SEQUENCE LISTING <110> JOINT-STOCK COMPANY "GENERIUM" <120> TARGETED DELIVERY OF THERAPEUTIC ENZYMES <130> PCT_RU2022_050251 <150> RU 2021124495 <151> 2021-08-18 <160> 15 <170> PatentIn version 3.5 <210> 1 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Insulin receptor epitope recognized by an IgG immunoglobulin <400> 1 Met Glu Glu Val Ser Gly Thr Lys Gly Arg Gln Glu Arg Asn Asp Ile 1 5 10 15 Ala Leu Lys Thr Asn Gly Asp Gln Ala Ser Cys Glu Asn Glu Leu Leu 20 25 30 Lys Phe Ser Tyr Ile Arg Thr Ser Phe Asp Lys Ile Leu Leu Arg Trp 35 40 45 Glu Pro Tyr Trp Pro Pro Asp Phe Arg Asp Leu Leu Gly Phe Met Leu 50 55 60 Phe Tyr Lys Glu Ala Pro Tyr Gln Asn Val Thr Glu Phe Asp Gly Gln 65 70 75 80 Asp Ala Cys Gly Ser Asn Ser Trp Thr Val Val Asp Ile Asp Pro Pro 85 90 95 Leu Arg Ser Asn Asp Pro Lys Ser Gln Asn His Pro Gly Trp Leu Met 100 105 110 Arg Gly Leu Lys Pro Trp Thr Gln Tyr Ala Ile Phe 115 120 <210> 2 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Immunoglobulin IgG light chain to the insulin receptor <400> 2 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Gly Asn 20 25 30 Leu Tyr Trp Leu Gln Gln Gly Pro Asp Gly Thr Ile Lys Arg Leu Ile 35 40 45 Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Phe Val Asp Tyr Tyr Cys Leu Gln Tyr Ser Ser Ser Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Met 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 Gln 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 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 3 <211> 221 <212> PRT <213> Artificial Sequence <220> <223> Fragment VH-CH1 of the immunoglobulin IgG heavy chain to the insulin receptor <400> 3 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Leu Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Asp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Ser Ser Leu Thr Ser Glu Lys Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Leu 210 215 220 <210> 4 <211> 748 <212> PRT <213> Artificial Sequence <220> <223> Fragment VH-CH1 of the immunoglobulin IgG heavy chain to the insulin receptor coupled to an iduronate-2-sulfatase sequence <400> 4 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Leu Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Asp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Ser Ser Leu Thr Ser Glu Lys Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Leu Ser Ser Ser 210 215 220 Glu Thr Gln Ala Asn Ser Thr Thr Asp Ala Leu Asn Val Leu Leu Ile 225 230 235 240 Ile Val Asp Asp Leu Arg Pro Ser Leu Gly Cys Tyr Gly Asp Lys Leu 245 250 255 Val Arg Ser Pro Asn Ile Asp Gln Leu Ala Ser His Ser Leu Leu Phe 260 265 270 Gln Asn Ala Phe Ala Gln Gln Ala Val Cys Ala Pro Ser Arg Val Ser 275 280 285 Phe Leu Thr Gly Arg Arg Pro Asp Thr Thr Arg Leu Tyr Asp Phe Asn 290 295 300 Ser Tyr Trp Arg Val His Ala Gly Asn Phe Ser Thr Ile Pro Gln Tyr 305 310 315 320 Phe Lys Glu Asn Gly Tyr Val Thr Met Ser Val Gly Lys Val Phe His 325 330 335 Pro Gly Ile Ser Ser Asn His Thr Asp Asp Ser Pro Tyr Ser Trp Ser 340 345 350 Phe Pro Pro Tyr His Pro Ser Ser Glu Lys Tyr Glu Asn Thr Lys Thr 355 360 365 Cys Arg Gly Pro Asp Gly Glu Leu His Ala Asn Leu Leu Cys Pro Val 370 375 380 Asp Val Leu Asp Val Pro Glu Gly Thr Leu Pro Asp Lys Gln Ser Thr 385 390 395 400 Glu Gln Ala Ile Gln Leu Leu Glu Lys Met Lys Thr Ser Ala Ser Pro 405 410 415 Phe Phe Leu Ala Val Gly Tyr His Lys Pro His Ile Pro Phe Arg Tyr 420 425 430 Pro Lys Glu Phe Gln Lys Leu Tyr Pro Leu Glu Asn Ile Thr Leu Ala 435 440 445 Pro Asp Pro Glu Val Pro Asp Gly Leu Pro Pro Val Ala Tyr Asn Pro 450 455 460 Trp Met Asp Ile Arg Gln Arg Glu Asp Val Gln Ala Leu Asn Ile Ser 465 470 475 