LISTADO DE SECUENCIAS <110> UCB Biopharma SPRL Oxford University Innovation Limited The University of Adelaide <120> ANTAGONISTA DE GREMLIN-1 PARA LA PREVENCIÓN Y TRATAMIENTO DEL CÁNCER <130> N412703WO <150> GB 1809946.5 <151> 18-06-2018 <150> GB 1815694.3 <151> 26-09-2018 <160> 43 <170> PatentIn versión 3.5 <210> 1 <211> 184 <212> PRT <213> Homo sapiens <400> 1 Met Ser Arg Thr Ala Tyr Thr Val Gly Ala Leu Leu Leu Leu Leu Gly 1 5 10 15 Thr Leu Leu Pro Ala Ala Glu Gly Lys Lys Lys Gly Ser Gln Gly Ala 20 25 30 Ile Pro Pro Pro Asp Lys Ala Gln His Asn Asp Ser Glu Gln Thr Gln 35 40 45 Ser Pro Gln Gln Pro Gly Ser Arg Asn Arg Gly Arg Gly Gln Gly Arg 50 55 60 Gly Thr Ala Met Pro Gly Glu Glu Val Leu Glu Ser Ser Gln Glu Ala 65 70 75 80 Leu His Val Thr Glu Arg Lys Tyr Leu Lys Arg Asp Trp Cys Lys Thr 85 90 95 Gln Pro Leu Lys Gln Thr Ile His Glu Glu Gly Cys Asn Ser Arg Thr 100 105 110 Ile Ile Asn Arg Phe Cys Tyr Gly Gln Cys Asn Ser Phe Tyr Ile Pro 115 120 125 Arg His Ile Arg Lys Glu Glu Gly Ser Phe Gln Ser Cys Ser Phe Cys 130 135 140 Lys Pro Lys Lys Phe Thr Thr Met Met Val Thr Leu Asn Cys Pro Glu 145 150 155 160 Leu Gln Pro Pro Thr Lys Lys Lys Arg Val Thr Arg Val Lys Gln Cys 165 170 175 Arg Cys Ile Ser Ile Asp Leu Asp 180 <210> 2 <211> 139 <212> PRT <213> Secuencia artificial <220> <223> Gremlin-1 truncado humano usado en cristalografía con marcador N-terminal <400> 2 Met Gly Ser Ser His His His His His His Ser Ser Gly Glu Asn Leu 1 5 10 15 Tyr Phe Gln Gly Ser Ala Met Pro Gly Glu Glu Val Leu Glu Ser Ser 20 25 30 Gln Glu Ala Leu His Val Thr Glu Arg Lys Tyr Leu Lys Arg Asp Trp 35 40 45 Cys Lys Thr Gln Pro Leu Lys Gln Thr Ile His Glu Glu Gly Cys Asn 50 55 60 Ser Arg Thr Ile Ile Asn Arg Phe Cys Tyr Gly Gln Cys Asn Ser Phe 65 70 75 80 Tyr Ile Pro Arg His Ile Arg Lys Glu Glu Gly Ser Phe Gln Ser Cys 85 90 95 Ser Phe Cys Lys Pro Lys Lys Phe Thr Thr Met Met Val Thr Leu Asn 100 105 110 Cys Pro Glu Leu Gln Pro Pro Thr Lys Lys Lys Arg Val Thr Arg Val 115 120 125 Lys Gln Cys Arg Cys Ile Ser Ile Asp Leu Asp 130 135 <210> 3 <211> 10 <212> PRT <213> Secuencia artificial <220> <223> Ab7326 HCDR1 combinado Kabat y Chothia <400> 3 Gly Tyr Thr Phe Thr Asp Tyr Tyr Met His 1 5 10 <210> 4 <211> 5 <212> PRT <213> Secuencia artificial <220> <223> Ab7326 HCDR1 Kabat <400> 4 Asp Tyr Tyr Met His 1 5 <210> 5 <211> 17 <212> PRT <213> Secuencia artificial <220> <223> Ab7326 HCDR2 Kabat <400> 5 Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe Gln 1 5 10 15 Gly <210> 6 <211> 15 <212> PRT <213> Secuencia artificial <220> <223> Ab7326 HCDR3 Kabat <400> 6 Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp Tyr 1 5 10 15 <210> 7 <211> 17 <212> PRT <213> Secuencia artificial <220> <223> Ab7326 LCDR1 Kabat <400> 7 Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu 1 5 10 15 Ala <210> 8 <211> 7 <212> PRT <213> Secuencia artificial <220> <223> Ab7326 LCDR2 Kabat <400> 8 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> 9 <211> 8 <212> PRT <213> Secuencia artificial <220> <223> Ab7326 LCDR3 Kabat <400> 9 Gln Gln Tyr Tyr Asp Thr Pro Thr 1 5 <210> 10 <211> 124 <212> PRT <213> Secuencia artificial <220> <223> Región variable de cadena pesada de Ab7326 variante 1 <400> 10 Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 11 <211> 112 <212> PRT <213> Secuencia artificial <220> <223> Región variable de cadena ligera de Ab7326 variante 1 <400> 11 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 <210> 12 <211> 124 <212> PRT <213> Secuencia artificial <220> <223> Región variable de cadena pesada de Ab7326 variante 2 <400> 12 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 13 <211> 112 <212> PRT <213> Secuencia artificial <220> <223> Región variable de cadena ligera de Ab7326 variante 2 <400> 13 Asp Ile Val Met Thr Gln Thr Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 <210> 14 <211> 448 <212> PRT <213> Secuencia artificial <220> <223> Cadena pesada IgG1 de extensión completa de ratón variante 1 <400> 14 Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr 115 120 125 Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn 130 135 140 Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val 180 185 190 Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val 195 200 205 Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg 210 215 220 Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser 225 230 235 240 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu 245 250 255 Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro 260 265 270 Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala 275 280 285 Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val 290 295 300 Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe 305 310 315 320 Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile 340 345 350 Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys 355 360 365 Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp 370 375 380 Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp 385 390 395 400 Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser 405 410 415 Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly 420 425 430 Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 445 <210> 15 <211> 219 <212> PRT <213> Secuencia artificial <220> <223> Cadena ligera IgG1 de extensión completa de ratón variante 1 <400> 15 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 Arg Thr Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu 115 120 125 Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe 130 135 140 Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg 145 150 155 160 Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu 180 185 190 Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 195 200 205 Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 <210> 16 <211> 454 <212> PRT <213> Secuencia artificial <220> <223> Cadena pesada IgG1 de extensión completa humana variante 2 <400> 16 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 355 360 365 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <210> 17 <211> 219 <212> PRT <213> Secuencia artificial <220> <223> Cadena ligera IgG1 de extensión completa humana variante 2 <400> 17 Asp Ile Val Met Thr Gln Thr Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 18 <211> 227 <212> PRT <213> Secuencia artificial <220> <223> Cadena pesada Fab variante 1 <400> 18 Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys 225 <210> 19 <211> 219 <212> PRT <213> Secuencia artificial <220> <223> Cadena ligera Fab variante 1 <400> 19 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 20 <211> 118 <212> PRT <213> Secuencia artificial <220> <223> Gremlin-1 truncado humano usado en cristalografía sin marcador N-terminal <400> 20 Ala Met Pro Gly Glu Glu Val Leu Glu Ser Ser Gln Glu Ala Leu His 1 5 10 15 Val Thr Glu Arg Lys Tyr Leu Lys Arg Asp Trp Cys Lys Thr Gln Pro 20 25 30 Leu Lys Gln Thr Ile His Glu Glu Gly Cys Asn Ser Arg Thr Ile Ile 35 40 45 Asn Arg Phe Cys Tyr Gly Gln Cys Asn Ser Phe Tyr Ile Pro Arg His 50 55 60 Ile Arg Lys Glu Glu Gly Ser Phe Gln Ser Cys Ser Phe Cys Lys Pro 65 70 75 80 Lys Lys Phe Thr Thr Met Met Val Thr Leu Asn Cys Pro Glu Leu Gln 85 90 95 Pro Pro Thr Lys Lys Lys Arg Val Thr Arg Val Lys Gln Cys Arg Cys 100 105 110 Ile Ser Ile Asp Leu Asp 115 <210> 21 <211> 160 <212> PRT <213> Secuencia artificial <220> <223> Secuencia de Gremlin-1 maduro de SEQ ID NO: 1 que carece del péptido señal de los aminoácidos 1-21 <400> 21 Lys Lys Lys Gly Ser Gln Gly Ala Ile Pro Pro Pro Asp Lys Ala Gln 1 5 10 15 His Asn Asp Ser Glu Gln Thr Gln Ser Pro Gln Gln Pro Gly Ser Arg 20 25 30 Asn Arg Gly Arg Gly Gln Gly Arg Gly Thr Ala Met Pro Gly Glu Glu 35 40 45 Val Leu Glu Ser Ser Gln Glu Ala Leu His Val Thr Glu Arg Lys Tyr 50 55 60 Leu Lys Arg Asp Trp Cys Lys Thr Gln Pro Leu Lys Gln Thr Ile His 65 70 75 80 Glu Glu Gly Cys Asn Ser Arg Thr Ile Ile Asn Arg Phe Cys Tyr Gly 85 90 95 Gln Cys Asn Ser Phe Tyr Ile Pro Arg His Ile Arg Lys Glu Glu Gly 100 105 110 Ser Phe Gln Ser Cys Ser Phe Cys Lys Pro Lys Lys Phe Thr Thr Met 115 120 125 Met Val Thr Leu Asn Cys Pro Glu Leu Gln Pro Pro Thr Lys Lys Lys 130 135 140 Arg Val Thr Arg Val Lys Gln Cys Arg Cys Ile Ser Ile Asp Leu Asp 145 150 155 160 <210> 22 <211> 451 <212> PRT <213> Secuencia artificial <220> <223> Cadena pesada IgG4P humana variante 1 <400> 22 Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 130 135 140 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn 195 200 205 Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser 210 215 220 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly 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 Glu Val Thr Cys Val Val Val Asp Val Ser Gln 260 265 270 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Leu Gly Lys 450 <210> 23 <211> 219 <212> PRT <213> Secuencia artificial <220> <223> Cadena ligera IgG4P humana variante 1 <400> 23 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 24 <211> 1362 <212> ADN <213> Secuencia artificial <220> <223> ADN de cadena pesada IgG1 humana variante 1 <400> 24 caagtgcaac tggtggaatc cggggccgaa gtgaaaaagc ccggagccac tgtgaagatc 60 tcttgcaaag tgtccggcta caccttcacc gactattaca tgcactgggt ccagcaggca 120 cctgggaagg gccttgagtg gatgggtctg gtcgatcccg aggacggcga aactatctac 180 gccgagaagt tccagggtcg cgtcaccatc accgccgaca cttccaccga caccgcgtac 240 atggagctgt ccagcttgag gtccgaggac acagccgtgt actactgcgc cacggatgct 300 cggggaagcg gcagctacta cccgaaccac ttcgactact ggggacaggg cactctcgtg 360 actgtctcga gcgcttctac aaagggcccc tccgtgttcc cgctcgctcc atcatcgaag 420 tctaccagcg gaggcactgc ggctctcggt tgcctcgtga aggactactt cccggagccg 480 gtgaccgtgt cgtggaacag cggagccctg accagcgggg tgcacacctt tccggccgtc 540 ttgcagtcaa gcggccttta ctccctgtca tcagtggtga ctgtcccgtc cagctcattg 600 ggaacccaaa cctacatctg caatgtgaat cacaaaccta gcaacaccaa ggttgacaag 660 