <211>9 <212> PRT <213> Artificial Sequence 197 EP 2 569 010 81 <220> <223> Synthetic peptide <400> 244 5 Ser Gly Glu Trp Gl y Ser Met Asp Tyr l 5 10 <210> 245 <211> 657 <212> DNA <213> Mus musculus 15 <400> 245 gacattgtgt tgacccagtc tccagcttct ttggctgtgt ctctagggca gagggccacc 20 atcgcctgca aggccagcca aagtgttgat tatgatggta ctagttatat gaattggtac caacagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa tctagaatct gagatcccag ccaggtttag tggcactggg tctgggacag acttcaccct caacatccat 25 cct gtggagg aggaggatat cacaacctat tact gtcagc aaagtaatga ggatccgttc acgttcggag gggggaccaa g t tggaaata aaacgggctg a t gctgcacc aactgtatcc 30 atcttcccac catccagtga gcagttaaca tctggaggtg cct cagtcgt gtgcttcttg aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa aatggcgtcc tgaacagttg gact gatcag gacagcaaag acagcaccta cagcatgagc 35 agcaccctca cgttgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc actcacaaga catcaacttc acccattgtc aagagcttca ac aggaatga gtgt tag 40 <210> 246 <211> 218 <212> PRT <213> Mus musculus 45 <400> 246 Asp Ile Va l Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gl y l 5 10 15 50 Gln Arg Ala Tbr Ile Ala Cy s Ly s Ala Ser Gl n Ser Val Asp Tyr Asp 20 25 30 55 Gly Thr Ser Tyr Met Asn Trp Ty r Gln Gln Lys Pro Gly Gln Pr o Pr o 198 , 60 120 180 2 40 300 360 420 480 540 600 657 5 10 15 20 25 30 35 40 45 EP 2 569 010 81 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Glu Ile Pro Ala 50 55 60 Arg Phe Ser Gly Thr Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Glu Glu Asp Ile Thr Thr Tyr Tyr Cys Gln Gln Ser Asn 85 90 95 Glu Asp Pro Phe Thr Phe Gly Gl y Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln 115 120 125 Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr 130 135 140 Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln 145 150 155 160 Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg 180 185 190 His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro 195 200 205 Ile Val Lys Ser Phe Asn Arg Asn Glu Cys <21 0> 247 <211> 442 210 215 50 <212> PRT <213> Mus musculus <400> 247 55 199 EP 2 569 010 B1 Gln Val Gln Leu Gln Gln Pro Gly Thr Glu Leu Val Arg Pro Gly Thr l 5 10 15 5 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Thr Tyr 20 25 30 10 15 20 25 30 35 40 45 50 55 200 5 10 15 20 25 30 35 40 45 50 55 EP 2 569 010 B1 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Ala Ser Glu Ile Arg Leu Asp Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Leu Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Ser Gly Pro Thr Ser Val Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gl y Gl u Tr p Gly Ser Met Asp Ty r Trp Gly Gl n Gl y Thr 100 105 110 Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro 115 120 125 Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gl y 130 135 140 Cys Leu Va l Lys Gly Tyr Phe Pro Glu Pro Va l Thr Val Thr Trp Asn 145 150 155 160 Ser Gly Ser Leu Ser Ser Gly Val Hi s Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Th r Val Pro Ser Ser Thr 180 185 190 Trp Pro Ser Glu Thr Val Thr Cys Asn Val Al a His Pro Ala Ser Ser 195 200 205 Thr Lys Val Asp Lys Lys Ile Va l Pro Arg Asp Cys Gly Cys Lys Pro 210 215 220 Cys I le Cys Thr Val Pro Glu Va l Ser Ser Val Phe Ile