AU2017200015B2 - Efficient systemic treatment of dystrophic pathologies - Google Patents
Efficient systemic treatment of dystrophic pathologies Download PDFInfo
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- AU2017200015B2 AU2017200015B2 AU2017200015A AU2017200015A AU2017200015B2 AU 2017200015 B2 AU2017200015 B2 AU 2017200015B2 AU 2017200015 A AU2017200015 A AU 2017200015A AU 2017200015 A AU2017200015 A AU 2017200015A AU 2017200015 B2 AU2017200015 B2 AU 2017200015B2
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Abstract
Description
Dose | Timing of follow-up | Name of the dog | Date of injection | Date of euthanasia | |
Still alive | |||||
IMAGE | pDys 1 | 6.11.2013 | |||
(17 months post-inj°) | |||||
Long term | ICI | 6.01.2014 | Still alive | ||
(15 months post-inj°) | |||||
lE14vg/kg | 7-8 months | ICE-T | pDys 3 | 28.08.2013 | 16.04.2014 |
post-injection | JAFFAR | pDys 4 | 16.09.2014 | May 2015 | |
JACADI | pDys 5 | 3.11.2014 | July 2015 |
Timing | Muscle | pDys 1 (IMAGE) | pDys 2 (ICI) | pDys 3 (ICE-T) | pDys 4 (JAFFAR) | pDys 5 (JACADI) | |||
% Dys i vg/dg | % Dys | vg/dg | % Dys ! vg/dg | % Dys | vg/dg | % Dys | vg/dg | ||
Before njection | Biceps femoris | <0.5% ΐ <i! 003 | <0,5% | <0.007 | <0,5% \ <0.003 | <0,5% | <0003 | <0,5% | -'0 003 |
3 months p.i. | Ext. carpi radialis R | 62% ! 1.3 | 82% | 2.8 | 43% \ 2.2 | 71% | 4,4 | 81% | .-: A·' |
Ext. digit, communis R | 68% j Is | 59% | 4.1 | 31% i 20 | 73% | 4.7' | 23% | 1.5 | |
Ext. carpi radialis L | 40% i [ i | 62% | 6.2 | 61% | 2.6 | 20% | 1.5 | 12% | 2,8 | |
Ext. digit, communis L | 40% 1 0.0 | 66% | 2 -5 | 42% j 7.3 | 21% | 1,0 | 11% | 1.0 | |
8 months p.i. | Biceps femoris R | N/A ΐ 0.S | 58% | 0 | 9% \ 7.0 | ||||
Biceps femoris L | N/A ΐ 06 | 56% | 0.8 | 38% ί 7.3 | |||||
14 months p.i. | Biceps femoris R | 44% ΐ 0 | 44% | ||||||
Biceps femoris L | 36% j 0.7 | 40% | 1 4 |
Tissu | vg/dg | |
Skeletal muscles of the right forelimb | m. flexor carpi ulnaris | 0,16 |
m. extensor digitorum communis | 0,25 | |
m. flexor digitorum superficialis | 0,12 | |
m. flexor carpi radialis | 0,19 | |
m. extensor carpi radialis | 0,97 | |
m. pectoralis | 1,01 | |
m. deltoideus | 1,86 |
Skeletal muscles of the left forelimb | m. flexor carpi ulnaris | 0,24 |
m. extensor digitorum communis | 0,56 | |
m. flexor digitorum superficialis | 0,11 | |
m. flexor carpi radialis | 0,13 | |
m. extensor carpi radialis | 0,29 | |
m. pectoralis | 2,47 | |
m. deltoideus | 1,88 |
Skeletal muscles of the body | m. paravertebral lumbar | 0,82 |
m. intercostales externi | 0,35 | |
m. rhomboideus cervicis | 1,42 | |
m. rectus abdominis | 0,68 |
Skeletal muscles of the right hindlimb | m. biceps femoris | 1,03 |
m.tibialis cranialis | 1,70 | |
m. semi—membranous | 2,06 | |
m. semi—tendinous | 1,33 | |
m. gluteus superficialis | 0,56 | |
m. vastus lateralis | 0,46 | |
m. sartorius | 0,80 | |
m. gastrocnemius lateralis | 0,81 | |
m. extensor digitorum longus | 0,53 | |
m. gracilis | 0,22 |
Skeletal muscles of the left hindlimb | m. biceps femoris | 1,26 |
m. tibialis cranialis | 0,96 | |
m. semi—membranous | 0,39 | |
m. semi—tendinous | 0,15 | |
m. gluteus superficialis | 1,11 | |
m. vastus lateralis | 2,19 | |
m. sartorius | 0,30 | |
m. gastrocnemius lateralis | 0,83 | |
m. extensor digitorum longus | 0,25 | |
m. gracilis | 0,37 |
Heart | heart (right + left ventricles) | 1,78 |
heart (septum + part of the atrioventricular node) | 0,97 |
Age of respiratory abnormalities appearance | |
pDys 1 (IMAGE) | 19 months |
pDys 2 (ICI) | None |
pDys 3 (ICE-T) | None |
pDys 4 (JAFFAR) | None |
pDys 5 (JACADI) | None |
GRMD Control 1 (1AMES) | 7 months |
GRMD Control 2 (1ESSY) | 7 months |
GRMD Control 3 (10SS) | 6 months |
GRMD Control 4 (EBOUGE) | 6 months |
GRMD Control 5 (FELIX) | 4 months |
GRMD Control 6 (FIASKO) | 7 months |
Age of dysphagia appearance | Severity | ||
pDys 1 (IMAGE) | 12 months | 10.2 months +/2.0 months | Weak |
pDys 2 (ICI) | 12 months | Very weak | |
pDys 3 (ICE-T) | 10 months | Weak | |
pDys 4 (JAFFAR) | 10 months | Weak | |
pDys 5 (JACADI) | 7 months | Weak | |
GRMD Control 1 (1AMES) | 8 months | 6.2 months +/-1-3 months | Marked |
GRMD Control 2 (1ESSY) | 4 months | Severe | |
GRMD Control 3 (10SS) | 6 months | Marked | |
GRMD Control 4 (EBOUGE) | 6 months | Weak | |
GRMD Control 5 (FELIX) | 6 months | Very weak | |
GRMD Control 6 (FIASKO) | 7 months | weak |
Before injection | Month +0.5 | Month +1.5 | Month +2 | Month +4 | Month +7.5 | ||
1E14 vg/kg | pDys 1 | Nd | Nd | ++ | Nd | Nd | Nd |
pDys 2 | Nd | + | ++ | ++ | + | Nd | |
pDys 3 | Nd | Nd | Nd | Nd | Nd | Nd | |
pDys 4 | Pending | Pending | Pending | Pending | Pending | Pending | |
pDys 5 | Pending | Pending | Pending | Pending | Pending | Pending |
Claims (18)
- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:1. A method of treating a dystrophic disease selected from Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) in a human or dog subject, said method comprising systemically administering to the subject a composition comprising a gene therapy product, wherein said gene therapy product comprises an adeno-associated viral (AAV) vector which harbors a nucleic acid sequence encoding a AR4-R23/ACT microdystrophin.
- 2. A method according to claim 1, wherein the composition is administered by intravenous injection.
- 3. A method according to claim 1 or 2, wherein the nucleic acid sequence encoding the microdystrophin is of human or canine origin.
- 4. A method according to any one of claims 1 to 3, wherein expression of the nucleic acid sequence encoding the microdystrophin is under the control of a muscle specific promoter.
- 5. A method according to any one of claims 1 to 4, wherein the gene therapy product comprises a sequence 90% homologous to SEQ ID NO: 1 or SEQ ID NO: 2.
- 6. A method according to claim 5, wherein the gene therapy product comprises a sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- 7. A method according to any one of claims 1 to 6, wherein the AAV vector is an AAV of serotype 2, 8 or 9.
- 8. A method according to claim 7, wherein the AAV vector is an AAV8 vector.
- 9. A method according to claim 7, wherein the AAV vector is an AAV2/8 vector.
- 10. A method according to any one of claims 1 to 9, wherein the step of administering the composition comprises administering a dose less or equal to 1015 vg/kg.
- 11. A method according to any one of claims 1 to 9, wherein the step of administering the composition comprises administering a dose between 1012 * vg/kg and 1014 vg/kg.
- 12. A method according to any one of claims 1 to 10, wherein the step of administering the composition comprises administering a single dose of the composition.2017200015 03 Apr 2018
- 13. A method according to any one of claims 1 to 12, wherein the method ameliorates muscular function.
- 14. A method according to any one of claims 1 to 13, wherein the method ameliorates cardiac function.
- 15. A method according to any one of claims 1 to 14, wherein the method ameliorates respiratory function.
- 16. A method according to any one of claims 1 to 15, wherein the method ameliorates digestive function.
- 17. A method according to any one of claims 1 to 16, wherein the method ameliorates gait.
