JP6759188B2 - 生物活性カーゴの経口送達のためのコリックス毒素由来融合分子 - Google Patents
生物活性カーゴの経口送達のためのコリックス毒素由来融合分子 Download PDFInfo
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Description
本出願は、その全内容が参照により本明細書に援用される2014年5月7日に出願された米国特許仮出願第61/990,054号の利益を主張するものである。
「ポリペプチド」、「ペプチド」、および「タンパク質」の用語は、アミノ酸残基のポリマーを意味するために、本明細書にて交換可能に用いられる。様々な実施形態では、「ペプチド」、「ポリペプチド」、および「タンパク質」は、アルファ炭素がペプチド結合を介して連結されたアミノ酸鎖である。従って、鎖の一方の端部にある末端アミノ酸(アミノ末端)は、遊離アミノ基を有し、鎖の他方の端部にある末端アミノ酸(カルボキシ末端)は、遊離のカルボキシル基を有する。本明細書で用いられる場合、「アミノ末端」(N末端と略される)の用語は、ペプチドのアミノ末端にあるアミノ酸上の遊離α‐アミノ基、またはペプチド内のその他のいずれかの位置にあるアミノ酸のα‐アミノ基(ペプチド結合に関与している場合はイミノ基)を意味する。同様に、「カルボキシ末端」の用語は、ペプチドのカルボキシ末端上の遊離カルボキシル基、またはペプチド内のその他のいずれかの位置にあるアミノ酸のカルボキシル基を意味する。ペプチドはまた、本質的にいずれのポリアミノ酸をも含み、これらに限定されないが、アミド結合ではなくエーテルによって結合されたアミノ酸などのペプチドミメティックが挙げられる。
1)アラニン(A)、セリン(S),およびスレオニン(T)
2)アスパラギン酸(D)およびグルタミン酸(E)
3)アスパラギン(N)およびグルタミン(Q)
4)アルギニン(R)およびリジン(K)
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、およびバリン(V)
6)フェニルアラニン(F)、チロシン(Y)、およびトリプトファン(W)
本明細書で用いられる場合、成熟コリックス毒素(Jorgensen, R. et al., J Biol Chem 283(16):10671-10678 (2008))は、70.7kD、634残基のタンパク質であり、その配列は、配列番号1に示される:
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDK
GESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGE
DSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPS
VSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYET
VAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDD
LSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQV
LTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESR
SGRSYLPENRAVITPQGVTNWTYQELEATHQALTREGYVFVGYHGTNHVAAQTIVNRI
APVPRGNNTENEEKWGGLYVATHAEVAHGYARIKEGTGEYGLPTRAERDARGVMLRV
YIPRASLERFYRTNTPLENAEEHITQVIGHSLPLRNEAFTGPESAGGEDETVIGWDMAIH
AVAIPSTIPGNAYEELAIDEEAVAKEQSISTKPPYKERKDELK(配列番号1)
ATGGTCGAAGAAGCTTTAAACATCTTTGATGAATGCCGTTCGCCATGTTCGTTGACCCCGGA
ACCGGGTAAGCCGATTCAATCAAAACTGTCTATCCCTAGTGATGTTGTTCTGGATGAAGGTG
TTCTGTATTACTCGATGACGATTAATGATGAGCAGAATGATATTAAGGATGAGGACAAAGGC
GAGTCCATTATCACTATTGGTGAATTTGCCACAGTACGCGCGACTAGACATTATGTTAATCAA
GATGCGCCTTTTGGTGTCATCCATTTAGATATTACGACAGAAAATGGTACAAAAACGTACTCT
TATAACCGCAAAGAGGGTGAATTTGCAATCAATTGGTTAGTGCCTATTGGTGAAGATTCTCCT
GCAAGCATCAAAATCTCCGTTGATGAGCTCGATCAGCAACGCAATATCATCGAGGTGCCTAA
ACTGTATAGTATTGATCTCGATAACCAAACGTTAGAGCAGTGGAAAACCCAAGGTAATGTTTC
TTTTTCGGTAACGCGTCCTGAACATAATATCGCTATCTCTTGGCCAAGCGTGAGTTACAAAG
CAGCGCAGAAAGAGGGTTCACGCCATAAGCGTTGGGCTCATTGGCATACAGGCTTAGCACT
GTGTTGGCTTGTGCCAATGGATGCTATCTATAACTATATCACCCAGCAAAATTGTACTTTAGG
GGATAATTGGTTTGGTGGCTCTTATGAGACTGTTGCAGGCACTCCGAAGGTGATTACGGTTA
AGCAAGGGATTGAACAAAAGCCAGTTGAGCAGCGCATCCATTTCTCCAAGGGGAATGCGAT
GAGCGCACTTGCTGCTCATCGCGTCTGTGGTGTGCCATTAGAAACTTTGGCGCGCAGTCGC
AAACCTCGTGATCTGACGGATGATTTATCATGTGCCTATCAAGCGCAGAATATCGTGAGTTTA
TTTGTCGCGACGCGTATCCTGTTCTCTCATCTGGATAGCGTATTTACTCTGAATCTTGACGAA
CAAGAACCAGAGGTGGCTGAACGTCTAAGTGATCTTCGCCGTATCAATGAAAATAACCCGG
GCATGGTTACACAGGTTTTAACCGTTGCTCGTCAGATCTATAACGATTATGTCACTCACCATC
CGGGCTTAACTCCTGAGCAAACCAGTGCGGGTGCACAAGCTGCCGATATCCTCTCTTTATTT
TGCCCAGATGCTGATAAGTCTTGTGTGGCTTCAAACAACGATCAAGCCAATATCAACATCGA
GTCTCGTTCTGGCCGTTCATATTTGCCTGAAAACCGTGCGGTAATCACCCCTCAAGGCGTCA
CAAATTGGACTTACCAGGAACTCGAAGCAACACATCAAGCTCTGACTCGTGAGGGTTATGTG
TTCGTGGGTTACCATGGTACGAATCATGTCGCTGCGCAAACCATCGTGAATCGCATTGCCCC
TGTTCCGCGCGGCAACAACACTGAAAACGAGGAAAAGTGGGGCGGGTTATATGTTGCAACT
CACGCTGAAGTTGCCCATGGTTATGCTCGCATCAAAGAAGGGACAGGGGAGTATGGCCTTC
CGACCCGTGCTGAGCGCGACGCTCGTGGGGTAATGCTGCGCGTGTATATCCCTCGTGCTTC
ATTAGAACGTTTTTATCGCACGAATACACCTTTGGAAAATGCTGAGGAGCATATCACGCAAGT
GATTGGTCATTCTTTGCCATTACGCAATGAAGCATTTACTGGTCCAGAAAGTGCGGGCGGGG
AAGACGAAACTGTCATTGGCTGGGATATGGCGATTCATGCAGTTGCGATCCCTTCGACTATC
CCAGGGAACGCTTACGAAGAATTGGCGATTGATGAGGAGGCTGTTGCAAAAGAGCAATCGA
TTAGCACAAAACCACCTTATAAAGAGCGCAAAGATGAACTTAAG(配列番号2)