Phe Pro Pro 225 230 235 240 Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys 245 250 255 Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp 260 265 270 201 5 10 15 20 25 30 35 40 EP 2 569 010 B1 Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu 275 280 285 Glu Gln Ph e Asn Ser Thr Phe Arg Ser Va l Ser Glu Leu Pro Ile Met 290 295 300 His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser 305 310 315 320 Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr I le Ser Lys Thr Lys Gly 325 330 335 Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln 340 345 350 Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe 355 360 365 Pro Glu Asp I le Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Gl u 370 375 380 Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe 385 390 395 400 Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn 405 410 415 Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr 420 425 430 Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 45 <210> 248 <211 > 1329 <212> DNA <21 3> Mus musculus 50 <400> 248 55 202 'l EP 2 569 010 B1 caggtccaac tacagcagcc tgggactgag ctggtgaggc ctggaacttc agtgaagttg 60 tcctgtaagg cttctggcta catcttcacc acctactgga tgaactgggt gaaacagagg 120 5 cctggacaag gccttgagtg gat t ggcatg attcatcctt ccgcaagtga aattaggttg 180 gatcagaaat tcaaggacaa ggccacattg actcttgaca aatcctccag cacagcctat 240 10 atgcacctca gcggcccgac atctgtggat tctgcggtct attactgtgc aagatcaggg 300 gaatgggggt ctatggacta ctggggtcaa ggaacctcag tcaccgtctc ctcagccaaa 360 acgacacccc catctgtcta tccactggcc cctggatctg ctgcccaaac taactccatg 420 15 gtgaccctgg gatgcctggt caagggctat ttccctgagc cagtgacagt gacctggaac 480 tctggatccc tgtccagcgg tgtgcacacc ttcccagctg tcctgcagtc tgacctctac 540 20 actctgagca gctcagtgac tgtcccctcc agcacctggc ccagcgagac cgtcacctgc 600 aacgttgccc acccggccag cagcaccaag gtggacaaga aaattgtgcc cagggattgt 660 25 ggttgtaagc cttgcatatg tacagtccca gaagtatcat ctgtcttcat cttcccccca 720 aagcccaagg atgtgctcac cat t actctg actcctaagg tcacgtgtgt tgtggtagac 780 atcagcaagg atgatcccga ggtccagttc agctggtttg tagatgatgt ggaggtgcac 840 30 acagctcaga cgcaaccccg ggaggagcag ttcaacagca ctttccgctc agtcagtgaa 900 cttcccatca tgcaccagga ctggctcaat ggcaaggagt tcaaatgcag ggtcaacagt 960 35 gcagctttcc ctgcccccat cgagaaaacc atctccaaaa ccaaaggcag accgaaggct 1020 ccacaggtgt acaccattcc acctcccaag gagcagatgg ccaaggataa agtcagtctg 1080 acctgcatga taacagactt cttccctgaa gacattactg tggagtggca gtggaatggg 1140 40 cagccagcgg agaactacaa gaacactcag cccatcatgg acacagatgg ctcttacttc 1200 atctacagca agctcaatgt gcagaagagc aactgggagg caggaaatac tttcacctgc 1260 45 tctgtgttac atgagggcct gcacaaccac catactgaga agagcctctc ccactctcct 1320 ggtaaat ga 1329 50 Claims 1. A steri le liquid formulation that has an absolute viscosity of 1 O cP or less comprising: (a) an anti-sclerostin im mu- noglobulin at a concentration of at least 70 mg/ml; and (b) calcium acetate at a concentration ranging from 1 mM to 20 mM, where in the anti-sclerostin immunoglobulin comprises amino acid sequences of SEQ ID NO: 86 and SEQ 55 ID NO: 84. 2. The formulation of claim 1, wherein the formulation comprises a total concentration of acetate between 1 O mM and 90 mM. 203