- 18. A method according to any one of claims 1 to 17, wherein the method ameliorates quality and/or expectancy of life.1 /62017200015 03 Jan 2017A/B/NOSFitii iength dystrophinSynEfcrs
ft®e reKtystFOphins SJOytMS _jaag^ng^ JB ΛίΜ H%2 3 ^bsmr»m .ΐ£ζί·0&Ί .... Λ3Ϊ8Β ^!5S$g|||^ &3&S0 ^^^BBaaaaaaBa..... ww ww ..... C/SPC5125’ITR promoter skeletal/cardiac musclesossi 1 n 1 2 3 1 1 24 n B CR sdddddNCCCCC©PA3’ITRFigure 12/62017200015 03 Jan 2017Intravenous injection of rAAV8-canine_pDysWeekly grading (clinical evaluation) Bi-monthly Loeometrix® (gait evaluation) Monthly thoracic radioscopy Monthly echocardiographySISfMSs-2 months >4+.... monthsEvaluation of the immune response (humoral and cellular anti-AAV and anti-Dys)KMeasuteSehidtflMD-eiKuJatihg-hiciiriarker's-levelSK k'DystrophiniexpressionHpattern Jn'the'rnusGte&:of :the'w:hoieHt>oHy'(VV:B<:iF)2:2:2:2:2:2:Figure 23/62017200015 03 Jan 2017A/m„ biceps femoris before injection B/Figure 34/62017200015 03 Jan 2017 s§ ioo%3054 §05470« «0«50% i40%3054205410540%10 12 Age Aiionihsj14 IS IS 20Figure 4F2Vector (rejectionAge in months 4 6H jiDys lE14vg/kg (N=5)FIFigure 55/62017200015 03 Jan 2017Figure 6Before injection Month +1 Month +2 Month +3Figure 72017200015 03 Jan 20176/6:< : ; X ; ; : : lu : i C+ i*i c+ Day ί Wk i Mo § ; (dog Mo Mo / Mo / : 1 i (dog o ; +3 ; +1.5 i s i Serum) + 2 5 . Cellular extract —..........- + 4 ί +7.5 i : ; serum) .·; + .k+ . *T ’+ . ’ 4r .+ _ i 777TT* ·+ ’+ . ' <- cpDys (137kDa) Figure 8SEQUENCE LISTING2017200015 03 Jan 2017 <110> GENETHONROYAL HOLLOWAY AND BEDFORD NEW COLLEGE <120> EFFICIENT SYSTEMIC TREATMENT OF DYSTROPHIC PATHOLOGIES <130> G143-B-43539 PCT <150> EP14174848.3 <151> 2014-06-27 <150> PCT/EP2015/058964 <151> 2015-04-24 <160> 8 <170> BiSSAP 1.3 <210> 1 <211> 4640 <212> DNA <213> Artificial Sequence <220><223> AAV_ITR_Spc512-human MD1 <400> 1 gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60 tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120 gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtagc catgctctag 180 acatggctcg acagatcgag ctccaccgcg gtggcggccg tccgccctcg gcaccatcct 240 cacgacaccc aaatatggcg acgggtgagg aatggtgggg agttattttt agagcggtga 300 ggaaggtggg caggcagcag gtgttggcgc tctaaaaata actcccggga gttattttta 3602017200015 03 Jan 2017 gagcggagga420 ggtgtccgcc480 gataaaaggc540 agctctagaa600 gaagtggagg660 aacgcccagt720 gatggcagga780 aagggcagca840 aacaacaacg900 ctgaccctgg960 aacatcatgg1020 cagagcacca1080 ggcctggccc1140 gtggtgtgtc1200 cagctgggca1260 atggtggaca ctcggccggg tccggggccg ctagtggatc actgctacga tcagcaagtt gactgctgga ccagagtgca tggacctggt gcctgatctg ccggcctgca gaaactaccc tgaacgccct agcagagcgc tcgagaagct cccaaatatg gccgcattcc gcggcggccc ccccgggctg gagagaggac cggcaagcag tctgctggag cgccctgaac gaatatcggc gaacatcatc gcagaccaac ccaggtgaac gatccacagc cacccagaga gctggacccc gcgacggttc tgggggccgg acgagctacc caggaattcg gtgcagaaga cacatcgaga ggactgaccg aacgtgaaca agcaccgaca ctgcactggc agcgagaaga gtgatcaact cacagacccg ctggagcacg gaggacgtgg ctcacccgtc gcggtgctcc cggaggagcg ccaccatgct aaaccttcac acctgttcag gccagaagct aggccctgag tcgtggacgg aggtgaagaa tcctgctgag tcaccacctc acctgttcga ccttcaacat acaccaccta gccatatttg cgcccgcctc ggaggcgcca gtggtgggag caagtgggtg cgacctgcag gcccaaggag agtgctgcag caaccacaag cgtgatgaag ctgggtgagg ctggagcgac ctggaacagc cgccagatac ccccgacaag2017200015 03 Jan 2017 aaaagcatcc1320 gaggccatcc1380 ttccagctgc1440 tatgagagaa1500 tacgtgacca1560 gaggacaaga1620 accgccctgg1680 ggcgagatca1740 atgatggatc1800 ctgatcggca1860 ctgctgaaca1920 caccgcgtgc1980 aagaccgagg2040 ctgaagagac2100 cgcgtgaaca2160 tgatgtatat aggaagtgga accaccagat ccagcagccc cctccgaccc gcttcggcag aggaagtgct gcaacgacgt tgaccgccca ccggcaagct gcagatggga tgatggacct agcggaccag aggtgcagca gcctgaccca tacctctctg aatgctgccc gcactatagc caagcccaga caccagaagc cagcctgatg gtcttggctg ggaagtggtg ccagggcaga gagcgaggac gtgcctgaga gcagaaccag aaagatggag gcacaaagtg catggtggtc tttcaggtgc aggcccccca cagcagatca ttcaagagct cccttcccca gagagcgaag ctgtccgccg aaggaccagt gtgggcaata gaggagaccg gtggccagca aagctgaagg gaggagcccc ctgcaggagg gtggtggacg tgccccagca aagtgaccaa ccgtgtccct acgcctacac gccagcacct tgaacctgga aggacaccct tccacaccca tcctgcagct aagtgcagga tggagaagca agctgaacga tgggccccga acctggaaca agagcagcgg ggtgtccatc ggaggagcac ggcccagggc ccaggccgcc ggaggccccc cagataccag gcaggcccag cgagggctac gggcagcaag gcagatgaac gagcaacctg ctggctgacc cctggaggac ggagcaggtg cgaccacgcc2017200015 03 Jan 2017 acagccgccc2220 tggaccgagg2280 gaggagcagt2340 cacaccaccg2400 ctgaaggccg2460 gacctgctgt2520 aatttcgccc2580 agccaggccg2640 accacagtga2700 cccccccctc2760 caggaagcca2820 tggcagcctg2880 gccctgcggg2940 agacagctga3000 ctgaacaccc3060 tggaagagca acagatgggt gcctgtttag gcttcaagga atctggagaa ccaccctgaa ggtgctggga tgaccaccac ccaccaggga agaagaagcg ccgacgagct tgggcgatct gcgagatcgc ccaccctggg ggtggaaact gctgaaagtg gctgctgcag cgcctggctg ccagaacgag gaaaaagcag gaacaagagc caatctggtg ccagcccagc gcagatcctg gcagatcaca ggacctgaag gctgatcgac ccccctgaag catccagctg gctgcaggtg ctgggcgaca gacatcctgc agcgagaagg atgctgagca agcatgggca gtgacccaga cagaaactgg ctgacacaga gtgaagcacg gtggacaccc ctgagacagg agcctgcagg gagaatgtga agcccctaca gccgtggagg gatgggccaa tgaagtggca aggacgccgt gcctgcagaa agctgtactc aaaccgaggc agaagagcac ccaccgtgat cccaggagga tggagagact ccgaagtgat accacctgga gccacgtgaa atctgagcac atagagtgag catctgccgg gagactgaca gaacaagatc gctggccgtg cctgaagcag ctggctggac cgcccagatc ggagaccgtg gctgccccct gcaggagctg caagggcagc gaaagtgaag cgacctggcc cctggaagat gcagctgcac2017200015 03 Jan 2017 gaggcccaca3120 ccctgggaga3180 accacctgct3240 aatgtgcggt3300 tgcctggacc3360 cagaacgacc3420 cggctggagc3480 aattggctgc3540 aagaccggca3600 aagcaggtgg3660 gatagcatcc3720 gagccctctg3780 ctgttcctgg3840 agagtggccg3900 cccatcatcg3960 gagacttcgg gagccatctc gggaccaccc tcagcgccta tgctgagcct agcccatgga aggagcacaa tgaacgtgta tcatcagcct ccagcagcac agatccctag tgaggagctg attggatgag ccgccgagac gcttccggta ccctgcctcc ccccaacaaa taagatgacc cagaaccgcc gagcgccgcc cattctgcag caacctggtg cgacaccggc gtgcaaggcc cggcttctgc gcagctgggc cttccagttc gctggagccc cgccaagcac caggagcctg cagcacttcc gtgccctact gagctgtacc atgaagctgc tgcgacgccc atcatcaact aacgtgcccc aggaccggca cacctggagg gatcagagga gaagtggcca gccaacaaca cagagcatgg caggccaagt aagcacttca tgagcaccag acatcaacca agagcctggc ggagactgca tggaccagca gcctgaccac tgtgcgtgga gaatcagagt