U.S. patent application number 15/981744 was filed with the patent office on 2018-09-06 for protease-regulated antibodies. This patent application is currently assigned to BAYER HEALTHCARE LLC. The applicant listed for this patent is BAYER HEALTHCARE LLC. Invention is credited to John MURPHY, Zhuozhi WANG, Ruth WINTER.
Application Number | 20180251570 15/981744 |
Document ID | / |
Family ID | 49261048 |
Filed Date | 2018-09-06 |
United States Patent Application | 20180251570 |
Kind Code | A1 |
WANG; Zhuozhi ; et al. | September 6, 2018 |
This disclosure provides protease-regulated antibodies which specifically bind to tissue factor pathway inhibitor (TFPI). The antibodies are useful for treating bleeding disorders such as hemophilia.
Inventors: | WANG; Zhuozhi; (Millbrae, CA) ; WINTER; Ruth; (Oakland, CA) ; MURPHY; John; (Boston, MA) | ||||||||||
Applicant: |
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Assignee: | BAYER HEALTHCARE LLC Whippany NJ |
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Family ID: | 49261048 | ||||||||||
Appl. No.: | 15/981744 | ||||||||||
Filed: | May 16, 2018 |
Application Number | Filing Date | Patent Number | ||
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14389219 | Sep 29, 2014 | 9975962 | ||
PCT/US2013/031363 | Mar 14, 2013 | |||
15981744 | ||||
61617837 | Mar 30, 2012 | |||
Current U.S. Class: | 1/1 |
Current CPC Class: | C07K 2317/92 20130101; A61K 39/3955 20130101; C07K 2317/55 20130101; A61P 43/00 20180101; A61P 7/04 20180101; C07K 14/745 20130101; C07K 16/38 20130101; C07K 2317/76 20130101; A61P 7/00 20180101; C07K 16/36 20130101 |
International Class: | C07K 16/38 20060101 C07K016/38; C07K 16/36 20060101 C07K016/36; C07K 14/745 20060101 C07K014/745 |
Sequence CWU 1
1
18018PRTArtificial Sequenceprotease cleavage site 1Ala His Pro Arg
Ile Ile Ser Ala1 528PRTArtificial Sequenceprotease cleavage site
2Ala Arg Thr Arg Ala Arg Arg Pro1 538PRTArtificial Sequenceprotease
cleavage site 3Ala Ser Ala Arg Thr Thr Gly Ser1 548PRTArtificial
Sequenceprotease cleavage site 4Ala Thr Pro Arg Gly Ala Ala Pro1
558PRTArtificial Sequenceprotease cleavage site 5Ala Val Val Arg
Thr Pro Pro Lys1 568PRTArtificial Sequenceprotease cleavage site
6Glu Arg Thr Arg Ser Phe Gln Leu1 578PRTArtificial Sequenceprotease
cleavage site 7Phe Gly Leu Arg Phe Tyr Ala Tyr1 588PRTArtificial
Sequenceprotease cleavage site 8Phe Asn Pro Arg Thr Phe Gly Ser1
598PRTArtificial Sequenceprotease cleavage site 9Phe Arg Pro Lys
His Thr Arg Ile1 5108PRTArtificial Sequenceprotease cleavage site
10Phe Ser Ala Arg Gly His Arg Pro1 5118PRTArtificial
Sequenceprotease cleavage site 11Gly Asp Ile Arg Gly Pro Arg Ile1
5128PRTArtificial Sequenceprotease cleavage site 12Gly Gly Val Arg
Gly Pro Arg Val1 5138PRTArtificial Sequenceprotease cleavage site
13Gly Ser Phe Arg Ala Gly Leu Phe1 5148PRTArtificial
Sequenceprotease cleavage site 14His Lys Gly Arg Ser Ala Leu Val1
5158PRTArtificial Sequenceprotease cleavage site 15Ile Ala Gly Arg
Ser Leu Asn Pro1 5168PRTArtificial Sequenceprotease cleavage site
16Ile Asp Gly Arg Ile Val Glu Gly1 5178PRTArtificial
Sequenceprotease cleavage site 17Ile Glu Pro Arg Ser Phe Ser Gln1
5188PRTArtificial Sequenceprotease cleavage site 18Ile Lys Pro Arg
Ile Val Gly Gly1 5198PRTArtificial Sequenceprotease cleavage site
19Ile Gln Ile Arg Ser Val Ala Lys1 5208PRTArtificial
Sequenceprotease cleavage site 20Ile Gln Ile Arg Ser Val Ala Lys1
5218PRTArtificial Sequenceprotease cleavage site 21Lys Asn Val Lys
Ser Lys Ile Gly1 5228PRTArtificial Sequenceprotease cleavage site
22Lys Pro Lys Asp Ser Ser Val Asp1 5238PRTArtificial
Sequenceprotease cleavage site 23Leu Asp Pro Arg Ser Phe Leu Leu1
5248PRTArtificial Sequenceprotease cleavage site 24Leu Gly Ile Arg
Ser Phe Arg Asn1 5258PRTArtificial Sequenceprotease cleavage site
25Leu Pro Ile Lys Thr Phe Arg Gly1 5268PRTArtificial
Sequenceprotease cleavage site 26Leu Arg Pro Arg Phe Lys Ile Ile1
5278PRTArtificial Sequenceprotease cleavage site 27Leu Arg Pro Arg
Ile Ile Gly Gly1 5288PRTArtificial Sequenceprotease cleavage site
28Leu Ser Pro Arg Gly Val His Ile1 5298PRTArtificial
Sequenceprotease cleavage site 29Leu Ser Pro Arg Thr Phe His Pro1
5308PRTArtificial Sequenceprotease cleavage site 30Met Thr Pro Arg
Ser Glu Gly Ser1 5318PRTArtificial Sequenceprotease cleavage site
31Met Thr Pro Arg Ser Gly Gly Ser1 5328PRTArtificial
Sequenceprotease cleavage site 32Met Thr Pro Arg Ser Arg Gly Ser1
5338PRTArtificial Sequenceprotease cleavage site 33Met Val Pro Arg
Ala Val Tyr Leu1 5348PRTArtificial Sequenceprotease cleavage site
34Asn Val Pro Arg Ile Leu Ser Pro1 5358PRTArtificial
Sequenceprotease cleavage site 35Pro Ala Pro Arg Gly Tyr Pro Gly1
5368PRTArtificial Sequenceprotease cleavage site 36Pro Asp Leu Arg
Ser Cys Val Asn1 5378PRTArtificial Sequenceprotease cleavage site
37Pro Gly Pro Arg Gly Pro Pro Pro1 5388PRTArtificial