Claims

1. Sterilna tečna formulacija koja ima apsolutnu viskoznost od 1 O cP ili manje obuhvata: (a) antisklerostin imunoglobulin pri koncentraciji od barem 70 mg/ml; i (b) kalcijum acetat u koncentraciji koja se kreće u opsegu od 1 mM do 20 mM, pri čemu anti-sklerostin imunoglobulin obuhvata sekvence amino kiseline sa SEK ID BR: 86 i SEK ID BR: 84.

2. Formulacija iz patentnog zahtjeva 1, pri čemu ova formulacija obuhvata ukupnu koncentraciju acetata između 1 O mM i 90 mM.

3. Formulacija iz patentnog zahtjeva 1 ili patentnog zahteva 2 pri čemu ova formulacija obuhvata ukupnu koncentraciju acetata između 30 mM i 90 mM ili između 30 mM i 75 mM.

4. Formulacija iz patentnog zahtjeva 2 ili patentnog zahteva 3 pri čemu je koncentracija soli kalcij uma barem 5 mM i ne veća od 15 mM, i ova koncentracija acetata je barem 50 mM.

5. Formulacija iz bilo kog od patentnih zahtjeva 1-4 pri čemu je imunoglobulin u koncentraciji od 70 mg/ml do 200 mg/ml.

6. Formulacija iz bilo kog od patentnih zahtjeva 1-5, čija je ukupna osmolarnost manja od 350 mOsm/L.

7. Formulacija iz bilo kog od patentnih zahtjeva 1-5, pri čemu je imunoglobulin prisutan u koncentraciji od 120 mg/ml.

8. Formulacija iz patentnog zahtjeva 7, pri čemu je imunoglobulin prisutan u koncentraciji od 140 mg/ml.

9. Formulacija iz bilo kog od patentnih zahtjeva 1-5, pri čemu je imunoglobulin prisutan u koncentraciji od 90 mg/ml.

10. Formulacija iz bilo kog od patentnih zahteva 1-5, pri čemu apsolutna viskoznost ove formulacije jeste 8 cP ili manja.

11.Formulacija iz patentnog zahteva 1 O, pri čemu apsolutna viskoznost ove formulacije jeste 6 cP ili manja.

12. Formulacija iz bilo kog od patentnih zahtjeva 1-11 , pri čemu ova formulacija još obuhvata poliol u količ i ni u opsegu od 4% w/v do 6% w/v.

13.Formulacija iz patentnog zahtjeva 12, pri čemu je poliol saharoza.

14.Formulacija iz bilo kog od patentnih zahtjeva 1-13, pri čemu ova formulacija ima pH u opsegu od 4,5 do 6.

15.Formulacija iz patentnog zahtjeva 14, pri čemu ova formulacija ima pH u opsegu od 5 do 5,5.

16.Postupak za smanjenje viskoznosti formulacije proteina, ovaj postupak obuhvata dodavanje kalcijum acetata pri koncentraciji između 1 mM i 20 mM, na anti-sklerostin imunoglobulin formulaciju, pri čemu ova formulacija obuhvata imunoglobulin u koncentraciji od 70 mg/ml do 200 mg/ml, pri čemu ovaj anti-sklerostin imunoglobulin obuhvata sekvence amino kisel ine SEK ID BR: 86 i SEK ID BR: 84, i pri čemu viskoznost ove formulacije sa kalcijum acetatom jeste smanjena u poređenju sa viskoznošću formulacije antitela bez kalcijum acetata.

17.Formulacija iz bilo kog od patentnih zahtjeva 1-15, pri čemu ovaj imunoglobulin ima teške lance SEK ID BR:. 90 i lake lance SEK ID BR:88.

18.Formulacija iz patentnog zahtjeva 17, još obuhvata surfaktant.

19.Formulacija iz patentnog zahtjeva 18, pri čemu ova koncentracija surfaktanta jeste od 0,004% w/v do 0,2% w/v.

20.Formulacija iz bilo kog od patentnih zahtjeva 1-15 i 17, pri čemu kalcijum acetat smanjuje apsolutnu viskoznost iz formulacije za barem 10% u poređenju sa viskoznošću formulacije antitela bez kalcijum acetata.

21.Formulacija iz patentnog zahteva 19, pri čemu je surfaktant polisorbat 20.

22.Formulacija iz jednog od patentnih zahtjeva 1-15 i 17-21 za upotrebu u postupku za poboljšanje ishoda ortopedskog postupka, stomatološkog postupka, ugradnje implanta, zamene zgloba, presađivanje kosti, kozmetičkoj hirurgiji kosti ili popravku kosti, ili za upotrebu u postupku za lečenje osteoporoze ili osteopenije.

23. Formulacija za upotrebu u ovom postupku iz patentnog zahtjeva 22, pri čemu je popravak kosti zaceljenje preloma, neujednačeno zaceljenje kosti, odloženo potpuno zaceljenje kosti ili rekonstrukcija lica.