ataagtaccg gactgggcct gctttggcgg agcccgagat tgtggctgcc gcaacatctg actacgacat cgtgcagggc cgagacccag cgacctgaac gaaggccctg caacctgaag catctacgat catgtgcctg gctgtccttc ctacctgttc gctgctgcac cagcaacatc cgaggccgcc tgtgctgcac caaggagtgc ctgccagagc2017200015 03 Jan 2017 tgctttttca gcggcagagt ggccaagggc cacaagatgc actaccccat 4020 tgcaccccca ccacctccgg cgaggatgtg agagacttcg ccaaagtgct 4080 ttccggacca agcggtactt tgccaagcac cccaggatgg gctacctgcc 4140 gtgctggagg gcgacaacat ggagaccgac accatgtgat gatgagcggc 4200 tagtgagggt taatgcttcg agcagacatg ataagataca ttgatgagtt 4260 acaactagaa tgcagtgaaa aaaatgcttt atttgtgaaa tttgtgatgc 4320 tttgtaacca ttataagctg caataaacaa gttaacaaca acaattgcat 4380 tttcaggttc agggggagat gtgggaggtt ttttaaagca agtaaaacct 4440 ggtaaaatcc gataaggact agagcatggc tacgtagata agtagcatgg 4500 attaactaca aggaacccct agtgatggag ttggccactc cctctctgcg 4560 ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg 4620 gtgagcgagc gagcg4640 ggtggagtac gaagaataag cgtgcagacc cgcttccctt tggacaaacc tattgcttta tcattttatg ctacaaatgt cgggttaatc cgctcgctcg ggcggcctca <210> 2 <211> 4643 <212> DNA <213> Artificial Sequence <220><223> AAV_ITR_Spc512-canine MD12017200015 03 Jan 2017 <400> 2 gcgcgctcgc 60 tcgcccggcc120 gggttccttg180 acatggctcg240 cacgacaccc300 ggaaggtggg360 gagcggagga420 ggtgtccgcc480 gataaaaggc540 agctctagaa600 gaagtggagg660 aacgcccagt720 gatggcagga780 aagggcagca840 aagaacaacg900 tcgctcactg tcagtgagcg tagttaatga acagatcgag aaatatggcg caggcagcag atggtggaca ctcggccggg tccggggccg ctagtggatc actgctacga tcagcaagtt gactgctgga ccagagtgca tggacctggt aggccgcccg agcgagcgcg ttaacccgcc ctccaccgcg acgggtgagg gtgttggcgc cccaaatatg gccgcattcc gcggcggccc ccccgggctg gagagaggac cggcaagcag tctgctggag cgccctgaac ggatatcggc ggcaaagccc cagagaggga atgctactta gtggcggccg aatggtgggg tctaaaaata gcgacggttc tgggggccgg acgagctacc caggaattcg gtgcagaaga cacatcgaga ggactgaccg aacgtgaaca agcaccgaca gggcgtcggg gtggccaact tctacgtagc tccgccctcg agttattttt actcccggga ctcacccgtc gcggtgctcc cggaggagcg ccaccatgct aaaccttcac acctgttcag gccagaagct aggccctgag tcgtggacgg cgacctttgg ccatcactag catgctctag gcaccatcct agagcggtga gttattttta gccatatttg cgcccgcctc ggaggcgcca gtggtgggag caagtggatc cgatctgcag gcccaaggag agtgctgcag caaccacaag2017200015 03 Jan 2017 ctgaccctgg960 aacatcatgg1020 cagagcacca1080 ggcctggccc1140 gtggtgtgtc1200 cagctgggca1260 aaaagcatcc1320 gaggccatcc1380 ttccagctgc1440 tatgagagag1500 gcctacgtga1560 cctgaggata1620 cagaccgccc1680 cagggcgaga1740 tacatgatgg1800 gcctgatctg ccggcctgca gaaactaccc tgaacgccct agcagagcgc tcgagaagct tgatgtatat aggaagtgga accaccagat cccctagcag ccacctccga agagcttcgg tggaggaagt tcagcaacga acctgaccag gaacatcatc gcagaccaac ccaggtgaac gatccacagc cacccagaga gctggacccc taccagcctg aatgctgccc gcactatagc ccccaagccc ccccaccaga cagaagcctg gctgtcttgg cgtggaagaa ccaccagggc ctgcactggc agcgagaaga gtgatcaact cacagacccg ctggagcacg gaggacgtgg ttccaggtgc aggcccagca cagcagatca cggttcaaga agccccctgc accgagaccg ctgctgtccg gtgaaggagc agagtgggca aggtgaagaa tcctgctgag tcaccacctc acctgttcga ccttcaacat ccaccaccta tgccccagca aagtgaccag ccgtgtccct gctacgccta ccagccagca aggccaacct ccgaggacgc agttccacac acgtgctgca cgtgatgaag ctgggtgagg ctggagcgac ctggaacagc cgccaagtac ccccgacaag ggtgtccatc ggaggagcac ggcccagggc cacccaggcc cctggagacc ggatagctac cctgcaggcc ccacgagggc gctgggcagc2017200015 03 Jan 2017 cagctgatcg1860 aacctgctga1920 ctgcacaaag1980 accaagacag2040 gacctgaaga2100 gtgcgcgtga2160 gccacagccg2220 cggtggaccg2280 accgaggagc2340 atccacacca2400 gtgctgaaaa2460 caggacctgc2520 gataatagcg2580 atcagccagg2640 gtgaccatgg2700 gcaccggcaa acagcagatg tgctgatgga aggagcggac ggcaggtgca acagcctgac ccctggaaga aggacagatg agtgcctgtt ccggcttcaa ccgacctgga tgagcgccct ctcagagatg ccgtgaccac tgaccaccag gctgagcgag ggagtgcctg tctgcagaac ccggaagatg gcagcataag ccacatggtg gcagctgaaa ggtgctgctg tagcgcctgg ggaccagagc gaagaaaaag gaagaacacc ggataatctg cacccagccc ggagcacatc gacgaggaga agagtggcca cagcagctga gagaaggagc gtcctgcagg gtcgtggtgg gtgctgggcg caggacatcc ctgagcgaga gaagtgctgt cagaccatgg gtggtggccc gtgcagaaac agcctgacac ctggtgaagc ccgaagtgca gcatggagaa aggagctgaa ccctgggccc aggatctgga acgagagcag gcagatgggc tgctgaagtg aggaggacgc ccaacctgca acaagctgtg acaagatgga tggagaagag agaccaccgt acgcccagga ggaacagatg gcagagcaac cgactggctg tgacatcgag gcaggagcag cggcgaccac caatatctgc gcagagattc cgtgaacaag gaagctggcc cagcctgaac ggcctggctg cagcgcccag gatggagacc ggagctgccc2017200015 03 Jan 2017 cctccccccc2760 ctgcaggaag2820 agctggcagc2880 aaggccctgc2940 gccagacagc3000 gatctgaaca3060 cacgaggccc3120 ggcccctggg3180 cagaccacct3240 aacaatgtgc3300 ctgtgcctgg3360 aagcagaacg3420 gatcggctgg3480 ctgaattggc3540 ttcaagaccg3600 ctcagaagaa ccaccgacga ctgtgggcga ggggcgagac tgaccaccct cccggtggaa acagagactt agagagccat gctgggacca ggttcagcgc acctgctgtc accagcccat agcaggagca tgctgaacgt gcatcatcag gcggcagatc gctggacctg tctgctgatc cacccccctg gggcattcag actgctgcag cggccctgct cagccccaac ccctaagatg ctacagaacc cctgagcgcc ggatatcctg caacaacctg gtacgacacc cctgtgcaag atcgtggatg aagctgagac gacagcctgc aaggagaacg ctgagcccct gtggccattg tctcagcatt aaagtgccct accgagctgt gccatgaagc gcctgcgacg caggtgatca gtgaacgtgc ggcaggaccg gcccacctgg ccctggagag aggccgaagt aggaccacct tgtcctacgt acaacctgaa aggaccggat tcctgagcac actacatcaa accagagcct tgcggagact ccctggacca actgcctgac ccctgtgcgt gcagaatcag aggataagta actgcaggag gatcaagggc ggagaaagtg gaacgacctg caccctggag caggcagctg cagcgtgcag ccacgagacc ggccgacctg gcagaaggcc gcacaacctg caccatctac ggacatgtgc agtgctgtcc ccgctacctg2017200015 03 Jan 2017 ttcaagcagg3660 cacgatagca3720 atcgagccct3780 gccctgttcc3840 cacagagtgg3900 tgccccatca3960 agctgctttt4020 tactgcaccc4080 aagttccgga4140 accgtgctgg4200 ctttagtgag4260 accacaacta4320 ttatttgtaa4380 atgtttcagg4440 tgtggtaaaa4500 tggccagcag tccagatccc ctgtgaggag tggattggat ccgccgccga tcggcttccg tcagcggcag ccaccacctc ccaagcggta agggcgacaa ggttaatgct gaatgcagtg ccattataag ttcaggggga tccgataagg caccggcttc taggcagctg ctgcttccag gaggctggag gaccgccaag gtacaggagc agtggccaag cggcgaggat ctttgccaag catggagacc tcgagcagac aaaaaaatgc ctgcaataaa gatgtgggag actagagcat tgcgatcaga ggcgaagtgg ttcgccaaca ccccagagca caccaggcca ctgaagcact ggccacaaga gtgagagact caccccagga gacaccatgt atgataagat tttatttgtg caagttaaca gttttttaaa ggctacgtag ggagactggg ccagctttgg acaagcccga tggtgtggct agtgcaacat tcaactacga tgcactaccc tcgccaaagt tgggctacct