Sequenceprotease cleavage site 38Pro Gly Ser Arg Ser Arg Thr Pro1
5398PRTArtificial Sequenceprotease cleavage site 39Pro Gln Gly Arg
Ile Val Gly Gly1 5408PRTArtificial Sequenceprotease cleavage site
40Pro Gln Gly Arg Thr Thr Ala His1 5418PRTArtificial
Sequenceprotease cleavage site 41Pro Arg Ser Phe Leu Leu Arg Asn1
5428PRTArtificial Sequenceprotease cleavage site 42Gln Ser Pro Arg
Ser Phe Gln Lys1 5438PRTArtificial Sequenceprotease cleavage site
43Gln Ser Pro Arg Ser Phe Gln Lys1 5448PRTArtificial
Sequenceprotease cleavage site 44Gln Tyr Leu Arg Val Pro Leu Val1
5458PRTArtificial Sequenceprotease cleavage site 45Ser Glu Phe Arg
Cys Leu Thr Pro1 5468PRTArtificial Sequenceprotease cleavage site
46Ser Ile Gly Arg Ala Ser Leu His1 5478PRTArtificial
Sequenceprotease cleavage site 47Ser Lys Gly Arg Ser Leu Ile Gly1
5488PRTArtificial Sequenceprotease cleavage site 48Ser Arg Leu Arg
Ala Tyr Leu Leu1 5498PRTArtificial Sequenceprotease cleavage site
49Thr Cys Leu Arg Ser Thr Lys Phe1 5508PRTArtificial
Sequenceprotease cleavage site 50Val Cys Leu Arg Ser Phe Gln Thr1
5518PRTArtificial Sequenceprotease cleavage site 51Val Asp Pro Arg
Leu Ile Asp Gly1 5528PRTArtificial Sequenceprotease cleavage site
52Val Glu Val Lys Ser Glu Lys Leu1 5538PRTArtificial
Sequenceprotease cleavage site 53Val Ile Pro Lys Arg Ile Ser Pro1
5548PRTArtificial Sequenceprotease cleavage site 54Val Ile Pro Arg
Ser Gly Gly Ser1 5558PRTArtificial Sequenceprotease cleavage site
55Val Asn Pro Arg Gly Ile Val Thr1 5568PRTArtificial
Sequenceprotease cleavage site 56Val Gln Pro Arg Ala Gln Lys Ile1
5578PRTArtificial Sequenceprotease cleavage site 57Val Ser Pro Arg
Ala Ser Ala Ser1 5588PRTArtificial Sequenceprotease cleavage site
58Val Val Pro Arg Gly Val Asn Leu1 5598PRTArtificial
Sequenceprotease cleavage site 59Trp Tyr Leu Arg Ser Asn Asn Gly1
5608PRTArtificial Sequenceprotease cleavage site 60Trp Tyr Leu Arg
Ser Asn Thr Gly1 5618PRTArtificial Sequenceprotease cleavage site
61Ala Phe Trp Lys Thr Asp Ala Ser1 5628PRTArtificial
Sequenceprotease cleavage site 62Ile Glu Gly Arg Thr Ala Thr Ser1
5638PRTArtificial Sequenceprotease cleavage site 63Thr Ala Ala Arg
Gln Ser Thr Asn1 5648PRTArtificial Sequenceprotease cleavage site
64Ile Asp Gly Arg Ile Val Glu Gly1 5658PRTArtificial
Sequenceprotease cleavage site 65Phe Asn Pro Arg Thr Phe Gly Ser1
5668PRTArtificial Sequenceprotease cleavage site 66Arg Val Pro Lys
Ser Phe Pro Phe1 5678PRTArtificial Sequenceprotease cleavage site
67Pro Gln Leu Arg Met Lys Asn Asn1 5688PRTArtificial
Sequenceprotease cleavage site 68Ser Ser Trp Arg Leu Thr Ser Ser1
5698PRTArtificial Sequenceprotease cleavage site 69Leu Gly Ile Arg
Ser Phe Arg Asn1 5708PRTArtificial Sequenceprotease cleavage site
70Ala Met Ser Arg Met Ser Leu Ser1 5718PRTArtificial
Sequenceprotease cleavage site 71Ala Asn Asn Arg Asp Asn Thr Tyr1
5728PRTArtificial Sequenceprotease cleavage site 72Ala Asn Val Arg
Arg Lys Arg Tyr1 5738PRTArtificial Sequenceprotease cleavage site
73Ala Arg Gly Arg Ala Phe Pro Gln1 5748PRTArtificial
Sequenceprotease cleavage site 74Ala Thr Leu Lys Ser Arg Lys Met1
5758PRTArtificial Sequenceprotease cleavage site 75Ala Thr Gln Lys
Lys Val Glu Arg1 5768PRTArtificial Sequenceprotease cleavage site
76Ala Thr Trp Lys Thr Arg Trp Tyr1 5778PRTArtificial
Sequenceprotease cleavage site 77Asp Val Gly Glu Tyr Asn Val Phe1
5788PRTArtificial Sequenceprotease cleavage site 78Glu Ala Arg Gly
Ser Val Ile Leu1 5798PRTArtificial Sequenceprotease cleavage site
79Glu Ala Tyr Arg Arg Phe Tyr Gly1 5808PRTArtificial
Sequenceprotease cleavage site 80Glu Asp Asn Arg Asp Ser Ser Met1
5818PRTArtificial Sequenceprotease cleavage site 81Glu Thr Leu Lys
Val Ile Asp Glu1 5828PRTArtificial Sequenceprotease cleavage site
82Phe Arg Ala Arg Ala Tyr Gly Phe1 5838PRTArtificial
Sequenceprotease cleavage site 83Gly Glu Ala Arg Gly Ser Val Ile1
5848PRTArtificial Sequenceprotease cleavage site 84Gly Gly Tyr Arg
Ala Arg Pro Ala1 5858PRTArtificial Sequenceprotease cleavage site
85Gly Ile Leu Lys Glu Asn Ala Ala1 5868PRTArtificial
Sequenceprotease cleavage site 86Gly Pro Lys Arg Gly Thr Glu Pro1
5878PRTArtificial Sequenceprotease cleavage site 87Ile Ile Arg Arg
Ser Ile Gln Ile1 5888PRTArtificial Sequenceprotease cleavage site
88Ile Thr Phe Arg Met Asn Val Ala1 5898PRTArtificial
Sequenceprotease cleavage site 89Lys His Ser Lys Arg His Ile His1
5908PRTArtificial Sequenceprotease cleavage site 90Lys Lys Asp Arg
Ala Arg Gln Glu1 5918PRTArtificial Sequenceprotease cleavage site
91Lys Lys Pro Arg Cys Gly Val Pro1 5928PRTArtificial
Sequenceprotease cleavage site 92Lys Gln Val Lys Asp Asn Glu Asn1
5938PRTArtificial Sequenceprotease cleavage site 93Leu Asp Pro Arg
Ser Phe Leu Leu1 5948PRTArtificial Sequenceprotease cleavage site
94Leu Pro Pro Lys Ser Gln Pro Pro1 5958PRTArtificial
