U.S. patent application number 15/417590 was filed with the patent office on 2017-05-25 for npp1 fusion proteins. The applicant listed for this patent is ALEXION PHARMACEUTICALS, INC.. Invention is credited to Alex J. HARVEY, Anthony QUINN, Zhinan XIA.
Application Number | 20170145393 15/417590 |
Document ID | / |
Family ID | 44564171 |
Filed Date | 2017-05-25 |
United States Patent Application | 20170145393 |
Kind Code | A1 |
QUINN; Anthony ; et al. | May 25, 2017 |
The present invention provides a novel fusion polypeptide containing a catalytic domain of NPP1 fused to a targeting moiety, nucleic acids encoding the fusion polypeptide, a vector containing the nucleic acid integrated thereinto, a host cell transformed with the vector and pharmaceutical compositions comprising the fusion polypeptide.
Inventors: | QUINN; Anthony; (Chestnut Hill, MA) ; HARVEY; Alex J.; (Athens, GA) ; XIA; Zhinan; (Wellesley, MA) | ||||||||||
Applicant: |
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Family ID: | 44564171 | ||||||||||
Appl. No.: | 15/417590 | ||||||||||
Filed: | January 27, 2017 |
Application Number | Filing Date | Patent Number | ||
---|---|---|---|---|
14004294 | Nov 14, 2013 | |||
PCT/US2011/051858 | Sep 15, 2011 | |||
15417590 | ||||
PCT/US2011/028233 | Mar 11, 2011 | |||
14004294 | ||||
Current U.S. Class: | 1/1 |
Current CPC Class: | A61P 3/10 20180101; C12N 15/8509 20130101; C12Y 301/04001 20130101; A61K 38/00 20130101; C12N 15/625 20130101; A61P 7/00 20180101; C07K 2319/02 20130101; C07K 2319/30 20130101; C07K 2319/00 20130101; C12N 15/86 20130101; C07K 7/06 20130101; C12N 9/00 20130101; Y10S 530/827 20130101; A61P 19/02 20180101; A61P 9/00 20180101; C12N 9/22 20130101; C12N 9/96 20130101; A61P 19/08 20180101; C12N 2840/007 20130101; A61P 21/00 20180101; C07K 2319/01 20130101; C07K 2319/33 20130101; A61P 9/10 20180101; C12N 9/16 20130101 |
International Class: | C12N 9/16 20060101 C12N009/16; C07K 7/06 20060101 C07K007/06; C12N 15/85 20060101 C12N015/85; C12N 15/62 20060101 C12N015/62; C12N 15/86 20060101 C12N015/86 |
Sequence CWU 1
1
221925PRTHomo sapiens 1Met Glu Arg Asp Gly Cys Ala Gly Gly Gly Ser
Arg Gly Gly Glu Gly 1 5 10 15 Gly Arg Ala Pro Arg Glu Gly Pro Ala
Gly Asn Gly Arg Asp Arg Gly 20 25 30 Arg Ser His Ala Ala Glu Ala
Pro Gly Asp Pro Gln Ala Ala Ala Ser 35 40 45 Leu Leu Ala Pro Met
Asp Val Gly Glu Glu Pro Leu Glu Lys Ala Ala 50 55 60 Arg Ala Arg
Thr Ala Lys Asp Pro Asn Thr Tyr Lys Val Leu Ser Leu 65 70 75 80 Val
Leu Ser Val Cys Val Leu Thr Thr Ile Leu Gly Cys Ile Phe Gly 85 90
95 Leu Lys Pro Ser Cys Ala Lys Glu Val Lys Ser Cys Lys Gly Arg Cys
100 105 110 Phe Glu Arg Thr Phe Gly Asn Cys Arg Cys Asp Ala Ala Cys
Val Glu 115 120 125 Leu Gly Asn Cys Cys Leu Asp Tyr Gln Glu Thr Cys
Ile Glu Pro Glu 130 135 140 His Ile Trp Thr Cys Asn Lys Phe Arg Cys
Gly Glu Lys Arg Leu Thr 145 150 155 160 Arg Ser Leu Cys Ala Cys Ser
Asp Asp Cys Lys Asp Lys Gly Asp Cys 165 170 175 Cys Ile Asn Tyr Ser
Ser Val Cys Gln Gly Glu Lys Ser Trp Val Glu 180 185 190 Glu Pro Cys
Glu Ser Ile Asn Glu Pro Gln Cys Pro Ala Gly Phe Glu 195 200 205 Thr
Pro Pro Thr Leu Leu Phe Ser Leu Asp Gly Phe Arg Ala Glu Tyr 210 215
220 Leu His Thr Trp Gly Gly Leu Leu Pro Val Ile Ser Lys Leu Lys Lys
225 230 235 240 Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro Val Tyr Pro
Thr Lys Thr 245 250 255 Phe Pro Asn His Tyr Ser Ile Val Thr Gly Leu
Tyr Pro Glu Ser His 260 265 270 Gly Ile Ile Asp Asn Lys Met Tyr Asp
Pro Lys Met Asn Ala Ser Phe 275 280 285 Ser Leu Lys Ser Lys Glu Lys
Phe Asn Pro Glu Trp Tyr Lys Gly Glu 290 295 300 Pro Ile Trp Val Thr
Ala Lys Tyr Gln Gly Leu Lys Ser Gly Thr Phe 305 310 315 320 Phe Trp
Pro Gly Ser Asp Val Glu Ile Asn Gly Ile Phe Pro Asp Ile 325 330 335
Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe Glu Glu Arg Ile Leu Ala 340
345 350 Val Leu Gln Trp Leu Gln Leu Pro Lys Asp Glu Arg Pro His Phe
Tyr 355 360 365 Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser Gly His Ser
Tyr Gly Pro 370 375 380 Val Ser Ser Glu Val Ile Lys Ala Leu Gln Arg
Val Asp Gly Met Val 385 390 395 400 Gly Met Leu Met Asp Gly Leu Lys
Glu Leu Asn Leu His Arg Cys Leu 405 410 415 Asn Leu Ile Leu Ile Ser
Asp His Gly Met Glu Gln Gly Ser Cys Lys 420 425 430 Lys Tyr Ile Tyr
Leu Asn Lys Tyr Leu Gly Asp Val Lys Asn Ile Lys 435 440 445 Val Ile
Tyr Gly Pro Ala Ala Arg Leu Arg Pro Ser Asp Val Pro Asp 450 455 460
Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile Ala Arg Asn Leu Ser Cys 465
470 475 480 Arg Glu Pro Asn Gln His Phe Lys Pro Tyr Leu Lys His Phe
Leu Pro 485 490 495 Lys Arg Leu His Phe Ala Lys Ser Asp Arg Ile Glu
Pro Leu Thr Phe 500 505 510 Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu
Asn Pro Ser Glu Arg Lys 515 520 525 Tyr Cys Gly Ser Gly Phe His Gly
Ser Asp Asn Val Phe Ser Asn Met 530 535 540 Gln Ala Leu Phe Val Gly
Tyr Gly Pro Gly Phe Lys His Gly Ile Glu 545 550 555 560 Ala Asp Thr
Phe Glu Asn Ile Glu Val Tyr Asn Leu Met Cys Asp Leu 565 570 575 Leu
Asn Leu Thr Pro Ala Pro Asn Asn Gly Thr His Gly Ser Leu Asn 580 585
590 His Leu Leu Lys Asn Pro Val Tyr Thr Pro Lys His Pro Lys Glu Val
595 600 605 His Pro Leu Val Gln Cys Pro Phe Thr Arg Asn Pro Arg Asp
Asn Leu 610 615 620 Gly Cys Ser Cys Asn Pro Ser Ile Leu Pro Ile Glu
Asp Phe Gln Thr 625 630 635 640 Gln Phe Asn Leu Thr Val Ala Glu Glu
Lys Ile Ile Lys His Glu Thr 645 650 655 Leu Pro Tyr Gly Arg Pro Arg
Val Leu Gln Lys Glu Asn Thr Ile Cys 660 665 670 Leu Leu Ser Gln His
Gln Phe Met Ser Gly Tyr Ser Gln Asp Ile Leu 675 680 685 Met Pro Leu
Trp Thr Ser Tyr Thr Val Asp Arg Asn Asp Ser Phe Ser 690 695 700 Thr
Glu Asp Phe Ser Asn Cys Leu Tyr Gln Asp Phe Arg Ile Pro Leu 705 710
715 720 Ser Pro Val His Lys Cys Ser Phe Tyr Lys Asn Asn Thr Lys Val
Ser 725 730 735 Tyr Gly Phe Leu Ser Pro Pro Gln Leu Asn Lys Asn Ser
Ser Gly Ile 740 745 750 Tyr Ser Glu Ala Leu Leu Thr Thr Asn Ile Val
Pro Met Tyr Gln Ser 755 760 765 Phe Gln Val Ile Trp Arg Tyr Phe His
Asp Thr Leu Leu Arg Lys Tyr 770 775 780 Ala Glu Glu Arg Asn Gly Val
Asn Val Val Ser Gly Pro Val Phe Asp 785 790 795 800 Phe Asp Tyr Asp
Gly Arg Cys Asp Ser Leu Glu Asn Leu Arg Gln Lys 805 810 815 Arg Arg
Val Ile Arg Asn Gln Glu Ile Leu Ile Pro Thr His Phe Phe 820 825 830
Ile Val Leu Thr Ser Cys Lys Asp Thr Ser Gln Thr Pro Leu His Cys 835
840 845 Glu Asn Leu Asp Thr Leu Ala Phe Ile Leu Pro His Arg Thr Asp
Asn 850 855 860 Ser Glu Ser Cys Val His Gly Lys His Asp Ser Ser Trp
Val Glu Glu 865 870 875 880 Leu Leu Met Leu His Arg Ala Arg Ile Thr
Asp Val Glu His Ile Thr 885 890 895 Gly Leu Ser Phe Tyr Gln Gln Arg
Lys Glu Pro Val Ser Asp Ile Leu 900 905 910 Lys Leu Lys Thr His Leu
Pro Thr Phe Ser Gln Glu Asp 915 920 925 2387PRTArtificial
sequenceNPP1 catalytic domain (sssNPP1) 2Ala Gly Phe Glu Thr Pro
Pro Thr Leu Leu Phe Ser Leu Asp Gly Phe 1 5 10 15 Arg Ala Glu Tyr
Leu His Thr Trp Gly Gly Leu Leu Pro Val Ile Ser 20 25 30 Lys Leu
Lys Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro Val Tyr 35 40 45
Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr Gly Leu Tyr 50
55 60 Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp Pro Lys
Met 65 70 75 80 Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn
Pro Glu Trp 85 90 95 Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys
Tyr Gln Gly Leu Lys 100 105 110 Ser Gly Thr Phe Phe Trp Pro Gly Ser
Asp Val Glu Ile Asn Gly Ile 115 120 125 Phe Pro Asp Ile Tyr Lys Met
Tyr Asn Gly Ser Val Pro Phe Glu Glu 130 135 140 Arg Ile Leu Ala Val
Leu Gln Trp Leu Gln Leu Pro Lys Asp Glu Arg 145 150 155 160 Pro His
Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser Gly His 165 170 175
Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu Gln Arg Val 180
185 190 Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu Leu Asn
Leu 195 200 205 His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly
Met Glu Gln 210 215 220 Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys
Tyr Leu Gly Asp Val 225 230 235 240 Lys Asn Ile Lys Val Ile Tyr Gly
Pro Ala Ala Arg Leu Arg Pro Ser 245 250 255 Asp Val Pro Asp Lys Tyr
Tyr Ser Phe Asn Tyr Glu Gly Ile Ala Arg 260 265 270 Asn Leu Ser Cys
Arg Glu Pro Asn Gln His Phe Lys Pro Tyr Leu Lys 275 280 285 His Phe
Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp Arg Ile Glu 290 295 300
Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu Asn Pro 305
310 315 320 Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser Asp
Asn Val 325 330 335 Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly
Pro Gly Phe Lys 340 345 350 His Gly Ile Glu Ala Asp Thr Phe Glu Asn
Ile Glu Val Tyr Asn Leu 355 360 365 Met Cys Asp Leu Leu Asn Leu Thr
Pro Ala Pro Asn Asn Gly Thr His 370 375 380 Gly Ser Leu 385
3420PRTArtificial sequenceD8 fused to NPP1 catalytic domain
(TAGsssNPP1) 3Ile Gly Val Leu Leu Thr Gln Arg Thr Leu Leu Ser Leu
Val Leu Ala 1 5 10 15 Leu Leu Phe Pro Ser Met Ala Ser Met Asp Asp
Asp Asp Asp Asp Asp 20 25 30 Asp Ala Gly Phe Glu Thr Pro Pro Thr
Leu Leu Phe Ser Leu Asp Gly 35 40 45 Phe Arg Ala Glu Tyr Leu His
Thr Trp Gly Gly Leu Leu Pro Val Ile 50 55 60 Ser Lys Leu Lys Lys
Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro Val 65 70 75 80 Tyr Pro Thr
Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr Gly Leu 85 90 95 Tyr
Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp Pro Lys 100 105
110 Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn Pro Glu
115 120 125 Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln
Gly Leu 130 135 140 Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val
Glu Ile Asn Gly 145 150 155 160 Ile Phe Pro Asp Ile Tyr Lys Met Tyr
Asn Gly Ser Val Pro Phe Glu 165 170 175 Glu Arg Ile Leu Ala Val Leu
Gln Trp Leu Gln Leu Pro Lys Asp Glu 180 185 190 Arg Pro His Phe Tyr
Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser Gly 195 200 205 His Ser Tyr
Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu Gln Arg 210 215 220 Val
Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu Leu Asn 225 230
235 240 Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly Met
Glu 245 250 255 Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr
Leu Gly Asp 260 265 270 Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala
Ala Arg Leu Arg Pro 275 280 285 Ser Asp Val Pro Asp Lys Tyr Tyr Ser
Phe Asn Tyr Glu Gly Ile Ala 290 295 300 Arg Asn Leu Ser Cys Arg Glu
Pro Asn Gln His Phe Lys Pro Tyr Leu 305 310 315 320 Lys His Phe Leu
Pro Lys Arg Leu His Phe Ala Lys Ser Asp Arg Ile 325 330 335 Glu Pro
Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu Asn 340 345 350
Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser Asp Asn 355
360 365 Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro Gly
Phe 370 375 380 Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu
Val Tyr Asn 385 390 395 400 Leu Met Cys Asp Leu Leu Asn Leu Thr Pro
Ala Pro Asn Asn Gly Thr 405 410 415 His Gly Ser Leu 420
4422PRTArtificial sequenceD10 fused to NPP1 catalytic domain 4Ile
Gly Val Leu Leu Thr Gln Arg Thr Leu Leu Ser Leu Val Leu Ala 1 5 10
15 Leu Leu Phe Pro Ser Met Ala Ser Met Ala Gly Phe Glu Thr Pro Pro
20 25 30 Thr Leu Leu Phe Ser Leu Asp Gly Phe Arg Ala Glu Tyr Leu
His Thr 35 40 45 Trp Gly Gly Leu Leu Pro Val Ile Ser Lys Leu Lys
Lys Cys Gly Thr 50 55 60 Tyr Thr Lys Asn Met Arg Pro Val Tyr Pro
Thr Lys Thr Phe Pro Asn 65 70 75 80 His Tyr Ser Ile Val Thr Gly Leu
Tyr Pro Glu Ser His Gly Ile Ile 85 90 95 Asp Asn Lys Met Tyr Asp
Pro Lys Met Asn Ala Ser Phe Ser Leu Lys 100 105 110 Ser Lys Glu Lys
Phe Asn Pro Glu Trp Tyr Lys Gly Glu Pro Ile Trp 115 120 125 Val Thr
Ala Lys Tyr Gln Gly Leu Lys Ser Gly Thr Phe Phe Trp Pro 130 135 140
Gly Ser Asp Val Glu Ile Asn Gly Ile Phe Pro Asp Ile Tyr Lys Met 145
150 155 160 Tyr Asn Gly Ser Val Pro Phe Glu Glu Arg Ile Leu Ala Val
Leu Gln 165 170 175 Trp Leu Gln Leu Pro Lys Asp Glu Arg Pro His Phe
Tyr Thr Leu Tyr 180 185 190 Leu Glu Glu Pro Asp Ser Ser Gly His Ser
Tyr Gly Pro Val Ser Ser 195 200 205 Glu Val Ile Lys Ala Leu Gln Arg
Val Asp Gly Met Val Gly Met Leu 210 215 220 Met Asp Gly Leu Lys Glu
Leu Asn Leu His Arg Cys Leu Asn Leu Ile 225 230 235 240 Leu Ile Ser
Asp His Gly Met Glu Gln Gly Ser Cys Lys Lys Tyr Ile 245 250 255 Tyr
Leu Asn Lys Tyr Leu Gly Asp Val Lys Asn Ile Lys Val Ile Tyr 260 265
270 Gly Pro Ala Ala Arg Leu Arg Pro Ser Asp Val Pro Asp Lys Tyr Tyr
275 280 285 Ser Phe Asn Tyr Glu Gly Ile Ala Arg Asn Leu Ser Cys Arg
Glu Pro 290 295 300 Asn Gln His Phe Lys Pro Tyr Leu Lys His Phe Leu
Pro Lys Arg Leu 305 310 315 320 His Phe Ala Lys Ser Asp Arg Ile Glu
Pro Leu Thr Phe Tyr Leu Asp 325 330 335 Pro Gln Trp Gln Leu Ala Leu
Asn Pro Ser Glu Arg Lys Tyr Cys Gly 340 345 350 Ser Gly Phe His Gly
Ser Asp Asn Val Phe Ser Asn Met Gln Ala Leu 355 360 365 Phe Val Gly
Tyr Gly Pro Gly Phe Lys His Gly Ile Glu Ala Asp Thr 370 375 380 Phe
Glu Asn Ile Glu Val Tyr Asn Leu Met Cys Asp Leu Leu Asn Leu 385 390
395 400 Thr Pro Ala Pro Asn Asn Gly Thr His Gly Ser Leu Asp Asp Asp
Asp 405 410 415 Asp Asp Asp Asp Asp Asp 420 52265DNAArtificial
sequenceNucleotide sequence encoding D8 NPP1 fusion protein
5atgggtgtac tgctcacaca gaggacgctg ctcagtctgg tccttgcact cctgtttcca
60agcatggcga gcatggatga cgatgatgac gacgatgacg cagggtttga aacgcctcct
120acactcttgt tttctttgga tggattcagg gcagaatatt tgcacacttg
gggtggactt 180cttcctgtta ttagcaaact caaaaaatgt ggaacatata
ctaaaaacat gagaccggtg 240tatccaacaa aaactttccc caatcactac
agcattgtca ccggattgta tccagaatct 300catggcataa tcgacaataa
gatgtatgat cccaaaatga atgcttcctt ttcacttaaa 360agtaaagaga
aatttaatcc ggagtggtac aaaggagaac caatttgggt cacagctaag
420tatcaaggcc tcaagtctgg cacatttttc tggccaggat cagatgtgga
aattaacgga 480attttcccag acatctataa aatgtataat ggttcagtgc
catttgaaga aaggattttg 540gctgttcttc agtggctgca gcttccaaaa
gatgaaagac cacactttta cactttgtat 600ttggaagaac cagattcttc
aggtcattca tatggaccag tcagcagtga agtcatcaaa 660gccttgcaga
gggttgatgg tatggttggt atgctgatgg atggtctgaa agagctgaac
720ttgcacagat gcctgaacct catccttatt tcagatcatg gcatggaaca
aggcagttgt 780aagaaataca tatatctgaa taagtatttg ggggatgtta
aaaatattaa agttatctat 840ggacctgcag ctcgattgag accctctgat
gtcccagata aatactattc atttaactat 900gaaggcattg cccgaaatct
ttcttgccgg gaaccaaacc agcacttcaa accttatctg 960aaacatttct
tgcctaagcg tttgcacttt gctaagagtg atagaattga gcccttgaca
1020ttctatttgg accctcagtg gcaacttgca ttgaatccct cagaaaggaa
atattgtgga 1080agtggatttc atggctctga caatgtgttt tcaaatatgc
aagccctctt tgttggctat 1140ggacctggat tcaagcatgg cattgaggct
gacacctttg aaaacattga agtctataac 1200ttgatgtgtg atttgctgaa
tttgacaccg gctcctaata acggaactca tggaagtctt 1260aaccaccttc
tgaagaatcc tgtttatacg ccaaagcatc ccaaagaagt gcaccccctg
1320gtgcagtgcc ccttcacaag aaaccccaga gataaccttg gctgctcatg
taacccttcc 1380attttgccga ttgaggattt tcaaacacag ttcaatctga
ccgtggcaga agagaagatt 1440attaagcatg aaactttgcc ctatggaaga
cctagagttc tccagaagga aaacaccatc 1500tgtcttcttt cccagcacca
gtttatgagt ggatacagcc aagacatctt gatgcccctt 1560tggacatcct
ataccgtgga cagaaatgac agtttctcta cggaagactt ctccaactgt
1620ctgtaccagg actttagaat tcctcttagt cctgtccata aatgttcatt
ttataaaaat 1680aacaccaaag tgagttacgg gttcctctcc ccaccacaac
tgaataagaa ttcaagtgga 1740atatattctg aagccttgct tactacaaat
atagtgccaa tgtaccagag ttttcaagtt 1800atatggcgct actttcatga
caccctcttg cgaaagtatg cagaagaaag aaatggtgtc 1860aatgtcgtca
gtggtcctgt gtttgacttt gattatgatg gacgttgtga ttccttggag
1920aatttgaggc aaaaaagaag agtcatccgt aaccaagaaa ttttgattcc
aactcatttc 1980ttcattgtgc tgacaagctg taaagataca tctcagacgc
ctttgcactg tgaaaacctg 2040gacaccttgg ctttcatttt gcctcacagg
actgataaca gcgagagctg tgtgcatggg 2100aagcatgact cctcatgggt
tgaagaattg ttgatgttgc acagagcacg gatcacagac 2160gtcgagcaca
tcactggact cagcttttat caacaaagaa aagagccagt ttcagacatt
2220ttgaagttga aaacacattt gccaaccttt agccaagaag attga
22656754PRTArtificial SequenceD8 NPP1 fusion protein 6Ile Gly Val
Leu Leu Thr Gln Arg Thr Leu Leu Ser Leu Val Leu Ala 1 5 10 15 Leu
Leu Phe Pro Ser Met Ala Ser Met Asp Asp Asp Asp Asp Asp Asp 20 25
30 Asp Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu Phe Ser Leu Asp Gly
35 40 45 Phe Arg Ala Glu Tyr Leu His Thr Trp Gly Gly Leu Leu Pro
Val Ile 50 55 60 Ser Lys Leu Lys Lys Cys Gly Thr Tyr Thr Lys Asn
Met Arg Pro Val 65 70 75 80 Tyr Pro Thr Lys Thr Phe Pro Asn His Tyr
Ser Ile Val Thr Gly Leu 85 90 95 Tyr Pro Glu Ser His Gly Ile Ile
Asp Asn Lys Met Tyr Asp Pro Lys 100 105 110 Met Asn Ala Ser Phe Ser
Leu Lys Ser Lys Glu Lys Phe Asn Pro Glu 115 120 125 Trp Tyr Lys Gly
Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln Gly Leu 130 135 140 Lys Ser
Gly Thr Phe Phe Trp Pro Gly Ser Asp Val Glu Ile Asn Gly 145 150 155
160 Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe Glu
165 170 175 Glu Arg Ile Leu Ala Val Leu Gln Trp Leu Gln Leu Pro Lys
Asp Glu 180 185 190 Arg Pro His Phe Tyr Thr Leu Tyr Leu Glu Glu Pro
Asp Ser Ser Gly 195 200 205 His Ser Tyr Gly Pro Val Ser Ser Glu Val
Ile Lys Ala Leu Gln Arg 210 215 220 Val Asp Gly Met Val Gly Met Leu
Met Asp Gly Leu Lys Glu Leu Asn 225 230 235 240 Leu His Arg Cys Leu
Asn Leu Ile Leu Ile Ser Asp His Gly Met Glu 245 250 255 Gln Gly Ser
Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly Asp 260 265 270 Val
Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala Arg Leu Arg Pro 275 280
285 Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile Ala
290 295 300 Arg Asn Leu Ser Cys Arg Glu Pro Asn Gln His Phe Lys Pro
Tyr Leu 305 310 315 320 Lys His Phe Leu Pro Lys Arg Leu His Phe Ala
Lys Ser Asp Arg Ile 325 330 335 Glu Pro Leu Thr Phe Tyr Leu Asp Pro
Gln Trp Gln Leu Ala Leu Asn 340 345 350 Pro Ser Glu Arg Lys Tyr Cys
Gly Ser Gly Phe His Gly Ser Asp Asn 355 360 365 Val Phe Ser Asn Met
Gln Ala Leu Phe Val Gly Tyr Gly Pro Gly Phe 370 375 380 Lys His Gly
Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu Val Tyr Asn 385 390 395 400
Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala Pro Asn Asn Gly Thr 405
410 415 His Gly Ser Leu Asn His Leu Leu Lys Asn Pro Val Tyr Thr Pro
Lys 420 425 430 His Pro Lys Glu Val His Pro Leu Val Gln Cys Pro Phe
Thr Arg Asn 435 440 445 Pro Arg Asp Asn Leu Gly Cys Ser Cys Asn Pro
Ser Ile Leu Pro Ile 450 455 460 Glu Asp Phe Gln Thr Gln Phe Asn Leu
Thr Val Ala Glu Glu Lys Ile 465 470 475 480 Ile Lys His Glu Thr Leu
Pro Tyr Gly Arg Pro Arg Val Leu Gln Lys 485 490 495 Glu Asn Thr Ile