aaagtcgagc ccaaatcgtg tgacaagact cacacttgtc cgccgtgccc ggcacccgaa 720 ctgctgggag gtcccagcgt ctttctgttc cctccaaagc cgaaagacac gctgatgatc 780 tcccgcaccc cggaggtcac ttgcgtggtc gtggacgtgt cacatgagga cccagaggtg 840 aagttcaatt ggtacgtgga tggcgtcgaa gtccacaatg ccaaaactaa gcccagagaa 900 gaacagtaca attcgaccta ccgcgtcgtg tccgtgctca cggtgttgca tcaggattgg 960 ctgaacggga aggaatacaa gtgcaaagtg tccaacaagg cgctgccggc accgatcgag 1020 aaaactatct ccaaagcgaa gggacagcct agggaacctc aagtctacac gctgccacca 1080 tcacgggatg aactgactaa gaatcaagtc tcactgactt gtctggtgaa ggggttttac 1140 cctagcgaca ttgccgtgga gtgggaatcc aacggccagc cagagaacaa ctacaagact 1200 acccctccag tgctcgactc ggatggatcg ttcttccttt actcgaagct caccgtggat 1260 aagtcccggt ggcagcaggg aaacgtgttc tcctgctcgg tgatgcatga agccctccat 1320 aaccactata cccaaaagtc gctgtccctg tcgccgggaa ag 1362 <210> 25 <211> 657 <212> ADN <213> Secuencia artificial <220> <223> Human IgG1 light chain ADN variante 1 <400> 25 gacattgtga tgacccagtc ccccgattcg cttgcggtgt ccctgggaga acgggccacc 60 attaactgca agagctcaca gtccgtcctg tattcatcga acaacaagaa ttacctcgca 120 tggtatcagc agaagcctgg acagcctccc aagctgctca tctactgggc tagcacccgc 180 gaatccgggg tgccggatag attctccgga tcgggttcgg gcactgactt cactctgact 240 atcaactcac tgcaagccga ggatgtcgcg gtgtacttct gtcagcagta ctacgacacc 300 ccgacctttg gacaaggcac cagactggag attaagcgta cggtggccgc tccctccgtg 360 ttcatcttcc caccctccga cgagcagctg aagtccggca ccgcctccgt cgtgtgcctg 420 ctgaacaact tctacccccg cgaggccaag gtgcagtgga aggtggacaa cgccctgcag 480 tccggcaact cccaggaatc cgtcaccgag caggactcca aggacagcac ctactccctg 540 tcctccaccc tgaccctgtc caaggccgac tacgagaagc acaaggtgta cgcctgcgaa 600 gtgacccacc agggcctgtc cagccccgtg accaagtcct tcaaccgggg cgagtgc 657 <210> 26 <211> 1353 <212> ADN <213> Secuencia artificial <220> <223> ADN de cadena pesada IgG4P humana variante 1 <400> 26 caagtgcaac tggtggaatc cggggccgaa gtgaaaaagc ccggagccac tgtgaagatc 60 tcttgcaaag tgtccggcta caccttcacc gactattaca tgcactgggt ccagcaggca 120 cctgggaagg gccttgagtg gatgggtctg gtcgatcccg aggacggcga aactatctac 180 gccgagaagt tccagggtcg cgtcaccatc accgccgaca cttccaccga caccgcgtac 240 atggagctgt ccagcttgag gtccgaggac acagccgtgt actactgcgc cacggatgct 300 cggggaagcg gcagctacta cccgaaccac ttcgactact ggggacaggg cactctcgtg 360 actgtctcga gcgcttctac aaagggcccc tccgtgttcc ctctggcccc ttgctcccgg 420 tccacctccg agtctaccgc cgctctgggc tgcctggtca aggactactt ccccgagccc 480 gtgacagtgt cctggaactc tggcgccctg acctccggcg tgcacacctt ccctgccgtg 540 ctgcagtcct ccggcctgta ctccctgtcc tccgtcgtga ccgtgccctc ctccagcctg 600 ggcaccaaga cctacacctg taacgtggac cacaagccct ccaacaccaa ggtggacaag 660 cgggtggaat ctaagtacgg ccctccctgc cccccctgcc ctgcccctga atttctgggc 720 ggaccttccg tgttcctgtt ccccccaaag cccaaggaca ccctgatgat ctcccggacc 780 cccgaagtga cctgcgtggt ggtggacgtg tcccaggaag atcccgaggt ccagttcaat 840 tggtacgtgg acggcgtgga agtgcacaat gccaagacca agcccagaga ggaacagttc 900 aactccacct accgggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 960 aaagagtaca agtgcaaggt gtccaacaag ggcctgccct ccagcatcga aaagaccatc 1020 tccaaggcca agggccagcc ccgcgagccc caggtgtaca ccctgccccc tagccaggaa 1080 gagatgacca agaaccaggt gtccctgacc tgtctggtca agggcttcta cccctccgac 1140 attgccgtgg aatgggagtc caacggccag cccgagaaca actacaagac caccccccct 1200 gtgctggaca gcgacggctc cttcttcctg tactctcggc tgaccgtgga caagtcccgg 1260 tggcaggaag gcaacgtctt ctcctgctcc gtgatgcacg aggccctgca caaccactac 1320 acccagaagt ccctgtccct gagcctgggc aag 1353 <210> 27 <211> 657 <212> ADN <213> Secuencia artificial <220> <223> ADN de cadena ligera IgG4P humana variante 1 <400> 27 gacattgtga tgacccagtc ccccgattcg cttgcggtgt ccctgggaga acgggccacc 60 attaactgca agagctcaca gtccgtcctg tattcatcga acaacaagaa ttacctcgca 120 tggtatcagc agaagcctgg acagcctccc aagctgctca tctactgggc tagcacccgc 180 gaatccgggg tgccggatag attctccgga tcgggttcgg gcactgactt cactctgact 240 atcaactcac tgcaagccga ggatgtcgcg gtgtacttct gtcagcagta ctacgacacc 300 ccgacctttg gacaaggcac cagactggag attaagcgta cggtggccgc tccctccgtg 360 ttcatcttcc caccctccga cgagcagctg aagtccggca ccgcctccgt cgtgtgcctg 420 ctgaacaact tctacccccg cgaggccaag gtgcagtgga aggtggacaa cgccctgcag 480 tccggcaact cccaggaatc cgtcaccgag caggactcca aggacagcac ctactccctg 540 tcctccaccc tgaccctgtc caaggccgac tacgagaagc acaaggtgta cgcctgcgaa 600 gtgacccacc agggcctgtc cagccccgtg accaagtcct tcaaccgggg cgagtgc 657 <210> 28 <211> 448 <212> PRT <213> Secuencia artificial <220> <223> Cadena pesada IgG1 de extensión completa de ratón variante 2 <400> 28 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr 115 120 125 Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn 130 135 140 Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val 180 185 190 Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val 195 200 205 Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg 210 215 220 Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser 225 230 235 240 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu 245 250 255 Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro 260 265 270 Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala 275 280 285 Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val 290 295 300 Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe 305 310 315 320 Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile 340 345 350 Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys 355 360 365 Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp 370 375 380 Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp 385 390 395 400 Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser 405 410 415 Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly 420 425 430 Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 445 <210> 29 <211> 219 <212> PRT <213> Secuencia artificial <220> <223> Cadena ligera IgG1 de extensión completa de ratón variante 2 <400> 29 Asp Ile Val Met Thr Gln Thr Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 Arg Thr Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu 115 120 125 Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe 130 135 140 Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg 145 150 155 160 Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu 180 185 190 Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 195 200 205 Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 <210> 30 <211> 454 <212> PRT <213> Secuencia artificial <220> <223> Cadena pesada IgG1 de extensión completa humana variante 1 <400> 30 Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 355 360 365 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <210> 31 <211> 219 <212> PRT <213> Secuencia artificial <220> <223> Cadena ligera IgG1 de extensión completa humana variante 1 <400> 31 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 32 <211> 227 <212> PRT <213> Secuencia artificial <220> <223> Cadena pesada Fab variante 2 <400> 32 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys 225 <210> 33 <211> 219 <212> PRT <213> Secuencia artificial <220> <223> Cadena ligera Fab variante 2 <400> 33 Asp Ile Val Met Thr Gln Thr Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 34 <211> 451 <212> PRT <213> Secuencia artificial <220> <223> Cadena pesada IgG4P humana variante 2 <400> 34 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Ala Thr Asp Ala Arg Gly Ser Gly Ser Tyr Tyr Pro Asn His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 130 135 140 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn 195 200 205 Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser 210 215 220 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly 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 Glu Val Thr Cys Val Val Val Asp Val Ser Gln 260 265 270 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Leu Gly Lys 450 <210> 35 <211> 219 <212> PRT <213> Secuencia artificial <220> <223> Cadena ligera IgG4P humana variante 2 <400> 35 Asp Ile Val Met Thr Gln Thr Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Asp Thr Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 36 <211> 16654 <212> ADN <213> Homo sapiens <400> 36 actcggtgcg ccttccgcgg accgggcgac ccagtgcacg gccgccgcgt cactctcggt 60 cccgctgacc ccgcgccgag ccccggcggc tctggccgcg gccgcactca gcgccacgcg 120 tcgaaagcgc aggccccgag gacccgccgc actgacaggt gagcgcggac gcacccggca 180 gggatgtgag tgggcggagg gaagagggcc gcaaaccaac ccaggacccg ctcagttcca 240 cgcgcggcag ccctccgtgc gcgcaggctc gggtgcgttg ttcgcggggg tgaattgtga 300 agaaccatcg cggggtcctt cctgctgagg ccgcggacac cgtgacctcg ctgctctggg 360 tctgcaggga aacgtaggaa aaaaagttgt caggagcggg caggatgacc cccacatccc 420 gtttccacct cccggaggcc cccgaacacg ctcctggtgc tggtggcagc agcgcctggc 480 agacgcgccc gcttagcgag ggcgcgaagt ccaggccgcc agagcgcagg agcatccgga 540 cctgctagtc ggccgctgac tgcgcggcga gttgccttga gagggtccca tgtgcttggg 600 gcgccgcgct gggtctgggg gcgtcttggg gcgcccattg gagtccgcgg gttggagcat 660 ccggagaatc catgatgtgt gcatttgccg atccccgagg tgagatggag actggcaagg 720 gcagagccgc tgtgttcagc cacagcggaa aaccgaacgg tgggtaatcc gacagctgcg 780 gtgcggggcg cggccctggc cgcggggtcc agcgaacccg cagtgctcac aaggcagaca 840 ccacacgcgc tcgcggaccg gccacgcact cgcgggcgct cgcttctcta ctccagcctc 900 ttccccgccc cgcgcacgcc cgagctgaat ggtagacgtt ctggcgccgg gcagcggcca 960 ccggctggtt cccacttccg cgcgcacccc ttaaactgtg ttctagaggc cccagcctcg 1020 ccttgcagcg cctcactagc tcctgaggac tagggactgg cggctgaggc gggttggcgg 1080 ctgcaacgag ctgggcgtct ttcgttctct ctcgctgcct ggctggctcc gctggcccct 1140 ccacagcttg cggagcaagg ccatagcagg ggagtgggag gtatattggg gctgtcacct 1200 ccttgctggc cggagttatt tgtagactac agactccgga agaacagacg cgccaccgct 1260 ctcgcttggc attgccttcg gatcgcagct cctccttggg ggtgccccag cttggcgttt 1320 atttgcctgc gccaggctct ggcgacggtc accgggccag gcggggaggg acggacggca 1380 ggtgaccagc ctctgctgtg aagaaattcc tgcgcgcccg gagctgtccc taatgcattc 1440 ccgggtcgaa tccgtctact gccttcccct cctcgaccga ctccgaatct