Sequenceprotease cleavage site 95Leu Ser Phe Arg Ala Arg Ala Tyr1
5968PRTArtificial Sequenceprotease cleavage site 96Met Ser Met Arg
Val Arg Arg His1 5978PRTArtificial Sequenceprotease cleavage site
97Asn Ser Gly Arg Ala Val Thr Tyr1 5988PRTArtificial
Sequenceprotease cleavage site 98Pro Ala Pro Arg Gly Tyr Pro Gly1
5998PRTArtificial Sequenceprotease cleavage site 99Pro Glu Ala Lys
Ala Ser Cys Tyr1 51008PRTArtificial Sequenceprotease cleavage site
100Pro Glu Ser Lys Ala Thr Asn Ala1 51018PRTArtificial
Sequenceprotease cleavage site 101Pro Gly Pro Lys Arg Gly Thr Glu1
51028PRTArtificial Sequenceprotease cleavage site 102Pro Lys Ala
Lys Ser His Ala Pro1 51038PRTArtificial Sequenceprotease cleavage
site 103Pro Leu Asp Lys Lys Arg Glu Glu1 51048PRTArtificial
Sequenceprotease cleavage site 104Pro Leu Gln Lys Gln Leu Pro Ala1
51058PRTArtificial Sequenceprotease cleavage site 105Pro Gln Phe
Arg Ile Lys Gly Gly1 51068PRTArtificial Sequenceprotease cleavage
site 106Pro Gln Leu Arg Leu Pro His Thr1 51078PRTArtificial
Sequenceprotease cleavage site 107Pro Gln Leu Arg Arg Gly Trp Arg1
51088PRTArtificial Sequenceprotease cleavage site 108Pro Gln Ser
Arg Ser Val Pro Pro1 51098PRTArtificial Sequenceprotease cleavage
site 109Pro Arg Phe Lys Ile Ile Gly Gly1 51108PRTArtificial
Sequenceprotease cleavage site 110Pro Tyr Leu Lys Val Phe Asn Pro1
51118PRTArtificial Sequenceprotease cleavage site 111Gln Lys Ser
Arg Asn Gly Leu Arg1 51128PRTArtificial Sequenceprotease cleavage
site 112Gln Leu Ile Lys Ala Ile Gln Leu1 51138PRTArtificial
Sequenceprotease cleavage site 113Gln Arg Tyr Lys Val Asp Tyr Glu1
51148PRTArtificial Sequenceprotease cleavage site 114Arg Ala Gln
Arg Ser Ala Gly Ala1 51158PRTArtificial Sequenceprotease cleavage
site 115Arg Gly Pro Arg Val Val Glu Arg1 51168PRTArtificial
Sequenceprotease cleavage site 116Arg Pro Ala Lys Ala Ala Ala Thr1
51178PRTArtificial Sequenceprotease cleavage site 117Arg Arg Lys
Arg Tyr Ala Ile Gln1 51188PRTArtificial Sequenceprotease cleavage
site 118Arg Ser Ser Lys Gly Arg Ser Leu1 51198PRTArtificial
Sequenceprotease cleavage site 119Arg Ser Thr Arg Phe Ala Ala Thr1
51208PRTArtificial Sequenceprotease cleavage site 120Ser Cys Asp
Lys Thr His Thr Cys1 51218PRTArtificial Sequenceprotease cleavage
site 121Ser Ile Asn Lys Ser Ser Pro Leu1 51228PRTArtificial
Sequenceprotease cleavage site 122Ser Gln Pro Pro Glu Lys Thr Glu1
51238PRTArtificial Sequenceprotease cleavage site 123Ser Gln Arg
Lys His Ser Lys Arg1 51248PRTArtificial Sequenceprotease cleavage
site 124Ser Ser Met Lys Leu Ser Phe Arg1 51258PRTArtificial
Sequenceprotease cleavage site 125Thr Glu Pro Lys Val Lys Leu Pro1
51268PRTArtificial Sequenceprotease cleavage site 126Thr Glu Tyr
Arg Leu Val Ser Ile1 51278PRTArtificial Sequenceprotease cleavage
site 127Thr His Glu Lys Gly Arg Gln Ser1 51288PRTArtificial
Sequenceprotease cleavage site 128Thr Tyr Ser Lys Ala Ser Thr Pro1
51298PRTArtificial Sequenceprotease cleavage site 129Thr Tyr Ser
Arg Ser Arg Tyr Leu1 51308PRTArtificial Sequenceprotease cleavage
site 130Val Ser Asn Lys Val Ser Met Ser1 5131228PRTArtificial
SequenceFab-1 light chain 131Ser Tyr Glu Leu Thr Gln Pro Pro Ser
Val Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Arg Ile Thr Cys Ser Gly
Asp Asn Leu Pro Lys Tyr Tyr Ala 20 25 30His Trp Tyr Gln Gln Lys Pro
Gly Gln Ala Pro Val Val Val Ile Phe 35 40 45Tyr Asp Val Asn Arg Pro
Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr
Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala
Asp Tyr Tyr Cys Gln Ala Trp Trp Ser Ser Thr Pro Val 85 90 95Phe Gly
Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Leu 100 105
110Val Pro Arg Gly Ser Gly Gly Gly Gly Ser Gly Gln Pro Lys Ala Ala
115 120 125Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln
Ala Asn 130 135 140Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
Pro Gly Ala Val145 150 155 160Thr Val Ala Trp Lys Ala Asp Ser Ser
Pro Val Lys Ala Gly Val Glu 165 170 175Thr Thr Thr Pro Ser Lys Gln
Ser Asn Asn Lys Tyr Ala Ala Ser Ser 180 185 190Tyr Leu Ser Leu Thr
Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 195 200 205Cys Gln Val
Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 210 215 220Thr
Glu Cys Ser22513216PRTArtificial Sequenceprotease cleavage site and
linker 132Gly Gly Gly Gly Ser Leu Val Pro Arg Gly Ser Gly Gly Gly
Gly Ser1 5 10 15133245PRTArtificial SequenceFab-1 heavy chain
133Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Gly Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ser Ile Arg Gly Ser Arg Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Leu Tyr Arg Tyr Trp Phe Asp
Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser Gly Gly
Gly Gly Ser Leu Val Pro Arg Gly Ser 115 120 125Gly Gly Gly Gly Ser
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 130 135 140Ala Pro Cys
Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys145 150 155
160Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
165 170 175Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
Gln Ser 180 185 190Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
Pro Ser Ser Asn 195 200 205Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
Asp His Lys Pro Ser Asn 210 215 220Thr Lys Val Asp Lys Thr Val Asp
Tyr Lys Asp Asp Asp Asp Lys His225 230 235 240His His His His His
2451341590DNAArtificial Sequencesequence encoding Fab-1
134ggtctcacat gaaaaaaacc gctatcgcta tcgccgtcgc actggctggc
ttcgcaaccg 60tggcacaggc atcctatgaa ctgacccaac cgccgagtgt ctccgtgtca
ccgggtcaga 120cggcacgtat tacctgcagc ggtgataacc tgccgaaata
ttacgcgcat tggtatcagc 180aaaaaccggg ccaagccccg gtggttgtca
tcttttatga cgttaatcgt ccgtccggta 240tcccggaacg cttctcgggc
agcaactctg gtaatacggc aaccctgacg atcagcggca 300cccaggcaat
ggatgaagct gactattact gtcaagcatg gtggagctct acgccggtgt
360ttggcggtgg cacgaaactg accgtgctgg gtggcggtgg ctctctggtt
ccgcgtggct 420ccggtggcgg tggctcaggc cagccgaaag cagcaccgag
tgttaccctg tttccgccga 480gttccgaaga actgcaagca aacaaagcta
ccctggtgtg cctgattagc gatttctatc 540cgggcgcagt tacggtcgcg
tggaaagccg actcatcgcc ggtgaaagct ggtgttgaaa 600ccacgacccc
gtcaaaacag tcgaacaata aatatgcagc tagctcttac ctgtctctga
660ccccggaaca gtggaaaagt catcgcagtt actcctgtca agttacgcac
gaaggctcca 720cggtcgaaaa aaccgtggca ccgacggaat gctcatgata
agcatgcgta ggagaaaata 780aaatgaaaca gtctaccatc gcactggcac
tgctgccgct gctgtttacg ccggtgacca 840aagcagaagt tcagctggtc
gaaagtggtg gcggtctggt tcaaccgggc ggttcactgc 900gtctgtcgtg
cgcagcaagc ggttttacct tcagttccta tggtatggat tgggtccgtc
960aggcaccggg taaaggtctg gaatgggtgt catcgattcg tggcagccgc
ggttctacct 1020attacgccga
ttcagttaaa ggccgtttta ccatctctcg cgacaacagt aaaaatacgc
1080tgtatctgca gatgaacagc ctgcgcgcgg aagataccgc cgtgtattac
tgtgcccgtc 1140tgtatcgcta ctggttcgac tactggggcc agggtacgct
ggtgaccgtt agctctggcg 1200gtggcggttc gctggtcccg cgtggcagcg
gcggtggcgg ttcagcgagc accaaaggtc 1260cgagcgtgtt tccgctggca
ccgtgcagcc gctctaccag tgaatccacg gcagctctgg 1320gttgtctggt
gaaagattat tttccggaac cggtcaccgt gagttggaac tccggcgcac
1380tgacctcggg tgttcatacg ttcccggctg tcctgcagag ttccggcctg
tatagcctgt 1440catcggtggt taccgttccg agctctaatt tcggcaccca
aacgtacacc tgcaacgtcg 1500atcacaaacc gtctaatacc aaagttgaca
aaacggttga ttacaaagac gacgacgaca 1560aacaccacca ccaccaccat
tgataagctt 1590135218PRTArtificial SequenceFab-2 light chain 135Ser
Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10
15Thr Ala Arg Ile Thr Cys Ser Gly Asp Asn Leu Pro Lys Tyr Tyr Ala
20 25 30His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Ile
Phe 35 40 45Tyr Asp Val Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser
Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr
Gln Ala Met65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Trp
Ser Ser Thr Pro Val 85 90 95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
Leu Val Pro Arg Gly Ser 100 105 110Gly Gln Pro Lys Ala Ala Pro Ser
Val Thr Leu Phe Pro Pro Ser Ser 115 120 125Glu Glu Leu Gln Ala Asn
Lys Ala Thr Leu Val Cys Leu Ile Ser Asp 130 135 140Phe Tyr Pro Gly
Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro145 150 155 160Val
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn 165 170
175Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
Thr Val 195 200 205Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 210
215136235PRTArtificial SequenceFab-2 Heavy Chain 136Glu Val Gln Leu
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met
Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser
Ser Ile Arg Gly Ser Arg Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Arg Leu Tyr Arg Tyr Trp Phe Asp Tyr Trp Gly Gln Gly
Thr Leu 100 105 110Val Thr Val Ser Ser Leu Val Pro Arg Gly Ser Ala
Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
Arg Ser Thr Ser Glu Ser 130 135 140Thr Ala Ala Leu Gly Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr
Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val 195 200
205Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Asp Tyr Lys
210 215 220Asp Asp Asp Asp Lys His His His His His His225 230
2351376PRTArtificial Sequenceprotease cleavage site 137Leu Val Pro
Arg Gly Ser1 51381530DNAArtificial SequenceFab-2 coding sequence
138ggtctcacat gaaaaaaacg gctatcgcaa tcgctgtggc actggcaggc
ttcgcaacgg 60tcgcgcaggc atcctatgaa ctgacgcaac cgccgagtgt ctccgtgtca
ccgggtcaga 120cggcacgtat tacctgctct ggtgataacc tgccgaaata
ttacgcgcat tggtatcagc 180aaaaaccggg ccaagccccg gtggttgtca
tcttttatga cgttaatcgt ccgtcgggta 240tcccggaacg cttctcgggc
agcaactctg gtaatacggc caccctgacg atctcaggca 300cccaggcaat
ggatgaagct gactattact gccaagcatg gtggagctct acgccggtgt
360ttggcggtgg cacgaaactg accgttctgc tggtcccgcg tggctccggt
cagccgaaag 420cagccccgtc agttaccctg tttccgccga gttccgaaga
actgcaagca aacaaagcta 480ccctggtgtg tctgattagc gatttctatc
cgggcgcagt tacggtcgcg tggaaagccg 540actcatcgcc ggtcaaagct
ggtgtggaaa ccaccacccc gtcaaaacag tcgaacaata 600aatatgcagc