gatgatgagc acattgatga aaatttgtga acaacaattg gcaagtaaaa ataagtagca cctgctgctg cggcagcaac gatcgaggcc gcctgtgctg ctgcaaggag catctgccag catggtggag gctgaagaat gcccgtgcag ggccgcttcc gtttggacaa tgctattgct cattcatttt cctctacaaa tggcgggtta2017200015 03 Jan 2017 atcattaact acaaggaacc cctagtgatg gagttggcca ctccctctct gcgcgctcgc4560 tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggctttgc ccgggcggcc 4620 tcagtgagcg agcgagcgcg cag4643 <210> 3 <211> 1197 <212> PRT <213> Artificial Sequence <220><223> human MD1 <400> 3Met Leu Trp Trp Glu Glu Val Glu Asp Cys Tyr Glu Arg Glu Asp Val 1 5 10 15 Gin Lys Lys Thr Phe Thr Lys Trp Val Asn Ala Gin Phe Ser Lys Phe 20 25 30 Gly Lys Gin His Ile Glu Asn Leu Phe Ser Asp Leu Gin Asp Gly Arg 35 40 45 Arg Leu Leu Asp Leu Leu Glu Gly Leu Thr Gly Gin Lys Leu Pro Lys 50 55 60 Glu Lys Gly Ser Thr Arg Val His Ala Leu Asn Asn Val Asn Lys Ala 65 70 75 80 Leu Arg Val Leu Gin Asn Asn Asn Val Asp Leu Val Asn Ile Gly Ser 85 90 95 Thr Asp Ile Val Asp Gly Asn His Lys Leu Thr Leu Gly Leu Ile Trp 100 105 110 Asn Ile Ile Leu His Trp Gin Val Lys Asn Val Met Lys Asn Ile Met 115 120 125 Ala Gly Leu Gin Gin Thr Asn Ser Glu Lys Ile Leu Leu Ser Trp Val 130 135 140 Arg Gin Ser Thr Arg Asn Tyr Pro Gin Val Asn Val Ile Asn Phe Thr 145 150 155 160 Thr Ser Trp Ser Asp Gly Leu Ala Leu Asn Ala Leu Ile His Ser His 165 170 175 Arg Pro Asp Leu Phe Asp Trp Asn Ser Val Val Cys Gin Gin Ser Ala 180 185 190 Thr Gin Arg Leu Glu His Ala Phe Asn Ile Ala Arg Tyr Gin Leu Gly 2017200015 03 Jan 2017195 200 205 Ile Glu Lys Leu Leu Asp Pro Glu Asp Val Asp Thr Thr Tyr Pro Asp 210 215 220 Lys Lys Ser Ile Leu Met Tyr Ile Thr Ser Leu Phe Gin Val Leu Pro 225 230 235 240 Gin Gin Val Ser Ile Glu Ala Ile Gin Glu Val Glu Met Leu Pro Arg 245 250 255 Pro Pro Lys Val Thr Lys Glu Glu His Phe Gin Leu His His Gin Met 260 265 270 His Tyr Ser Gin Gin Ile Thr Val Ser Leu Ala Gin Gly Tyr Glu Arg 275 280 285 Thr Ser Ser Pro Lys Pro Arg Phe Lys Ser Tyr Ala Tyr Thr Gin Ala 290 295 300 Ala Tyr Val Thr Thr Ser Asp Pro Thr Arg Ser Pro Phe Pro Ser Gin 305 310 315 320 His Leu Glu Ala Pro Glu Asp Lys Ser Phe Gly Ser Ser Leu Met Glu 325 330 335 Ser Glu Val Asn Leu Asp Arg Tyr Gin Thr Ala Leu Glu Glu Val Leu 340 345 350 Ser Trp Leu Leu Ser Ala Glu Asp Thr Leu Gin Ala Gin Gly Glu Ile 355 360 365 Ser Asn Asp Val Glu Val Val Lys Asp Gin Phe His Thr His Glu Gly 370 375 380 Tyr Met Met Asp Leu Thr Ala His Gin Gly Arg Val Gly Asn Ile Leu 385 390 395 400 Gin Leu Gly Ser Lys Leu Ile Gly Thr Gly Lys Leu Ser Glu Asp Glu 405 410 415 Glu Thr Glu Val Gin Glu Gin Met Asn Leu Leu Asn Ser Arg Trp Glu 420 425 430 Cys Leu Arg Val Ala Ser Met Glu Lys Gin Ser Asn Leu His Arg Val 435 440 445 Leu Met Asp Leu Gin Asn Gin Lys Leu Lys Glu Leu Asn Asp Trp Leu 450 455 460 Thr Lys Thr Glu Glu Arg Thr Arg Lys Met Glu Glu Glu Pro Leu Gly 465 470 475 480 Pro Asp Leu Glu Asp Leu Lys Arg Gin Val Gin Gin His Lys Val Leu 485 490 495 Gin Glu Asp Leu Glu Gin Glu Gin Val Arg Val Asn Ser Leu Thr His 500 505 510 Met Val Val Val Val Asp Glu Ser Ser Gly Asp His Ala Thr Ala Ala 515 520 525 Leu Glu Glu Gin Leu Lys Val Leu Gly Asp Arg Trp Ala Asn Ile Cys 530 535 540 Arg Trp Thr Glu Asp Arg Trp Val Leu Leu Gin Asp Ile Leu Leu Lys 545 550 555 560 2017200015 03 Jan 2017Trp Gin Arg Leu Thr 565 Glu Glu Gin Cys Leu 570 Phe Ser Ala Trp Leu 575 Ser Glu Lys Glu Asp Ala Val Asn Lys Ile His Thr Thr Gly Phe Lys Asp 580 585 590 Gin Asn Glu Met Leu Ser Ser Leu Gin Lys Leu Ala Val Leu Lys Ala 595 600 605 Asp Leu Glu Lys Lys Lys Gin Ser Met Gly Lys Leu Tyr Ser Leu Lys 610 615 620 Gin Asp Leu Leu Ser Thr Leu Lys Asn Lys Ser Val Thr Gin Lys Thr 625 630 635 640 Glu Ala Trp Leu Asp Asn Phe Ala Arg Cys Trp Asp Asn Leu Val Gin 645 650 655 Lys Leu Glu Lys Ser Thr Ala Gin Ile Ser Gin Ala Val Thr Thr Thr 660 665 670 Gin Pro Ser Leu Thr Gin Thr Thr Val Met Glu Thr Val Thr Thr Val 675 680 685 Thr Thr Arg Glu Gin Ile Leu Val Lys His Ala Gin Glu Glu Leu Pro 690 695 700 Pro Pro Pro Pro Gin Lys Lys Arg Gin Ile Thr Val Asp Thr Leu Glu 705 710 715 720 Arg Leu Gin Glu Leu Gin Glu Ala Thr Asp Glu Leu Asp Leu Lys Leu 725 730 735 Arg Gin Ala Glu Val Ile Lys Gly Ser Trp Gin Pro Val Gly Asp Leu 740 745 750 Leu Ile Asp Ser Leu Gin Asp His Leu Glu Lys Val Lys Ala Leu Arg 755 760 765 Gly Glu Ile Ala Pro Leu Lys Glu Asn Val Ser His Val Asn Asp Leu 770 775 780 Ala Arg Gin Leu Thr Thr Leu Gly Ile Gin Leu Ser Pro Tyr Asn Leu 785 790 795 800 Ser Thr Leu Glu Asp Leu Asn Thr Arg Trp Lys Leu Leu Gin Val Ala 805 810 815 Val Glu Asp Arg Val Arg Gin Leu His Glu Ala His Arg Asp Phe Gly 820 825 830 Pro Ala Ser Gin His Phe Leu Ser Thr Ser Val Gin Gly Pro Trp Glu 835 840 845 Arg Ala Ile Ser Pro Asn Lys Val Pro Tyr Tyr Ile Asn His Glu Thr 850 855 860 Gin Thr Thr Cys Trp Asp His Pro Lys Met Thr Glu Leu Tyr Gin Ser 865 870 875 880 Leu Ala Asp Leu Asn Asn Val Arg Phe Ser Ala Tyr Arg Thr Ala Met 885 890 895 Lys Leu Arg Arg Leu Gin Lys Ala Leu Cys Leu Asp Leu Leu Ser Leu 900 905 910 Ser Ala Ala Cys Asp Ala Leu Asp Gin His Asn Leu Lys Gin Asn Asp 2017200015 03 Jan 2017915 920 925 Gin Pro 930 Met Asp Ile Leu Gin 935 Ile Ile Asn Cys Leu 940 Thr Thr Ile Tyr Asp Arg 945 Leu Glu Gin Glu His 950 Asn Asn Leu Val Asn 955 Val Pro Leu Cys 960 Val Asp Met Cys Leu Asn Trp 965 Leu Leu Asn Val Tyr 970 Asp Thr Gly Arg 975 Thr Gly Arg Ile Arg Val Leu 980 Ser Phe Lys Thr Gly 985 Ile Ile Ser Leu 990 Cys Lys Ala His Leu Glu Asp 995 Lys Tyr Arg Tyr Leu 1000 Phe Lys Gin Val 1005 Ala Ser Ser Thr Gly Phe Cys Asp Gin Arg Arg Leu Gly Leu Leu Leu 1010 1015 1020 His Asp 1025 Ser Ile Gin Ile Pro 1030 Arg Gin Leu Gly Glu 1035 Val Ala Ser Phe 1040 Gly Gly Ser Asn Ile Glu Pro 1045 Ser Val Arg Ser Cys 1050 Phe Gin Phe Ala 1055 Asn Asn Lys Pro Glu Ile Glu 1060 Ala Ala Leu Phe Leu 1065 Asp Trp Met Arg 1070 Leu Glu Pro Gin Ser Met Val 1075 Trp Leu Pro Val Leu 1080 His Arg Val Ala 1085 Ala Ala Glu Thr Ala Lys His Gin Ala Lys Cys Asn Ile Cys Lys Glu 1090 1095 1100 Cys Pro 1105 Ile Ile Gly Phe Arg 1110 Tyr Arg Ser Leu Lys 1115 His Phe Asn Tyr 1120 Asp Ile Cys Gin Ser Cys Phe 1125 Phe Ser Gly Arg Val 1130 Ala Lys Gly His 1135 Lys Met His Tyr Pro Met Val 1140 Glu Tyr Cys Thr Pro 1145 Thr Thr Ser Gly 1150 Glu Asp Val Arg Asp Phe Ala 1155 Lys Val Leu Lys Asn 1160 Lys Phe Arg Thr 1165 Lys Arg Tyr Phe Ala Lys His Pro Arg Met Gly Tyr Leu Pro Val Gin 1170 1175 1180 Thr Val