480 Val Pro Tyr Gly Pro Ile Pro Val Asp Phe Gln Arg Lys Ile Arg Gln 485 490 495 Ser Tyr Phe Ala Ser Val Ser Tyr Leu Asp Thr Gln Val Gly Arg Leu 500 505 510 Leu Ser Ala Leu Asp Asp Leu Gln Leu Ala Asn Ser Thr Ile Ile Ala 515 520 525 Phe Thr Ser Asp His Gly Trp Ala Leu Gly Glu His Gly Glu Trp Ala 530 535 540 Lys Tyr Ser Asn Phe Asp Val Ala Thr His Val Pro Leu Ile Phe Tyr 545 550 555 560 Val Pro Gly Arg Thr Ala Ser Leu Pro Glu Ala Gly Glu Lys Leu Phe 565 570 575 Pro Tyr Leu Asp Pro Phe Asp Ser Ala Ser Gln Leu Met Glu Pro Gly 580 585 590 Arg Gln Ser Met Asp Leu Val Glu Leu Val Ser Leu Phe Pro Thr Leu 595 600 605 Ala Gly Leu Ala Gly Leu Gln Val Pro Pro Arg Cys Pro Val Pro Ser 610 615 620 Phe His Val Glu Leu Cys Arg Glu Gly Lys Asn Leu Leu Lys His Phe 625 630 635 640 Arg Phe Arg Asp Leu Glu Glu Asp Pro Tyr Leu Pro Gly Asn Pro Arg 645 650 655 Glu Leu Ile Ala Tyr Ser Gln Tyr Pro Arg Pro Ser Asp Ile Pro Gln 660 665 670 Trp Asn Ser Asp Lys Pro Ser Leu Lys Asp Ile Lys Ile Met Gly Tyr 675 680 685 Ser Ile Arg Thr Ile Asp Tyr Arg Tyr Thr Val Trp Val Gly Phe Asn 690 695 700 Pro Asp Glu Phe Leu Ala Asn Phe Ser Asp Ile His Ala Gly Glu Leu 705 710 715 720 Tyr Phe Val Asp Ser Asp Pro Leu Gln Asp His Asn Met Tyr Asn Asp 725 730 735 Ser Gln Gly Gly Asp Leu Phe Gln Leu Leu Met Pro 740 745 <210> 5 <211> 760 <212> PRT <213> Artificial Sequence <220> <223> Fragment VH-CH1 of the immunoglobulin IgG heavy chain to the insulin receptor coupled to the iduronate-2-sulfatase sequence by a linker composed of glycine and serine <400> 5 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Leu Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Asp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Ser Ser Leu Thr Ser Glu Lys Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Glu Thr Gln Ala 225 230 235 240 Asn Ser Thr Thr Asp Ala Leu Asn Val Leu Leu Ile Ile Val Asp Asp 245 250 255 Leu Arg Pro Ser Leu Gly Cys Tyr Gly Asp Lys Leu Val Arg Ser Pro 260 265 270 Asn Ile Asp Gln Leu Ala Ser His Ser Leu Leu Phe Gln Asn Ala Phe 275 280 285 Ala Gln Gln Ala Val Cys Ala Pro Ser Arg Val Ser Phe Leu Thr Gly 290 295 300 Arg Arg Pro Asp Thr Thr Arg Leu Tyr Asp Phe Asn Ser Tyr Trp Arg 305 310 315 320 Val His Ala Gly Asn Phe Ser Thr Ile Pro Gln Tyr Phe Lys Glu Asn 325 330 335 Gly Tyr Val Thr Met Ser Val Gly Lys Val Phe His Pro Gly Ile Ser 340 345 350 Ser Asn His Thr Asp Asp Ser Pro Tyr Ser Trp Ser Phe Pro Pro Tyr 355 360 365 His Pro Ser Ser Glu Lys Tyr Glu Asn Thr Lys Thr Cys Arg Gly Pro 370 375 380 Asp Gly Glu Leu His Ala Asn Leu Leu Cys Pro Val Asp Val Leu Asp 385 390 395 400 Val Pro Glu Gly Thr Leu Pro Asp Lys Gln Ser Thr Glu Gln Ala Ile 405 410 415 Gln Leu Leu Glu Lys Met Lys Thr Ser Ala Ser Pro Phe Phe Leu Ala 420 425 430 Val Gly Tyr His Lys Pro His Ile Pro Phe Arg Tyr Pro Lys Glu Phe 435 440 445 Gln Lys Leu Tyr Pro Leu Glu Asn Ile Thr Leu Ala Pro Asp Pro Glu 450 455 460 Val Pro Asp Gly Leu Pro Pro Val Ala Tyr Asn Pro Trp Met Asp Ile 465 470 475 480 Arg Gln Arg Glu Asp Val Gln Ala Leu Asn Ile Ser Val Pro Tyr Gly 485 490 495 Pro Ile Pro Val Asp Phe Gln Arg Lys Ile Arg Gln Ser Tyr Phe Ala 500 505 510 Ser Val Ser Tyr Leu Asp Thr Gln Val Gly Arg Leu Leu Ser Ala Leu 515 520 525 Asp Asp Leu Gln Leu Ala Asn Ser Thr Ile Ile Ala Phe Thr Ser Asp 530 535 540 His Gly Trp Ala Leu Gly Glu His Gly Glu Trp Ala Lys Tyr Ser Asn 545 550 555 560 Phe Asp Val Ala Thr His Val Pro Leu Ile Phe Tyr Val Pro Gly Arg 565 570 575 Thr Ala Ser Leu Pro Glu Ala Gly Glu Lys Leu Phe Pro Tyr Leu Asp 580 585 590 Pro Phe Asp Ser Ala Ser Gln Leu Met Glu Pro Gly Arg Gln Ser Met 595 600 605 Asp Leu Val Glu Leu Val Ser