tagctcttac ctgtcgctga ccccggaaca gtggaaaagc catcgcagtt
660actcctgcca agttacgcac gaaggctcta cggttgaaaa aaccgtcgca
ccgacggaat 720gcagttgata agcatgcgta ggagaaaata aaatgaaaca
gagcaccatc gcactggcac 780tgctgccgct gctgtttacg ccggtcacca
aagcagaagt gcagctggtt gaatctggtg 840gcggtctggt gcaaccgggc
ggttcactgc gtctgtcgtg tgcggccagc ggctttacct 900tcagttccta
tggtatggat tgggtccgtc aggcaccggg taaaggtctg gaatgggtgt
960catcgattcg tggcagccgc ggttctacct attacgccga ttccgttaaa
ggccgtttca 1020ccatctctcg cgacaacagt aaaaatacgc tgtatctgca
gatgaacagt ctgcgcgcgg 1080aagataccgc cgtgtattac tgcgcccgtc
tgtatcgcta ctggtttgac tactggggcc 1140agggtacgct ggtgaccgtt
agctctctgg ttccgcgtgg ctcagcgagc accaaaggtc 1200cgagtgtctt
cccgctggca ccgtgcagcc gctctaccag tgaatccacg gcagctctgg
1260gttgtctggt gaaagattat tttccggaac cggtcaccgt gagttggaac
tccggcgcac 1320tgacctccgg tgtgcatacg ttcccggctg ttctgcagag
ttccggcctg tattcactgt 1380catcggtggt taccgtgccg agctctaatt
ttggcaccca aacgtacacc tgtaacgttg 1440atcacaaacc gagcaatacc
aaagttgaca aaaccgttga ctacaaagac gacgacgaca 1500aacaccacca
ccaccaccac tgataagctt 1530139228PRTArtificial SequenceIgG2-linker
1, Light chain amino acid sequence 139Ser Tyr Glu Leu Thr Gln Pro
Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Arg Ile Thr Cys
Ser Gly Asp Asn Leu Pro Lys Tyr Tyr Ala 20 25 30His Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Val Val Val Ile Phe 35 40 45Tyr Asp Val Asn
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly
Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp
Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Trp Ser Ser Thr Pro Val 85 90
95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Leu
100 105 110Val Pro Arg Gly Ser Gly Gly Gly Gly Ser Gly Gln Pro Lys
Ala Ala 115 120 125Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
Leu Gln Ala Asn 130 135 140Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
Phe Tyr Pro Gly Ala Val145 150 155 160Thr Val Ala Trp Lys Ala Asp
Ser Ser Pro Val Lys Ala Gly Val Glu 165 170 175Thr Thr Thr Pro Ser
Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 180 185 190Tyr Leu Ser
Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 195 200 205Cys
Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 210 215
220Thr Glu Cys Ser225140458PRTArtificial SequenceIgG2-linker1,
heavy chain amino acid sequence 140Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala
Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met Asp Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Arg Gly
Ser Arg Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala
Arg Leu Tyr Arg Tyr Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105
110Val Thr Val Ser Ser Ala Ser Gly Gly Gly Gly Ser Leu Val Pro Arg
115 120 125Gly Ser Gly Gly Gly Gly Ser Thr Lys Gly Pro Ser Val Phe
Pro Leu 130 135 140Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
Ala Leu Gly Cys145 150 155 160Leu Val Lys Asp Tyr Phe Pro Glu Pro
Val Thr Val Ser Trp Asn Ser 165 170 175Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn 195 200 205Phe Gly Thr
Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 210 215 220Thr
Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro225 230
235 240Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe
Pro 245 250 255Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
Glu Val Thr 260 265 270Cys Val Val Val Asp Val Ser His Glu Asp Pro
Glu Val Gln Phe Asn 275 280 285Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala Lys Thr Lys Pro Arg 290 295 300Glu Glu Gln Phe Asn Ser Thr
Phe Arg Val Val Ser Val Leu Thr Val305 310 315 320Val His Gln Asp
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 325 330 335Asn Lys
Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys 340 345
350Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
355 360 365Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
Gly Phe 370 375 380Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
Gly Gln Pro Glu385 390 395 400Asn Asn Tyr Lys Thr Thr Pro Pro Met
Leu Asp Ser Asp Gly Ser Phe 405 410 415Phe Leu Tyr Ser Lys Leu Thr
Val Asp Lys Ser Arg Trp Gln Gln Gly 420 425 430Asn Val Phe Ser Cys
Ser Val Met His Glu Ala Leu His Asn His Tyr 435 440 445Thr Gln Lys
Ser Leu Ser Leu Ser Pro Gly 450 455141684DNAArtificial
SequenceIgG2-linker 1, Light chain DNA sequence 141tcctacgagc
tgacccagcc cccttccgtg tccgtgtctc ctggccagac cgcccggatc 60acctgttccg
gcgacaacct gcccaagtac tacgcccact ggtatcagca gaagcccggc
120caggcccccg tggtggtcat cttctacgac gtgaaccggc cctccggcat
ccccgagaga 180ttctccggct ccaactccgg caacaccgcc accctgacca
tctccggcac ccaggccatg 240gacgaggccg actactactg ccaggcttgg
tggtcctcca cccccgtgtt tggcggcgga 300acaaagttaa ccgtgctggg
cggtggagga tcactggttc cgcgtggctc tggcggtgga 360ggatcaggcc
agcccaaggc cgctccttcc gtgaccctgt tccccccatc ctccgaggaa
420ctgcaggcca acaaggccac cctggtctgc ctgatctccg acttctaccc