cggctcttat 1500 agacagaaat acagcctcag cgttaggggt taaaatcccc ctcttaaacg gtccgagggc 1560 agagaggtga ccaccgatag gtaattggat ctcctgctgg aaagagcaaa tctgagcggt 1620 gtgcgcgtct gtttatgttc cccttcgaga tggtgccagg acacgaactg attaaaacaa 1680 tctattgtgt taagtgggtc actagggttt taagctgtcc cagggacccc agagtagtgg 1740 cttccttctg gctgtacaca caagttaaat aaatagcgta gaagaggtta agataacccc 1800 attctagggt gaggagtcct ctttcatccc tagggcttcc ccctcccctt ttctcttttt 1860 ttggaaggag ggggagcatg agagtcttga gggggggatg tacttttcaa agcaaggagg 1920 gaaagatctt aagaaaacta tatattctca ctgcccccca agccaagtct ataacagtag 1980 gtgatttgat tactatctct ggataaatgg cactgtcaaa ttgttaatat taactatttc 2040 agggattttt agcagggtag tggcagtatg tgtgcgtgtg tgtgtgtgtg tctgtgtgtg 2100 tgtgtttaac ctccaggtca ttgtaggaat tagagtcttt tgtaaacttt gtaatttcac 2160 aggtttccta ttttcttaaa agttcatttt tagtgaaatg ttttggtaac ccacgctctg 2220 taggaaatcc aggttggcta atgcggtctt tatgtgagta gttacacagg gaaggataaa 2280 aaccttttat gtcctacatc tctgaatgag ggctgcctac cctgtctttg aaactaagcc 2340 gaagatgcct tcagtctgaa tggtcaagta ttaaaagtga taaaatgcaa agaaatttca 2400 tgccgcagac acctccccca agaactgctt gttgacagca aagctgtgga acatgttcca 2460 caacagagag taaaggacag ccaggaaata taaacctttt atgtaaagga aaggcaggtg 2520 ggggacagtg gttaggggag gtgactgcag cctctaacca aaaggcaacc atcaggcaag 2580 tgctaccagc ccgtgtcttc gatctgcaag gaattttctt tagttttaac atatgctctt 2640 agaaattcaa agtacaacag gaattcctgg gacaagagaa atctttttat tcacatgtga 2700 acatgaagat acaaaataga taattatttt atttatagca ctcttcaaat tgtattgcat 2760 tagaaaacat atccattgac ccactgttaa ggacagcact gggtgtcaat aggacagtgg 2820 ttaaggacct gtgtttgggg ctagatagaa ttgggtttaa actgctggct gggctgggca 2880 cagtggctca caccggtaat cccagcactt tgggaggcca aggaggacgg atcacctgag 2940 gtcgggagtt cgacaccagc ctgaccaaca tggaaaaatc ccgtctctac taaaaacaca 3000 aaattagcca ggcatggtgg tgcatgcctg caatcccagc tacttgggag gctgaggcag 3060 gagaattgct tgaaaccggg aggcggaggt tgtggtgagc ccagatagcg ccattgcatt 3120 ccagcctggg caacacgagt gaaaactccg tcaaaaaaac aaaacaaaac aaacaaacaa 3180 aaaaatgctg gctttcccac ttatgagctg tgtgaccttg gacaaatttc caacttttct 3240 gagtgtagat tccctgattg gtaaaaggaa gatgatatta tctacctcat attttgttat 3300 gaaaaataaa tgataaaatt gggtcagaaa tcagcataat gcctggcaca gtaagggctt 3360 caaaataaaa ggtagctctt attattagta atggtgttag gaaaagtagc aatgttatac 3420 agaaccagga tatatcacag ggcagttctg aaattaaatc ctgaatcctg gccgggtgag 3480 gtggctcacg cttgtaatcc taagcacttt cggagactga ggcaggcgga tcacgaggtc 3540 aggagtttga gaccagcctg gccaacacac tgaaatcccg tctctactaa aaatacaaaa 3600 attagctggg tgtggtggca ggcgcctata atctcagcta cttgggaggc tgaggcagga 3660 gaatcacttg agcccaggag gcggaggttg cagtgagctg atatcgtgcc agtgcactcc 3720 agcctgggtg acatctctta aaaaaaaaaa tcctgaatac cacactacgc agtgactaac 3780 acatctttca ctacagaaca gaacctgtaa cttggccgtc tctcagcagt gctgctcagt 3840 gaacatttaa taatttatta ctttctaact cgtttcttgt tgacctcaag aattgtacat 3900 agtcattaac tttcctaaga aaatctttga caaacataga gctcctgaga tatttcacaa 3960 ccaggtggtc tcctccctgt cctatgcaat gttgggcccc agcctgattt agccgacctg 4020 gtcttcagac ttgagaggct gtttagggtt cttacaacac aaaggggatg agactttatc 4080 ctctacctgt gtgccaacaa gggattcttc ttatctcctt ggtgcaactt gtctgaaaaa 4140 gaaagtcaac acaattatct tcttaaaagt taaagatcaa attaaaaata agctatagtt 4200 ttcccaaaga tttagacctg agaaaaagga atagatcttt ctaaaacctg gcctgcactt 4260 agagcatttg tagtcacttc cactatttct tatgctgaga gaataatttg atgtcatgcc 4320 tattgaatgt ctttctaaag cttgattcat caggaggaac tgaccagaag tccatgcaca 4380 gacatttggc tttcactgta attcctactc aaaactccct ttcactgatt atgagcaggt 4440 tgcttagcta aaatgagaaa tacagcaaga agagggatgg aaagagctgg cttaaacttt 4500 cccaaagaca tcatgaacac tgggaacagg tcatacatat accattttta tttctcagtc 4560 ctcagtatta gaatattgtg ttcctagagg ctttgtgaaa attggaatac attgccatga 4620 cctgcacagg atagaggtgg ttaatatggc ttaccttgct tgtagatgtt tactcttgat 4680 ccctaaggga aactggaagg aaagcatgct gtagagagga cctgctttga gagtatgtgt 4740 cctctgggac aagtggaatg aaagagagga tagaggcaaa gagaaaaaaa ggtggagatg 4800 gggtgagact tgctggtgga cagttgcaaa gaaaactcat gatgagaata acatcacatt 4860 tcttgaagaa gctgaactgc attgatggga agttgaggca gagtttgaaa agaagatata 4920 ctgtctgcaa aaaagaatca acggagatgt caggtatctt gatgcaccct gagtctatga 4980 gatgcagctt aatttaattt aatgatatga gtaggccatt tcataagtgg tggaaattac 5040 cataaagtgt ttgcagctaa tgacggcgca tgaatgatgt cataggaacc taagtctgga 5100 tgagctatgg attgaatttt tactatggga cacccttcta catgttgctg tggaaaagaa 5160 ttgtcctcaa gaaatgtaca tcttctgcat ttcctctaca tctctgatat ttacaaagtg 5220 cacattattt ggtgatacta caactgggat ttcaagtgca catcactact atttccttca 5280 ctgaagaatc aagagcagtc tgggggtggg gagagcttga gtgattgaca aggatgtggc 5340 agagccctgg ttccactatg aattatagtt cttaccctgc ttactgtcac tcatgtagag 5400 cagctagtgt gcctcagagc actgctgttc tctgagaagc tgaggtctcg attgacattc 5460 ttgaagttgg tgtttacttc tctctgaata aacaaaggtt ggcaactcag acatcttaca 5520 ataagtacta aagatttttg aagaataggt ttttaaaaaa tgaaaaaaca tttcactttc 5580 catagctaat aaatcttatt ttgaggaaaa tgtacttttc tttaaaaaaa