Cys Leu Leu Ser Gln His Gln Phe Met Ser Gly Tyr 500 505 510 Ser Gln
Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr Val Asp Arg 515 520 525
Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn Cys Leu Tyr Gln Asp 530
535 540 Phe Arg Ile Pro Leu Ser Pro Val His Lys Cys Ser Phe Tyr Lys
Asn 545 550 555 560 Asn Thr Lys Val Ser Tyr Gly Phe Leu Ser Pro Pro
Gln Leu Asn Lys 565 570 575 Asn Ser Ser Gly Ile Tyr Ser Glu Ala Leu
Leu Thr Thr Asn Ile Val 580 585 590 Pro Met Tyr Gln Ser Phe Gln Val
Ile Trp Arg Tyr Phe His Asp Thr 595 600 605 Leu Leu Arg Lys Tyr Ala
Glu Glu Arg Asn Gly Val Asn Val Val Ser 610 615 620 Gly Pro Val Phe
Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser Leu Glu 625 630 635 640 Asn
Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln Glu Ile Leu Ile 645 650
655 Pro Thr His Phe Phe Ile Val Leu Thr Ser Cys Lys Asp Thr Ser Gln
660 665 670 Thr Pro Leu His Cys Glu Asn Leu Asp Thr Leu Ala Phe Ile
Leu Pro 675 680 685 His Arg Thr Asp Asn Ser Glu Ser Cys Val His Gly
Lys His Asp Ser 690 695 700 Ser Trp Val Glu Glu Leu Leu Met Leu His
Arg Ala Arg Ile Thr Asp 705 710 715 720 Val Glu His Ile Thr Gly Leu
Ser Phe Tyr Gln Gln Arg Lys Glu Pro 725 730 735 Val Ser Asp Ile Leu
Lys Leu Lys Thr His Leu Pro Thr Phe Ser Gln 740 745 750 Glu Asp
72238DNAArtificial SequenceNucleotide sequence encoding ssNPP1
protein 7atgggtgtac tgctcacaca gaggacgctg ctcagtctgg tccttgcact
cctgtttcca 60agcatggcga gcatggcagg gtttgaaacg cctcctacac tcttgttttc
tttggatgga 120ttcagggcag aatatttgca cacttggggt ggacttcttc
ctgttattag caaactcaaa 180aaatgtggaa catatactaa aaacatgaga
ccggtgtatc caacaaaaac tttccccaat 240cactacagca ttgtcaccgg
attgtatcca gaatctcatg gcataatcga caataagatg 300tatgatccca
aaatgaatgc ttccttttca cttaaaagta aagagaaatt taatccggag
360tggtacaaag gagaaccaat ttgggtcaca gctaagtatc aaggcctcaa
gtctggcaca 420tttttctggc caggatcaga tgtggaaatt aacggaattt
tcccagacat ctataaaatg 480tataatggtt cagtgccatt tgaagaaagg
attttggctg ttcttcagtg gctgcagctt 540ccaaaagatg aaagaccaca
cttttacact ttgtatttgg aagaaccaga ttcttcaggt 600cattcatatg
gaccagtcag cagtgaagtc atcaaagcct tgcagagggt tgatggtatg
660gttggtatgc tgatggatgg tctgaaagag ctgaacttgc acagatgcct
gaacctcatc 720cttatttcag atcatggcat ggaacaaggc agttgtaaga
aatacatata tctgaataag 780tatttggggg atgttaaaaa tattaaagtt
atctatggac ctgcagctcg attgagaccc 840tctgatgtcc cagataaata
ctattcattt aactatgaag gcattgcccg aaatctttct 900tgccgggaac
caaaccagca cttcaaacct tatctgaaac atttcttgcc taagcgtttg
960cactttgcta agagtgatag aattgagccc ttgacattct atttggaccc
tcagtggcaa 1020cttgcattga atccctcaga aaggaaatat tgtggaagtg
gatttcatgg ctctgacaat 1080gtgttttcaa atatgcaagc cctctttgtt
ggctatggac ctggattcaa gcatggcatt 1140gaggctgaca cctttgaaaa
cattgaagtc tataacttga tgtgtgattt gctgaatttg 1200acaccggctc
ctaataacgg aactcatgga agtcttaacc accttctgaa gaatcctgtt
1260tatacgccaa agcatcccaa agaagtgcac cccctggtgc agtgcccctt
cacaagaaac 1320cccagagata accttggctg ctcatgtaac ccttccattt
tgccgattga ggattttcaa 1380acacagttca atctgaccgt ggcagaagag
aagattatta agcatgaaac tttgccctat 1440ggaagaccta gagttctcca
gaaggaaaac accatctgtc ttctttccca gcaccagttt 1500atgagtggat
acagccaaga catcttgatg cccctttgga catcctatac cgtggacaga
1560aatgacagtt tctctacgga agacttctcc aactgtctgt accaggactt
tagaattcct 1620cttagtcctg tccataaatg ttcattttat aaaaataaca
ccaaagtgag ttacgggttc 1680ctctccccac cacaactgaa taagaattca
agtggaatat attctgaagc cttgcttact 1740acaaatatag tgccaatgta
ccagagtttt caagttatat ggcgctactt tcatgacacc 1800ctcttgcgaa
agtatgcaga agaaagaaat ggtgtcaatg tcgtcagtgg tcctgtgttt
1860gactttgatt atgatggacg ttgtgattcc ttggagaatt tgaggcaaaa
aagaagagtc 1920atccgtaacc aagaaatttt gattccaact catttcttca
ttgtgctgac aagctgtaaa 1980gatacatctc agacgccttt gcactgtgaa
aacctggaca ccttggcttt cattttgcct 2040cacaggactg ataacagcga
gagctgtgtg catgggaagc atgactcctc atgggttgaa 2100gaattgttga
tgttgcacag agcacggatc acagacgtcg agcacatcac tggactcagc
2160ttttatcaac aaagaaaaga gccagtttca gacattttga agttgaaaac
acatttgcca 2220acctttagcc aagaagat 22388746PRTArtificial
sequencessNPP1 protein 8Ile Gly Val Leu Leu Thr Gln Arg Thr Leu Leu
Ser Leu Val Leu Ala 1 5 10 15 Leu Leu Phe Pro Ser Met Ala Ser Met
Ala Gly Phe Glu Thr Pro Pro 20 25 30 Thr Leu Leu Phe Ser Leu Asp
Gly Phe Arg Ala Glu Tyr Leu His Thr 35 40 45 Trp Gly Gly Leu Leu
Pro Val Ile Ser Lys Leu Lys Lys Cys Gly Thr 50 55 60 Tyr Thr Lys
Asn Met Arg Pro Val Tyr Pro Thr Lys Thr Phe Pro Asn 65 70 75 80 His
Tyr Ser Ile Val Thr Gly Leu Tyr Pro Glu Ser His Gly Ile Ile 85 90
95 Asp Asn Lys Met Tyr Asp Pro Lys Met Asn Ala Ser Phe Ser Leu Lys
100 105 110 Ser Lys Glu Lys Phe Asn Pro Glu Trp Tyr Lys Gly Glu Pro
Ile Trp 115 120 125 Val Thr Ala Lys Tyr Gln Gly Leu Lys Ser Gly Thr
Phe Phe Trp Pro 130 135 140 Gly Ser Asp Val Glu Ile Asn Gly Ile Phe
Pro Asp Ile Tyr Lys Met 145 150 155 160 Tyr Asn Gly Ser Val Pro Phe
Glu Glu Arg Ile Leu Ala Val Leu Gln 165 170 175 Trp Leu Gln Leu Pro
Lys Asp Glu Arg Pro His Phe Tyr Thr Leu Tyr 180 185 190 Leu Glu Glu
Pro Asp Ser Ser Gly His Ser Tyr Gly Pro Val Ser Ser 195 200 205 Glu
Val Ile Lys Ala Leu Gln Arg Val Asp Gly Met Val Gly Met Leu 210 215
220 Met Asp Gly Leu Lys Glu Leu Asn Leu His Arg Cys Leu Asn Leu Ile
225 230 235 240 Leu Ile Ser Asp His Gly Met Glu Gln Gly Ser Cys Lys
Lys Tyr Ile 245 250 255 Tyr Leu Asn Lys Tyr Leu Gly Asp Val Lys Asn
Ile Lys Val Ile Tyr 260 265 270 Gly Pro Ala Ala Arg Leu Arg Pro Ser
Asp Val Pro Asp Lys Tyr Tyr 275 280 285 Ser Phe Asn Tyr Glu Gly Ile
Ala Arg Asn Leu Ser Cys Arg Glu Pro 290 295 300 Asn Gln His Phe Lys
Pro Tyr Leu Lys His Phe Leu Pro Lys Arg Leu 305 310 315 320 His Phe
Ala Lys Ser Asp Arg Ile Glu Pro Leu Thr Phe Tyr Leu Asp 325 330 335
Pro Gln Trp Gln Leu Ala Leu Asn Pro Ser Glu Arg Lys Tyr Cys Gly 340
345 350 Ser Gly Phe His Gly Ser Asp Asn Val Phe Ser Asn Met Gln Ala
Leu 355 360 365 Phe Val Gly Tyr Gly Pro Gly Phe Lys His Gly Ile Glu
Ala Asp Thr 370 375 380 Phe Glu Asn Ile Glu Val Tyr Asn Leu Met Cys
Asp Leu Leu Asn Leu 385 390 395 400 Thr Pro Ala Pro Asn Asn Gly Thr
His Gly Ser Leu Asn His Leu Leu 405 410 415 Lys Asn Pro Val Tyr Thr
Pro Lys His Pro Lys Glu Val His Pro Leu 420 425 430 Val Gln Cys Pro
Phe Thr Arg Asn Pro Arg Asp Asn Leu Gly Cys Ser 435 440 445 Cys Asn
Pro Ser Ile Leu Pro Ile Glu Asp Phe Gln Thr Gln Phe Asn 450 455 460
Leu Thr Val Ala Glu Glu Lys Ile Ile Lys His Glu Thr Leu Pro Tyr 465
470 475 480 Gly Arg Pro Arg Val Leu Gln Lys Glu Asn Thr Ile Cys Leu
Leu Ser 485 490 495 Gln His Gln Phe Met Ser Gly Tyr Ser Gln Asp Ile
Leu Met Pro Leu 500 505 510 Trp Thr Ser Tyr Thr Val Asp Arg Asn Asp
Ser Phe Ser Thr Glu Asp 515 520 525 Phe Ser Asn Cys Leu Tyr Gln Asp
Phe Arg Ile Pro Leu Ser Pro Val 530 535 540 His Lys Cys Ser Phe Tyr
Lys Asn Asn Thr Lys Val Ser Tyr Gly Phe 545 550 555 560 Leu Ser Pro
Pro Gln Leu Asn Lys Asn Ser Ser Gly Ile Tyr Ser Glu 565 570 575 Ala
Leu Leu Thr Thr Asn Ile Val Pro Met Tyr Gln Ser Phe Gln Val 580 585
590 Ile Trp Arg Tyr Phe His Asp Thr Leu Leu Arg Lys Tyr Ala Glu Glu
595 600 605 Arg Asn Gly Val Asn Val Val Ser Gly Pro Val Phe Asp Phe
Asp Tyr 610 615 620 Asp Gly Arg Cys Asp Ser Leu Glu Asn Leu Arg Gln
Lys Arg Arg Val 625 630 635 640 Ile Arg Asn Gln Glu Ile Leu Ile Pro
Thr His Phe Phe Ile Val Leu 645 650 655 Thr Ser Cys Lys Asp Thr Ser
Gln Thr Pro Leu His Cys Glu Asn Leu 660 665 670 Asp Thr Leu Ala Phe
Ile Leu Pro His Arg Thr Asp Asn Ser Glu Ser 675 680 685 Cys Val His
Gly Lys His Asp Ser Ser Trp Val Glu Glu Leu Leu Met 690 695 700 Leu
His Arg Ala Arg Ile Thr Asp Val Glu His Ile Thr Gly Leu Ser 705 710
715 720 Phe Tyr Gln Gln Arg Lys Glu Pro Val Ser Asp Ile Leu Lys Leu
Lys 725 730 735 Thr His Leu Pro Thr Phe Ser Gln Glu Asp 740 745
92556DNAArtificial sequenceNucleotide sequence encoding sNPP1
9atgggtgtac tgctcacaca gaggacgctg ctcagtctgg tccttgcact cctgtttcca
60agcatggcga gcatgccaag ttgtgccaaa gaagttaaaa gttgcaaagg tcgctgtttc
120gagagaacat ttgggaactg tcgctgtgat gctgcctgtg ttgagcttgg
aaactgctgt 180ttggattacc aggagacgtg catagaacca gaacatatat
ggacttgcaa caaattcagg 240tgtggtgaga aaagattgac cagaagcctc
tgtgcctgtt cagatgattg caaggacaag 300ggcgactgct gcatcaacta
cagttcagtg tgtcaaggtg agaaaagttg ggtggaagaa 360ccatgtgaga
gcattaatga gccacagtgc ccagcagggt ttgaaacgcc tcctacactc
420ttgttttctt tggatggatt cagggcagaa tatttgcaca cttggggtgg
acttcttcct 480gttattagca aactcaaaaa atgtggaaca tatactaaaa
acatgagacc ggtgtatcca 540acaaaaactt tccccaatca ctacagcatt
gtcaccggat tgtatccaga atctcatggc 600ataatcgaca ataagatgta
tgatcccaaa atgaatgctt ccttttcact taaaagtaaa 660gagaaattta
atccggagtg gtacaaagga gaaccaattt gggtcacagc taagtatcaa
720ggcctcaagt ctggcacatt tttctggcca ggatcagatg tggaaattaa
cggaattttc 780ccagacatct ataaaatgta taatggttca gtgccatttg
aagaaaggat tttggctgtt 840cttcagtggc tgcagcttcc aaaagatgaa
agaccacact tttacacttt gtatttggaa 900gaaccagatt cttcaggtca
ttcatatgga ccagtcagca gtgaagtcat caaagccttg 960cagagggttg
atggtatggt tggtatgctg atggatggtc tgaaagagct gaacttgcac
1020agatgcctga acctcatcct tatttcagat catggcatgg aacaaggcag
ttgtaagaaa 1080tacatatatc tgaataagta tttgggggat gttaaaaata
ttaaagttat ctatggacct 1140gcagctcgat tgagaccctc tgatgtccca
gataaatact attcatttaa ctatgaaggc 1200attgcccgaa