Leu Glu Gly Asp Asn Met Glu Thr Asp Thr Met 1185 1190 1195 <210> 4 <211> 1198 <212> PRT <213> Artificial Sequence <220><223> canine MD1 <400> 42017200015 03 Jan 2017Met Leu Trp Trp Glu Glu Val Glu Asp Cys Tyr Glu Arg Glu Asp Val 1 5 10 15 Gln Lys Lys Thr Phe Thr Lys Trp Ile Asn Ala Gln Phe Ser Lys Phe 20 25 30 Gly Lys Gln His Ile Glu Asn Leu Phe Ser Asp Leu Gln Asp Gly Arg 35 40 45 Arg Leu Leu Asp Leu Leu Glu Gly Leu Thr Gly Gln Lys Leu Pro Lys 50 55 60 Glu Lys Gly Ser Thr Arg Val His Ala Leu Asn Asn Val Asn Lys Ala 65 70 75 80 Leu Arg Val Leu Gln Lys Asn Asn Val Asp Leu Val Asp Ile Gly Ser 85 90 95 Thr Asp Ile Val Asp Gly Asn His Lys Leu Thr Leu Gly Leu Ile Trp 100 105 110 Asn Ile Ile Leu His Trp Gln Val Lys Asn Val Met Lys Asn Ile Met 115 120 125 Ala Gly Leu Gln Gln Thr Asn Ser Glu Lys Ile Leu Leu Ser Trp Val 130 135 140 Arg Gln Ser Thr Arg Asn Tyr Pro Gln Val Asn Val Ile Asn Phe Thr 145 150 155 160 Thr Ser Trp Ser Asp Gly Leu Ala Leu Asn Ala Leu Ile His Ser His 165 170 175 Arg Pro Asp Leu Phe Asp Trp Asn Ser Val Val Cys Gln Gln Ser Ala 180 185 190 Thr Gln Arg Leu Glu His Ala Phe Asn Ile Ala Lys Tyr Gln Leu Gly 195 200 205 Ile Glu Lys Leu Leu Asp Pro Glu Asp Val Ala Thr Thr Tyr Pro Asp 210 215 220 Lys Lys Ser Ile Leu Met Tyr Ile Thr Ser Leu Phe Gln Val Leu Pro 225 230 235 240 Gln Gln Val Ser Ile Glu Ala Ile Gln Glu Val Glu Met Leu Pro Arg 245 250 255 Pro Ser Lys Val Thr Arg Glu Glu His Phe Gln Leu His His Gln Met 260 265 270 His Tyr Ser Gln Gln Ile Thr Val Ser Leu Ala Gln Gly Tyr Glu Arg 275 280 285 Ala Pro Ser Ser Pro Lys Pro Arg Phe Lys Ser Tyr Ala Tyr Thr Gln 290 295 300 Ala Ala Tyr Val Thr Thr Ser Asp Pro Thr Arg Ser Pro Leu Pro Ser 305 310 315 320 Gln His Leu Glu Thr Pro Glu Asp Lys Ser Phe Gly Arg Ser Leu Thr 325 330 335 Glu Thr Glu Ala Asn Leu Asp Ser Tyr Gln Thr Ala Leu Glu Glu Val 340 345 350 Leu Ser Trp Leu Leu Ser Ala Glu Asp Ala Leu Gln Ala Gln Gly Glu 2017200015 03 Jan 2017355 360 365 lie Ser Asn Asp Val Glu Glu Val Lys Glu Gin Phe His Thr His Glu 370 375 380 Gly Tyr Met Met Asp Leu Thr Ser His Gin Gly Arg Val Gly Asn Val 385 390 395 400 Leu Gin Leu Gly Ser Gin Leu lie Gly Thr Gly Lys Leu Ser Glu Asp 405 410 415 Glu Glu Thr Glu Val Gin Glu Gin Met Asn Leu Leu Asn Ser Arg Trp 420 425 430 Glu Cys Leu Arg Val Ala Ser Met Glu Lys Gin Ser Asn Leu His Lys 435 440 445 Val Leu Met Asp Leu Gin Asn Gin Gin Leu Lys Glu Leu Asn Asp Trp 450 455 460 Leu Thr Lys Thr Glu Glu Arg Thr Arg Lys Met Glu Lys Glu Pro Leu 465 470 475 480 Gly Pro Asp lie Glu Asp Leu Lys Arg Gin Val Gin Gin His Lys Val 485 490 495 Leu Gin Glu Asp Leu Glu Gin Glu Gin Val Arg Val Asn Ser Leu Thr 500 505 510 His Met Val Val Val Val Asp Glu Ser Ser Gly Asp His Ala Thr Ala 515 520 525 Ala Leu Glu Glu Gin Leu Lys Val Leu Gly Gly Arg Trp Ala Asn lie 530 535 540 Cys Arg Trp Thr Glu Asp Arg Trp Val Leu Leu Gin Asp lie Leu Leu 545 550 555 560 Lys Trp Gin Arg Phe Thr Glu Glu Gin Cys Leu Phe Ser Ala Trp Leu 565 570 575 Ser Glu Lys Glu Asp Ala Val Asn Lys lie His Thr Thr Gly Phe Lys 580 585 590 Asp Gin Ser Glu Val Leu Ser Asn Leu Gin Lys Leu Ala Val Leu Lys 595 600 605 Thr Asp Leu Glu Lys Lys Lys Gin Thr Met Asp Lys Leu Cys Ser Leu 610 615 620 Asn Gin Asp Leu Leu Ser Ala Leu Lys Asn Thr Val Val Ala His Lys 625 630 635 640 Met Glu Ala Trp Leu Asp Asn Ser Ala Gin Arg Trp Asp Asn Leu Val 645 650 655 Gin Lys Leu Glu Lys Ser Ser Ala Gin lie Ser Gin Ala Val Thr Thr 660 665 670 Thr Gin Pro Ser Leu Thr Gin Thr Thr Val Met Glu Thr Val Thr Met 675 680 685 Val Thr Thr Arg Glu His lie Leu Val Lys His Ala Gin Glu Glu Leu 690 695 700 Pro Pro Pro Pro Pro Gin Lys Lys Arg Gin lie lie Val Asp Ala Leu 705 710 715 720 2017200015 03 Jan 2017Glu Arg Leu Gin Glu 725 Leu Gin Glu Ala Thr 730 Asp Glu Leu Asp Leu 735 Lys Leu Arg Gin Ala 740 Glu Val Ile Lys Gly 745 Ser Trp Gin Pro Val 750 Gly Asp Leu Leu Ile 755 Asp Ser Leu Gin Asp 760 His Leu Glu Lys Val Lys 765 Ala Leu Arg Gly Glu 770 Thr Thr Pro Leu 775 Lys Glu Asn Val Ser 780 Tyr Val Asn Asp Leu 785 Ala Arg Gin Leu Thr 790 Thr Leu Gly Ile Gin 795 Leu Ser Pro Tyr Asn 800 Leu Asn Thr Leu Glu 805 Asp Leu Asn Thr Arg 810 Trp Lys Leu Leu Gin 815 Val Ala Ile Glu Asp 820 Arg Ile Arg Gin Leu 825 His Glu Ala His Arg 830 Asp Phe Gly Pro Ala 835 Ser Gin His Phe Leu S40 Ser Thr Ser Val Gin Gly 845 Pro Trp Glu Arg Ala 850 Ile Ser Pro Asn 855 Lys Val Pro Tyr Tyr 860 Ile Asn His Glu Thr 865 Gin Thr Thr Cys Trp 870 Asp His Pro Lys Met 875 Thr Glu Leu Tyr Gin 880 Ser Leu Ala Asp Leu 885 Asn Asn Val Arg Phe 890 Ser Ala Tyr Arg Thr 895 Ala Met Lys Leu Arg 900 Arg Leu Gin Lys Ala 905 Leu Cys Leu Asp Leu 910 Leu Ser Leu Ser Ala 915 Ala Cys Asp Ala Leu 920 Asp Gin His Asn Leu Lys 925 Gin Asn Asp Gin Pro 930 Met Asp Ile Leu 935 Gin Val Ile Asn Cys 940 Leu Thr Thr Ile Tyr 945 Asp Arg Leu Glu Gin 950 Glu His Asn Asn Leu 955 Val Asn Val Pro Leu 960 Cys Val Asp Met Cys 965 Leu Asn Trp Leu Leu 970 Asn Val Tyr Asp Thr 975 Gly Arg Thr Gly Arg 980 Ile Arg Val Leu Ser 985 Phe Lys Thr Gly Ile 990 Ile Ser Leu Cys Lys 995 Ala His Leu Glu Asp Lys 1000 Tyr Arg Tyr Leu Phe 1005 Lys Gin Val Ala Ser 1010 Ser Thr Gly Phe Cys 1015 Asp Gin Arg Arg Leu Gly 1020 Leu Leu Leu His Asp 1025 Ser Ile Gin Ile 1030 Pro Arg Gin Leu Gly 1035 Glu Val Ala Ser 1040 Phe Gly Gly Ser Asn Ile 1045 Glu Pro Ser Val Arg 1050 Ser Cys Phe Gin Phe 1055 Ala Asn Asn Lys Pro 1060 Glu Ile Glu Ala Ala 1065 Leu Phe Leu Asp Trp 1070 Met Arg Leu Glu Pro Gin Ser Met Val Trp Leu Pro Val Leu His Arg Val 2017200015 03 Jan 2017107510801085Ala Ala Ala Glu Thr Ala Lys His Gin Ala Lys Cys Asn Ile Cys Lys 1090 1095 1100 Glu Cys Pro Ile Ile Gly Phe Arg Tyr Arg Ser Leu Lys His Phe Asn 1105 1110 1115 1120 Tyr Asp Ile Cys Gin Ser Cys Phe Phe Ser Gly Arg Val Ala Lys Gly 1125 1130 1135 His Lys Met His Tyr Pro Met Val Glu Tyr Cys Thr Pro Thr Thr Ser 1140 1145 1150 Gly Glu Asp Val Arg Asp Phe Ala Lys Val Leu Lys Asn Lys Phe Arg 1155 1160 1165 Thr Lys Arg Tyr Phe Ala Lys His Pro Arg Met Gly Tyr Leu Pro Val 1170 1175 1180 Gin Thr Val Leu Glu Gly Asp Asn Met Glu Thr Asp Thr Met 1185 1190 1195 <210> 5 <211> 3600 <212> DNA <213> Artificial Sequence <220><223> opt human MD1 <400> 5 atgctgtggt gggaggaagt ggaggactgc tacgagagag aggacgtgca gaagaaaacc 60 ttcaccaagt gggtgaacgc ccagttcagc aagttcggca agcagcacat cgagaacctg 120 ttcagcgacc tgcaggatgg caggagactg ctggatctgc tggagggact