aaaaaagcct 5640 gtctgtcact ctagaccctt tggcttagaa ggtaggcaca ctcacataga aacagaaagt 5700 ctgtccaaat taaaactgaa aaccacagtt gactaatttt gaatttatag ctctgctgtt 5760 ggcttctgcg atagtattaa tttcaatggc ttcaattaga aaatgaaacc catagcattc 5820 catatgagaa caggtaaaaa gtcagggaca tttggagttt tccaagaaaa agaaagacaa 5880 gtcttaggaa gctctctagg atggaaggaa tttgccacac tgagagttag acatccaaag 5940 gatagcaatt ggctcttctg ctcatgggca ctggtgaagg cattttaaaa tgcgaagaat 6000 ggtacctctg taaatcaatg aggttcataa taatcatgca tttaccaaat ttttataagc 6060 acctgccttg tgccaggcac tgagggtaag gtgatgaata agccctcatc aactgtcaga 6120 ctagatattt actcaataac agatgtgaaa atgccaagaa ggaaaagttg agtataaaga 6180 aagccttaag ttggttcaga gaaataaaat tgcatttttc ggatagatgt ttatggaatc 6240 ggccttatga ggtaaacttg tcctatgcag tgaacataca ttcccagtta gtctcagatt 6300 ggcctctgtg atgacaaact cagagggtcc tggtctagga ggggtgaatt tgtctggagg 6360 ccattttcag gaggtatgga ggaagactgg ggcataggcc tggggccatc ccatgtactc 6420 ctcctctgaa atggggagca actgaattgt gttttatttt agatcttcgt ccaacttgaa 6480 taccagaaat tcgtgaaacc ttctcaaatt cacactatat tttgagacca ggagaaggct 6540 ccttgagaaa ttgccacact gtcttatcct agtctctgga aaaattcagt cctgtattat 6600 aactgggcgt ttctcataag tgcttttttt ttttcttttt ctttttataa tactttaagt 6660 tctgggatac atgtgcagaa tgtgcaggtt tgttacatag gtatacacgt gccatggtgg 6720 tttgctgcac ccatcaaccc atcatctaca ttaggtattt ctcctaatgc taccccttcc 6780 ctagcccccc acccctcgac aggccccagt gtttgatgtt cccctccctg tgtccatgtg 6840 ttctcattgt tcaactccca cttatgagtg agagcatgcg gtgtttggtt ttctgttcct 6900 gtgttagttt gctgagaatg atggtttttg gcttcatcca cgtccctgca aaggacatga 6960 actcatcctt tttatggctg catagtattc catggtgtat atgtgccaca tttgctttat 7020 ccagtctatc attgatgagc acttgggttg gctccaagtc tttgctatta tgactagtac 7080 tgcgataaac atgtgtatat gtgtctttat attagaatga tttataatcc tttaggtcta 7140 tacccagtaa taggattcct gggtcaaatg gtatttctgg ttctagatcc ttgaggaatt 7200 gccacactgt cttccacaac ggttgaacta atttacactc ccaccaacag tgtaaaagca 7260 ttcctatttc tccacatcct ctccaacatc tgttgtttcc tgactcttta atgacggcca 7320 ttctaactgg cgtgaaatgg tatctcattg tggttttgat ttgcatttct ctaatgacca 7380 ccgatgatga gctttttctc atatgtttgc tggccccata aatgtcttct tttgagaaat 7440 gtctgttcat atcctttgcc cactttttga tggggttgtt tgcttttttc ttgtaaattt 7500 gtttgagttc ctggtagatt ctggatatta gccctttgtc agatggatag actgcaaaaa 7560 ttttctccca ttctgtaggt tgcctgttca ctctgatggt agtttctttt gccatgcaga 7620 agctgtttag tttaattaga tccaatttgt cagttttggc ttttgttgcc attgcttttg 7680 gtgttttagt catgaagtct ttgcccatgc ctatgtcctg aattgtattg ccctggtttt 7740 cttctaggat ttttatggtt ttaggtctta catttaagtc tttaatccat cttgaattaa 7800 tttttgtata aggtgtaagg aaagggtcca gtttcagttt tctgcgtatg gctagccagt 7860 tttcccaacg ttatttatta aatagggaat cctttcccca ttgcttgttt ttgtcaggtt 7920 tgtcaaagat cagacggttg tagatgtgtg gtgttatttc tgaggcctct gttctgttcc 7980 attggtctgt atatctgctt tgataccagt accgtgctgt tttggttact gtagccttgt 8040 agtacagttt gaagtcaggt agcgtgatgc tttgttcttt ttgcttagga ttgtcttggc 8100 tatatgggct cttttttggt tctatatgaa atttaaagta gttttttcat agacatctat 8160 agaactctcc accccaaatc aacagaatat acattcttct cagtatcgca tcacacttat 8220 tctaaaatga ccacataatt agaagtaaaa cactcctcag caaatgcaaa aaacagaaat 8280 cctaacagtc tgtcagaccc cagtgcaatc aaattagaac tcaggattaa gaaacttact 8340 gaaaaccaca caactgcatg gaaactgaac aacctgctcc tgaatgacta ctgggtaaat 8400 aacaaaatta aggcagaaat aaataggttc tttgaaagaa atgagaacaa agacacaata 8460 taccagaatc tctgggacac agctaaagca gtgtttagag ggaaattgat agcactaaat 8520 gcccacagga gaaagcggga cagatctaaa atcgacaccc taatatcaca attaaaagaa 8580 ctagagaaac aagagcaaac aaattcaaaa gctagcagaa gacaagaaat aactaagatc 8640 agagcagaac tgaaggagat agagacacaa aaaacccttc aaaaaatcaa tgaatccagg 8700 agctgttttt ttttttttga aaagattaat gaaatagact gctagccaaa ctaataaagg 8760 agaaaagaga gaagaatcaa atagacaata gacacaataa aaagtgataa aggggatatc 8820 accactgatc ccacagaaat acaaactacc atcagagaat actataaaca cctctacgca 8880 aataaactag aaaattggga agaaatggat acattcctga acgcatacac cctcccaaga 8940 ctaaaccagg aagaagttga atccctgaat agaccaatag caagttctga aattgaggca 9000 gtaattagta gcctaccaac caaaaaaagc ccaggaccag acagattcac agccgaagtc 9060 taccagaggt acaaagagga gctagtacca ttccttctga aactattcca aacaatagaa 9120 aaagaaggac tcctccctaa ctcattttat gaggccagca tcatcctgat accaaaacct 9180 ggcagagaca caacataaag gaaattcagg ccaatatccc tgatgaacat tgatgtgaaa 9240 atcctcaata aaatactggc agcacatcaa aaagcttacc tgccatgatc aagttggctt 9300 catccctggg atgcaaggct ggttcaacat acgcaaatca ataaacgtaa tcaatcacat 9360 acacagaacc aatgacaaaa accacatgat tatctcaata gatgcagaaa aggccttcga 9420 taaaattcaa caccccttca atgctaagaa ctctcaataa actaggtatt gatgaaacat 9480 atctcaaaat aataagagtt atttatgaca aacccacagc cagtatcata ctgaatgggc 9540 aaaagctgga agcattccct ttgaaaaccg ccacaaggat gacttctctc accactccta 9600 ttcaacatac tattggaagt tctggccagg gcaagcaggc aagacaaata aataaagggt 9660 attcaaatag gaagagagga agtcaaattg tctctgtttg cagatgacat gattgtatat 9720 ttagaaaacc ccatcatctc agcccaaaat ctccttaagc