atctttcttg ccgggaacca aaccagcact tcaaacctta tctgaaacat
1260ttcttgccta agcgtttgca ctttgctaag agtgatagaa ttgagccctt
gacattctat 1320ttggaccctc agtggcaact tgcattgaat ccctcagaaa
ggaaatattg tggaagtgga 1380tttcatggct ctgacaatgt gttttcaaat
atgcaagccc tctttgttgg ctatggacct 1440ggattcaagc atggcattga
ggctgacacc tttgaaaaca ttgaagtcta taacttgatg 1500tgtgatttgc
tgaatttgac accggctcct aataacggaa ctcatggaag tcttaaccac
1560cttctgaaga atcctgttta tacgccaaag catcccaaag aagtgcaccc
cctggtgcag 1620tgccccttca caagaaaccc cagagataac cttggctgct
catgtaaccc ttccattttg 1680ccgattgagg attttcaaac acagttcaat
ctgaccgtgg cagaagagaa gattattaag 1740catgaaactt tgccctatgg
aagacctaga gttctccaga aggaaaacac catctgtctt 1800ctttcccagc
accagtttat gagtggatac agccaagaca tcttgatgcc cctttggaca
1860tcctataccg tggacagaaa tgacagtttc tctacggaag acttctccaa
ctgtctgtac 1920caggacttta gaattcctct tagtcctgtc cataaatgtt
cattttataa aaataacacc 1980aaagtgagtt acgggttcct ctccccacca
caactgaata agaattcaag tggaatatat 2040tctgaagcct tgcttactac
aaatatagtg ccaatgtacc agagttttca agttatatgg 2100cgctactttc
atgacaccct cttgcgaaag tatgcagaag aaagaaatgg tgtcaatgtc
2160gtcagtggtc ctgtgtttga ctttgattat gatggacgtt gtgattcctt
ggagaatttg 2220aggcaaaaaa gaagagtcat ccgtaaccaa gaaattttga
ttccaactca tttcttcatt 2280gtgctgacaa gctgtaaaga tacatctcag
acgcctttgc actgtgaaaa cctggacacc 2340ttggctttca ttttgcctca
caggactgat aacagcgaga gctgtgtgca tgggaagcat 2400gactcctcat
gggttgaaga attgttgatg ttgcacagag cacggatcac agacgtcgag
2460cacatcactg gactcagctt ttatcaacaa agaaaagagc cagtttcaga
cattttgaag 2520ttgaaaacac atttgccaac ctttagccaa gaagat
255610852PRTArtificial seqeuncesNPP1 protein 10Ile Gly Val Leu Leu
Thr Gln Arg Thr Leu Leu Ser Leu Val Leu Ala 1 5 10 15 Leu Leu Phe
Pro Ser Met Ala Ser Met Pro Ser Cys Ala Lys Glu Val 20 25 30 Lys
Ser Cys Lys Gly Arg Cys Phe Glu Arg Thr Phe Gly Asn Cys Arg 35 40
45 Cys Asp Ala Ala Cys Val Glu Leu Gly Asn Cys Cys Leu Asp Tyr Gln
50 55 60 Glu Thr Cys Ile Glu Pro Glu His Ile Trp Thr Cys Asn Lys
Phe Arg 65 70 75 80 Cys Gly Glu Lys Arg Leu Thr Arg Ser Leu Cys Ala
Cys Ser Asp Asp 85 90 95 Cys Lys Asp Lys Gly Asp Cys Cys Ile Asn
Tyr Ser Ser Val Cys Gln 100 105 110 Gly Glu Lys Ser Trp Val Glu Glu
Pro Cys Glu Ser Ile Asn Glu Pro 115 120 125 Gln Cys Pro Ala Gly Phe
Glu Thr Pro Pro Thr Leu Leu Phe Ser Leu 130 135 140 Asp Gly Phe Arg
Ala Glu Tyr Leu His Thr Trp Gly Gly Leu Leu Pro 145 150 155 160 Val
Ile Ser Lys Leu Lys Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg 165 170
175 Pro Val Tyr Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr
180 185 190 Gly Leu Tyr Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met
Tyr Asp 195 200 205 Pro Lys Met Asn Ala Ser Phe Ser Leu Lys Ser Lys
Glu Lys Phe Asn 210 215 220 Pro Glu Trp Tyr Lys Gly Glu Pro Ile Trp
Val Thr Ala Lys Tyr Gln 225 230 235 240 Gly Leu Lys Ser Gly Thr Phe
Phe Trp Pro Gly Ser Asp Val Glu Ile 245 250 255 Asn Gly Ile Phe Pro
Asp Ile Tyr Lys Met Tyr Asn Gly Ser Val Pro 260 265 270 Phe Glu Glu
Arg Ile Leu Ala Val Leu Gln Trp Leu Gln Leu Pro Lys 275 280 285 Asp
Glu Arg Pro His Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser 290 295
300 Ser Gly His Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu
305 310 315 320 Gln Arg Val Asp Gly Met Val Gly Met Leu Met Asp Gly
Leu Lys Glu 325 330 335 Leu Asn Leu His Arg Cys Leu Asn Leu Ile Leu
Ile Ser Asp His Gly 340 345 350 Met Glu Gln Gly Ser Cys Lys Lys Tyr
Ile Tyr Leu Asn Lys Tyr Leu 355 360 365 Gly Asp Val Lys Asn Ile Lys
Val Ile Tyr Gly Pro Ala Ala Arg Leu 370 375 380 Arg Pro Ser Asp Val
Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly 385 390 395 400 Ile Ala
Arg Asn Leu Ser Cys Arg Glu Pro Asn Gln His Phe Lys Pro 405 410 415
Tyr Leu Lys His Phe Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp 420
425 430 Arg Ile Glu Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu
Ala 435 440 445 Leu Asn Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe
His Gly Ser 450 455 460 Asp Asn Val Phe Ser Asn Met Gln Ala Leu Phe
Val Gly Tyr Gly Pro 465 470 475 480 Gly Phe Lys His Gly Ile Glu Ala
Asp Thr Phe Glu Asn Ile Glu Val 485 490 495 Tyr Asn Leu Met Cys Asp
Leu Leu Asn Leu Thr Pro Ala Pro Asn Asn 500 505 510 Gly Thr His Gly
Ser Leu Asn His Leu Leu Lys Asn Pro Val Tyr Thr 515 520 525 Pro Lys
His Pro Lys Glu Val His Pro Leu Val Gln Cys Pro Phe Thr 530 535 540
Arg Asn Pro Arg Asp Asn Leu Gly Cys Ser Cys Asn Pro Ser Ile Leu 545
550 555 560 Pro Ile Glu Asp Phe Gln Thr Gln Phe Asn Leu Thr Val Ala
Glu Glu 565 570 575 Lys Ile Ile Lys His Glu Thr Leu Pro Tyr Gly Arg
Pro Arg Val Leu 580 585 590 Gln Lys Glu Asn Thr Ile Cys Leu Leu Ser
Gln His Gln Phe Met Ser 595 600 605 Gly Tyr Ser Gln Asp Ile Leu Met
Pro Leu Trp Thr Ser Tyr Thr Val 610 615 620 Asp Arg Asn Asp Ser Phe
Ser Thr Glu Asp Phe Ser Asn Cys Leu Tyr 625 630 635 640 Gln Asp Phe
Arg Ile Pro Leu Ser Pro Val His Lys Cys Ser Phe Tyr 645 650 655 Lys
Asn Asn Thr Lys Val Ser Tyr Gly Phe Leu Ser Pro Pro Gln Leu 660 665
670 Asn Lys Asn Ser Ser Gly Ile Tyr Ser Glu Ala Leu Leu Thr Thr Asn
675 680 685 Ile Val Pro Met Tyr Gln Ser Phe Gln Val Ile Trp Arg Tyr
Phe His 690 695 700 Asp Thr Leu Leu Arg Lys Tyr Ala Glu Glu Arg Asn
Gly Val Asn Val 705 710 715 720 Val Ser Gly Pro Val Phe Asp Phe Asp
Tyr Asp Gly Arg Cys Asp Ser 725 730 735 Leu Glu Asn Leu Arg Gln Lys
Arg Arg Val Ile Arg Asn Gln Glu Ile 740 745 750 Leu Ile Pro Thr His
Phe Phe Ile Val Leu Thr Ser Cys Lys Asp Thr 755 760 765 Ser Gln Thr
Pro Leu His Cys Glu Asn Leu Asp Thr Leu Ala Phe Ile 770 775 780 Leu
Pro His Arg Thr Asp Asn Ser Glu Ser Cys Val His Gly Lys His 785 790
795 800 Asp Ser Ser Trp Val Glu Glu Leu Leu Met Leu His Arg Ala Arg
Ile 805 810 815 Thr Asp Val Glu His Ile Thr Gly Leu Ser Phe Tyr Gln
Gln Arg Lys 820 825 830 Glu Pro Val Ser Asp Ile Leu Lys Leu Lys Thr
His Leu Pro Thr Phe 835 840 845 Ser Gln Glu Asp 850
112580DNAArtificial sequenceNucleotide sequence encoding a TAGsNPP1
fusion protein 11atgggtgtac tgctcacaca gaggacgctg ctcagtctgg
tccttgcact cctgtttcca 60agcatggcga gcatggatga cgatgatgac gacgatgacc
caagttgtgc caaagaagtt 120aaaagttgca aaggtcgctg tttcgagaga
acatttggga actgtcgctg tgatgctgcc 180tgtgttgagc ttggaaactg
ctgtttggat taccaggaga cgtgcataga accagaacat 240atatggactt
gcaacaaatt caggtgtggt gagaaaagat tgaccagaag cctctgtgcc
300tgttcagatg attgcaagga caagggcgac tgctgcatca actacagttc
agtgtgtcaa 360ggtgagaaaa gttgggtgga agaaccatgt gagagcatta
atgagccaca gtgcccagca 420gggtttgaaa cgcctcctac actcttgttt
tctttggatg gattcagggc agaatatttg 480cacacttggg gtggacttct
tcctgttatt agcaaactca aaaaatgtgg aacatatact 540aaaaacatga
gaccggtgta tccaacaaaa actttcccca atcactacag cattgtcacc
600ggattgtatc cagaatctca tggcataatc gacaataaga tgtatgatcc
caaaatgaat 660gcttcctttt cacttaaaag taaagagaaa tttaatccgg
agtggtacaa aggagaacca 720atttgggtca cagctaagta tcaaggcctc
aagtctggca catttttctg gccaggatca 780gatgtggaaa ttaacggaat
tttcccagac atctataaaa tgtataatgg ttcagtgcca 840tttgaagaaa
ggattttggc tgttcttcag tggctgcagc ttccaaaaga tgaaagacca
900cacttttaca ctttgtattt ggaagaacca gattcttcag gtcattcata
tggaccagtc 960agcagtgaag tcatcaaagc cttgcagagg gttgatggta
tggttggtat gctgatggat 1020ggtctgaaag agctgaactt gcacagatgc
ctgaacctca tccttatttc agatcatggc 1080atggaacaag gcagttgtaa
gaaatacata tatctgaata agtatttggg ggatgttaaa 1140aatattaaag
ttatctatgg acctgcagct cgattgagac cctctgatgt cccagataaa
1200tactattcat ttaactatga aggcattgcc cgaaatcttt cttgccggga
accaaaccag 1260cacttcaaac cttatctgaa acatttcttg cctaagcgtt
tgcactttgc taagagtgat 1320agaattgagc ccttgacatt ctatttggac
cctcagtggc aacttgcatt gaatccctca 1380gaaaggaaat attgtggaag
tggatttcat ggctctgaca atgtgttttc aaatatgcaa 1440gccctctttg
ttggctatgg acctggattc aagcatggca ttgaggctga cacctttgaa
1500aacattgaag tctataactt gatgtgtgat ttgctgaatt tgacaccggc
tcctaataac 1560ggaactcatg gaagtcttaa ccaccttctg aagaatcctg
tttatacgcc aaagcatccc 1620aaagaagtgc accccctggt gcagtgcccc
ttcacaagaa accccagaga taaccttggc 1680tgctcatgta acccttccat
tttgccgatt gaggattttc aaacacagtt caatctgacc 1740gtggcagaag
agaagattat taagcatgaa actttgccct atggaagacc tagagttctc
1800cagaaggaaa acaccatctg tcttctttcc cagcaccagt ttatgagtgg
atacagccaa 1860gacatcttga tgcccctttg gacatcctat accgtggaca
gaaatgacag tttctctacg 1920gaagacttct ccaactgtct gtaccaggac
tttagaattc ctcttagtcc tgtccataaa 1980tgttcatttt ataaaaataa
caccaaagtg agttacgggt tcctctcccc accacaactg 2040aataagaatt
caagtggaat atattctgaa gccttgctta ctacaaatat agtgccaatg
2100taccagagtt ttcaagttat atggcgctac tttcatgaca ccctcttgcg
aaagtatgca 2160gaagaaagaa atggtgtcaa tgtcgtcagt ggtcctgtgt
ttgactttga ttatgatgga 2220cgttgtgatt ccttggagaa tttgaggcaa
aaaagaagag tcatccgtaa ccaagaaatt 2280ttgattccaa ctcatttctt
cattgtgctg acaagctgta aagatacatc tcagacgcct 2340ttgcactgtg
aaaacctgga caccttggct ttcattttgc ctcacaggac tgataacagc
2400gagagctgtg tgcatgggaa gcatgactcc tcatgggttg aagaattgtt
gatgttgcac 2460agagcacgga tcacagacgt cgagcacatc actggactca
gcttttatca acaaagaaaa 2520gagccagttt cagacatttt gaagttgaaa
acacatttgc caacctttag ccaagaagat 258012860PRTArtificial sequenceD8
TAGsNPP1 fusion protein 12Ile Gly Val Leu Leu Thr Gln Arg Thr Leu
Leu Ser Leu Val Leu Ala 1 5 10 15 Leu Leu Phe Pro Ser Met Ala Ser