tggcgccgtg 480accgtggcct ggaaggccga cagctctcct gtgaaggccg
gcgtggaaac caccaccccc 540tccaagcagt ccaacaacaa atacgccgcc
tcctcctacc tgtccctgac ccccgagcag 600tggaagtccc accggtccta
cagctgccag gtcacacacg agggctccac cgtggaaaag 660acagtggccc
ccaccgagtg ctct 6841421374DNAArtificial SequenceIgG2-linker 1,
Heavy chain DNA sequence 142gaggtgcagc tggtggaatc cggcggaggc
ctggtccagc ctggcggatc tctgagactg 60tcctgcgccg cctccggctt caccttctcc
agctacggca tggactgggt ccgacaggcc 120cctggcaagg gcctggaatg
ggtgtcctcc atccggggct ctcggggctc cacctactac 180gccgactccg
tgaagggccg gttcaccatc tcccgggaca actccaagaa caccctgtac
240ctgcagatga actccctgcg ggccgaggac accgccgtgt actactgcgc
cagactgtac 300cggtattggt tcgactactg gggccagggc accctggtca
ccgtcagctc agcttctggc 360ggaggcggct ctctggtgcc tagaggatct
ggcggcggag gctccaccaa gggcccttcc 420gtgttccctc tggccccttg
ctcccggtcc acctccgagt ctaccgccgc tctgggctgc 480ctggtcaagg
attacttccc cgagcccgtg accgtgtcct ggaactctgg cgccctgacc
540agcggcgtgc acaccttccc tgccgtgctg cagtcctccg gcctgtactc
cctgtcctcc 600gtcgtgacag tgccctcctc caacttcggc acccagacct
acacctgtaa cgtggaccac 660aagccctcca acaccaaggt ggacaagacc
gtggaacgga agtgctgcgt ggaatgcccc 720ccctgtcctg cacctcctgt
ggctggacct agcgtgttcc tgttcccccc aaagcccaag 780gacaccctga
tgatctcccg gacccccgaa gtgacctgcg tggtggtgga cgtgtcccac
840gaggaccccg aggtgcagtt caattggtac gtggacggcg tggaagtgca
caacgccaag 900accaagccca gagaggaaca gttcaactcc accttccggg
tggtgtccgt gctgaccgtg 960gtgcaccagg actggctgaa cggcaaagag
tacaagtgca aggtctccaa caagggcctg 1020cctgccccca tcgaaaagac
catcagcaag accaagggcc agccccgcga gccccaggtg 1080tacacactgc
cacctagccg ggaagagatg accaagaacc aggtgtccct gacctgtctg
1140gtcaagggct tctacccatc cgacattgcc gtggaatggg agtccaacgg
ccagcccgag 1200aacaactaca agaccacccc ccccatgctg gactccgacg
gctcattctt cctgtactcc 1260aagctgacag tggacaagtc ccggtggcag
cagggcaacg tgttctcctg ctccgtgatg 1320cacgaggccc tgcacaacca
ctacacccag aagtccctgt ccctgagccc cggc 1374143218PRTArtificial
SequenceIgG2-linker 2, Light chain amino acid sequence 143Ser Tyr
Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Thr
Ala Arg Ile Thr Cys Ser Gly Asp Asn Leu Pro Lys Tyr Tyr Ala 20 25
30His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Ile Phe
35 40 45Tyr Asp Val Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly
Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln
Ala Met65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Trp Ser
Ser Thr Pro Val 85 90 95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Leu
Val Pro Arg Gly Ser 100 105 110Gly Gln Pro Lys Ala Ala Pro Ser Val
Thr Leu Phe Pro Pro Ser Ser 115 120 125Glu Glu Leu Gln Ala Asn Lys
Ala Thr Leu Val Cys Leu Ile Ser Asp 130 135 140Phe Tyr Pro Gly Ala
Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro145 150 155 160Val Lys
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn 165 170
175Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
Thr Val 195 200 205Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 210
215144448PRTArtificial SequenceIgG2-linker 2, heavy chain amino
acid sequence 144Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe Ser Ser Tyr 20 25 30Gly Met Asp Trp Val Arg Gln Ala Pro Gly
Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Arg Gly Ser Arg Gly Ser
Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg
Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Leu Tyr Arg
Tyr Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val
Ser Ser Ala Ser Leu Val Pro Arg Gly Ser Thr Lys Gly 115 120 125Pro
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135
140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Asn Phe Gly
Thr Gln Thr Tyr Thr Cys Asn Val 195 200 205Asp His Lys Pro Ser Asn
Thr Lys Val Asp Lys Thr Val Glu Arg Lys 210 215 220Cys Cys Val Glu
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro225 230 235 240Ser
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250
255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
Thr Phe Arg Val 290 295 300Val Ser Val Leu Thr Val Val His Gln Asp
Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn
Lys Gly Leu Pro Ala Pro Ile Glu Lys
325 330 335Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Met Leu385 390 395 400Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440
445145654DNAArtificial SequenceIgG2-linker 2, Light chain DNA
sequence 145tcctacgagc tgacccagcc cccttccgtg tccgtgtctc ctggccagac
cgcccggatc 60acctgttccg gcgacaacct gcccaagtac tacgcccact ggtatcagca
gaagcccggc 120caggcccccg tggtggtcat cttctacgac gtgaaccggc
cctccggcat ccccgagaga 180ttctccggct ccaactccgg caacaccgcc
accctgacca tctccggcac ccaggccatg 240gacgaggccg actactactg
ccaggcttgg tggtcctcca cccccgtgtt tggcggcgga 300acaaagttaa
ccgtgctgct ggttccgcgt ggctctggcc agcccaaggc cgctccttcc
360gtgaccctgt tccccccatc ctccgaggaa ctgcaggcca acaaggccac
cctggtctgc 420ctgatctccg acttctaccc tggcgccgtg accgtggcct
ggaaggccga cagctctcct 480gtgaaggccg gcgtggaaac caccaccccc