gaccggccag 180 aagctgccca aggagaaggg cagcaccaga gtgcacgccc tgaacaacgt gaacaaggcc 240 ctgagagtgc tgcagaacaa caacgtggac ctggtgaata tcggcagcac cgacatcgtg 300 gacggcaacc acaagctgac cctgggcctg atctggaaca tcatcctgca ctggcaggtg 360 aagaacgtga tgaagaacat catggccggc ctgcagcaga ccaacagcga gaagatcctg 4202017200015 03 Jan 2017 ctgagctggg480 acctcctgga540 ttcgactgga600 aacatcgcca660 acctaccccg720 cagcaggtgt780 accaaggagg840 tccctggccc900 tacacccagg960 cacctggagg1020 ctggacagat1080 accctgcagg1140 acccacgagg1200 cagctgggca1260 caggagcaga1320 tgaggcagag gcgacggcct acagcgtggt gataccagct acaagaaaag ccatcgaggc agcacttcca agggctatga ccgcctacgt cccccgagga accagaccgc cccagggcga gctacatgat gcaagctgat tgaacctgct caccagaaac ggccctgaac gtgtcagcag gggcatcgag catcctgatg catccaggaa gctgcaccac gagaaccagc gaccacctcc caagagcttc cctggaggaa gatcagcaac ggatctgacc cggcaccggc gaacagcaga tacccccagg gccctgatcc agcgccaccc aagctgctgg tatattacct gtggaaatgc cagatgcact agccccaagc gaccccacca ggcagcagcc gtgctgtctt gacgtggaag gcccaccagg aagctgagcg tgggagtgcc tgaacgtgat acagccacag agagactgga accccgagga ctctgtttca tgcccaggcc atagccagca ccagattcaa gaagcccctt tgatggagag ggctgctgtc tggtgaagga gcagagtggg aggacgagga tgagagtggc caacttcacc acccgacctg gcacgccttc cgtggacacc ggtgctgccc ccccaaagtg gatcaccgtg gagctacgcc ccccagccag cgaagtgaac cgccgaggac ccagttccac caatatcctg gaccgaagtg cagcatggag2017200015 03 Jan 2017 aagcagagca1380 aacgactggc1440 cccgacctgg1500 gaacaggagc1560 agcggcgacc1620 gccaacatct1680 tggcagagac1740 gccgtgaaca1800 cagaagctgg1860 tactccctga1920 gaggcctggc1980 agcaccgccc2040 gtgatggaga2100 gaggagctgc2160 agactgcagg2220 acctgcaccg tgaccaagac aggacctgaa aggtgcgcgt acgccacagc gccggtggac tgacagagga agatccacac ccgtgctgaa agcaggacct tggacaattt agatcagcca ccgtgaccac cccctccccc agctgcagga cgtgctgatg cgaggagcgg gagacaggtg gaacagcctg cgccctggaa cgaggacaga gcagtgcctg caccggcttc ggccgatctg gctgtccacc cgcccggtgc ggccgtgacc agtgaccacc ccctcagaag agccaccgac gacctgcaga accagaaaga cagcagcaca acccacatgg gagcagctga tgggtgctgc tttagcgcct aaggaccaga gagaagaaaa ctgaagaaca tgggacaatc accacccagc agggagcaga aagcggcaga gagctggacc accagaagct tggaggagga aagtgctgca tggtcgtggt aagtgctggg tgcaggacat ggctgagcga acgagatgct agcagagcat agagcgtgac tggtgcagaa ccagcctgac tcctggtgaa tcacagtgga tgaagctgag gaaggagctg gcccctgggc ggaggacctg ggacgagagc cgacagatgg cctgctgaag gaaggaggac gagcagcctg gggcaagctg ccagaaaacc actggagaag acagaccacc gcacgcccag caccctggag acaggccgaa2017200015 03 Jan 2017 gtgatcaagg2280 ctggagaaag2340 gtgaacgacc2400 agcaccctgg2460 gtgaggcagc2520 accagcgtgc2580 aaccacgaga2640 ctggccgacc2700 ctgcagaagg2760 cagcacaacc2820 accaccatct2880 gtggacatgt2940 agagtgctgt3000 taccgctacc3060 ggcctgctgc3120 gcagctggca tgaaggccct tggccagaca aagatctgaa tgcacgaggc agggcccctg cccagaccac tgaacaatgt ccctgtgcct tgaagcagaa acgatcggct gcctgaattg ccttcaagac tgttcaagca tgcacgatag gcctgtgggc gcggggcgag gctgaccacc cacccggtgg ccacagagac ggagagagcc ctgctgggac gcggttcagc ggacctgctg cgaccagccc ggagcaggag gctgctgaac cggcatcatc ggtggccagc catccagatc gatctgctga atcgcccccc ctgggcatcc aaactgctgc ttcggccctg atctccccca caccctaaga gcctacagaa agcctgagcg atggacattc cacaacaacc gtgtacgaca agcctgtgca agcaccggct cctaggcagc tcgacagcct tgaaggagaa agctgagccc aggtggccgt cctcccagca acaaagtgcc tgaccgagct ccgccatgaa ccgcctgcga tgcagatcat tggtgaacgt ccggcaggac aggcccacct tctgcgatca tgggcgaagt gcaggaccac tgtgagccac ctacaatctg ggaggataga cttcctgagc ctactacatc gtaccagagc gctgcggaga cgccctggac caactgcctg gcccctgtgc cggcagaatc ggaggataag gaggagactg ggccagcttt2017200015 03 Jan 2017 ggcggcagca acatcgagcc ctctgtgagg agctgcttcc agttcgccaa 3180 gagatcgagg ccgccctgtt cctggattgg atgaggctgg agccccagag 3240 ctgcctgtgc tgcacagagt ggccgccgcc gagaccgcca agcaccaggc 3300 atctgcaagg agtgccccat catcggcttc cggtacagga gcctgaagca 3360 gacatctgcc agagctgctt tttcagcggc agagtggcca agggccacaa 3420 cccatggtgg agtactgcac ccccaccacc tccggcgagg atgtgagaga 3480 gtgctgaaga ataagttccg gaccaagcgg tactttgcca agcaccccag 3540 ctgcccgtgc agaccgtgct ggagggcgac aacatggaga ccgacaccat 3600 caacaagccc catggtgtgg caagtgcaac cttcaactac gatgcactac cttcgccaaa gatgggctac gtgatgatga <210> 6 <211> 3603 <212> DNA <213> Artificial Sequence <220><223> opt canine MD1 <400> 6 atgctgtggt gggaggaagt ggaggactgc tacgagagag aggacgtgca 60 ttcaccaagt ggatcaacgc ccagttcagc aagttcggca agcagcacat 120 ttcagcgatc tgcaggatgg caggagactg ctggatctgc tggagggact 180 aagctgccca aggagaaggg cagcaccaga gtgcacgccc tgaacaacgt 240 gaagaaaacc cgagaacctg gaccggccag gaacaaggcc2017200015 03 Jan 2017 ctgagagtgc300 gacggcaacc360 aagaacgtga420 ctgagctggg480 acctcctgga540 ttcgactgga600 aacatcgcca660 acctaccccg720 cagcaggtgt780 accagggagg840 tccctggccc900 gcctacaccc960 cagcacctgg1020 aacctggata1080 gacgccctgc1140 tgcagaagaa acaagctgac tgaagaacat tgaggcagag gcgacggcct acagcgtggt agtaccagct acaagaaaag ccatcgaggc agcacttcca agggctatga aggccgccta agacccctga gctaccagac aggcccaggg caacgtggac cctgggcctg catggccggc caccagaaac ggccctgaac gtgtcagcag gggcatcgag catcctgatg catccaggaa gctgcaccac gagagcccct cgtgaccacc ggataagagc cgccctggag cgagatcagc ctggtggata atctggaaca ctgcagcaga tacccccagg gccctgatcc agcgccaccc aagctgctgg tatattacca gtggaaatgc cagatgcact agcagcccca tccgacccca ttcggcagaa gaagtgctgt aacgacgtgg tcggcagcac tcatcctgca ccaacagcga tgaacgtgat acagccacag agagactgga accccgagga gcctgttcca tgcccaggcc atagccagca agccccggtt ccagaagccc gcctgaccga cttggctgct aagaagtgaa cgacatcgtg ctggcaggtg gaagatcctg caacttcacc acccgacctg gcacgccttc cgtggccacc ggtgctgccc cagcaaagtg gatcaccgtg caagagctac cctgcccagc gaccgaggcc gtccgccgag ggagcagttc2017200015 03 Jan 2017 cacacccacg1200 ctgcagctgg1260 gtgcaggaac1320 gagaagcaga1380 ctgaacgact1440 ggccctgaca1500 ctggagcagg1560 agcagcggcg1620 tgggccaata1680 aagtggcaga1740 gacgccgtga1800 ctgcagaagc1860 ctgtgcagcc1920 atggaggcct1980 aagagcagcg2040 agggctacat gcagccagct agatgaacct gcaacctgca ggctgaccaa tcgaggacct agcaggtgcg accacgccac tctgccggtg gattcaccga acaagatcca tggccgtgct tgaaccagga ggctggataa cccagatcag gatggacctg gatcggcacc gctgaacagc caaagtgctg gacagaggag gaagaggcag cgtgaacagc agccgccctg gaccgaggac ggagcagtgc caccaccggc gaaaaccgac cctgctgagc tagcgctcag ccaggccgtg accagccacc ggcaagctga agatgggagt atggatctgc cggacccgga gtgcagcagc ctgacccaca gaagagcagc agatgggtgc ctgtttagcg ttcaaggacc ctggagaaga gccctgaaga agatgggata accaccaccc agggcagagt gcgaggacga gcctgagagt