Met Asp Asp Asp Asp Asp Asp Asp 20 25 30 Asp Pro Ser Cys Ala Lys
Glu Val Lys Ser Cys Lys Gly Arg Cys Phe 35 40 45 Glu Arg Thr Phe
Gly Asn Cys Arg Cys Asp Ala Ala Cys Val Glu Leu 50 55 60 Gly Asn
Cys Cys Leu Asp Tyr Gln Glu Thr Cys Ile Glu Pro Glu His 65 70 75 80
Ile Trp Thr Cys Asn Lys Phe Arg Cys Gly Glu Lys Arg Leu Thr Arg 85
90 95 Ser Leu Cys Ala Cys Ser Asp Asp Cys Lys Asp Lys Gly Asp Cys
Cys 100 105 110 Ile Asn Tyr Ser Ser Val Cys Gln Gly Glu Lys Ser Trp
Val Glu Glu 115 120 125 Pro Cys Glu Ser Ile Asn Glu Pro Gln Cys Pro
Ala Gly Phe Glu Thr 130 135 140 Pro Pro Thr Leu Leu Phe Ser Leu Asp
Gly Phe Arg Ala Glu Tyr Leu 145 150 155 160 His Thr Trp Gly Gly Leu
Leu Pro Val Ile Ser Lys Leu Lys Lys Cys 165 170 175 Gly Thr Tyr Thr
Lys Asn Met Arg Pro Val Tyr Pro Thr Lys Thr Phe 180 185 190 Pro Asn
His Tyr Ser Ile Val Thr Gly Leu Tyr Pro Glu Ser His Gly 195 200 205
Ile Ile Asp Asn Lys Met Tyr Asp Pro Lys Met Asn Ala Ser Phe Ser 210
215 220 Leu Lys Ser Lys Glu Lys Phe Asn Pro Glu Trp Tyr Lys Gly Glu
Pro 225 230 235 240 Ile Trp Val Thr Ala Lys Tyr Gln Gly Leu Lys Ser
Gly Thr Phe Phe 245 250 255 Trp Pro Gly Ser Asp Val Glu Ile Asn Gly
Ile Phe Pro Asp Ile Tyr 260 265 270 Lys Met Tyr Asn Gly Ser Val Pro
Phe Glu Glu Arg Ile Leu Ala Val 275 280 285 Leu Gln Trp Leu Gln Leu
Pro Lys Asp Glu Arg Pro His Phe Tyr Thr 290 295 300 Leu Tyr Leu Glu
Glu Pro Asp Ser Ser Gly His Ser Tyr Gly Pro Val 305 310 315 320 Ser
Ser Glu Val Ile Lys Ala Leu Gln Arg Val Asp Gly Met Val Gly 325 330
335 Met Leu Met Asp Gly Leu Lys Glu Leu Asn Leu His Arg Cys Leu Asn
340 345 350 Leu Ile Leu Ile Ser Asp His Gly Met Glu Gln Gly Ser Cys
Lys Lys 355 360 365 Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly Asp Val Lys
Asn Ile Lys Val 370 375 380 Ile Tyr Gly Pro Ala Ala Arg Leu Arg Pro
Ser Asp Val Pro Asp Lys 385 390 395 400 Tyr Tyr Ser Phe Asn Tyr Glu
Gly Ile Ala Arg Asn Leu Ser Cys Arg 405 410 415 Glu Pro Asn Gln His
Phe Lys Pro Tyr Leu Lys His Phe Leu Pro Lys 420 425 430 Arg Leu His
Phe Ala Lys Ser Asp Arg Ile Glu Pro Leu Thr Phe Tyr 435 440 445 Leu
Asp Pro Gln Trp Gln Leu Ala Leu Asn Pro Ser Glu Arg Lys Tyr 450 455
460 Cys Gly Ser Gly Phe His Gly Ser Asp Asn Val Phe Ser Asn Met Gln
465 470 475 480 Ala Leu Phe Val Gly Tyr Gly Pro Gly Phe Lys His Gly
Ile Glu Ala 485 490 495 Asp Thr Phe Glu Asn Ile Glu Val Tyr Asn Leu
Met Cys Asp Leu Leu 500 505 510 Asn Leu Thr Pro Ala Pro Asn Asn Gly
Thr His Gly Ser Leu Asn His 515 520 525 Leu Leu Lys Asn Pro Val Tyr
Thr Pro Lys His Pro Lys Glu Val His 530 535 540 Pro Leu Val Gln Cys
Pro Phe Thr Arg Asn Pro Arg Asp Asn Leu Gly 545 550 555 560 Cys Ser
Cys Asn Pro Ser Ile Leu Pro Ile Glu Asp Phe Gln Thr Gln 565 570 575
Phe Asn Leu Thr Val Ala Glu Glu Lys Ile Ile Lys His Glu Thr Leu 580
585 590 Pro Tyr Gly Arg Pro Arg Val Leu Gln Lys Glu Asn Thr Ile Cys
Leu 595 600 605 Leu Ser Gln His Gln Phe Met Ser Gly Tyr Ser Gln Asp
Ile Leu Met 610 615 620 Pro Leu Trp Thr Ser Tyr Thr Val Asp Arg Asn
Asp Ser Phe Ser Thr 625 630 635 640 Glu Asp Phe Ser Asn Cys Leu Tyr
Gln Asp Phe Arg Ile Pro Leu Ser 645 650 655 Pro Val His Lys Cys Ser
Phe Tyr Lys Asn Asn Thr Lys Val Ser Tyr 660 665 670 Gly Phe Leu Ser
Pro Pro Gln Leu Asn Lys Asn Ser Ser Gly Ile Tyr 675 680 685 Ser Glu
Ala Leu Leu Thr Thr Asn Ile Val Pro Met Tyr Gln Ser Phe 690 695 700
Gln Val Ile Trp Arg Tyr Phe His Asp Thr Leu Leu Arg Lys Tyr Ala 705
710 715 720 Glu Glu Arg Asn Gly Val Asn Val Val Ser Gly Pro Val Phe
Asp Phe 725 730 735 Asp Tyr Asp Gly Arg Cys Asp Ser Leu Glu Asn Leu
Arg Gln Lys Arg 740 745 750 Arg Val Ile Arg Asn Gln Glu Ile Leu Ile
Pro Thr His Phe Phe Ile 755 760 765 Val Leu Thr Ser Cys Lys Asp Thr
Ser Gln Thr Pro Leu His Cys Glu 770 775 780 Asn Leu Asp Thr Leu Ala
Phe Ile Leu Pro His Arg Thr Asp Asn Ser 785 790 795 800 Glu Ser Cys
Val His Gly Lys His Asp Ser Ser Trp Val Glu Glu Leu 805 810 815 Leu
Met Leu His Arg Ala Arg Ile Thr Asp Val Glu His Ile
Thr Gly 820 825 830 Leu Ser Phe Tyr Gln Gln Arg Lys Glu Pro Val Ser
Asp Ile Leu Lys 835 840 845 Leu Lys Thr His Leu Pro Thr Phe Ser Gln
Glu Asp 850 855 860 132580DNAArtificial sequenceNucleotide sequence
encoding C-terminal D8 TAGsNPP1 protein 13gtgggtgtac tgctcacaca
gaggacgctg ctcagtctgg tccttgcact cctgtttcca 60agcatggcga gcatgccaag
ttgtgccaaa gaagttaaaa gttgcaaagg tcgctgtttc 120gagagaacat
ttgggaactg tcgctgtgat gctgcctgtg ttgagcttgg aaactgctgt
180ttggattacc aggagacgtg catagaacca gaacatatat ggacttgcaa
caaattcagg 240tgtggtgaga aaagattgac cagaagcctc tgtgcctgtt
cagatgattg caaggacaag 300ggcgactgct gcatcaacta cagttcagtg
tgtcaaggtg agaaaagttg ggtggaagaa 360ccatgtgaga gcattaatga
gccacagtgc ccagcagggt ttgaaacgcc tcctacactc 420ttgttttctt
tggatggatt cagggcagaa tatttgcaca cttggggtgg acttcttcct
480gttattagca aactcaaaaa atgtggaaca tatactaaaa acatgagacc
ggtgtatcca 540acaaaaactt tccccaatca ctacagcatt gtcaccggat
tgtatccaga atctcatggc 600ataatcgaca ataagatgta tgatcccaaa
atgaatgctt ccttttcact taaaagtaaa 660gagaaattta atccggagtg
gtacaaagga gaaccaattt gggtcacagc taagtatcaa 720ggcctcaagt
ctggcacatt tttctggcca ggatcagatg tggaaattaa cggaattttc
780ccagacatct ataaaatgta taatggttca gtgccatttg aagaaaggat
tttggctgtt 840cttcagtggc tgcagcttcc aaaagatgaa agaccacact
tttacacttt gtatttggaa 900gaaccagatt cttcaggtca ttcatatgga
ccagtcagca gtgaagtcat caaagccttg 960cagagggttg atggtatggt
tggtatgctg atggatggtc tgaaagagct gaacttgcac 1020agatgcctga
acctcatcct tatttcagat catggcatgg aacaaggcag ttgtaagaaa
1080tacatatatc tgaataagta tttgggggat gttaaaaata ttaaagttat
ctatggacct 1140gcagctcgat tgagaccctc tgatgtccca gataaatact
attcatttaa ctatgaaggc 1200attgcccgaa atctttcttg ccgggaacca
aaccagcact tcaaacctta tctgaaacat 1260ttcttgccta agcgtttgca
ctttgctaag agtgatagaa ttgagccctt gacattctat 1320ttggaccctc
agtggcaact tgcattgaat ccctcagaaa ggaaatattg tggaagtgga
1380tttcatggct ctgacaatgt gttttcaaat atgcaagccc tctttgttgg
ctatggacct 1440ggattcaagc atggcattga ggctgacacc tttgaaaaca
ttgaagtcta taacttgatg 1500tgtgatttgc tgaatttgac accggctcct
aataacggaa ctcatggaag tcttaaccac 1560cttctgaaga atcctgttta
tacgccaaag catcccaaag aagtgcaccc cctggtgcag 1620tgccccttca
caagaaaccc cagagataac cttggctgct catgtaaccc ttccattttg
1680ccgattgagg attttcaaac acagttcaat ctgaccgtgg cagaagagaa
gattattaag 1740catgaaactt tgccctatgg aagacctaga gttctccaga
aggaaaacac catctgtctt 1800ctttcccagc accagtttat gagtggatac
agccaagaca tcttgatgcc cctttggaca 1860tcctataccg tggacagaaa
tgacagtttc tctacggaag acttctccaa ctgtctgtac 1920caggacttta
gaattcctct tagtcctgtc cataaatgtt cattttataa aaataacacc
1980aaagtgagtt acgggttcct ctccccacca caactgaata agaattcaag
tggaatatat 2040tctgaagcct tgcttactac aaatatagtg ccaatgtacc
agagttttca agttatatgg 2100cgctactttc atgacaccct cttgcgaaag
tatgcagaag aaagaaatgg tgtcaatgtc 2160gtcagtggtc ctgtgtttga
ctttgattat gatggacgtt gtgattcctt ggagaatttg 2220aggcaaaaaa
gaagagtcat ccgtaaccaa gaaattttga ttccaactca tttcttcatt
2280gtgctgacaa gctgtaaaga tacatctcag acgcctttgc actgtgaaaa
cctggacacc 2340ttggctttca ttttgcctca caggactgat aacagcgaga
gctgtgtgca tgggaagcat 2400gactcctcat gggttgaaga attgttgatg
ttgcacagag cacggatcac agacgtcgag 2460cacatcactg gactcagctt
ttatcaacaa agaaaagagc cagtttcaga cattttgaag 2520ttgaaaacac
atttgccaac ctttagccaa gaagatgatg acgatgatga cgacgattga
258014859PRTArtificial sequenceC-terminal D8 TAGsNPP1 fusion
protein 14Gln Gly Val Leu Leu Thr Gln Arg Thr Leu Leu Ser Leu Val
Leu Ala 1 5 10 15 Leu Leu Phe Pro Ser Met Ala Ser Met Pro Ser Cys
Ala Lys Glu Val 20 25 30 Lys Ser Cys Lys Gly Arg Cys Phe Glu Arg
Thr Phe Gly Asn Cys Arg 35 40 45 Cys Asp Ala Ala Cys Val Glu Leu
Gly Asn Cys Cys Leu Asp Tyr Gln 50 55 60 Glu Thr Cys Ile Glu Pro
Glu His Ile Trp Thr Cys Asn Lys Phe Arg 65 70 75 80 Cys Gly Glu Lys
Arg Leu Thr Arg Ser Leu Cys Ala Cys Ser Asp Asp 85 90 95 Cys Lys
Asp Lys Gly Asp Cys Cys Ile Asn Tyr Ser Ser Val Cys Gln 100 105 110
Gly Glu Lys Ser Trp Val Glu Glu Pro Cys Glu Ser Ile Asn Glu Pro 115
120 125 Gln Cys Pro Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu Phe Ser
Leu 130 135 140 Asp Gly Phe Arg Ala Glu Tyr Leu His Thr Trp Gly Gly
Leu Leu Pro 145 150 155 160 Val Ile Ser Lys Leu Lys Lys Cys Gly Thr
Tyr Thr Lys Asn Met Arg 165 170 175 Pro Val Tyr Pro Thr Lys Thr Phe
Pro Asn His Tyr Ser Ile Val Thr 180 185 190 Gly Leu Tyr Pro Glu Ser
His Gly Ile Ile Asp Asn Lys Met Tyr Asp 195 200 205 Pro Lys Met Asn
Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn 210 215 220 Pro Glu
Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln 225 230 235
240 Gly Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val Glu Ile
245 250 255 Asn Gly Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn Gly Ser
Val Pro 260 265 270 Phe Glu Glu Arg Ile Leu Ala Val Leu Gln Trp Leu
Gln Leu Pro Lys 275 280 285 Asp Glu Arg Pro His Phe Tyr Thr Leu Tyr
Leu Glu Glu Pro Asp Ser 290 295 300 Ser Gly His Ser Tyr Gly Pro Val
Ser Ser Glu Val Ile Lys Ala Leu 305 310 315 320 Gln Arg Val Asp Gly
Met Val Gly Met Leu Met Asp Gly Leu Lys Glu 325 330 335 Leu Asn Leu
His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly 340 345 350 Met
Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu 355 360