tccaagcagt ccaacaacaa atacgccgcc 540tcctcctacc tgtccctgac
ccccgagcag tggaagtccc accggtccta cagctgccag 600gtcacacacg
agggctccac cgtggaaaag acagtggccc ccaccgagtg ctct
6541461344DNAArtificial SequenceIgG2-linker 2, Heavy chain DNA
sequence 146gaggtgcagc tggtggaatc cggcggaggc ctggtccagc ctggcggatc
tctgagactg 60tcctgcgccg cctccggctt caccttctcc agctacggca tggactgggt
ccgacaggcc 120cctggcaagg gcctggaatg ggtgtcctcc atccggggct
ctcggggctc cacctactac 180gccgactccg tgaagggccg gttcaccatc
tcccgggaca actccaagaa caccctgtac 240ctgcagatga actccctgcg
ggccgaggac accgccgtgt actactgcgc cagactgtac 300cggtattggt
tcgactactg gggccagggc accctggtca ccgtcagctc agcttctctg
360gtgcctagag gatctaccaa gggcccttcc gtgttccctc tggccccttg
ctcccggtcc 420acctccgagt ctaccgccgc tctgggctgc ctggtcaagg
attacttccc cgagcccgtg 480accgtgtcct ggaactctgg cgccctgacc
agcggcgtgc acaccttccc tgccgtgctg 540cagtcctccg gcctgtactc
cctgtcctcc gtcgtgacag tgccctcctc caacttcggc 600acccagacct
acacctgtaa cgtggaccac aagccctcca acaccaaggt ggacaagacc
660gtggaacgga agtgctgcgt ggaatgcccc ccctgtcctg cacctcctgt
ggctggacct 720agcgtgttcc tgttcccccc aaagcccaag gacaccctga
tgatctcccg gacccccgaa 780gtgacctgcg tggtggtgga cgtgtcccac
gaggaccccg aggtgcagtt caattggtac 840gtggacggcg tggaagtgca
caacgccaag accaagccca gagaggaaca gttcaactcc 900accttccggg
tggtgtccgt gctgaccgtg gtgcaccagg actggctgaa cggcaaagag
960tacaagtgca aggtctccaa caagggcctg cctgccccca tcgaaaagac
catcagcaag 1020accaagggcc agccccgcga gccccaggtg tacacactgc
cacctagccg ggaagagatg 1080accaagaacc aggtgtccct gacctgtctg
gtcaagggct tctacccatc cgacattgcc 1140gtggaatggg agtccaacgg
ccagcccgag aacaactaca agaccacccc ccccatgctg 1200gactccgacg
gctcattctt cctgtactcc aagctgacag tggacaagtc ccggtggcag
1260cagggcaacg tgttctcctg ctccgtgatg cacgaggccc tgcacaacca
ctacacccag 1320aagtccctgt ccctgagccc cggc 13441476PRTArtificial
SequenceThrombin cleavage siteVARIANT(1)...(2)Xaa = hydrophobic
amino acidVARIANT(5)...(6)Xaa = nonacidic amino acid 147Xaa Xaa Pro
Arg Xaa Xaa1 51484PRTArtificial SequenceFactor Xa cleavage
siteVARIANT(2)...(2)Xaa = Glu or Asp 148Ile Xaa Gly
Arg11495PRTArtificial Sequenceamino acid linker 149Gly Gly Gly Gly
Ser1 515058PRTArtificial Sequenceamino acids 95-152 of SEQ ID NO133
150Tyr Cys Ala Arg Leu Tyr Arg Tyr Trp Phe Asp Tyr Trp Gly Gln Gly1
5 10 15Thr Leu Val Thr Val Ser Ser Ala Ser Gly Ser Gly Gly Gly Leu
Val 20 25 30Pro Arg Gly Ser Gly Gly Gly Gly Ser Thr Lys Gly Pro Ser
Val Phe 35 40 45Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 50
5515116PRTArtificial Sequenceamino acid linker 151Ala Lys Thr Thr
Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg1 5 10
1515217PRTArtificial Sequenceamino acid linker 152Ala Lys Thr Thr
Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg1 5 10 15Val
1539PRTArtificial Sequenceamino acid linker 153Ala Lys Thr Thr Pro
Lys Leu Gly Gly1 515410PRTArtificial Sequenceamino acid linker
154Ser Ala Lys Thr Thr Pro Lys Leu Gly Gly1 5 101556PRTArtificial
Sequenceamino acid linker 155Ser Ala Lys Thr Thr Pro1
51566PRTArtificial Sequenceamino acid linker 156Arg Ala Asp Ala Ala
Pro1 51579PRTArtificial Sequenceamino acid linker 157Arg Ala Asp
Ala Ala Pro Thr Val Ser1 515812PRTArtificial Sequenceamino acid
linker 158Arg Ala Asp Ala Ala Ala Ala Gly Gly Pro Gly Ser1 5
1015927PRTArtificial Sequenceamino acid linker 159Arg Ala Asp Ala
Ala Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly1 5 10 15Ser Gly Gly
Gly Gly Ser Gly Gly Gly Gly Ser 20 2516018PRTArtificial
Sequenceamino acid linker 160Ser Ala Lys Thr Thr Pro Lys Leu Glu
Glu Gly Glu Phe Ser Glu Ala1 5 10 15Arg Val 1615PRTArtificial
Sequenceamino acid linker 161Ala Asp Ala Ala Pro1
516212PRTArtificial Sequenceamino acid linker 162Ala Asp Ala Ala
Pro Thr Val Ser Ile Phe Pro Pro1 5 101635PRTArtificial
Sequenceamino acid linker 163Thr Val Ala Ala Pro1
516412PRTArtificial Sequenceamino acid linker 164Thr Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro1 5 101656PRTArtificial
Sequenceamino acid linker 165Gln Pro Lys Ala Ala Pro1
516613PRTArtificial Sequenceamino acid linker 166Gln Pro Lys Ala
Ala Pro Ser Val Thr Leu Phe Pro Pro1 5 101676PRTArtificial
Sequenceamino acid linker 167Ala Lys Thr Thr Pro Pro1
516813PRTArtificial Sequenceamino acid linker 168Ala Lys Thr Thr
Pro Pro Ser Val Thr Pro Leu Ala Pro1 5 101696PRTArtificial
Sequenceamino acid linker 169Ala Lys Thr Thr Ala Pro1
517013PRTArtificial Sequenceamino acid linker 170Ala Lys Thr Thr
Ala Pro Ser Val Tyr Pro Leu Ala Pro1 5 101716PRTArtificial
Sequenceamino acid linker 171Ala Ser Thr Lys Gly Pro1
517213PRTArtificial Sequenceamino acid linker 172Ala Ser Thr Lys
Gly Pro Ser Val Phe Pro Leu Ala Pro1 5 1017315PRTArtificial
Sequenceamino acid linker 173Gly Gly Gly Gly Ser Gly Gly Gly Gly
Ser Gly Gly Gly Gly Ser1 5 10 1517415PRTArtificial Sequenceamino
acid linker 174Gly Glu Asn Lys Val Glu Tyr Ala Pro Ala Leu Met Ala