tgataagcaa cttcagcaaa 9780 gtctcaggat acaaaatcaa tgtgcaaaaa tcacaagcat tcctatacac caataataga 9840 caaacagcca aatcatgagt gaactcccat tcacaagtgc tacaaagaat aaaataccta 9900 ggaatccaac ttacaaggga tgtgaaggac ctcttcaagg agaactacag accactgctc 9960 aaggtaataa gagaggacac aaacaaatgg aaaaacattc catgctcatg gataggaaga 10020 atcaatatta tgaaaatggc catactgccc aaaacaattt atagattcaa tgccatcccc 10080 atcaagctac cactgacttc cttcacagaa ttagaaaaaa actactttaa atttcatatg 10140 gaactgaaaa aagagccggt atagccaaga cgatcctaag caaaaagaaa aaagctggaa 10200 gcatcatgct acctgacttc aaactatact acaaggctac agtaacaaaa acagcatggt 10260 atagtataag tgcttttttt taaaagacaa agtaaagtaa tttttttgtt gttggggtaa 10320 aacaaaagct ctgcataaag agcagggatg ttgtaacata cactgaccaa aggtgggaaa 10380 cctacagttg gagcagaagc tgaatgtcac attatcagct ccgaacttat aatggtctaa 10440 aagtactagg ttaatgttgg aaagatggtg ccatttaaag atatcttaaa ttcaatattt 10500 aattatttta atttgacatt atcctagagt tgaatggtgt ttacttacca tgtgctgttc 10560 attagaaaat ctagatccta cactgccttt gcgcaaggta gttgctctaa taataccaac 10620 ctgtccagtt ttggtgggag aaataatgtt actgttaagt tgcacttagt ggttattatg 10680 tgtaatactg gtattccaaa gagagaagga aaatgtttgc tacacagctg tgttcttagg 10740 ttcagaaaac cacaggagtg ggacaggaga accttcagga ttcaggtccg attgttgtga 10800 tggccgcagg agggagactg tgaatttgaa actgcatcca ttgaaaagaa aatccctcca 10860 cactttaata attctctccg tgccccatgg cagcaagtgc ttataggcct tgctactcaa 10920 agcttaataa aaaggcagac ctgctgaatc ataatctgca tcttaacaat atccccagat 10980 attgtctgca ctttcttttt ttttttcttt ctttctttct tctttttttt gagacagagt 11040 ctcgctcagt cacccaggct ggagtgcagt ggcgcgatct cggctcactg caagctctga 11100 ctcccgggtt cacgccattc tcctgcctta gactcccgag tagctggcac tacaggcgcc 11160 cgccactacg cccggctaat ttttttgtat ttttagtaga gatggggttt caccgtgtta 11220 gccaggatgg tctcgatctc ctgacctcgt gatccgccgc ccatctgggc ctcccaaagt 11280 gctgggatta caggcgtgag ccactgcgcc cggccaattg tctgcacttt caagtctaag 11340 aagcactgtc ccaggaggaa aatcttttta gtctgaggct tctctcttgc actctccttt 11400 ttaaaaatat gctgctcctt ctccaccttt ccctcttctt ccgccttttc tgtctgcctt 11460 tactacctcc cctgaacatt caacttgtag aagagttccc ctttctctga attgcattct 11520 tcacttcatt cattcttttc tctctctgtc tatggtttcc tattttttgt cggttttccc 11580 tcacctcacc tccttgttat tttttgccat tgttcacata tcactgccct ttcagaccca 11640 tatctagctt ctgacccatc cactaatcca ttgccactaa tttattcagc atgcccatgc 11700 catttattaa tgtaaatatt tgcacatact tgttctatca tgcccatttt tctacctttt 11760 aaattgtata tacacagaca catgtgaatg acatatttca ctatttaaaa ggtagaaaaa 11820 tgtatatcgt ggtacaaagt gatacattga gtatctgtgc ccagtttcaa gatgagaata 11880 agtgagaggt gaagcctcat gagtcacgtc acctacacgc tactgtcttt cattccatct 11940 gcagtactgc cacacatttg gttagttctc caattgctgt cacattgaca tcgagttgga 12000 tctgaacagc gtacctgggg agacgaagta ttggtatctt tgcttaaatg gagtgattta 12060 ctgagagaca aagtgacatc tttaagatca gatagcaagt tactgcacca ggagcgcgac 12120 ctttcctgtt ttgttgtttt ccctctgtca aatgccttct ggtctccatg aatctctcct 12180 tccacatatg ataaaaatgc aaagtctcat aagcattcac agctcaggaa gcctcaggct 12240 agttggggag aaaagactgg gaggtttccg gaggaatgaa gtcctctgag cagagaggtt 12300 aattcatctt gctgtaaaac aaaatagaaa ataagttccc ctcaataagt gaacgtaata 12360 caaagacaaa tgtggttggt gccagaggcc aggaagaagt tcttgtgaga ataggtgcag 12420 agaagagcta ggccctggct gagtttaaac cttgacttag tcactgtggg actctgggtg 12480 agttactcca tggattgatg gctgggtcat ggagataata gtacctaatt catacaggta 12540 ctgtgagaag taaatggaat atttcacgtt aagtgtttaa cggtgcgttt aaatgctagg 12600 tgctattatt attaattttt aaattaactt tgccatgttt tgtgtcttcc cctctctgtg 12660 cttcctttct ttagtatgag ccgcacagcc tacacggtgg gagccctgct tctcctcttg 12720 gggaccctgc tgccggctgc tgaagggaaa aagaaagggt cccaaggtgc catccccccg 12780 ccagacaagg cccagcacaa tgactcagag cagactcagt cgccccagca gcctggctcc 12840 aggaaccggg ggcggggcca agggcggggc actgccatgc ccggggagga ggtgctggag 12900 tccagccaag aggccctgca tgtgacggag cgcaaatacc tgaagcgaga ctggtgcaaa 12960 acccagccgc ttaagcagac catccacgag gaaggctgca acagtcgcac catcatcaac 13020 cgcttctgtt acggccagtg caactctttc tacatcccca ggcacatccg gaaggaggaa 13080 ggttcctttc agtcctgctc cttctgcaag cccaagaaat tcactaccat gatggtcaca 13140 ctcaactgcc ctgaactaca gccacctacc aagaagaaga gagtcacacg tgtgaagcag 13200 tgtcgttgca tatccatcga tttggattaa gccaaatcca ggtgcaccca gcatgtccta 13260 ggaatgcagc cccaggaagt cccagaccta aaacaaccag attcttactt ggcttaaacc 13320 tagaggccag aagaaccccc agctgcctcc tggcaggagc ctgcttgtgc gtagttcgtg 13380 tgcatgagtg tggatgggtg cctgtgggtg tttttagaca ccagagaaaa cacagtctct 13440 gctagagagc actccctatt ttgtaaacat atctgcttta atggggatgt accagaaacc 13500 cacctcaccc cggctcacat ctaaaggggc ggggccgtgg tctggttctg actttgtgtt 13560 tttgtgccct cctggggacc agaatctcct ttcggaatga atgttcatgg aagaggctcc 13620 tctgagggca agagacctgt tttagtgctg cattcgacat ggaaaagtcc ttttaacctg 13680 tgcttgcatc ctcctttcct cctcctcctc acaatccatc tcttcttaag ttgatagtga 13740 ctatgtcagt ctaatctctt gtttgccaag gttcctaaat taattcactt aaccatgatg 13800 caaatgtttt tcattttgtg aagaccctcc agactctggg