Leu Phe Pro Thr Leu Ala Gly Leu Ala 610 615 620 Gly Leu Gln Val Pro Pro Arg Cys Pro Val Pro Ser Phe His Val Glu 625 630 635 640 Leu Cys Arg Glu Gly Lys Asn Leu Leu Lys His Phe Arg Phe Arg Asp 645 650 655 Leu Glu Glu Asp Pro Tyr Leu Pro Gly Asn Pro Arg Glu Leu Ile Ala 660 665 670 Tyr Ser Gln Tyr Pro Arg Pro Ser Asp Ile Pro Gln Trp Asn Ser Asp 675 680 685 Lys Pro Ser Leu Lys Asp Ile Lys Ile Met Gly Tyr Ser Ile Arg Thr 690 695 700 Ile Asp Tyr Arg Tyr Thr Val Trp Val Gly Phe Asn Pro Asp Glu Phe 705 710 715 720 Leu Ala Asn Phe Ser Asp Ile His Ala Gly Glu Leu Tyr Phe Val Asp 725 730 735 Ser Asp Pro Leu Gln Asp His Asn Met Tyr Asn Asp Ser Gln Gly Gly 740 745 750 Asp Leu Phe Gln Leu Leu Met Pro 755 760 <210> 6 <211> 850 <212> PRT <213> Artificial Sequence <220> <223> Fragment VH-CH1 of the immunoglobulin heavy chain to the human insulin receptor coupled to an alpha-L-iduronidase sequence <400> 6 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Leu Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Asp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Ser Ser Leu Thr Ser Glu Lys Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Leu Ser Ser Glu 210 215 220 Ala Pro His Leu Val Gln Val Asp Ala Ala Arg Ala Leu Trp Pro Leu 225 230 235 240 Arg Arg Phe Trp Arg Ser Thr Gly Phe Cys Pro Pro Leu Pro His Ser 245 250 255 Gln Ala Asp Gln Tyr Val Leu Ser Trp Asp Gln Gln Leu Asn Leu Ala 260 265 270 Tyr Val Gly Ala Val Pro His Arg Gly Ile Lys Gln Val Arg Thr His 275 280 285 Trp Leu Leu Glu Leu Val Thr Thr Arg Gly Ser Thr Gly Arg Gly Leu 290 295 300 Ser Tyr Asn Phe Thr His Leu Asp Gly Tyr Leu Asp Leu Leu Arg Glu 305 310 315 320 Asn Gln Leu Leu Pro Gly Phe Glu Leu Met Gly Ser Ala Ser Gly His 325 330 335 Phe Thr Asp Phe Glu Asp Lys Gln Gln Val Phe Glu Trp Lys Asp Leu 340 345 350 Val Ser Ser Leu Ala Arg Arg Tyr Ile Gly Arg Tyr Gly Leu Ala His 355 360 365 Val Ser Lys Trp Asn Phe Glu Thr Trp Asn Glu Pro Asp His His Asp 370 375 380 Phe Asp Asn Val Ser Met Thr Met Gln Gly Phe Leu Asn Tyr Tyr Asp 385 390 395 400 Ala Cys Ser Glu Gly Leu Arg Ala Ala Ser Pro Ala Leu Arg Leu Gly 405 410 415 Gly Pro Gly Asp Ser Phe His Thr Pro Pro Arg Ser Pro Leu Ser Trp 420 425 430 Gly Leu Leu Arg His Cys His Asp Gly Thr Asn Phe Phe Thr Gly Glu 435 440 445 Ala Gly Val Arg Leu Asp Tyr Ile Ser Leu His Arg Lys Gly Ala Arg 450 455 460 Ser Ser Ile Ser Ile Leu Glu Gln Glu Lys Val Val Ala Gln Gln Ile 465 470 475 480 Arg Gln Leu Phe Pro Lys Phe Ala Asp Thr Pro Ile Tyr Asn Asp Glu 485 490 495 Ala Asp Pro Leu Val Gly Trp Ser Leu Pro Gln Pro Trp Arg Ala Asp 500 505 510 Val Thr Tyr Ala Ala Met Val Val Lys Val Ile Ala Gln His Gln Asn 515 520 525 Leu Leu Leu Ala Asn Thr Thr Ser Ala Phe Pro Tyr Ala Leu Leu Ser 530 535 540 Asn Asp Asn Ala Phe Leu Ser Tyr His Pro His Pro Phe Ala Gln Arg 545 550 555 560 Thr Leu Thr Ala Arg Phe Gln Val Asn Asn Thr Arg Pro Pro His Val 565 570 575 Gln Leu Leu Arg Lys Pro Val Leu Thr Ala Met Gly Leu Leu Ala Leu 580 585 590 Leu Asp Glu Glu Gln Leu Trp Ala Glu Val Ser Gln Ala Gly Thr Val 595 600 605 Leu Asp Ser Asn His Thr Val Gly Val Leu Ala Ser Ala His Arg Pro 610 615 620 Gln Gly Pro Ala Asp Ala Trp Arg Ala Ala Val Leu Ile Tyr Ala Ser 625 630 635 640 Asp Asp Thr Arg Ala His Pro Asn Arg Ser Val Ala Val Thr Leu Arg 645 650 655 Leu Arg Gly Val Pro Pro Gly Pro Gly Leu Val Tyr Val Thr Arg Tyr 660 665 670 Leu Asp Asn Gly Leu Cys Ser Pro Asp Gly Glu Trp Arg Arg Leu Gly 675 680 685 Arg Pro Val Phe Pro Thr Ala Glu Gln Phe Arg Arg Met Arg Ala Ala 690 695 700 Glu Asp Pro Val Ala Ala Ala Pro Arg Pro Leu Pro Ala Gly Gly Arg 705 710 715 720 Leu Thr Leu Arg Pro Ala Leu Arg Leu Pro