Leu Ser1 5 10 1517515PRTArtificial Sequenceamino acid linker 175Gly
Pro Ala Lys Glu Leu Thr Pro Leu Lys Glu Ala Lys Val Ser1 5 10
1517615PRTArtificial Sequenceamino acid linker 176Gly His Glu Ala
Ala Ala Val Met Gln Val Gln Tyr Pro Ala Ser1 5 10 15177442PRTHomo
sapiens 177Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Ser Ser Tyr 20 25 30Gly Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly
Leu Glu Trp Val 35 40 45Ser Ser Ile Arg Gly Ser Arg Gly Ser Thr Tyr
Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Leu Tyr Arg Tyr Trp
Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys
Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150
155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
Ser Ser Asn 180 185 190Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp
His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Thr Val Glu Arg
Lys Cys Cys Val Glu Cys Pro 210 215 220Pro Cys Pro Ala Pro Pro Val
Ala Gly Pro Ser Val Phe Leu Phe Pro225 230 235 240Pro Lys Pro Lys
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255Cys Val
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn 260 265
270Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu
Thr Val 290 295 300Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
Cys Lys Val Ser305 310 315 320Asn Lys Gly Leu Pro Ala Pro Ile Glu
Lys Thr Ile Ser Lys Thr Lys 325 330 335Gly Gln Pro Arg Glu Pro Gln
Val Tyr Thr Leu Pro Pro Ser Arg Glu 340 345 350Glu Met Thr Lys Asn
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365Tyr Pro Ser
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380Asn
Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe385 390
395 400Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
Gly 405 410 415Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
Asn His Tyr 420 425 430Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435
440178212PRTHomo sapiens 178Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val
Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Arg Ile Thr Cys Ser Gly Asp
Asn Leu Pro Lys Tyr Tyr Ala 20 25 30His Trp Tyr Gln Gln Lys Pro Gly
Gln Ala Pro Val Val Val Ile Phe 35 40 45Tyr Asp Val Asn Arg Pro Ser
Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala
Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala Asp
Tyr Tyr Cys Gln Ala Trp Trp Ser Ser Thr Pro Val 85 90 95Phe Gly Gly
Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110Pro
Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120
125Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val
130 135 140Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly
Val Glu145 150 155 160Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
Tyr Ala Ala Ser Ser 165 170 175Tyr Leu Ser Leu Thr Pro Glu Gln Trp
Lys Ser His Arg Ser Tyr Ser 180 185 190Cys Gln Val Thr His Glu Gly
Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205Thr Glu Cys Ser
210179239PRTArtificial Sequenceprotease-cleavable anti-TFPI scFv
antibody 179Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Ser Ser Tyr 20 25 30Gly Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly
Leu Glu Trp Val 35 40 45Ser Ser Ile Arg Gly Ser Arg Gly Ser Thr Tyr
Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Leu Tyr Arg Tyr Trp
Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser
Gly Gly Gly Gly Ser Leu Val Pro Arg Gly Ser 115 120 125Gly Gly Gly
Gly Ser Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser 130 135 140Val
Ser Pro Gly Gln Thr Ala Arg Ile Thr Cys Ser Gly Asp Asn Leu145 150
155 160Pro Lys Tyr Tyr Ala His Trp Tyr Gln Gln Lys Pro Gly Gln Ala
Pro 165 170 175Val Val Val Ile Phe Tyr Asp Val Asn Arg Pro Ser Gly
Ile Pro Glu 180 185 190Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala
Thr Leu Thr Ile Ser 195 200 205Gly Thr Gln Ala Met Asp Glu Ala Asp
Tyr Tyr Cys Gln Ala Trp Trp 210 215 220Ser Ser Thr Pro Val Phe Gly
Gly Gly Thr Lys Leu Thr Val Leu225 230 235180717DNAArtificial
Sequenceprotease-cleavable anti-TFPI scFv antibody coding sequence
180gaagttcagc tggtcgaaag tggtggcggt ctggttcaac cgggcggttc
actgcgtctg 60tcgtgcgcag caagcggttt taccttcagt tcctatggta tggattgggt
ccgtcaggca 120ccgggtaaag gtctggaatg ggtgtcatcg attcgtggca
gccgcggttc tacctattac 180gccgattcag ttaaaggccg ttttaccatc
tctcgcgaca acagtaaaaa tacgctgtat 240ctgcagatga acagcctgcg
cgcggaagat accgccgtgt attactgtgc ccgtctgtat 300cgctactggt
tcgactactg gggccagggt acgctggtga ccgttagctc tggtggcggt
360ggctctctgg ttccgcgtgg ctccggtggc ggtggctcat cctatgaact
gacccaaccg 420ccgagtgtct ccgtgtcacc gggtcagacg gcacgtatta
cctgcagcgg tgataacctg 480ccgaaatatt acgcgcattg gtatcagcaa
aaaccgggcc aagccccggt ggttgtcatc 540ttttatgacg ttaatcgtcc
gtccggtatc ccggaacgct tctcgggcag caactctggt 600aatacggcaa
ccctgacgat cagcggcacc caggcaatgg atgaagctga ctattactgt
660caagcatggt ggagctctac gccggtgttt ggcggtggca cgaaactgac cgtgctg
717
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