agaaccagca agatggagaa ataaggtcct tggtggtcgt tgaaagtgct tgctgcagga cctggctgag agagcgaagt aaaagcagac acaccgtggt atctggtgca agcccagcct gggcaacgtg ggagaccgaa ggccagcatg gctgaaggag ggagcccctg gcaggaggat ggtggacgag gggcggcaga catcctgctg cgagaaggag gctgtccaac catggacaag ggcccacaag gaaactggag gacacagacc2017200015 03 Jan 2017 accgtgatgg2100 caggaggagc2160 gagagactgc2220 gaagtgatca2280 cacctggaga2340 tacgtgaacg2400 ctgaacaccc2460 cggatcaggc2520 agcaccagcg2580 atcaaccacg2640 agcctggccg2700 agactgcaga2760 gaccagcaca2820 ctgaccacca2880 tgcgtggaca2940 agaccgtgac tgccccctcc aggagctgca agggcagctg aagtgaaggc acctggccag tggaggatct agctgcacga tgcagggccc agacccagac acctgaacaa aggccctgtg acctgaagca tctacgatcg tgtgcctgaa catggtgacc cccccctcag ggaagccacc gcagcctgtg cctgcggggc acagctgacc gaacacccgg ggcccacaga ctgggagaga cacctgctgg tgtgcggttc cctggacctg gaacgaccag gctggagcag ttggctgctg accagggagc aagaagcggc gacgagctgg ggcgatctgc gagaccaccc accctgggca tggaaactgc gacttcggcc gccatcagcc gaccacccta agcgcctaca ctgtccctga cccatggata gagcacaaca aacgtgtacg acatcctggt agatcatcgt acctgaagct tgatcgacag ccctgaagga ttcagctgag tgcaggtggc ctgcttctca ccaacaaagt agatgaccga gaaccgccat gcgccgcctg tcctgcaggt acctggtgaa acaccggcag gaagcacgcc ggatgccctg gagacaggcc cctgcaggac gaacgtgtcc cccctacaac cattgaggac gcatttcctg gccctactac gctgtaccag gaagctgcgg cgacgccctg gatcaactgc cgtgcccctg gaccggcaga2017200015 03 Jan 2017 atcagagtgc tgtccttcaa gaccggcatc atcagcctgt gcaaggccca 3000 aagtaccgct acctgttcaa gcaggtggcc agcagcaccg gcttctgcga 3060 ctgggcctgc tgctgcacga tagcatccag atccctaggc agctgggcga 3120 tttggcggca gcaacatcga gccctctgtg aggagctgct tccagttcgc 3180 cccgagatcg aggccgccct gttcctggat tggatgaggc tggagcccca 3240 tggctgcctg tgctgcacag agtggccgcc gccgagaccg ccaagcacca 3300 aacatctgca aggagtgccc catcatcggc ttccggtaca ggagcctgaa 3360 tacgacatct gccagagctg ctttttcagc ggcagagtgg ccaagggcca 3420 taccccatgg tggagtactg cacccccacc acctccggcg aggatgtgag 3480 aaagtgctga agaataagtt ccggaccaag cggtactttg ccaagcaccc 3540 tacctgcccg tgcagaccgt gctggagggc gacaacatgg agaccgacac 3600 t g3603 cctggaggat tcagaggaga agtggccagc caacaacaag gagcatggtg ggccaagtgc gcacttcaac caagatgcac agacttcgcc caggatgggc catgtgatga <210> 7 <211> 1199 <212> PRT <213> Artificial Sequence <220><223> murine MD12017200015 03 Jan 2017<400> 7 Met Leu Trp Trp Glu Glu Val Glu Asp Cys Tyr Glu Arg Glu Asp Val 1 5 10 15 Gin Lys Lys Thr Phe Thr Lys Trp Ile Asn Ala Gin Phe Ser Lys Phe 20 25 30 Gly Lys Gin His Ile Asp Asn Leu Phe Ser Asp Leu Gin Asp Gly Lys 35 40 45 Arg Leu Leu Asp Leu Leu Glu Gly Leu Thr Gly Gin Lys Leu Pro Lys 50 55 60 Glu Lys Gly Ser Thr Arg Val His Ala Leu Asn Asn Val Asn Lys Ala 65 70 75 80 Leu Arg Val Leu Gin Lys Asn Asn Val Asp Leu Val Asn Ile Gly Ser 85 90 95 Thr Asp Ile Val Asp Gly Asn His Lys Leu Thr Leu Gly Leu Ile Trp 100 105 110 Asn Ile Ile Leu His Trp Gin Val Lys Asn Val Met Lys Thr Ile Met 115 120 125 Ala Gly Leu Gin Gin Thr Asn Ser Glu Lys Ile Leu Leu Ser Trp Val 130 135 140 Arg Gin Ser Thr Arg Asn Tyr Pro Gin Val Asn Val Ile Asn Phe Thr 145 150 155 160 Ser Ser Trp Ser Asp Gly Leu Ala Leu Asn Ala Leu Ile His Ser His 165 170 175 Arg Pro Asp Leu Phe Asp Trp Asn Ser Val Val Ser Gin His Ser Ala 180 185 190 Thr Gin Arg Leu Glu His Ala Phe Asn Ile Ala Lys Cys Gin Leu Gly 195 200 205 Ile Glu Lys Leu Leu Asp Pro Glu Asp Val Ala Thr Thr Tyr Pro Asp 210 215 220 Lys Lys Ser Ile Leu Met Tyr Ile Thr Ser Leu Phe Gin Val Leu Pro 225 230 235 240 Gin Gin Val Ser Ile Glu Ala Ile Gin Glu Val Glu Met Leu Pro Arg 245 250 255 Thr Ser Ser Lys Val Thr Arg Glu Glu His Phe Gin Leu His His Gin 260 265 270 Met His Tyr Ser Gin Gin Ile Thr Val Ser Leu Ala Gin Gly Tyr Glu 275 280 285 Gin Thr Ser Ser Ser Pro Lys Pro Arg Phe Lys Ser Tyr Ala Phe Thr 290 295 300 Gin Ala Ala Tyr Val Ala Thr Ser Asp Ser Thr Gin Ser Pro Tyr Pro 305 310 315 320 Ser Gin His Leu Glu Ala Pro Arg Asp Lys Ser Leu Asp Ser Ser Leu 325 330 335 Met Glu Thr Glu Val Asn Leu Asp Ser Tyr Gin Thr Ala Leu Glu Glu 2017200015 03 Jan 2017340 345 350 Val Leu Ser Trp Leu Leu Ser Ala Glu Asp Thr Leu Arg Ala Gin Gly 355 360 365 Glu Ile Ser Asn Asp Val Glu Glu Val Lys Glu Gin Phe His Ala His 370 375 380 Glu Gly Phe Met Met Asp Leu Thr Ser His Gin Gly Leu Val Gly Asn 385 390 395 400 Val Leu Gin Leu Gly Ser Gin Leu Val Gly Lys Gly Lys Leu Ser Glu 405 410 415 Asp Glu Glu Ala Glu Val Gin Glu Gin Met Asn Leu Leu Asn Ser Arg 420 425 430 Trp Glu Cys Leu Arg Val Ala Ser Met Glu Lys Gin Ser Lys Leu His 435 440 445 Lys Val Leu Met Asp Leu Gin Asn Gin Lys Leu Lys Glu Leu Asp Asp 450 455 460 Trp Leu Thr Lys Thr Glu Glu Arg Thr Lys Lys Met Glu Glu Glu Pro 465 470 475 480 Phe Gly Pro Asp Leu Glu Asp Leu Lys Cys Gin Val Gin Gin His Lys 485 490 495 Val Leu Gin Glu Asp Leu Glu Gin Glu Gin Val Arg Val Asn Ser Leu 500 505 510 Thr His Met Val Val Val Val Asp Glu Ser Ser Gly Asp His Ala Thr 515 520 525 Ala Ala Leu Glu Glu Gin Leu Lys Val Leu Gly Asp Arg Trp Ala Asn 530 535 540 Ile Cys Arg Trp Thr Glu Asp Arg Trp Ile Val Leu Gin Asp Ile Leu 545 550 555 560 Leu Lys Trp Gin His Phe Thr Glu Glu Gin Cys Leu Phe Ser Thr Trp 565 570 575 Leu Ser Glu Lys Glu Asp Ala Met Lys Asn Ile Gin Thr Ser Gly Phe 580 585 590 Lys Asp Gin Asn Glu Met Met Ser Ser Leu His Lys Ile Ser Thr Leu 595 600 605 Lys Ile Asp Leu Glu Lys Lys Lys Pro Thr Met Glu Lys Leu Ser Ser 610 615 620 Leu Asn Gin Asp Leu Leu Ser Ala Leu Lys Asn Lys Ser Val Thr Gin 625 630 635 640 Lys Met Glu Ile Trp Met Glu Asn Phe Ala Gin Arg Trp Asp Asn Leu 645 650 655 Thr Gin Lys Leu Glu Lys Ser Ser Ala Gin Ile Ser Gin Ala Val Thr 660 665 670 Thr Thr Gin Pro Ser Leu Thr Gin Thr Thr Val Met Glu Thr Val Thr 675 680 685 Met Val Thr Thr Arg Glu Gin Ile Met Val Lys His Ala Gin Glu Glu 690 695 700 2017200015 03 Jan 2017Leu Pro Pro Pro Pro Pro Gin Lys Lys Arg Gin Ile Thr Val Asp Ala 705 710 715 720 Leu Glu Arg Leu Gin Glu Leu Gin Glu Ala Ala Asp Glu Leu Asp Leu 725 730 735 Lys Leu Arg Gin Ala Glu Val Ile Lys Gly Ser Trp Gin Pro Val Gly 740 745 750 Asp Leu Leu Ile Asp Ser Leu Gin Asp His Leu Glu Lys Val Lys Ala 755 760 765 Leu Arg Gly Glu Ile Ala Pro Leu Lys Glu Asn Val Asn Arg Val Asn 770 775 780 Asp Leu Ala His Gin Leu Thr Thr Leu Gly Ile Gin Leu Ser Pro Tyr 785 790 795 800 Asn Leu Ser Thr Leu Glu Asp Leu Asn Thr Arg Trp Arg Leu Leu Gin 805 810 815 Val Ala Val Glu Asp Arg Val Arg Gin Leu His Glu Ala His