365 Gly Asp Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala Arg Leu
370 375 380 Arg Pro Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr
Glu Gly 385 390 395 400 Ile Ala Arg Asn Leu Ser Cys Arg Glu Pro Asn
Gln His Phe Lys Pro 405 410 415 Tyr Leu Lys His Phe Leu Pro Lys Arg
Leu His Phe Ala Lys Ser Asp 420 425 430 Arg Ile Glu Pro Leu Thr Phe
Tyr Leu Asp Pro Gln Trp Gln Leu Ala 435 440 445 Leu Asn Pro Ser Glu
Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser 450 455 460 Asp Asn Val
Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro 465 470 475 480
Gly Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu Val 485
490 495 Tyr Asn Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala Pro Asn
Asn 500 505 510 Gly Thr His Gly Ser Leu Asn His Leu Leu Lys Asn Pro
Val Tyr Thr 515 520 525 Pro Lys His Pro Lys Glu Val His Pro Leu Val
Gln Cys Pro Phe Thr 530 535 540 Arg Asn Pro Arg Asp Asn Leu Gly Cys
Ser Cys Asn Pro Ser Ile Leu 545 550 555 560 Pro Ile Glu Asp Phe Gln
Thr Gln Phe Asn Leu Thr Val Ala Glu Glu 565 570 575 Lys Ile Ile Lys
His Glu Thr Leu Pro Tyr Gly Arg Pro Arg Val Leu 580 585 590 Gln Lys
Glu Asn Thr Ile Cys Leu Leu Ser Gln His Gln Phe Met Ser 595 600 605
Gly Tyr Ser Gln Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr Val 610
615 620 Asp Arg Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn Cys Leu
Tyr 625 630 635 640 Gln Asp Phe Arg Ile Pro Leu Ser Pro Val His Lys
Cys Ser Phe Tyr 645 650 655 Lys Asn Asn Thr Lys Val Ser Tyr Gly Phe
Leu Ser Pro Pro Gln Leu 660 665 670 Asn Lys Asn Ser Ser Gly Ile Tyr
Ser Glu Ala Leu Leu Thr Thr Asn 675 680 685 Ile Val Pro Met Tyr Gln
Ser Phe Gln Val Ile Trp Arg Tyr Phe His 690 695 700 Asp Thr Leu Leu
Arg Lys Tyr Ala Glu Glu Arg Asn Gly Val Asn Val 705 710 715 720 Val
Ser Gly Pro Val Phe Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser 725 730
735 Leu Glu Asn Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln Glu Ile
740 745 750 Leu Ile Pro Thr His Phe Phe Ile Val Leu Thr Ser Cys Lys
Asp Thr 755 760 765 Ser Gln Thr Pro Leu His Cys Glu Asn Leu Asp Thr
Leu Ala Phe Ile 770 775 780 Leu Pro His Arg Thr Asp Asn Ser Glu Ser
Cys Val His Gly Lys His 785 790 795 800 Asp Ser Ser Trp Val Glu Glu
Leu Leu Met Leu His Arg Ala Arg Ile 805 810 815 Thr Asp Val Glu His
Ile Thr Gly Leu Ser Phe Tyr Gln Gln Arg Lys 820 825 830 Glu Pro Val
Ser Asp Ile Leu Lys Leu Lys Thr His Leu Pro Thr Phe 835 840 845 Ser
Gln Glu Asp Asp Asp Asp Asp Asp Asp Asp 850 855 1510PRTArtificial
sequenceLinker peptide 15Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1
5 10 16232PRTArtificial sequenceFc amino acid sequence 16Glu Pro
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 20
25 30 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val 35 40 45 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val 50 55 60 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln 65 70 75 80 Tyr Asn Ser Thr Tyr Arg Val Val Ser
Val Leu Thr Val Leu His Gln 85 90 95 Asp Trp Leu Asn Gly Lys Glu
Tyr Lys Cys Lys Val Ser Asn Lys Ala 100 105 110 Leu Pro Ala Pro Ile
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 115 120 125 Arg Glu Pro
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 130 135 140 Lys
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150
155 160 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr 165 170 175 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
Phe Leu Tyr 180 185 190 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
Gln Gly Asn Val Phe 195 200 205 Ser Cys Ser Val Met His Glu Ala Leu
His Asn His Tyr Thr Gln Lys 210 215 220 Ser Leu Ser Leu Ser Pro Gly
Lys 225 230 17662PRTArtificial sequenceN-terminus Fc-D8 TAGsssNPP1
fusion protein 17Ile Gly Val Leu Leu Thr Gln Arg Thr Leu Leu Ser
Leu Val Leu Ala 1 5 10 15 Leu Leu Phe Pro Ser Met Ala Ser Met Glu
Pro Lys Ser Cys Asp Lys 20 25 30 Thr His Thr Cys Pro Pro Cys Pro
Ala Pro Glu Ala Ala Gly Ala Pro 35 40 45 Ser Val Phe Leu Phe Pro
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 50 55 60 Arg Thr Pro Glu
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 65 70 75 80 Pro Glu
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 85 90 95
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 100
105 110 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
Glu 115 120 125 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
Ile Glu Lys 130 135 140 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
Pro Gln Val Tyr Thr 145 150 155 160 Leu Pro Pro Ser Arg Glu Glu Met
Thr Lys Asn Gln Val Ser Leu Thr 165 170 175 Cys Leu Val Lys Gly Phe
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 180 185 190 Ser Asn Gly Gln
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 195 200 205 Asp Ser
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 210 215 220
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 225
230 235 240 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
Pro Gly 245 250 255 Lys Asp Asp Asp Asp Asp Asp Asp Asp Gly Gly Gly
Gly Ser Gly Gly 260 265 270 Gly Gly Ser Ala Gly Phe Glu Thr Pro Pro
Thr Leu Leu Phe Ser Leu 275 280 285 Asp Gly Phe Arg Ala Glu Tyr Leu
His Thr Trp Gly Gly Leu Leu Pro 290 295 300 Val Ile Ser Lys Leu Lys
Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg 305 310 315 320 Pro Val Tyr
Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr 325 330 335 Gly
Leu Tyr Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp 340 345
350 Pro Lys Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn
355 360 365 Pro Glu Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys
Tyr Gln 370 375 380 Gly Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser
Asp Val Glu Ile 385 390 395 400 Asn Gly Ile Phe Pro Asp Ile Tyr Lys
Met Tyr Asn Gly Ser Val Pro 405 410 415 Phe Glu Glu Arg Ile Leu Ala
Val Leu Gln Trp Leu Gln Leu Pro Lys 420 425 430 Asp Glu Arg Pro His
Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser 435 440 445 Ser Gly His
Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu 450 455 460 Gln
Arg Val Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu 465 470
475 480 Leu Asn Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His
Gly 485 490 495 Met Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn
Lys Tyr Leu 500 505 510 Gly Asp Val Lys Asn Ile Lys Val Ile Tyr Gly
Pro Ala Ala Arg Leu 515 520 525 Arg Pro Ser Asp Val Pro Asp Lys Tyr
Tyr Ser Phe Asn Tyr Glu Gly 530 535 540 Ile Ala Arg Asn Leu Ser Cys
Arg Glu Pro Asn Gln His Phe Lys Pro 545 550 555 560 Tyr Leu Lys His
Phe Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp 565 570 575 Arg Ile
Glu Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala 580 585 590
Leu Asn Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser 595
600 605 Asp Asn Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly
Pro 610 615 620 Gly Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn
Ile Glu Val 625 630 635 640 Tyr Asn Leu Met Cys Asp Leu Leu Asn Leu
Thr Pro Ala Pro Asn Asn 645 650 655 Gly Thr His Gly Ser Leu 660
18662PRTArtificial sequenceC-termininal Fc-D8 TAGsssNPP1 fusion
protein 18Ile Gly Val Leu Leu Thr Gln Arg Thr Leu Leu Ser Leu Val
Leu Ala 1 5 10 15 Leu Leu Phe Pro Ser Met Ala Ser Met Glu Pro Lys
Ser Cys Asp Lys 20 25 30 Thr His Thr Cys Pro Pro Cys Pro Ala Pro
Glu Ala Ala Gly Ala Pro 35 40 45 Ser Val Phe Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met
Ile Ser 50 55 60 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp 65 70 75 80 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn 85 90 95 Ala Lys Thr Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val 100 105 110 Val Ser Val Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu 115 120 125 Tyr Lys Cys Lys
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 130 135 140 Thr Ile
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 145 150 155
160 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
165 170 175 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
Trp Glu 180 185 190 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
Pro Pro Val Leu 195 200 205 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
Lys Leu Thr Val Asp Lys 210 215 220 Ser Arg Trp Gln Gln Gly Asn Val
Phe Ser Cys Ser Val Met His Glu 225 230 235 240 Ala Leu His Asn His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 245 250 255 Lys Ala Gly
Phe Glu Thr Pro Pro Thr Leu Leu Phe Ser Leu Asp Gly 260 265 270 Phe
Arg Ala Glu Tyr Leu His Thr Trp Gly Gly Leu Leu Pro Val Ile 275 280
285 Ser Lys Leu Lys Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro Val
290 295 300 Tyr Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr
Gly Leu 305 310 315 320 Tyr Pro Glu Ser His Gly Ile Ile Asp Asn Lys
Met Tyr Asp Pro Lys 325 330 335 Met Asn Ala Ser Phe Ser Leu Lys Ser
Lys Glu Lys Phe Asn Pro Glu 340 345 350 Trp Tyr Lys Gly Glu Pro Ile
Trp Val Thr Ala Lys Tyr Gln Gly Leu 355 360 365 Lys Ser Gly Thr Phe
Phe Trp Pro Gly Ser Asp Val Glu Ile Asn Gly 370 375 380 Ile Phe Pro
Asp Ile Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe Glu 385 390 395 400
Glu Arg Ile Leu Ala Val Leu Gln Trp Leu Gln Leu Pro Lys Asp Glu 405