Ser Leu Leu Leu Val His 725 730 735 Val Cys Ala Arg Pro Glu Lys Pro Pro Gly Gln Val Thr Arg Leu Arg 740 745 750 Ala Leu Pro Leu Thr Gln Gly Gln Leu Val Leu Val Trp Ser Asp Glu 755 760 765 His Val Gly Ser Lys Cys Leu Trp Thr Tyr Glu Ile Gln Phe Ser Gln 770 775 780 Asp Gly Lys Ala Tyr Thr Pro Val Ser Arg Lys Pro Ser Thr Phe Asn 785 790 795 800 Leu Phe Val Phe Ser Pro Asp Thr Gly Ala Val Ser Gly Ser Tyr Arg 805 810 815 Val Arg Ala Leu Asp Tyr Trp Ala Arg Pro Gly Pro Phe Ser Asp Pro 820 825 830 Val Pro Tyr Leu Glu Val Pro Val Pro Arg Gly Pro Pro Ser Pro Gly 835 840 845 Asn Pro 850 <210> 7 <211> 862 <212> PRT <213> Artificial Sequence <220> <223> Fragment VH-CH1 of the immunoglobulin heavy chain to the human insulin receptor coupled to the alpha-L-iduronidase sequence by a linker composed of glycine and serine <400> 7 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Leu Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Asp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Ser Ser Leu Thr Ser Glu Lys Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Pro His Leu 225 230 235 240 Val Gln Val Asp Ala Ala Arg Ala Leu Trp Pro Leu Arg Arg Phe Trp 245 250 255 Arg Ser Thr Gly Phe Cys Pro Pro Leu Pro His Ser Gln Ala Asp Gln 260 265 270 Tyr Val Leu Ser Trp Asp Gln Gln Leu Asn Leu Ala Tyr Val Gly Ala 275 280 285 Val Pro His Arg Gly Ile Lys Gln Val Arg Thr His Trp Leu Leu Glu 290 295 300 Leu Val Thr Thr Arg Gly Ser Thr Gly Arg Gly Leu Ser Tyr Asn Phe 305 310 315 320 Thr His Leu Asp Gly Tyr Leu Asp Leu Leu Arg Glu Asn Gln Leu Leu 325 330 335 Pro Gly Phe Glu Leu Met Gly Ser Ala Ser Gly His Phe Thr Asp Phe 340 345 350 Glu Asp Lys Gln Gln Val Phe Glu Trp Lys Asp Leu Val Ser Ser Leu 355 360 365 Ala Arg Arg Tyr Ile Gly Arg Tyr Gly Leu Ala His Val Ser Lys Trp 370 375 380 Asn Phe Glu Thr Trp Asn Glu Pro Asp His His Asp Phe Asp Asn Val 385 390 395 400 Ser Met Thr Met Gln Gly Phe Leu Asn Tyr Tyr Asp Ala Cys Ser Glu 405 410 415 Gly Leu Arg Ala Ala Ser Pro Ala Leu Arg Leu Gly Gly Pro Gly Asp 420 425 430 Ser Phe His Thr Pro Pro Arg Ser Pro Leu Ser Trp Gly Leu Leu Arg 435 440 445 His Cys His Asp Gly Thr Asn Phe Phe Thr Gly Glu Ala Gly Val Arg 450 455 460 Leu Asp Tyr Ile Ser Leu His Arg Lys Gly Ala Arg Ser Ser Ile Ser 465 470 475 480 Ile Leu Glu Gln Glu Lys Val Val Ala Gln Gln Ile Arg Gln Leu Phe 485 490 495 Pro Lys Phe Ala Asp Thr Pro Ile Tyr Asn Asp Glu Ala Asp Pro Leu 500 505 510 Val Gly Trp Ser Leu Pro Gln Pro Trp Arg Ala Asp Val Thr Tyr Ala 515 520 525 Ala Met Val Val Lys Val Ile Ala Gln His Gln Asn Leu Leu Leu Ala 530 535 540 Asn Thr Thr Ser Ala Phe Pro Tyr Ala Leu Leu Ser Asn Asp Asn Ala 545 550 555 560 Phe Leu Ser Tyr His Pro His Pro Phe Ala Gln Arg Thr Leu Thr Ala 565 570 575 Arg Phe Gln Val Asn Asn Thr Arg Pro Pro His Val Gln Leu Leu Arg 580 585 590 Lys Pro Val Leu Thr Ala Met Gly Leu Leu Ala Leu Leu Asp Glu Glu 595 600 605 Gln Leu Trp Ala Glu Val Ser Gln Ala Gly Thr Val Leu Asp Ser Asn 610 615 620 His Thr Val Gly Val Leu Ala Ser Ala His Arg Pro Gln Gly Pro Ala 625 630 635 640 Asp Ala Trp Arg Ala Ala Val Leu Ile Tyr Ala Ser Asp Asp Thr Arg 645 650 655 Ala His Pro Asn Arg Ser Val Ala Val Thr Leu Arg Leu Arg Gly Val 660 665 670 Pro Pro Gly Pro Gly Leu Val Tyr Val Thr Arg Tyr Leu Asp Asn Gly 675 680 685 Leu Cys Ser Pro Asp Gly Glu Trp Arg Arg Leu Gly Arg Pro Val Phe 690 695 700 Pro Thr Ala Glu Gln Phe Arg Arg Met Arg Ala Ala Glu Asp Pro Val 705 710 715 720 Ala Ala Ala Pro Arg Pro Leu Pro Ala Gly Gly Arg Leu Thr Leu Arg 725 730 735 Pro Ala Leu Arg Leu Pro Ser Leu Leu Leu Val His Val Cys Ala Arg 740 745 750 Pro Glu Lys Pro Pro Gly Gln Val Thr Arg