Arg Asp 820 825 830 Phe Gly Pro Ala Ser Gin His Phe Leu Ser Thr Ser Val Gin Gly Pro 835 840 845 Trp Glu Arg Ala Ile Ser Pro Asn Lys Val Pro Tyr Tyr Ile Asn His 850 855 860 Glu Thr Gin Thr Thr Cys Trp Asp His Pro Lys Met Thr Glu Leu Tyr 865 870 875 880 Gin Ser Leu Ala Asp Leu Asn Asn Val Arg Phe Ser Ala Tyr Arg Thr 885 890 895 Ala Met Lys Leu Arg Arg Leu Gin Lys Ala Leu Cys Leu Asp Leu Leu 900 905 910 Ser Leu Ser Ala Ala Cys Asp Ala Leu Asp Gin His Asn Leu Lys Gin 915 920 925 Asn Asp Gin Pro Met Asp Ile Leu Gin Ile Ile Asn Cys Leu Thr Thr 930 935 940 Ile Tyr Asp Arg Leu Glu Gin Glu His Asn Asn Leu Val Asn Val Pro 945 950 955 960 Leu Cys Val Asp Met Cys Leu Asn Trp Leu Leu Asn Val Tyr Asp Thr 965 970 975 Gly Arg Thr Gly Arg Ile Arg Val Leu Ser Phe Lys Thr Gly Ile Ile 980 985 990 Ser Leu Cys Lys Ala His Leu Glu Asp Lys Tyr Arg Tyr Leu Phe Lys 995 1000 1005 Gin Val Ala Ser Ser Thr Gly Phe Cys Asp Gin Arg Arg Leu Gly Leu 1010 1015 1020 Leu Leu His Asp Ser Ile Gin Ile Pro Arg Gin Leu Gly Glu Val Ala 1025 1030 1035 1040 Ser Phe Gly Gly Ser Asn Ile Glu Pro Ser Val Arg Ser Cys Phe Gin 1045 1050 1055 Phe Ala Asn Asn Lys Pro Glu Ile Glu Ala Ala Leu Phe Leu Asp Trp 2017200015 03 Jan 20171060 1065 1070Met Arg Leu Glu Pro Gin Ser Met Val 1080 Trp Leu Pro Val Leu His 1085 Arg 1075 Val Ala Ala Ala Glu Thr Ala Lys His Gin Ala Lys Cys Asn lie Cys 1090 1095 1100 Lys Glu Cys Pro lie lie Gly Phe Arg Tyr Arg Ser Leu Lys His Phe 1105 1110 1115 1120 Asn Tyr Asp lie Cys Gin Ser Cys Phe Phe Ser Gly Arg Val Ala Lys 1125 1130 1135 Gly His Lys Met His Tyr Pro Met Val Glu Tyr Cys Thr Pro Thr Thr 1140 1145 1150 Ser Gly Glu Asp Val Arg Asp Phe Ala Lys Val Leu Lys Asn Lys Phe 1155 1160 1165 Arg Thr Lys Arg Tyr Phe Ala Lys His Pro Arg Met Gly Tyr Leu Pro 1170 1175 1180 Val Gin Thr Val Leu Glu Gly Asp Asn Met Glu Thr Asp Thr Met 1185 1190 1195 <210> 8 <211> 3611 <212> DNA <213> Artificial Sequence <220><223> opt murine MD1 <400> 8atgctgtggt 60 gggaggaagt ggaggactgc tacgagagag aggacgtgca gaagaaaacc ttcaccaagt 120 ggatcaacgc ccagttcagc aagttcggca agcagcacat cgacaacctg ttcagcgacc 180 tgcaggacgg caagagactg ctggatctgc tggagggact gaccggccag aagctgccca 240 aggagaaggg cagcaccaga gtgcacgccc tgaacaacgt gaacaaggcc ctgagagtgc 300 tgcagaagaa caacgtggac ctggtgaata tcggcagcac cgacatcgtg gacggcaacc 360 acaagctgac cctgggcctg atctggaaca tcatcctgca ctggcaggtg 2017200015 03 Jan 2017 aagaacgtga420 ctgagctggg480 agcagctgga540 ttcgactgga600 aacatcgcca660 acctaccccg720 cagcaggtgt780 gtgacccggg840 gtgtccctgg900 tacgccttca960 agccagcacc1020 gtgaacctgg1080 gaggacaccc1140 ttccacgccc1200 gtgctgcagc1260 tgaaaaccat tgaggcagag gcgacggcct acagcgtggt agtgccagct acaagaaaag ccatcgaggc aggagcactt cccagggcta cccaggccgc tggaggcccc acagctacca tgagagccca acgagggctt tgggcagcca catggccggc caccagaaac ggccctgaac gtcccagcac gggcatcgag catcctcatg catccaggaa ccagctgcac cgagcagacc ctacgtggcc tagagacaag gaccgccctg gggcgagatc catgatggac gctcgtggga ctgcagcaga tacccccagg gccctgatcc agcgccaccc aagctgctgg tatatcacct gtggaaatgc caccagatgc agcagctccc acaagcgata agcctggaca gaggaagtgc agcaacgacg ctgacctccc aagggcaagc ccaacagcga tgaacgtgat acagccacag agagactgga accccgagga ctctgtttca tgccccggac actatagcca ccaagcccag gcacccagag gcagcctgat tgtcttggct tggaagaagt atcagggcct tgagcgagga gaagatcctg caacttcacc acccgacctg gcacgccttc cgtggccacc ggtgctgccc cagcagcaaa gcagatcacc attcaagagc cccctacccc ggagacagaa gctgtccgcc gaaggagcag ggtgggcaac cgaggaggcc2017200015 03 Jan 2017 gaagtgcagg1320 atggagaagc1380 gaactggacg1440 ttcggccccg1500 gacctggaac1560 gagagcagcg1620 agatgggcca1680 ctgaagtggc1740 gaggacgcca1800 agcctgcaca1860 aagctgtcca1920 aaaatggaga1980 gagaagagca2040 accaccgtga2100 gcccaggagg2160 aacagatgaa agagcaagct actggctgac acctggagga aggagcaggt gcgaccacgc atatctgccg agcacttcac tgaagaacat agatcagcac gcctgaacca tctggatgga gcgcccagat tggagaccgt agctgccccc cctgctgaac gcacaaagtg caagaccgag cctgaagtgc gcgcgtgaac cacagccgcc gtggaccgag cgaggagcag ccagaccagc cctgaagatc ggacctgctg gaatttcgca cagccaggcc gaccatggtg tcccccccct agcagatggg ctgatggatc gagcggacca caggtgcagc agcctgaccc ctggaagagc gatagatgga tgcctgttta ggcttcaagg gacctggaga agcgccctga cagaggtggg gtgaccacca accacccggg cagaagaagc agtgcctgag tgcagaacca agaagatgga agcataaggt acatggtggt agctgaaagt tcgtgctgca gcacctggct accagaacga agaaaaagcc agaacaagag acaacctgac cccagcccag agcagatcat ggcagatcac agtggccagc gaagctgaag ggaggagccc cctgcaggag cgtggtggac gctgggcgac ggacatcctg gagcgagaaa gatgatgagc cacaatggag cgtgacccag ccagaagctg cctgacacag ggtgaagcac agtggatgcc2017200015 03 Jan 2017 ctggagagac2220 gccgaagtga2280 gaccacctgg2340 aaccgcgtga2400 aacctgagca2460 gatagagtga2520 ctgagcacca2580 tacatcaacc2640 cagagcctgg2700 cggagactgc2760 ctggaccagc2820 tgcctgacca2880 ctgtgcgtgg2940 agaatcagag3000 gataagtacc3060 tgcaggagct tcaagggcag agaaagtgaa acgacctggc ccctggagga ggcagctgca gcgtgcaggg acgagaccca ccgacctgaa agaaggccct acaacctgaa ccatctacga acatgtgcct tgctgtcctt gctacctgtt gcaggaagcc ctggcagcct ggccctgcgg ccatcagctg tctgaacacc cgaggcccac cccctgggag gaccacctgc caatgtgcgg gtgcctggac gcagaacgac tcggctggag gaattggctg caagaccggc caagcaggtg gccgacgagc gtgggcgatc ggcgagatcg accaccctgg cggtggagac agagacttcg agagccatca tgggaccacc ttcagcgcct ctgctgtccc cagcccatgg caggagcaca ctgaacgtgt atcatcagcc gccagcagca tggatctgaa tgctgatcga cccccctgaa gcattcagct tgctgcaggt gccctgcctc gccccaacaa ctaagatgac acagaaccgc tgagcgccgc atatcctgca acaacctggt acgacaccgg tgtgcaaggc ccggcttctg gctgagacag cagcctgcag ggagaacgtg gagcccctac ggccgtggag ccagcacttc agtgccctac cgagctgtac catgaagctg ctgcgacgcc gatcatcaac gaacgtgccc caggaccggc ccacctggag cgatcagagg2017200015 03 Jan 2017 agactgggcc tgctgctgca cgatagcatc cagatcccta ggcagctggg 3120 agctttggcg gcagcaacat cgagccctct gtgaggagct gcttccagtt 3180 aagcccgaga tcgaggccgc cctgttcctg gattggatga ggctggagcc 3240 gtgtggctgc ctgtgctgca cagagtggcc gccgccgaga ccgccaagca 3300 tgcaacatct gcaaggagtg ccccatcatc ggcttccggt acaggagcct 3360 aactacgaca tctgccagag ctgctttttc agcggcagag tggccaaggg 3420 cactacccca tggtggagta ctgcaccccc accacctccg gcgaggatgt 3480 gccaaagtgc tgaagaataa gttccggacc aagcggtact ttgccaagca 3540 ggctacctgc ccgtgcagac cgtgctggag ggcgacaaca tggagaccga 3600 tgtgatgatg3611 cgaagtggcc cgccaacaac ccagagcatg ccaggccaag gaagcacttc ccacaagatg gagagacttc ccccaggatg caccatgtga
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