粘膜の頂端膜側に接する管腔から粘膜の側底側へのトランスサイトーシスを媒介する「トランスサイトーシスドメイン」である。本明細書で言及される場合、「トランスサイトーシス」は、極性化上皮細胞を通しての融合分子の輸送を意味する。そのような輸送により、極性化上皮細胞の側底膜からの生物活性カーゴの放出が可能となる。本開示の融合分子は、ドメインIIの全アミノ酸配列を含んでいる修飾コリックス毒素を含んでよく、またはトランスサイトーシス活性が実質的に除去されない限りにおいて、ドメインIIの一部分を含んでいてもよい。さらに、トランスサイトーシス活性が実質的に除去されない限りにおいて、トランスサイトーシスドメインのアミノ酸配列に対して、保存的または非保存的置換が行われてもよい。トランスサイトーシスドメインがトランスサイトーシス活性を有するかどうかを特定するために当業者によって通常の手順として用いられてよい代表的なアッセイは、本明細書に記載される。本明細書で用いられる場合、トランスサイトーシス活性は、活性が、例えば、ドメインIIの全アミノ酸配列を含む修飾コリックス毒素と比較して、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、または少なくとも99%である限りにおいて、実質的に除去されていない。
修飾コリックス毒素ポリペプチドに加えて、本開示の融合分子は、さらに、対象へ送達するための生物活性カーゴを含む。本明細書で用いられる場合、「生物活性カーゴ」としては、これらに限定されないが;高分子、小分子、ペプチド、ポリペプチド、核酸、mRNA、miRNA、shRNA、siRNA、アンチセンス分子、抗体、DNA、プラスミド、ワクチン、ポリマーナノ粒子、または触媒活性物質が挙げられる。
インターロイキン‐10(IL‐10)は、多くの細胞集団によって産生される重要な免疫調節性サイトカインであり、その主たる生物学的機能は、炎症応答の制限および停止、ならびにT細胞、B細胞、ナチュラルキラー細胞、抗原提示細胞、マスト細胞、および顆粒球などのいくつかの免疫細胞の分化ならびに増殖の制御であると思われる。より最近データから、IL‐10は、炎症が限定的である感染性および非感染性粒子の除去を助ける免疫賦活性も媒介することが示唆されている;Asadullah et al., Pharmacol Rev, 55:241-269, 2003。さらに、数多くの研究から、炎症性、悪性、および自己免疫性疾患においてIL‐10が大きな影響を及ぼすことが示唆されており、IL‐10の過剰発現が、黒色腫、基底細胞癌および扁平上皮癌、ならびにいくつかのリンパ腫などの特定の腫瘍で見出された;同著。IL‐10と構造的に関連する5種類の新しいヒト分子、IL‐19(Gallagher et al., Genes Immun., 1:442-450, 2000)、IL‐20(Blumberg et al., Cell, 104:9-19, 2001)、IL‐22(Dumoutier et al., Genes Immun., 1:488-494, 2000)、IL‐24(Jiang et al., Oncogene, 11:2477-2486, 1995)、およびIL‐26(Knappe et al., J. Virol., 74:3881-3887, 2000)が発見されており、データから、免疫細胞が、新しいIL‐10ファミリーメンバーの主要源であることが示唆される;Wolk et al., J. Immunol., 168:5397-5402, 2002。
MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQM
KDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENL
KTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKI
RN(配列番号82)
に示されるアミノ酸配列を有するヒトインターロイキン‐10、またはその断片もしくはバリアントである。
MKLQCVSLWLLGTILILCSVDNHGLRRCLISTDMHHIEESFQEIKRAIQAKDTFPNVTILST
LETLQIIKPLDVCCVTKNLLAFYVDRVFKDHQEPNPKILRKISSIANSFLYMQKTLRQCQE
QRQCHCRQEATNATRVI HDNYDQLEVHAAAIKSLGELDVFLAWINKNHEVMSSA
(配列番号83)
に示されるアミノ酸配列を有するヒトインターロイキン‐19、またはその断片もしくはバリアントである。
MKASSLAFSLLSAAFYLLWTPSTGLKTLNLGSCVIATNLQEIRNGFSEIRGSVQAKDGNI
DIRILRRTESLQDTKPANRCCLLRHLLRLYLDRVFKNYQTPDHYTLRKISSLANSFLTIKK
DLRLCHAHMTCHCGEEAMK KYSQILSHFEKLEPQAAVVKALGELDILLQWMEETE
(配列番号84)
に示されるアミノ酸配列を有するヒトインターロイキン‐20、またはその断片もしくはバリアントである。
MAALQKSVSSFLMGTLATSCLLLLALLVQGGAAAPISSHCRLDKSNFQQPYITNRTFML
AKEASLADNNTDVRLIGEKLFHGVSMSERCYLMKQVLNFTLEEVLFPQSDRFQPYMQE
VVPFLARLSNRLSTCHIEGDDLHIQRNVQKLKDTVKKLGESGEIKAIGELDLLFMSLRNA
CI(配列番号85)
に示されるアミノ酸配列を有するヒトインターロイキン‐22、またはその断片もしくはバリアントである。
MNFQQRLQSLWTLASRPFCPPLLATASQMQMVVLPCLGFTLLLWSQVSGAQGQEFHF
GPCQVKGVVPQKLWEAFWAVKDTMQAQDNITSARLLQQEVLQNVSDAESCYLVHTLL
EFYLKTVFKNYHNRTVEVRTLKSFSTLANNFVLIVSQLQPSQENEMFSIRDSAHRRFLLF
RRAFKQLDVEAALTKALGEVDILLTWMQKFYKL(配列番号86)
に示されるアミノ酸配列を有するヒトインターロイキン‐24、またはその断片もしくはバリアントである。
MLVNFILRCGLLLVTLSLAIAKHKQSSFTKSCYPRGTLSQAVDALYIKAAWLKATIPEDRI
KNIRLLKKKTKKQFMKNCQFQEQLLSFFMEDVFGQLQLQGCKKIRFVEDFHSLRQKLS
HCISCASSAREMKSITRMKRIFYRIGNKGIYKAISELDILLSWIKKLLESSQ
(配列番号87)
に示されるアミノ酸配列を有するヒトインターロイキン‐26、またはその断片もしくはバリアントである。
腫瘍壊死因子は、対応する受容体のスーパーファミリー(以降「TNFSFR」)と相互作用する増殖能の高いサイトカインのスーパーファミリー(以降「TNFSF」)である。約25年前に腫瘍壊死因子‐アルファ(「TNF‐α」)が発見されて以来、TNFSFは、30を超える受容体を通してシグナル伝達する20を超えるメンバーから成る関連するタンパク質の大きいファミリーとなった(例えば、“Therapeutic Targets of the TNF Superfamily”, edited by Iqbal S. Grewal, Landes Bioscience/Springer Science+Business Media, LLC dual imprint / Springer series: Advances in Experimental Medicine and Biology, 2009を参照)。TNFSFのメンバーは、広く組織中に分布しており、TNFSFリガンド‐受容体相互作用は、活性化、増殖、分化、およびアポトーシスを含む造血から多面細胞応答(pleiotropic cellular responses)までの数多くの生物学的プロセスに関与している。TNFSFリガンド‐受容体相互作用は、腫瘍発生、移植片拒絶、敗血症性ショック、ウィルス複製、骨吸収、および自己免疫とも関連付けられている。特定の応答は、シグナル伝達する受容体、細胞型、および細胞が同時に受けるシグナルに依存する。
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGK
GLEWVSAITWNSGHIDYADSVERGFTISRDNAKNSLYLQMNSLRAE
DTAVYYCAKVSYLSTASSLDYWGQGTLVTVSSASTKGPSVFPLAPS
SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
(配列番号88)
に示される重鎖可変領域配列、および配列番号89:
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAA
STLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQG
TKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT
KSFNRGEC(配列番号89)
に示される軽鎖可変領域配列を含むヒト抗体もしくは抗原結合断片、またはその抗原結合もしくは免疫学的機能性免疫グロブリン断片である。