Leu Arg Ala Leu Pro Leu 755 760 765 Thr Gln Gly Gln Leu Val Leu Val Trp Ser Asp Glu His Val Gly Ser 770 775 780 Lys Cys Leu Trp Thr Tyr Glu Ile Gln Phe Ser Gln Asp Gly Lys Ala 785 790 795 800 Tyr Thr Pro Val Ser Arg Lys Pro Ser Thr Phe Asn Leu Phe Val Phe 805 810 815 Ser Pro Asp Thr Gly Ala Val Ser Gly Ser Tyr Arg Val Arg Ala Leu 820 825 830 Asp Tyr Trp Ala Arg Pro Gly Pro Phe Ser Asp Pro Val Pro Tyr Leu 835 840 845 Glu Val Pro Val Pro Arg Gly Pro Pro Ser Pro Gly Asn Pro 850 855 860 <210> 8 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Immunoglobulin IgG light chain to the insulin receptor LFR1 <400> 8 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Gly Gly Asn 20 25 30 Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val 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 Val Ala Thr Tyr Tyr Cys Leu Gln Tyr Ser Ser Ser Pro Trp 85 90 95 Thr Phe Gly Gln 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 Gln 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 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 9 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Immunoglobulin IgG light chain to the insulin receptor LFR2 <400> 9 Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys 1 5 10 15 Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Gly Gly Asn 20 25 30 Leu Tyr Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile 35 40 45 Lys Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Ala Tyr Tyr Cys Leu Gln Tyr Ser Ser Ser Pro Trp 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp 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 Gln 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 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 10 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Immunoglobulin IgG light chain to the insulin receptor LFR3 <400> 10 Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Gly Gly Asn 20 25 30 Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val 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 Leu Gln Tyr Ser Ser Ser Pro Trp 85 90 95 Thr Phe Gly Gln 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 Gln 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 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 11 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Immunoglobulin IgG light chain to the insulin receptor LFR4 <400> 11 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Gly Gly Asn 20 25 30 Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Thr Ser Ser Leu Asp Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Tyr Ser Ser Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu 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 Gln 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 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 12 <211> 748 <212> PRT <213> Artificial Sequence <220> <223> Fragment VH-CH1 of the immunoglobulin heavy chain to the human insulin receptor coupled to the iduronate-2-sulfatase sequence HFR1 <400> 12 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asn Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Glu Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Leu Ser Ser Ser 210 215 220 Glu Thr Gln Ala Asn Ser Thr Thr Asp Ala Leu Asn Val Leu Leu Ile 225 230 235 240 Ile Val Asp Asp Leu Arg Pro Ser Leu Gly Cys Tyr Gly Asp Lys Leu 245 250 255 Val Arg Ser Pro Asn Ile Asp Gln Leu Ala Ser His Ser Leu Leu Phe 260 265 270 Gln Asn Ala Phe Ala Gln Gln Ala Val Cys Ala Pro Ser Arg Val Ser 275 280 285 Phe Leu Thr Gly Arg Arg Pro Asp Thr Thr Arg Leu Tyr Asp Phe Asn 290 295 300 Ser Tyr Trp Arg Val