410 415 Arg Pro His Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser
Gly 420 425 430 His Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala
Leu Gln Arg 435 440 445 Val Asp Gly Met Val Gly Met Leu Met Asp Gly
Leu Lys Glu Leu Asn 450 455 460 Leu His Arg Cys Leu Asn Leu Ile Leu
Ile Ser Asp His Gly Met Glu 465 470 475 480 Gln Gly Ser Cys Lys Lys
Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly Asp 485 490 495 Val Lys Asn Ile
Lys Val Ile Tyr Gly Pro Ala Ala Arg Leu Arg Pro 500 505 510 Ser Asp
Val Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile Ala 515 520 525
Arg Asn Leu Ser Cys Arg Glu Pro Asn Gln His Phe Lys Pro Tyr Leu 530
535 540 Lys His Phe Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp Arg
Ile 545 550 555 560 Glu Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln
Leu Ala Leu Asn 565 570 575 Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly
Phe His Gly Ser Asp Asn 580 585 590 Val Phe Ser Asn Met Gln Ala Leu
Phe Val Gly Tyr Gly Pro Gly Phe 595 600 605 Lys His Gly Ile Glu Ala
Asp Thr Phe Glu Asn Ile Glu Val Tyr Asn 610 615 620 Leu Met Cys Asp
Leu Leu Asn Leu Thr Pro Ala Pro Asn Asn Gly Thr 625 630 635 640 His
Gly Ser Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Asp 645 650
655 Asp Asp Asp Asp Asp Asp 660 192580DNAArtificial
sequenceNucleotide sequence encoding D8 TAGsNPP1 fusion protein
19atgggtgtac tgctcacaca gaggacgctg ctcagtctgg tccttgcact cctgtttcca
60agcatggcga gcatgccaag ttgtgccaaa gaagttaaaa gttgcaaagg tcgctgtttc
120gagagaacat ttgggaactg tcgctgtgat gctgcctgtg ttgagcttgg
aaactgctgt 180ttggattacc aggagacgtg catagaacca gaacatatat
ggacttgcaa caaattcagg 240tgtggtgaga aaagattgac cagaagcctc
tgtgcctgtt cagatgattg caaggacaag 300ggcgactgct gcatcaacta
cagttcagtg tgtcaaggtg agaaaagttg ggtggaagaa 360ccatgtgaga
gcattaatga gccacagtgc ccagcagggt ttgaaacgcc tcctacactc
420ttgttttctt tggatggatt cagggcagaa tatttgcaca cttggggtgg
acttcttcct 480gttattagca aactcaaaaa atgtggaaca tatactaaaa
acatgagacc ggtgtatcca 540acaaaaactt tccccaatca ctacagcatt
gtcaccggat tgtatccaga atctcatggc 600ataatcgaca ataagatgta
tgatcccaaa atgaatgctt ccttttcact taaaagtaaa 660gagaaattta
atccggagtg gtacaaagga gaaccaattt gggtcacagc taagtatcaa
720ggcctcaagt ctggcacatt tttctggcca ggatcagatg tggaaattaa
cggaattttc 780ccagacatct ataaaatgta taatggttca gtgccatttg
aagaaaggat tttggctgtt 840cttcagtggc tgcagcttcc aaaagatgaa
agaccacact tttacacttt gtatttggaa 900gaaccagatt cttcaggtca
ttcatatgga ccagtcagca gtgaagtcat caaagccttg 960cagagggttg
atggtatggt tggtatgctg atggatggtc tgaaagagct gaacttgcac
1020agatgcctga acctcatcct tatttcagat catggcatgg aacaaggcag
ttgtaagaaa 1080tacatatatc tgaataagta tttgggggat gttaaaaata
ttaaagttat ctatggacct 1140gcagctcgat tgagaccctc tgatgtccca
gataaatact attcatttaa ctatgaaggc 1200attgcccgaa atctttcttg
ccgggaacca aaccagcact tcaaacctta tctgaaacat 1260ttcttgccta
agcgtttgca ctttgctaag agtgatagaa ttgagccctt gacattctat
1320ttggaccctc agtggcaact tgcattgaat ccctcagaaa ggaaatattg
tggaagtgga 1380tttcatggct ctgacaatgt gttttcaaat atgcaagccc
tctttgttgg ctatggacct 1440ggattcaagc atggcattga ggctgacacc
tttgaaaaca ttgaagtcta taacttgatg 1500tgtgatttgc tgaatttgac
accggctcct aataacggaa ctcatggaag tcttaaccac 1560cttctgaaga
atcctgttta tacgccaaag catcccaaag aagtgcaccc cctggtgcag
1620tgccccttca caagaaaccc cagagataac cttggctgct catgtaaccc
ttccattttg 1680ccgattgagg attttcaaac acagttcaat ctgaccgtgg
cagaagagaa gattattaag 1740catgaaactt tgccctatgg aagacctaga
gttctccaga aggaaaacac catctgtctt 1800ctttcccagc accagtttat
gagtggatac agccaagaca tcttgatgcc cctttggaca 1860tcctataccg
tggacagaaa tgacagtttc tctacggaag acttctccaa ctgtctgtac
1920caggacttta gaattcctct tagtcctgtc cataaatgtt cattttataa
aaataacacc 1980aaagtgagtt acgggttcct ctccccacca caactgaata
agaattcaag tggaatatat 2040tctgaagcct tgcttactac aaatatagtg
ccaatgtacc agagttttca agttatatgg 2100cgctactttc atgacaccct
cttgcgaaag tatgcagaag aaagaaatgg tgtcaatgtc 2160gtcagtggtc
ctgtgtttga ctttgattat gatggacgtt gtgattcctt ggagaatttg
2220aggcaaaaaa gaagagtcat ccgtaaccaa gaaattttga ttccaactca
tttcttcatt 2280gtgctgacaa gctgtaaaga tacatctcag acgcctttgc
actgtgaaaa cctggacacc 2340ttggctttca ttttgcctca caggactgat
aacagcgaga gctgtgtgca tgggaagcat 2400gactcctcat gggttgaaga
attgttgatg ttgcacagag cacggatcac agacgtcgag 2460cacatcactg
gactcagctt ttatcaacaa agaaaagagc cagtttcaga cattttgaag
2520ttgaaaacac atttgccaac ctttagccaa gaagatgatg acgatgatga
cgacgattga 258020859PRTArtificial sequenceC-terminal D8 TAGsNPP1
fusion protein 20Met Gly Val Leu Leu Thr Gln Arg Thr Leu Leu Ser
Leu Val Leu Ala 1 5 10 15 Leu Leu Phe Pro Ser Met Ala Ser Met Pro
Ser Cys Ala Lys Glu Val 20 25 30 Lys Ser Cys Lys Gly Arg Cys Phe
Glu Arg Thr Phe Gly Asn Cys Arg 35 40 45 Cys Asp Ala Ala Cys Val
Glu Leu Gly Asn Cys Cys Leu Asp Tyr Gln 50 55 60 Glu Thr Cys Ile
Glu Pro Glu His Ile Trp Thr Cys Asn Lys Phe Arg 65 70 75 80 Cys Gly
Glu Lys Arg Leu Thr Arg Ser Leu Cys Ala Cys Ser Asp Asp 85 90 95
Cys Lys Asp Lys Gly Asp Cys Cys Ile Asn Tyr Ser Ser Val Cys Gln 100
105 110 Gly Glu Lys Ser Trp Val Glu Glu Pro Cys Glu Ser Ile Asn Glu
Pro 115 120 125 Gln Cys Pro Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu
Phe Ser Leu 130 135 140 Asp Gly Phe Arg Ala Glu Tyr Leu His Thr Trp
Gly Gly Leu Leu Pro 145 150 155 160 Val Ile Ser Lys Leu Lys Lys Cys
Gly Thr Tyr Thr Lys Asn Met Arg 165 170 175 Pro Val Tyr Pro Thr Lys
Thr Phe Pro Asn His Tyr Ser Ile Val Thr 180 185 190 Gly Leu Tyr Pro
Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp 195 200 205 Pro Lys
Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn 210 215 220
Pro Glu Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln 225
230 235 240 Gly Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val
Glu Ile 245 250 255 Asn Gly Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn
Gly Ser Val Pro 260 265 270 Phe Glu Glu Arg Ile Leu Ala Val Leu Gln
Trp Leu Gln Leu Pro Lys 275 280 285 Asp Glu Arg Pro His Phe Tyr Thr
Leu Tyr Leu Glu Glu Pro Asp Ser 290 295 300 Ser Gly His Ser Tyr Gly
Pro Val Ser Ser Glu Val Ile Lys Ala Leu 305 310 315 320 Gln Arg Val
Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu 325 330 335 Leu
Asn Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly 340 345
350 Met Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu
355 360 365 Gly Asp Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala
Arg Leu 370 375 380 Arg Pro Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe
Asn Tyr Glu Gly 385 390 395 400 Ile Ala Arg Asn Leu Ser Cys Arg Glu
Pro Asn Gln His Phe Lys Pro 405 410 415 Tyr Leu Lys His Phe Leu Pro
Lys Arg Leu His Phe Ala Lys Ser Asp 420 425 430 Arg Ile Glu Pro Leu
Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala 435 440 445 Leu Asn Pro
Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser 450 455 460 Asp
Asn Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro 465 470
475 480 Gly Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu
Val 485 490 495 Tyr Asn Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala
Pro Asn Asn 500 505 510 Gly Thr His Gly Ser Leu Asn His Leu Leu Lys
Asn Pro Val Tyr Thr 515 520 525 Pro Lys His Pro Lys Glu Val His Pro
Leu Val Gln Cys Pro Phe Thr 530 535 540 Arg Asn Pro Arg Asp Asn Leu
Gly Cys Ser Cys Asn Pro Ser Ile Leu 545 550 555 560 Pro Ile Glu Asp
Phe Gln Thr Gln Phe Asn Leu Thr Val Ala Glu Glu 565 570 575 Lys Ile
Ile Lys His Glu Thr Leu Pro Tyr Gly Arg Pro Arg Val Leu 580 585 590
Gln Lys Glu Asn Thr Ile Cys Leu Leu Ser Gln His Gln Phe Met Ser 595
600 605 Gly Tyr Ser Gln Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr
Val 610 615 620 Asp Arg Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn
Cys Leu Tyr 625 630 635 640 Gln Asp Phe Arg Ile Pro Leu Ser Pro Val
His Lys Cys Ser Phe Tyr 645 650 655 Lys Asn Asn Thr Lys Val Ser Tyr
Gly Phe Leu Ser Pro Pro Gln Leu 660 665 670 Asn Lys Asn Ser Ser Gly
Ile Tyr Ser Glu Ala Leu Leu Thr Thr Asn 675 680 685 Ile Val Pro Met
Tyr Gln Ser Phe Gln Val Ile Trp Arg Tyr Phe His 690 695 700 Asp Thr
Leu Leu Arg Lys Tyr Ala Glu Glu Arg Asn Gly Val Asn Val 705 710 715
720 Val Ser Gly Pro Val Phe Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser
725 730 735 Leu Glu Asn Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln
Glu Ile 740 745 750 Leu Ile Pro Thr His Phe Phe Ile Val Leu Thr Ser
Cys Lys Asp Thr 755 760 765 Ser Gln Thr Pro Leu His Cys Glu Asn Leu
Asp Thr Leu Ala Phe Ile 770 775 780 Leu Pro His Arg Thr Asp Asn Ser
Glu Ser Cys Val His Gly Lys His 785 790 795 800 Asp Ser Ser Trp Val
Glu Glu Leu Leu Met Leu His Arg Ala Arg Ile 805 810 815 Thr Asp Val
Glu His Ile Thr Gly Leu Ser Phe Tyr Gln Gln Arg Lys 820 825 830 Glu
Pro Val Ser Asp Ile Leu Lys Leu Lys Thr His Leu Pro Thr Phe 835 840
845 Ser Gln Glu Asp Asp Asp Asp Asp Asp Asp Asp 850 855
213255DNAArtificial sequenceNucleotide sequence encoding sNPP1-Fc
fusion protein 21atgggtgtac tgctcacaca gaggacgctg ctcagtctgg
tccttgcact cctgtttcca 60agcatggcga gcatgccaag ttgtgccaaa gaagttaaaa
gttgcaaagg tcgctgtttc 120gagagaacat ttgggaactg tcgctgtgat
gctgcctgtg ttgagcttgg aaactgctgt 180ttggattacc aggagacgtg
catagaacca gaacatatat ggacttgcaa caaattcagg 240tgtggtgaga