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQA
PGKGLEWVAIISFDGSNKSSADSVKGRFTUSRRNSKNALFLQM
NSLRAEDTAVFYCARDRGVSAGGNYYYYGMDVWGQGTTVTVSS
(配列番号90)
に示される重鎖可変領域配列、および配列番号91:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA
PRLLIYDASNRATGIPARFSGSGSGTRFTLTISSLEPEDFAVYYC
QQRSNWPPFTFGPGTKVDIL(配列番号91)
に示される軽鎖可変領域配列を含むヒト抗体もしくは抗原結合断片、またはその抗原結合もしくは免疫学的機能性免疫グロブリン断片である。
LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTS
DTVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPG
WYCALSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSS
TDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQ
HTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDEPKSCDKTHTCPPCPAPE
LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV
EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK
TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK
SLSLSPGK(配列番号92)
に示される配列を含む二量体融合タンパク質、またはその断片もしくはバリアントであるTNF阻害剤である。
様々な実施形態では、生物活性カーゴは、血糖降下剤である。様々な実施形態では、血糖降下剤は、約5、約6、約7、約8、約9、約10、約11、約12、約13、約14、約15、約16、約17、約18、約19、約20、約25、約30、約35、約40、約45、約50、約55、約60、約65、約70、約75、約80、約85、約90、約95、約100、約150、約200、約250、約300、約400、約500、約600、約700、約800、約900、または約1000のアミノ酸を含むペプチドである。
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS(配列番号93)
に示されるアミノ酸配列を有するGLP‐1アゴニスト、またはその断片もしくはバリアントである。
HAEGTFTSDVSSYLEGQAAKEEFIIAWLVKGRG(配列番号94)
に示されるアミノ酸配列を有するGLP‐1アゴニスト、またはその断片もしくはバリアントである。
成長ホルモン(GH)(ソマトロピンまたはソマトトロピンとしても知られる)は、人体における支配的なホルモンであり、内分泌系によって合成、分泌される。このホルモンは、身体の様々な器官にある細胞の成長および複製といった必須機能を制御する。GHの必須機能のいくつかとしては、筋肉成長の制御、骨のミネラル化および強度の向上、脂肪沈着の低減、ならびに良好なエネルギーレベルの維持が挙げられる。成長ホルモンの産生および分泌は、成長ホルモン放出ホルモン(GHRH)によって制御され、それは、視床下部によって分泌される。GHRHは、下垂体を刺激してGHを産生させ、それは、血流中に直接放出される。続いてGHは、肝臓を刺激してインスリン様成長因子(IGF‐1)を産生し、これが、コンドロサイト(軟骨細胞)の増殖を刺激し、筋芽細胞の分化を促進し、およびタンパク質合成を高め、次にこのことが、他の筋肉および組織細胞の成長を補助する。
FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFS
ESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSNV
YDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLL
YCFRKDMDKVETFLRIVQCRSVEGSCGF(配列番号95)
融合分子の生物活性カーゴは、当業者に公知の限定されないいずれの方法によって融合分子の残りの部分と結合されてもよい。生物活性カーゴは、修飾コリックス毒素の細胞結合またはトランスサイトーシス活性を阻害することのない融合分子のいずれの部分に導入されてもよい。様々な実施形態では、生物活性カーゴは、修飾コリックス毒素のN末端またはC末端に直接カップリングされる。様々な実施形態では、生物活性カーゴは、修飾コリックス毒素のアミノ酸の側鎖と接続されてよい。様々な実施形態では、生物活性カーゴは、非開裂性ペプチドリンカーによって修飾コリックス毒素とカップリングされる。様々な実施形態では、生物活性カーゴは、開裂性リンカーによって修飾コリックス毒素とカップリングされ、それによって、(1もしくは複数の)開裂性リンカーでの開裂により、融合分子の残りの部分から生物活性カーゴが分離される。様々な実施形態では、生物活性カーゴは、開裂性リンカーの開裂後もポリペプチドに結合した状態が維持される短鎖リーダーペプチドも含んでよいポリペプチドである。例えば、生物活性カーゴは、1アミノ酸超、5アミノ酸超、10アミノ酸超、15アミノ酸超、20アミノ酸超、25アミノ酸超、30アミノ酸超、50アミノ酸超、または100アミノ酸超の短鎖リーダーペプチドを含んでよい。ある場合では、生物活性カーゴは、100アミノ酸未満、50アミノ酸未満、30アミノ酸未満、25アミノ酸未満、20アミノ酸未満、15アミノ酸未満、10アミノ酸未満、または5アミノ酸未満の短鎖リーダーペプチドを含んでよい。ある場合では、生物活性カーゴは、1〜100アミノ酸、5〜10アミノ酸、10から50アミノ酸、または20から80アミノ酸の短鎖リーダーペプチドを含んでよい。自然のコリックス毒素では、ドメインIbループは、アミノ酸387から425までにわたり、構造的には、395番目および402番目の位置にある2つのシステイン間のジスルフィド結合を特徴とする。コリックス毒素のこのドメインIb部分は、細胞結合、トランスロケーション、ER残留、またはADPリボシル化活性を含むコリックス毒素の公知のいずれの活性に対しても必須ではない。従って、ドメインIbは、完全に欠失されてよく、または生物活性カーゴを含有するように修飾されてもよい。従って、様々な実施形態では、生物活性カーゴは、コリックス毒素ドメインIbに挿入されてよい。所望される場合、生物活性カーゴは、395番目および402番目の位置にある架橋されていないシステイン間のコリックス毒素ドメインIbに挿入されてよい。これは、これらのシステイン間のジスルフィド結合を還元すること、一方もしくは両方のシステインをIbドメインから完全に欠失させること、一方もしくは両方のシステインを、セリンを例とする他の残基へ変異させること、またはその他の類似の技術によって達成することができる。別の選択肢として、生物活性カーゴは、395番目および402番目の位置にあるシステイン間のドメインIbループに挿入されてもよい。そのような実施形態では、これらのシステイン間のジスルフィド結合を用いて、生物活性カーゴドメインを拘束することができる。
様々な実施形態では、非天然融合分子は、組換えDNA法を用いて合成される。一般的には、これは、融合分子をコードするDNA配列の作製、特定のプロモーターの支配下の発現カセット中へのこのDNAの配置、ホスト中での分子の発現、発現された分子の単離、および必要に応じて、分子の再生を含む。
様々な実施形態では、修飾コリックス毒素および生物活性カーゴは、1つ以上のアミノ酸(例:25アミノ酸まで)から成るペプチドスペーサーによって分離されていてよい。一般的に、スペーサーは、タンパク質を繋げること、またはそれらの間の何らかの最小距離もしくはその他の空間的関係を保持することを除いては、特異的な生物活性を有しない。しかし、様々な実施形態では、スペーサーの成分アミノ酸は、フォールディング、正味の電荷、または疎水性などの分子のある特性に影響を与えるように選択されてよい。
様々な実施形態では、対象に送達されるべき生物活性カーゴは、1つ以上の開裂性リンカーを用いて修飾コリックス毒素とカップリングされる。融合分子に存在する開裂性リンカーの数は、少なくとも部分的に、修飾コリックス毒素に対する生物活性カーゴの位置、および生物活性カーゴの性質に依存する。生物活性カーゴが、単一リンカーでの開裂によって融合分子の残りの部分から分離可能である場合、融合分子は、単一開裂性リンカーを含んでよい。さらに、生物活性カーゴが、例えば、二量体またはその他の多量体である場合、生物活性カーゴの各サブユニットは、融合分子の残りの部分から、および/または生物活性カーゴの他のサブユニットから、開裂性リンカーの開裂によって分離可能である。