His Ala Gly Asn Phe Ser Thr Ile Pro Gln Tyr 305 310 315 320 Phe Lys Glu Asn Gly Tyr Val Thr Met Ser Val Gly Lys Val Phe His 325 330 335 Pro Gly Ile Ser Ser Asn His Thr Asp Asp Ser Pro Tyr Ser Trp Ser 340 345 350 Phe Pro Pro Tyr His Pro Ser Ser Glu Lys Tyr Glu Asn Thr Lys Thr 355 360 365 Cys Arg Gly Pro Asp Gly Glu Leu His Ala Asn Leu Leu Cys Pro Val 370 375 380 Asp Val Leu Asp Val Pro Glu Gly Thr Leu Pro Asp Lys Gln Ser Thr 385 390 395 400 Glu Gln Ala Ile Gln Leu Leu Glu Lys Met Lys Thr Ser Ala Ser Pro 405 410 415 Phe Phe Leu Ala Val Gly Tyr His Lys Pro His Ile Pro Phe Arg Tyr 420 425 430 Pro Lys Glu Phe Gln Lys Leu Tyr Pro Leu Glu Asn Ile Thr Leu Ala 435 440 445 Pro Asp Pro Glu Val Pro Asp Gly Leu Pro Pro Val Ala Tyr Asn Pro 450 455 460 Trp Met Asp Ile Arg Gln Arg Glu Asp Val Gln Ala Leu Asn Ile Ser 465 470 475 480 Val Pro Tyr Gly Pro Ile Pro Val Asp Phe Gln Arg Lys Ile Arg Gln 485 490 495 Ser Tyr Phe Ala Ser Val Ser Tyr Leu Asp Thr Gln Val Gly Arg Leu 500 505 510 Leu Ser Ala Leu Asp Asp Leu Gln Leu Ala Asn Ser Thr Ile Ile Ala 515 520 525 Phe Thr Ser Asp His Gly Trp Ala Leu Gly Glu His Gly Glu Trp Ala 530 535 540 Lys Tyr Ser Asn Phe Asp Val Ala Thr His Val Pro Leu Ile Phe Tyr 545 550 555 560 Val Pro Gly Arg Thr Ala Ser Leu Pro Glu Ala Gly Glu Lys Leu Phe 565 570 575 Pro Tyr Leu Asp Pro Phe Asp Ser Ala Ser Gln Leu Met Glu Pro Gly 580 585 590 Arg Gln Ser Met Asp Leu Val Glu Leu Val Ser Leu Phe Pro Thr Leu 595 600 605 Ala Gly Leu Ala Gly Leu Gln Val Pro Pro Arg Cys Pro Val Pro Ser 610 615 620 Phe His Val Glu Leu Cys Arg Glu Gly Lys Asn Leu Leu Lys His Phe 625 630 635 640 Arg Phe Arg Asp Leu Glu Glu Asp Pro Tyr Leu Pro Gly Asn Pro Arg 645 650 655 Glu Leu Ile Ala Tyr Ser Gln Tyr Pro Arg Pro Ser Asp Ile Pro Gln 660 665 670 Trp Asn Ser Asp Lys Pro Ser Leu Lys Asp Ile Lys Ile Met Gly Tyr 675 680 685 Ser Ile Arg Thr Ile Asp Tyr Arg Tyr Thr Val Trp Val Gly Phe Asn 690 695 700 Pro Asp Glu Phe Leu Ala Asn Phe Ser Asp Ile His Ala Gly Glu Leu 705 710 715 720 Tyr Phe Val Asp Ser Asp Pro Leu Gln Asp His Asn Met Tyr Asn Asp 725 730 735 Ser Gln Gly Gly Asp Leu Phe Gln Leu Leu Met Pro 740 745 <210> 13 <211> 748 <212> PRT <213> Artificial Sequence <220> <223> Fragment VH-CH1 of the immunoglobulin heavy chain to the human insulin receptor coupled to the iduronate-2-sulfatase sequence HFR2 <400> 13 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Leu Ser Ser Ser 210 215 220 Glu Thr Gln Ala Asn Ser Thr Thr Asp Ala Leu Asn Val Leu Leu Ile 225 230 235 240 Ile Val Asp Asp Leu Arg Pro Ser Leu Gly Cys Tyr Gly Asp Lys Leu 245 250 255 Val Arg Ser Pro Asn Ile Asp Gln Leu Ala Ser His Ser Leu Leu Phe 260 265 270 Gln Asn Ala Phe Ala Gln Gln Ala Val Cys Ala Pro Ser Arg Val Ser 275 280 285 Phe Leu Thr Gly Arg Arg Pro Asp Thr Thr Arg Leu Tyr Asp Phe Asn 290 295 300 Ser Tyr Trp Arg Val His Ala Gly Asn Phe Ser Thr Ile Pro Gln Tyr 305 310 315 320 Phe Lys Glu Asn Gly Tyr Val Thr Met Ser Val Gly Lys Val Phe His 325 330 335 Pro Gly Ile Ser Ser Asn His Thr Asp Asp Ser Pro Tyr Ser Trp Ser 340 345 350 Phe Pro Pro Tyr His Pro Ser Ser Glu Lys Tyr Glu Asn Thr Lys Thr 355 360 365 Cys Arg Gly Pro Asp Gly Glu Leu His Ala Asn Leu Leu Cys Pro Val 370 375 380 Asp Val Leu Asp Val Pro Glu Gly Thr Leu Pro Asp Lys Gln Ser Thr 385 390 395 400 Glu Gln Ala Ile Gln Leu Leu Glu Lys Met Lys Thr Ser Ala Ser Pro 405 410 415 Phe Phe Leu Ala Val Gly Tyr His Lys Pro His Ile Pro Phe Arg Tyr 420 425 430 Pro Lys Glu Phe Gln Lys Leu Tyr Pro Leu Glu Asn Ile Thr Leu Ala 435 440 445 Pro Asp Pro Glu Val Pro Asp Gly Leu Pro Pro Val Ala Tyr Asn Pro 450 455 460 Trp Met Asp Ile Arg Gln Arg Glu Asp Val Gln Ala