aaagattgac cagaagcctc tgtgcctgtt cagatgattg caaggacaag
300ggcgactgct gcatcaacta cagttcagtg tgtcaaggtg agaaaagttg
ggtggaagaa 360ccatgtgaga gcattaatga gccacagtgc ccagcagggt
ttgaaacgcc tcctacactc 420ttgttttctt tggatggatt cagggcagaa
tatttgcaca cttggggtgg acttcttcct 480gttattagca aactcaaaaa
atgtggaaca tatactaaaa acatgagacc ggtgtatcca 540acaaaaactt
tccccaatca ctacagcatt gtcaccggat tgtatccaga atctcatggc
600ataatcgaca ataagatgta tgatcccaaa atgaatgctt ccttttcact
taaaagtaaa 660gagaaattta atccggagtg gtacaaagga gaaccaattt
gggtcacagc taagtatcaa 720ggcctcaagt ctggcacatt tttctggcca
ggatcagatg tggaaattaa cggaattttc 780ccagacatct ataaaatgta
taatggttca gtgccatttg aagaaaggat tttggctgtt 840cttcagtggc
tgcagcttcc aaaagatgaa agaccacact tttacacttt gtatttggaa
900gaaccagatt cttcaggtca ttcatatgga ccagtcagca gtgaagtcat
caaagccttg 960cagagggttg atggtatggt tggtatgctg atggatggtc
tgaaagagct gaacttgcac 1020agatgcctga acctcatcct tatttcagat
catggcatgg aacaaggcag ttgtaagaaa 1080tacatatatc tgaataagta
tttgggggat gttaaaaata ttaaagttat ctatggacct 1140gcagctcgat
tgagaccctc tgatgtccca gataaatact attcatttaa ctatgaaggc
1200attgcccgaa atctttcttg ccgggaacca aaccagcact tcaaacctta
tctgaaacat 1260ttcttgccta agcgtttgca ctttgctaag agtgatagaa
ttgagccctt gacattctat 1320ttggaccctc agtggcaact tgcattgaat
ccctcagaaa ggaaatattg tggaagtgga 1380tttcatggct ctgacaatgt
gttttcaaat atgcaagccc tctttgttgg ctatggacct 1440ggattcaagc
atggcattga ggctgacacc tttgaaaaca ttgaagtcta taacttgatg
1500tgtgatttgc tgaatttgac accggctcct aataacggaa ctcatggaag
tcttaaccac 1560cttctgaaga atcctgttta tacgccaaag catcccaaag
aagtgcaccc cctggtgcag 1620tgccccttca caagaaaccc cagagataac
cttggctgct catgtaaccc ttccattttg 1680ccgattgagg attttcaaac
acagttcaat ctgaccgtgg cagaagagaa gattattaag 1740catgaaactt
tgccctatgg aagacctaga gttctccaga aggaaaacac catctgtctt
1800ctttcccagc accagtttat gagtggatac agccaagaca tcttgatgcc
cctttggaca 1860tcctataccg tggacagaaa tgacagtttc tctacggaag
acttctccaa ctgtctgtac 1920caggacttta gaattcctct tagtcctgtc
cataaatgtt cattttataa aaataacacc 1980aaagtgagtt acgggttcct
ctccccacca caactgaata agaattcaag tggaatatat 2040tctgaagcct
tgcttactac aaatatagtg ccaatgtacc agagttttca agttatatgg
2100cgctactttc atgacaccct cttgcgaaag tatgcagaag aaagaaatgg
tgtcaatgtc 2160gtcagtggtc ctgtgtttga ctttgattat gatggacgtt
gtgattcctt ggagaatttg 2220aggcaaaaaa gaagagtcat ccgtaaccaa
gaaattttga ttccaactca tttcttcatt 2280gtgctgacaa gctgtaaaga
tacatctcag acgcctttgc actgtgaaaa cctggacacc 2340ttggctttca
ttttgcctca caggactgat aacagcgaga gctgtgtgca tgggaagcat
2400gactcctcat gggttgaaga attgttgatg ttgcacagag cacggatcac
agacgtcgag 2460cacatcactg gactcagctt ttatcaacaa agaaaagagc
cagtttcaga cattttgaag 2520ttgaaaacac atttgccaac ctttagccaa
gaagatgagc ccaaatcttg tgacaaaact 2580cacacatgcc caccgtgccc
agcacctgaa ctcctggggg gaccgtcagt cttcctcttc 2640cccccaaaac
ccaaggacac cctcatgatc tcccggaccc ctgaggtcac
atgcgtggtg 2700gtggacgtga gccacgaaga ccctgaggtc aagttcaact
ggtacgtgga cggcgtggag 2760gtgcataatg ccaagacaaa gccgcgggag
gagcagtaca acagcacgta ccgtgtggtc 2820agcgtcctca ccgtcctgca
ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 2880tccaacaaag
ccctcccagc ccccatcgag aaaaccatct ccaaagccaa agggcagccc
2940cgagaaccac aggtgtacac cctgccccca tcccgggagg agatgaccaa
gaaccaggtc 3000agcctgacct gcctggtcaa aggcttctat cccagcgaca
tcgccgtgga gtgggagagc 3060aatgggcagc cggagaacaa ctacaagacc
acgcctcccg tgctggactc cgacggctcc 3120ttcttcctct atagcaagct
caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 3180tcatgctccg
tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg
3240tccccgggta aatga 3255221084PRTArtificial sequencesNPP1-Fc
fusion protein 22Met Gly Val Leu Leu Thr Gln Arg Thr Leu Leu Ser
Leu Val Leu Ala 1 5 10 15 Leu Leu Phe Pro Ser Met Ala Ser Met Pro
Ser Cys Ala Lys Glu Val 20 25 30 Lys Ser Cys Lys Gly Arg Cys Phe
Glu Arg Thr Phe Gly Asn Cys Arg 35 40 45 Cys Asp Ala Ala Cys Val
Glu Leu Gly Asn Cys Cys Leu Asp Tyr Gln 50 55 60 Glu Thr Cys Ile
Glu Pro Glu His Ile Trp Thr Cys Asn Lys Phe Arg 65 70 75 80 Cys Gly
Glu Lys Arg Leu Thr Arg Ser Leu Cys Ala Cys Ser Asp Asp 85 90 95
Cys Lys Asp Lys Gly Asp Cys Cys Ile Asn Tyr Ser Ser Val Cys Gln 100
105 110 Gly Glu Lys Ser Trp Val Glu Glu Pro Cys Glu Ser Ile Asn Glu
Pro 115 120 125 Gln Cys Pro Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu
Phe Ser Leu 130 135 140 Asp Gly Phe Arg Ala Glu Tyr Leu His Thr Trp
Gly Gly Leu Leu Pro 145 150 155 160 Val Ile Ser Lys Leu Lys Lys Cys
Gly Thr Tyr Thr Lys Asn Met Arg 165 170 175 Pro Val Tyr Pro Thr Lys
Thr Phe Pro Asn His Tyr Ser Ile Val Thr 180 185 190 Gly Leu Tyr Pro
Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp 195 200 205 Pro Lys
Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn 210 215 220
Pro Glu Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln 225
230 235 240 Gly Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val
Glu Ile 245 250 255 Asn Gly Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn
Gly Ser Val Pro 260 265 270 Phe Glu Glu Arg Ile Leu Ala Val Leu Gln
Trp Leu Gln Leu Pro Lys 275 280 285 Asp Glu Arg Pro His Phe Tyr Thr
Leu Tyr Leu Glu Glu Pro Asp Ser 290 295 300 Ser Gly His Ser Tyr Gly
Pro Val Ser Ser Glu Val Ile Lys Ala Leu 305 310 315 320 Gln Arg Val
Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu 325 330 335 Leu
Asn Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly 340 345
350 Met Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu
355 360 365 Gly Asp Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala
Arg Leu 370 375 380 Arg Pro Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe
Asn Tyr Glu Gly 385 390 395 400 Ile Ala Arg Asn Leu Ser Cys Arg Glu
Pro Asn Gln His Phe Lys Pro 405 410 415 Tyr Leu Lys His Phe Leu Pro
Lys Arg Leu His Phe Ala Lys Ser Asp 420 425 430 Arg Ile Glu Pro Leu
Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala 435 440 445 Leu Asn Pro
Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser 450 455 460 Asp
Asn Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro 465 470
475 480 Gly Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu
Val 485 490 495 Tyr Asn Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala
Pro Asn Asn 500 505 510 Gly Thr His Gly Ser Leu Asn His Leu Leu Lys
Asn Pro Val Tyr Thr 515 520 525 Pro Lys His Pro Lys Glu Val His Pro
Leu Val Gln Cys Pro Phe Thr 530 535 540 Arg Asn Pro Arg Asp Asn Leu
Gly Cys Ser Cys Asn Pro Ser Ile Leu 545 550 555 560 Pro Ile Glu Asp
Phe Gln Thr Gln Phe Asn Leu Thr Val Ala Glu Glu 565 570 575 Lys Ile
Ile Lys His Glu Thr Leu Pro Tyr Gly Arg Pro Arg Val Leu 580 585 590
Gln Lys Glu Asn Thr Ile Cys Leu Leu Ser Gln His Gln Phe Met Ser 595
600 605 Gly Tyr Ser Gln Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr
Val 610 615 620 Asp Arg Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn
Cys Leu Tyr 625 630 635 640 Gln Asp Phe Arg Ile Pro Leu Ser Pro Val
His Lys Cys Ser Phe Tyr 645 650 655 Lys Asn Asn Thr Lys Val Ser Tyr
Gly Phe Leu Ser Pro Pro Gln Leu 660 665 670 Asn Lys Asn Ser Ser Gly
Ile Tyr Ser Glu Ala Leu Leu Thr Thr Asn 675 680 685 Ile Val Pro Met
Tyr Gln Ser Phe Gln Val Ile Trp Arg Tyr Phe His 690 695 700 Asp Thr
Leu Leu Arg Lys Tyr Ala Glu Glu Arg Asn Gly Val Asn Val 705 710 715
720 Val Ser Gly Pro Val Phe Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser
725 730 735 Leu Glu Asn Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln
Glu Ile 740 745 750 Leu Ile Pro Thr His Phe Phe Ile Val Leu Thr Ser
Cys Lys Asp Thr 755 760 765 Ser Gln Thr Pro Leu His Cys Glu Asn Leu
Asp Thr Leu Ala Phe Ile 770 775 780 Leu Pro His Arg Thr Asp Asn Ser
Glu Ser Cys Val His Gly Lys His 785 790 795 800 Asp Ser Ser Trp Val
Glu Glu Leu Leu Met Leu His Arg Ala Arg Ile 805 810 815 Thr Asp Val
Glu His Ile Thr Gly Leu Ser Phe Tyr Gln Gln Arg Lys 820 825 830 Glu
Pro Val Ser Asp Ile Leu Lys Leu Lys Thr His Leu Pro Thr Phe 835 840
845 Ser Gln Glu Asp Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
850 855 860 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
Leu Phe 865 870 875 880 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
Arg Thr Pro Glu Val 885 890 895 Thr Cys Val Val Val Asp Val Ser His
Glu Asp Pro Glu Val Lys Phe 900 905 910 Asn Trp Tyr Val Asp Gly Val
Glu Val His Asn Ala Lys Thr Lys Pro 915 920 925 Arg Glu Glu Gln Tyr
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 930 935 940 Val Leu His
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 945 950 955 960
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 965
970 975 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
Arg 980 985 990 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
Val Lys Gly 995 1000 1005 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
Glu Ser Asn Gly Gln 1010 1015 1020 Pro Glu Asn Asn Tyr Lys Thr Thr
Pro Pro Val Leu Asp Ser Asp 1025 1030 1035 Gly Ser Phe Phe Leu Tyr
Ser Lys Leu Thr Val Asp Lys Ser Arg 1040 1045 1050 Trp Gln Gln Gly
Asn Val Phe Ser Cys Ser Val Met His Glu Ala 1055 1060 1065 Leu His
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 1070 1075 1080
Lys
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