様々な実施形態では、対象に送達されるべき生物活性カーゴは、修飾コリックス毒素と化学的に結合される。分子を化学的に結合する手段は、当業者に公知である。
本開示の医薬組成物は、ヒト対象への投与のための組成物に関する。医薬組成物は、本明細書で挙げる非天然融合分子を、単独で、または組み合わせて含む。医薬組成物は、非天然融合分子の特性を変化させることができる、例えば、その機能を安定化、調節、および/または活性化することができる追加の分子を含んでよい。組成物は、例えば、固体または液体の形態であってよく、とりわけ、粉末、錠剤、溶液、またはエアロゾルの形態であってよい。本開示の医薬組成物は、所望に応じて、および追加として、薬理学的に許容されるキャリアを含んでよい。「薬理学的に許容されるキャリア」は、無毒性の固体、半固体、または液体の充填剤、希釈剤、カプセル化剤、ならびに標準的な医薬キャリア、媒体、緩衝剤、および賦形剤のいずれをも意味し、リン酸緩衝生理食塩水溶液、5%デキストロース水溶液、ならびに油/水型または水/油型エマルジョンなどのエマルジョン、ならびに様々な種類の湿潤剤および/または補助剤などである。
別の態様では、経口送達用に製剤された医薬組成物は、特に経口製剤および送達の対象となる特定の種類の疾患または医学的病状の治療に用いられる。そのような種類の疾患または病状としては、例えば、ウィルス性疾患または感染、癌、代謝疾患、肥満症、自己免疫性疾患、炎症性疾患、アレルギー、移植片対宿主病、全身性微生物感染、貧血症、心血管疾患、精神病、遺伝性疾患、神経変性疾患、造血細胞の障害、内分泌系または生殖系の疾患、胃腸疾患が挙げられる。多くの慢性疾患において、本開示の融合分子の経口製剤は、注射剤治療または薬物プロトコルに頼ることなく、在宅での経口投与を介する長期的な患者ケアおよび治療法が可能となることから、特に有用である。
別の態様では、本開示は、非天然融合分子をコードするヌクレオチド配列を含むポリヌクレオチドを提供する。このようなポリヌクレオチドは、例えば、融合分子の作製に有用である。なお別の態様では、本開示は、修飾コリックス毒素をコードする組換えポリヌクレオチド配列、および生物活性カーゴをコードするポリヌクレオチド配列のためのポリリンカー挿入部位を含む発現系を提供する。ポリリンカー挿入部位は、ポリリンカー挿入が修飾コリックス毒素の受容体結合ドメインまたはトランスサイトーシスドメインを破壊しない限りにおいて、ポリヌクレオチド配列のいずれの部位に存在してもよい。様々な実施形態では、発現系は、開裂性リンカーをコードするポリヌクレオチド配列を含んでよく、それによって、開裂性リンカーでの開裂が、ポリリンカー挿入部位に挿入された核酸によってコードされた生物活性カーゴを、コードされた融合分子の残りの部分から分離する。従って、コードされたコンストラクトの末端にポリリンカー挿入部位が存在する実施形態では、ポリヌクレオチドは、ポリリンカー挿入部位とポリヌクレオチドの残りの部分との間に、開裂性リンカーをコードする1つのヌクレオチド配列を含む。コードされたコンストラクトの末端にポリリンカー挿入部位が存在しない実施形態では、ポリリンカー挿入部位は、各々が開裂性リンカーをコードするヌクレオチド配列と隣接していてよい。
トランスサイトーシスドメインの機能は、上皮膜を透過する融合分子の能力の関数として試験することができる。トランスサイトーシスは最初に細胞と結合することが必要であることから、このようなアッセイは、細胞認識ドメインの機能の評価にも用いることができる。
開裂性リンカーの機能は、一般的に、開裂アッセイで試験されてよい。開裂性リンカーの試験には、当業者に公知の適切ないずれの開裂アッセイも、限定されることなく用いられてよい。細胞アッセイおよび無細胞アッセイの両方が、開裂性リンカーを開裂する酵素の能力の試験に用いられてよい。
本開示の実施形態は、これらに限定されないが、表7に示す融合分子を含む。
この例では、修飾コリックス毒素配列、開裂性リンカー配列、および生物活性カーゴを含む単一アミノ酸配列としての非天然融合分子の作製について全般的に記載する。
この例では、生物活性カーゴを無傷の上皮を通して運搬するその能力に関して、融合分子の適切なフォールディングを確認するための生体外法について記載する。
この例では、二量体コリックス415−(G4S)3−IL‐10融合分子を、Caco‐2細胞単層のバリア特性に対するその効果について生体外で評価した。側底コンパートメントからの培地を含むCaco‐2細胞(ヒト結腸癌由来細胞株)を、数時間にわたって定期的にサンプリングする(Rubas W, et al., J Pharm Sci., 85(2):165-9, 1996)。Caco‐2(ATCC HTB‐37(商標))細胞を、完全培地:10% ウシ胎仔血清、2.5mM グルタミン、100U ペニシリン/ml、および100μg ストレプトマイシン/mlを添加したダルベッコ変法イーグル培地F12(DMEM F12)(ギブコBRL(Gibco BRL)、ニューヨーク州、グランドアイランド)中、5% CO2、37℃で維持する。2から3日ごとにこの培地(指定した完全培地)を細胞に供給し、5から7日ごとに継代培養する。アッセイでは、24または96ウェルプレートに細胞を播種し、コンフルエントまで成長させる。
この例では、ELISAアッセイを行って、二量体コリックス415−(G4S)3−IL‐10融合分子がCaco‐2細胞単層を通って移動する能力を評価する。A549(ATCC CCL‐185(商標))、L929(ATCC CRL‐2148(商標))、およびCaco‐2(ATCC HTB‐37(商標))細胞を、完全培地:10% ウシ胎仔血清、2.5mM グルタミン、100U ペニシリン/ml、および100μg ストレプトマイシン/mlを添加したダルベッコ変法イーグル培地F12(DMEM F12)(ギブコBRL、ニューヨーク州、グランドアイランド)中、5% CO2、37℃で維持する。2から3日ごとにこの培地(指定した完全培地)を細胞に供給し、5から7日ごとに継代培養する。アッセイでは、24または96ウェルプレートに細胞を播種し、コンフルエントまで成長させる。
この例では、開裂性配列を持たない非天然融合分子の作製について記載する。これらの融合分子は、粘膜下/GI腔を特異的にターゲティングし、生物活性カーゴの作用をその腔に限定するように設計されている。
コリックス毒素ΔE581−カーゴの経上皮輸送を、Caco‐2単層を用いて生体外で評価する。Caco‐2細胞(継代数25〜35)を、既に報告されているように、コンフルエントな単層まで成長させる;Rubas, W. et al., Pharm Res, 10:113-118 (1993)。簡潔に述べると、細胞を、2mM L‐グルタミン、10% ウシ胎仔血清、および100単位のペニシリン/ストレプトマイシンで高濃度化したDMEM/高成長培地中、5% CO2および湿度90%の雰囲気下、37℃で維持する。細胞を、1:3の分割比で、75cm2 フラスコ中にて毎週継代培養し、予備湿潤およびコラーゲンコーティングしたコーニングコスター(マサチューセッツ州、ケンブリッジ)製の透過性(0.4μmポアサイズ)ポリカーボネート(Transwell(商標))フィルターサポート上に、63000細胞/cm2の密度で播種する。成長培地を、1日おきに交換する。電圧抵抗計(ワールドプレシジョンインスツルメンツ(World Precision Instruments)、フロリダ州、サラソタ)を用いて特定される著しい経上皮電気抵抗(TEER)の取得によって判断される播種の20〜26日後のコンフルエントな単層を用いる。
この例では、そのC末端でIL‐10ポリペプチドと直接融合した配列番号1のアミノ酸1〜415をコードする配列を含む修飾コリックス毒素を含む融合分子(「コリックス415−IL‐10融合分子」と称する)の大腸菌での作製および発現について記載する。タンパク質発現は、大腸菌DH5α細胞(インビトロジェン、カリフォルニア州、カールスバッド)を用い、適切なプラスミドを用いたヒートショック(42℃で1分間)による形質転換の後に行う。抗生物質含有培地上で選択された形質転換細胞を単離し、ルリア・ベルターニ培地(Difco)で成長させる。タンパク質発現は、1mM イソプロピル‐D‐チオガラクトピラノシド(IPTG)を添加することによって誘導する。IPTG誘導の2時間後、4℃、5000xgで10分間の遠心分離によって細胞を回収する。細胞溶解後に封入体を単離し、タンパク質を、6M グアニジンHClおよび2mM EDTA(pH8.0)プラス65mM ジチオスレイトールで可溶化させる。リフォールディングおよび精製の後、タンパク質を、Ca2+およびMg2+を含まないPBS(pH7.4)中の約5ml/mlにて、−80℃で保存する。これらの研究に用いるタンパク質はすべて、分子ふるいクロマトグラフィに基づいて、純度>90%であることを確認した。