Leu Asn Ile Ser 465 470 475 480 Val Pro Tyr Gly Pro Ile Pro Val Asp Phe Gln Arg Lys Ile Arg Gln 485 490 495 Ser Tyr Phe Ala Ser Val Ser Tyr Leu Asp Thr Gln Val Gly Arg Leu 500 505 510 Leu Ser Ala Leu Asp Asp Leu Gln Leu Ala Asn Ser Thr Ile Ile Ala 515 520 525 Phe Thr Ser Asp His Gly Trp Ala Leu Gly Glu His Gly Glu Trp Ala 530 535 540 Lys Tyr Ser Asn Phe Asp Val Ala Thr His Val Pro Leu Ile Phe Tyr 545 550 555 560 Val Pro Gly Arg Thr Ala Ser Leu Pro Glu Ala Gly Glu Lys Leu Phe 565 570 575 Pro Tyr Leu Asp Pro Phe Asp Ser Ala Ser Gln Leu Met Glu Pro Gly 580 585 590 Arg Gln Ser Met Asp Leu Val Glu Leu Val Ser Leu Phe Pro Thr Leu 595 600 605 Ala Gly Leu Ala Gly Leu Gln Val Pro Pro Arg Cys Pro Val Pro Ser 610 615 620 Phe His Val Glu Leu Cys Arg Glu Gly Lys Asn Leu Leu Lys His Phe 625 630 635 640 Arg Phe Arg Asp Leu Glu Glu Asp Pro Tyr Leu Pro Gly Asn Pro Arg 645 650 655 Glu Leu Ile Ala Tyr Ser Gln Tyr Pro Arg Pro Ser Asp Ile Pro Gln 660 665 670 Trp Asn Ser Asp Lys Pro Ser Leu Lys Asp Ile Lys Ile Met Gly Tyr 675 680 685 Ser Ile Arg Thr Ile Asp Tyr Arg Tyr Thr Val Trp Val Gly Phe Asn 690 695 700 Pro Asp Glu Phe Leu Ala Asn Phe Ser Asp Ile His Ala Gly Glu Leu 705 710 715 720 Tyr Phe Val Asp Ser Asp Pro Leu Gln Asp His Asn Met Tyr Asn Asp 725 730 735 Ser Gln Gly Gly Asp Leu Phe Gln Leu Leu Met Pro 740 745 <210> 14 <211> 748 <212> PRT <213> Artificial Sequence <220> <223> Fragment VH-CH1 of the immunoglobulin heavy chain to the human insulin receptor coupled to the iduronate-2-sulfatase sequence HFR3 <400> 14 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr Asn Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Glu Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Leu Ser Ser Ser 210 215 220 Glu Thr Gln Ala Asn Ser Thr Thr Asp Ala Leu Asn Val Leu Leu Ile 225 230 235 240 Ile Val Asp Asp Leu Arg Pro Ser Leu Gly Cys Tyr Gly Asp Lys Leu 245 250 255 Val Arg Ser Pro Asn Ile Asp Gln Leu Ala Ser His Ser Leu Leu Phe 260 265 270 Gln Asn Ala Phe Ala Gln Gln Ala Val Cys Ala Pro Ser Arg Val Ser 275 280 285 Phe Leu Thr Gly Arg Arg Pro Asp Thr Thr Arg Leu Tyr Asp Phe Asn 290 295 300 Ser Tyr Trp Arg Val His Ala Gly Asn Phe Ser Thr Ile Pro Gln Tyr 305 310 315 320 Phe Lys Glu Asn Gly Tyr Val Thr Met Ser Val Gly Lys Val Phe His 325 330 335 Pro Gly Ile Ser Ser Asn His Thr Asp Asp Ser Pro Tyr Ser Trp Ser 340 345 350 Phe Pro Pro Tyr His Pro Ser Ser Glu Lys Tyr Glu Asn Thr Lys Thr 355 360 365 Cys Arg Gly Pro Asp Gly Glu Leu His Ala Asn Leu Leu Cys Pro Val 370 375 380 Asp Val Leu Asp Val Pro Glu Gly Thr Leu Pro Asp Lys Gln Ser Thr 385 390 395 400 Glu Gln Ala Ile Gln Leu Leu Glu Lys Met Lys Thr Ser Ala Ser Pro 405 410 415 Phe Phe Leu Ala Val Gly Tyr His Lys Pro His Ile Pro Phe Arg Tyr 420 425 430 Pro Lys Glu Phe Gln Lys Leu Tyr Pro Leu Glu Asn Ile Thr Leu Ala 435 440 445 Pro Asp Pro Glu Val Pro Asp Gly Leu Pro Pro Val Ala Tyr Asn Pro 450 455 460 Trp Met Asp Ile Arg Gln Arg Glu Asp Val Gln Ala Leu Asn Ile Ser 465 470 475 480 Val Pro Tyr Gly Pro Ile Pro Val Asp Phe Gln Arg Lys Ile Arg Gln 485 490 495 Ser Tyr Phe Ala Ser Val Ser Tyr Leu Asp Thr Gln Val Gly Arg Leu 500 505 510 Leu Ser Ala Leu Asp Asp Leu Gln Leu Ala Asn Ser Thr Ile Ile Ala 515 520 525 Phe Thr Ser Asp His Gly Trp Ala Leu Gly Glu His Gly Glu Trp Ala 530 535 540 Lys Tyr Ser Asn Phe Asp Val Ala Thr His Val Pro Leu Ile Phe Tyr 545 550 555 560 Val Pro Gly Arg Thr Ala Ser Leu Pro Glu Ala Gly Glu Lys Leu Phe 565 570 575 Pro Tyr Leu Asp Pro Phe Asp Ser Ala Ser Gln Leu Met Glu Pro Gly 580 585 590 Arg Gln Ser Met Asp Leu Val Glu Leu Val Ser Leu Phe Pro Thr Leu 595 600 605 Ala Gly Leu Ala Gly Leu Gln Val