agaggctggt gtgggcaagg 13860 acaagcagga tagtggagtg agaaagggag ggtggagggt gaggccaaat caggtccagc 13920 aaaagtcagt agggacattg cagaagcttg aaaggccaat accagaacac aggctgatgc 13980 ttctgagaaa gtcttttcct agtatttaac agaacccaag tgaacagagg agaaatgaga 14040 ttgccagaaa gtgattaact ttggccgttg caatctgctc aaacctaaca ccaaactgaa 14100 aacataaata ctgaccactc ctatgttcgg acccaagcaa gttagctaaa ccaaaccaac 14160 tcctctgctt tgtccctcag gtggaaaaga gaggtagttt agaactctct gcataggggt 14220 gggaattaat caaaaaccgc agaggctgaa attcctaata cctttccttt atcgtggtta 14280 tagtcagctc atttccattc cactatttcc cataatgctt ctgagagcca ctaacttgat 14340 tgataaagat cctgcctctg ctgagtgtac ctgacagtag tctaagatga gagagtttag 14400 ggactactct gttttagcaa gagatatttt gggggtcttt ttgttttaac tattgtcagg 14460 agattgggct aaagagaaga cgacgagagt aaggaaataa agggaattgc ctctggctag 14520 agagtagtta ggtgttaata cctggtagag atgtaaggga tatgacctcc ctttctttat 14580 gtgctcactg aggatctgag gggaccctgt taggagagca tagcatcatg atgtattagc 14640 tgttcatctg ctactggttg gatggacata actattgtaa ctattcagta tttactggta 14700 ggcactgtcc tctgattaaa cttggcctac tggcaatggc tacttaggat tgatctaagg 14760 gccaaagtgc agggtgggtg aactttattg tactttggat ttggttaacc tgttttcttc 14820 aagcctgagg ttttatatac aaactccctg aatactcttt ttgccttgta tcttctcagc 14880 ctcctagcca agtcctatgt aatatggaaa acaaacactg cagacttgag attcagttgc 14940 cgatcaaggc tctggcattc agagaaccct tgcaactcga gaagctgttt ttatttcgtt 15000 tttgttttga tccagtgctc tcccatctaa caactaaaca ggagccattt caaggcggga 15060 gatattttaa acacccaaaa tgttgggtct gattttcaaa cttttaaact cactactgat 15120 gattctcacg ctaggcgaat ttgtccaaac acatagtgtg tgtgttttgt atacactgta 15180 tgaccccacc ccaaatcttt gtattgtcca cattctccaa caataaagca cagagtggat 15240 ttaattaagc acacaaatgc taaggcagaa ttttgagggt gggagagaag aaaagggaaa 15300 gaagctgaaa atgtaaaacc acaccaggga ggaaaaatga cattcagaac cagcaaacac 15360 tgaatttctc ttgttgtttt aactctgcca caagaatgca atttcgttaa cggagatgac 15420 ttaagttggc agcagtaatc ttcttttagg agcttgtacc acagtcttgc acataagtgc 15480 agatttggct caagtaaaga gaatttcctc aacactaact tcactgggat aatcagcagc 15540 gtaactaccc taaaagcata tcactagcca aagagggaaa tatctgttct tcttactgtg 15600 cctatattaa gactagtaca aatgtggtgt gtcttccaac tttcattgaa aatgccatat 15660 ctataccata ttttattcga gtcactgatg atgtaatgat atattttttc attattatag 15720 tagaatattt ttatggcaag atatttgtgg tcttgatcat acctattaaa ataatgccaa 15780 acaccaaata tgaattttat gatgtacact ttgtgcttgg cattaaaaga aaaaaacaca 15840 catcctggaa gtctgtaagt tgttttttgt tactgtaggt cttcaaagtt aagagtgtaa 15900 gtgaaaaatc tggaggagag gataatttcc actgtgtgga atgtgaatag ttaaatgaaa 15960 agttatggtt atttaatgta attattactt caaatccttt ggtcactgtg atttcaagca 16020 tgttttcttt ttctccttta tatgactttc tctgagttgg gcaaagaaga agctgacaca 16080 ccgtatgttg ttagagtctt ttatctggtc aggggaaaca aaatcttgac ccagctgaac 16140 atgtcttcct gagtcagtgc ctgaatcttt attttttaaa ttgaatgttc cttaaaggtt 16200 aacatttcta aagcaatatt aagaaagact ttaaatgtta ttttggaaga cttacgatgc 16260 atgtatacaa acgaatagca gataatgatg actagttcac acataaagtc cttttaagga 16320 gaaaatctaa aatgaaaagt ggataaacag aacatttata agtgatcagt taatgcctaa 16380 gagtgaaagt agttctattg acattcctca agatatttaa tatcaactgc attatgtatt 16440 atgtctgctt aaatcattta aaaacggcaa agaattatat agactatgag gtaccttgct 16500 gtgtaggagg atgaaagggg agttgatagt ctcataaaac taatttggct tcaagtttca 16560 tgaatctgta actagaattt aattttcacc ccaataatgt tctatatagc ctttgctaaa 16620 gagcaactaa taaattaaac ctattctttc tgtg 16654 <210> 37 <211> 555 <212> ADN <213> Homo sapiens <400> 37 atgagccgca cagcctacac ggtgggagcc ctgcttctcc tcttggggac cctgctgccg 60 gctgctgaag ggaaaaagaa agggtcccaa ggtgccatcc ccccgccaga caaggcccag 120 cacaatgact cagagcagac tcagtcgccc cagcagcctg gctccaggaa ccgggggcgg 180 ggccaagggc ggggcactgc catgcccggg gaggaggtgc tggagtccag ccaagaggcc 240 ctgcatgtga cggagcgcaa atacctgaag cgagactggt gcaaaaccca gccgcttaag 300 cagaccatcc acgaggaagg ctgcaacagt cgcaccatca tcaaccgctt ctgttacggc 360 cagtgcaact ctttctacat ccccaggcac atccggaagg aggaaggttc ctttcagtcc 420 tgctccttct gcaagcccaa gaaattcact accatgatgg tcacactcaa ctgccctgaa 480 ctacagccac ctaccaagaa gaagagagtc acacgtgtga agcagtgtcg ttgcatatcc 540 atcgatttgg attaa 555 <210> 38 <211> 20 <212> ADN <213> Secuencia artificial <220> <223> Cebador directo de Grem1 de ratón <400> 38 gcgcaagtat ctgaagcgag 20 <210> 39 <211> 20 <212> ADN <213> Secuencia artificial <220> <223> Cebador inverso de Grem1 de ratón <400> 39 cggttgatga tagtgcggct 20 <210> 40 <211> 21 <212> ADN <213> Secuencia artificial <220> <223> Cebador directo de Grem1 humano <400> 40 aggcccagca caatgactca g 21 <210> 41 <211> 21 <212> ADN <213> Secuencia artificial <220> <223> Cebador inverso de Grem1 humano <400> 41 gtctcgcttc aggtatttgc g 21 <210> 42 <211> 20 <212> ADN <213> Secuencia artificial <220> <223> Cebador directo de beta-actina <400> 42 gatcattgct cctcctgagc 20 <210> 43 <211> 22 <212> ADN <213> Secuencia artificial <220> <223> Cebador inverso de beta-actina <400> 43 gtcatagtcc gcctagaagc at 22