この例では、配列番号52の修飾コリックス毒素配列(コリックス415)、開裂性リンカー配列(配列番号121)または非開裂性リンカー(配列番号98)、およびTNFSF阻害剤である生物活性カーゴを含む非天然単離融合分子を、例1に記載のように作製し、上記の例に記載のように評価して、適切なフォールディング、適切なサイズを確認する。
この例では、配列番号52の修飾コリックス毒素配列(コリックス415)、開裂性リンカー配列(配列番号121)または非開裂性リンカー(配列番号98)、および血糖降下剤である生物活性カーゴを含む非天然単離融合分子を、例1に記載のように作製し、上記の例に記載のように評価して、適切なフォールディング、適切なサイズを確認する。
この例では、配列番号52の修飾コリックス毒素配列(コリックス415)、開裂性リンカー配列(配列番号121)または非開裂性リンカー(配列番号98)、およびヒト成長ホルモンである生物活性カーゴを含む非天然単離融合分子を、例1に記載のように作製し、上記の例に記載のように評価して、適切なフォールディング、適切なサイズを確認する。
この例では、例1で作製した融合分子の代表的な生物活性カーゴの組織における組織学的検出について記載する。融合分子の投与後、動物をCO2窒息によって安楽死させ、心臓穿刺によって失血させた。特定の組織(リンパ節、気管、脳、脾臓 肝臓、GI管)を取り出し、PBSで少しリンスしていかなる残留血液をも除去し、OCTで凍結する。セクション(5ミクロン厚)をスライド上に載せる。スライドをアセトン中で10分間固定し、PBSでリンスする。スライドを、3% ペルオキシダーゼと共に5分間インキュベートする。次に、スライドを、タンパク質でさらに5分間ブロックする。反応性生物活性カーゴに対する一次抗体を、1:100の希釈率で30分間スライド上でインキュベートし、続いてPBS洗浄を行う。次に、ビオチン標識二次抗体を、およそ15分間インキュベートし、続いてPBS洗浄を行う。ストレプトアビジンHRP標識を、スライド上で15分間インキュベートし、続いてPBS洗浄を行う。HRPクロマゲン(HRP Chromagen)を5分間適用し、続いて蒸留H2O中で複数回リンスする。最後に、スライドをヘマトキシリンで1分間対比染色し、カバーグラスを掛け、生物活性カーゴの存在を調べる。
添付の配列表に挙げるアミノ酸配列は、米国特許法施行規則第1.822条の定めに従い、アミノ酸に対する標準的な3文字表記を用いて示される。
配列番号2は、634アミノ酸配列成熟コレラ菌コリックス毒素をコードする核酸配列である。
配列番号3〜80は、配列番号1に示される成熟コリックス毒素配列から誘導される様々な切断型コリックス毒素のアミノ酸配列である。
配列番号81は、配列番号1のアミノ酸残基E581が欠失された成熟コリックス毒素のアミノ酸配列である。
配列番号82は、ヒトインターロイキン‐10(IL‐10)のアミノ酸配列である。
配列番号83は、ヒトインターロイキン‐19(IL‐19)のアミノ酸配列である。
配列番号84は、ヒトインターロイキン‐20(IL‐20)のアミノ酸配列である。
配列番号85は、ヒトインターロイキン‐22(IL‐22)のアミノ酸配列である。
配列番号86は、ヒトインターロイキン‐24(IL‐24)のアミノ酸配列である。
配列番号87は、ヒトインターロイキン‐26(IL‐26)のアミノ酸配列である。
配列番号88 − 抗TNFアルファ抗体の重鎖可変領域配列
配列番号89 − 抗TNFアルファ抗体の軽鎖可変領域配列
配列番号90 − 抗TNFアルファ抗体の重鎖可変領域配列
配列番号91 − 抗TNFアルファ抗体の軽鎖可変領域配列
配列番号92 − ヒトTNFR‐p75‐Fc二量体融合タンパク質のアミノ酸配列
配列番号93 − GLP‐1アゴニストペプチドアミノ酸配列(エキセナチド)
配列番号94 − GLP‐1アゴニストペプチドアミノ酸配列(リラグルチド)
配列番号95 − ヒト成長ホルモンのアミノ酸配列(ソマトトロピン)
配列番号96〜121は、様々なペプチドリンカーのアミノ酸配列である。
配列番号122は、コリックス415−TEV−IL‐10融合分子のアミノ酸配列である。
配列番号123は、コリックス415−(G4S)3−IL‐10融合分子のアミノ酸配列である。
配列番号1 − 成熟コレラ菌コリックス毒素アミノ酸配列
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSGRSYLPENRAVITPQGVTNWTYQELEATHQALTREGYVFVGYHGTNHVAAQTIVNRIAPVPRGNNTENEEKWGGLYVATHAEVAHGYARIKEGTGEYGLPTRAERDARGVMLRVYIPRASLERFYRTNTPLENAEEHITQVIGHSLPLRNEAFTGPESAGGEDETVIGWDMAIHAVAIPSTIPGNAYEELAIDEEAVAKEQSISTKPPYKERKDELK
配列番号2 − 成熟コレラ菌コリックス毒素をコードする核酸配列
ATGGTCGAAGAAGCTTTAAACATCTTTGATGAATGCCGTTCGCCATGTTCGTTGACCCCGGAACCGGGTAAGCCGATTCAATCAAAACTGTCTATCCCTAGTGATGTTGTTCTGGATGAAGGTGTTCTGTATTACTCGATGACGATTAATGATGAGCAGAATGATATTAAGGATGAGGACAAAGGCGAGTCCATTATCACTATTGGTGAATTTGCCACAGTACGCGCGACTAGACATTATGTTAATCAAGATGCGCCTTTTGGTGTCATCCATTTAGATATTACGACAGAAAATGGTACAAAAACGTACTCTTATAACCGCAAAGAGGGTGAATTTGCAATCAATTGGTTAGTGCCTATTGGTGAAGATTCTCCTGCAAGCATCAAAATCTCCGTTGATGAGCTCGATCAGCAACGCAATATCATCGAGGTGCCTAAACTGTATAGTATTGATCTCGATAACCAAACGTTAGAGCAGTGGAAAACCCAAGGTAATGTTTCTTTTTCGGTAACGCGTCCTGAACATAATATCGCTATCTCTTGGCCAAGCGTGAGTTACAAAGCAGCGCAGAAAGAGGGTTCACGCCATAAGCGTTGGGCTCATTGGCATACAGGCTTAGCACTGTGTTGGCTTGTGCCAATGGATGCTATCTATAACTATATCACCCAGCAAAATTGTACTTTAGGGGATAATTGGTTTGGTGGCTCTTATGAGACTGTTGCAGGCACTCCGAAGGTGATTACGGTTAAGCAAGGGATTGAACAAAAGCCAGTTGAGCAGCGCATCCATTTCTCCAAGGGGAATGCGATGAGCGCACTTGCTGCTCATCGCGTCTGTGGTGTGCCATTAGAAACTTTGGCGCGCAGTCGCAAACCTCGTGATCTGACGGATGATTTATCATGTGCCTATCAAGCGCAGAATATCGTGAGTTTATTTGTCGCGACGCGTATCCTGTTCTCTCATCTGGATAGCGTATTTACTCTGAATCTTGACGAACAAGAACCAGAGGTGGCTGAACGTCTAAGTGATCTTCGCCGTATCAATGAAAATAACCCGGGCATGGTTACACAGGTTTTAACCGTTGCTCGTCAGATCTATAACGATTATGTCACTCACCATCCGGGCTTAACTCCTGAGCAAACCAGTGCGGGTGCACAAGCTGCCGATATCCTCTCTTTATTTTGCCCAGATGCTGATAAGTCTTGTGTGGCTTCAAACAACGATCAAGCCAATATCAACATCGAGTCTCGTTCTGGCCGTTCATATTTGCCTGAAAACCGTGCGGTAATCACCCCTCAAGGCGTCACAAATTGGACTTACCAGGAACTCGAAGCAACACATCAAGCTCTGACTCGTGAGGGTTATGTGTTCGTGGGTTACCATGGTACGAATCATGTCGCTGCGCAAACCATCGTGAATCGCATTGCCCCTGTTCCGCGCGGCAACAACACTGAAAACGAGGAAAAGTGGGGCGGGTTATATGTTGCAACTCACGCTGAAGTTGCCCATGGTTATGCTCGCATCAAAGAAGGGACAGGGGAGTATGGCCTTCCGACCCGTGCTGAGCGCGACGCTCGTGGGGTAATGCTGCGCGTGTATATCCCTCGTGCTTCATTAGAACGTTTTTATCGCACGAATACACCTTTGGAAAATGCTGAGGAGCATATCACGCAAGTGATTGGTCATTCTTTGCCATTACGCAATGAAGCATTTACTGGTCCAGAAAGTGCGGGCGGGGAAGACGAAACTGTCATTGGCTGGGATATGGCGATTCATGCAGTTGCGATCCCTTCGACTATCCCAGGGAACGCTTACGAAGAATTGGCGATTGATGAGGAGGCTGTTGCAAAAGAGCAATCGATTAGCACAAAACCACCTTATAAAGAGCGCAAAGATGAACTTAAG