Pro Pro Arg Cys Pro Val Pro Ser 610 615 620 Phe His Val Glu Leu Cys Arg Glu Gly Lys Asn Leu Leu Lys His Phe 625 630 635 640 Arg Phe Arg Asp Leu Glu Glu Asp Pro Tyr Leu Pro Gly Asn Pro Arg 645 650 655 Glu Leu Ile Ala Tyr Ser Gln Tyr Pro Arg Pro Ser Asp Ile Pro Gln 660 665 670 Trp Asn Ser Asp Lys Pro Ser Leu Lys Asp Ile Lys Ile Met Gly Tyr 675 680 685 Ser Ile Arg Thr Ile Asp Tyr Arg Tyr Thr Val Trp Val Gly Phe Asn 690 695 700 Pro Asp Glu Phe Leu Ala Asn Phe Ser Asp Ile His Ala Gly Glu Leu 705 710 715 720 Tyr Phe Val Asp Ser Asp Pro Leu Gln Asp His Asn Met Tyr Asn Asp 725 730 735 Ser Gln Gly Gly Asp Leu Phe Gln Leu Leu Met Pro 740 745 <210> 15 <211> 748 <212> PRT <213> Artificial Sequence <220> <223> Fragment VH-CH1 of the immunoglobulin heavy chain to the human insulin receptor coupled to the iduronate-2-sulfatase sequence HFR4 <400> 15 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Glu Trp Ala Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Gly Ser 115 120 125 Ser Lys Ser Thr Ser Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Leu Ser Ser Ser 210 215 220 Glu Thr Gln Ala Asn Ser Thr Thr Asp Ala Leu Asn Val Leu Leu Ile 225 230 235 240 Ile Val Asp Asp Leu Arg Pro Ser Leu Gly Cys Tyr Gly Asp Lys Leu 245 250 255 Val Arg Ser Pro Asn Ile Asp Gln Leu Ala Ser His Ser Leu Leu Phe 260 265 270 Gln Asn Ala Phe Ala Gln Gln Ala Val Cys Ala Pro Ser Arg Val Ser 275 280 285 Phe Leu Thr Gly Arg Arg Pro Asp Thr Thr Arg Leu Tyr Asp Phe Asn 290 295 300 Ser Tyr Trp Arg Val His Ala Gly Asn Phe Ser Thr Ile Pro Gln Tyr 305 310 315 320 Phe Lys Glu Asn Gly Tyr Val Thr Met Ser Val Gly Lys Val Phe His 325 330 335 Pro Gly Ile Ser Ser Asn His Thr Asp Asp Ser Pro Tyr Ser Trp Ser 340 345 350 Phe Pro Pro Tyr His Pro Ser Ser Glu Lys Tyr Glu Asn Thr Lys Thr 355 360 365 Cys Arg Gly Pro Asp Gly Glu Leu His Ala Asn Leu Leu Cys Pro Val 370 375 380 Asp Val Leu Asp Val Pro Glu Gly Thr Leu Pro Asp Lys Gln Ser Thr 385 390 395 400 Glu Gln Ala Ile Gln Leu Leu Glu Lys Met Lys Thr Ser Ala Ser Pro 405 410 415 Phe Phe Leu Ala Val Gly Tyr His Lys Pro His Ile Pro Phe Arg Tyr 420 425 430 Pro Lys Glu Phe Gln Lys Leu Tyr Pro Leu Glu Asn Ile Thr Leu Ala 435 440 445 Pro Asp Pro Glu Val Pro Asp Gly Leu Pro Pro Val Ala Tyr Asn Pro 450 455 460 Trp Met Asp Ile Arg Gln Arg Glu Asp Val Gln Ala Leu Asn Ile Ser 465 470 475 480 Val Pro Tyr Gly Pro Ile Pro Val Asp Phe Gln Arg Lys Ile Arg Gln 485 490 495 Ser Tyr Phe Ala Ser Val Ser Tyr Leu Asp Thr Gln Val Gly Arg Leu 500 505 510 Leu Ser Ala Leu Asp Asp Leu Gln Leu Ala Asn Ser Thr Ile Ile Ala 515 520 525 Phe Thr Ser Asp His Gly Trp Ala Leu Gly Glu His Gly Glu Trp Ala 530 535 540 Lys Tyr Ser Asn Phe Asp Val Ala Thr His Val Pro Leu Ile Phe Tyr 545 550 555 560 Val Pro Gly Arg Thr Ala Ser Leu Pro Glu Ala Gly Glu Lys Leu Phe 565 570 575 Pro Tyr Leu Asp Pro Phe Asp Ser Ala Ser Gln Leu Met Glu Pro Gly 580 585 590 Arg Gln Ser Met Asp Leu Val Glu Leu Val Ser Leu Phe Pro Thr Leu 595 600 605 Ala Gly Leu Ala Gly Leu Gln Val Pro Pro Arg Cys Pro Val Pro Ser 610 615 620 Phe His Val Glu Leu Cys Arg Glu Gly Lys Asn Leu Leu Lys His Phe 625 630 635 640 Arg Phe Arg Asp Leu Glu Glu Asp Pro Tyr Leu Pro Gly Asn Pro Arg 645 650 655 Glu Leu Ile Ala Tyr Ser Gln Tyr Pro Arg Pro Ser Asp Ile Pro Gln 660 665 670 Trp Asn Ser Asp Lys Pro Ser Leu Lys Asp Ile Lys Ile Met Gly Tyr 675 680 685 Ser Ile Arg Thr Ile Asp Tyr Arg Tyr Thr Val Trp Val Gly Phe Asn 690 695 700 Pro Asp Glu Phe Leu Ala Asn Phe Ser Asp Ile His Ala Gly Glu Leu 705 710 715 720 Tyr Phe Val Asp Ser Asp Pro Leu Gln Asp His Asn Met Tyr Asn Asp 725 730 735 Ser Gln Gly Gly Asp Leu Phe Gln Leu Leu Met Pro 740 745