配列番号3 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス386
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQA
配列番号4 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス385
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQ
配列番号5 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス384
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGA
配列番号6 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス383
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAG
配列番号7 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス382
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSA
配列番号8 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス381
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTS
配列番号9 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス380
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQT
配列番号10 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス379
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQ
配列番号11 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス378
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPE
配列番号12 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス377
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTP
配列番号13 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス376
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLT
配列番号14 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス375
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGL
配列番号15 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス374
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPG
配列番号16 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス373
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHP
配列番号17 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス372
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHH
配列番号18 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス371
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTH
配列番号19 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス370
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVT
配列番号20 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス369
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYV
配列番号21 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス368
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDY
配列番号22 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス367
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYND
配列番号23 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス366
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYN
配列番号24 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス365
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIY
配列番号25 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス364
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQI
配列番号26 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス363
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQ
配列番号27 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス362
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVAR
配列番号28 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス361
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVA
配列番号29 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス360
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTV
配列番号30 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス359
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLT
配列番号31 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス358
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVL
配列番号32 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス357
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQV
配列番号33 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス356
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQ
配列番号34 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス355
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVT
配列番号35 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス354
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMV
配列番号36 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス353
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGM
配列番号37 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス352
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPG
配列番号38 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス351
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNP
配列番号39 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス350
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENN
配列番号40 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス349
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINEN
配列番号41 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス348
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINE
配列番号42 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス425
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSGRSYLPEN
配列番号43 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス424
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSGRSYLPE
配列番号44 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス423
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSGRSYLP
配列番号45 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス422
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSGRSYL
配列番号46 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス421
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSGRSY
配列番号47 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス420
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSGRS
配列番号48 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス419
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSGR
配列番号49 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス418
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSG
配列番号50 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス417
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRS
配列番号51 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス416
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESR
配列番号52 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス415
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIES
配列番号53 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス414
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIE
配列番号54 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス413
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINI
配列番号55 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス412
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANIN
配列番号56 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス411
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANI
配列番号57 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス410
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQAN
配列番号58 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス409
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQA
配列番号59 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス408
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQ
配列番号60 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス407
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNND
配列番号61 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス406
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNN
配列番号62 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス405
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASN
配列番号63 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス404
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVAS
配列番号64 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス403
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVA
配列番号65 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス402
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCV
配列番号66 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス401
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSC
配列番号67 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス400
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKS
配列番号68 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス399
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADK
配列番号69 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス398
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDAD
配列番号70 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス397
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDA
配列番号71 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス396
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPD
配列番号72 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス395
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCP
配列番号73 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス394
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFC
配列番号74 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス393
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLF
配列番号75 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス392
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSL
配列番号76 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス391
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILS
配列番号77 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス390
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADIL
配列番号78 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス389
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADI
配列番号79 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス388
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAAD
配列番号80 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックス387
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAA
配列番号81 − 修飾コレラ菌コリックス毒素アミノ酸配列コリックスΔ581
VEDELNIFDECRSPCSLTPEPGKPIQSKLSIPSDVVLDEGVLYYSMTINDEQNDIKDEDKGESIITIGEFATVRATRHYVNQDAPFGVIHLDITTENGTKTYSYNRKEGEFAINWLVPIGEDSPASIKISVDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPMDAIYNYITQQNCTLGDNWFGGSYETVAGTPKVITVKQGIEQKPVEQRIHFSKGNAMSALAAHRVCGVPLETLARSRKPRDLTDDLSCAYQAQNIVSLFVATRILFSHLDSVFTLNLDEQEPEVAERLSDLRRINENNPGMVTQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNNDQANINIESRSGRSYLPENRAVITPQGVTNWTYQELEATHQALTREGYVFVGYHGTNHVAAQTIVNRIAPVPRGNNTENEEKWGGLYVATHAEVAHGYARIKEGTGEYGLPTRAERDARGVMLRVYIPRASLERFYRTNTPLENAEEHITQVIGHSLPLRNEAFTGPESAGGEDTVIGWDMAIHAVAIPSTIPGNAYEELAIDEEAVAKEQSISTKPPYKERKDELK
配列番号82 − ヒトインターロイキン‐10アミノ酸配列
MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN
配列番号83 − ヒトインターロイキン‐19アミノ酸配列
MKLQCVSLWLLGTILILCSVDNHGLRRCLISTDMHHIEESFQEIKRAIQAKDTFPNVTILSTLETLQIIKPLDVCCVTKNLLAFYVDRVFKDHQEPNPKILRKISSIANSFLYMQKTLRQCQEQRQCHCRQEATNATRVI HDNYDQLEVHAAAIKSLGELDVFLAWINKNHEVMSSA
配列番号84 − ヒトインターロイキン‐20アミノ酸配列
MKASSLAFSLLSAAFYLLWTPSTGLKTLNLGSCVIATNLQEIRNGFSEIRGSVQAKDGNIDIRILRRTESLQDTKPANRCCLLRHLLRLYLDRVFKNYQTPDHYTLRKISSLANSFLTIKKDLRLCHAHMTCHCGEEAMK KYSQILSHFEKLEPQAAVVKALGELDILLQWMEETE
配列番号85 − ヒトインターロイキン‐22アミノ酸配列
MAALQKSVSSFLMGTLATSCLLLLALLVQGGAAAPISSHCRLDKSNFQQPYITNRTFMLAKEASLADNNTDVRLIGEKLFHGVSMSERCYLMKQVLNFTLEEVLFPQSDRFQPYMQEVVPFLARLSNRLSTCHIEGDDLHIQRNVQKLKDTVKKLGESGEIKAIGELDLLFMSLRNACI
配列番号86 − ヒトインターロイキン‐24アミノ酸配列
MNFQQRLQSLWTLASRPFCPPLLATASQMQMVVLPCLGFTLLLWSQVSGAQGQEFHFGPCQVKGVVPQKLWEAFWAVKDTMQAQDNITSARLLQQEVLQNVSDAESCYLVHTLLEFYLKTVFKNYHNRTVEVRTLKSFSTLANNFVLIVSQLQPSQENEMFSIRDSAHRRFLLFRRAFKQLDVEAALTKALGEVDILLTWMQKFYKL
配列番号87 − ヒトインターロイキン‐26アミノ酸配列
MLVNFILRCGLLLVTLSLAIAKHKQSSFTKSCYPRGTLSQAVDALYIKAAWLKATIPEDRIKNIRLLKKKTKKQFMKNCQFQEQLLSFFMEDVFGQLQLQGCKKIRFVEDFHSLRQKLSHCISCASSAREMKSITRMKRIFYRIGNKGIYKAISELDILLSWIKKLLESSQ
配列番号88 − 抗TNFアルファ抗体の重鎖可変領域配列
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVERGFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
配列番号89 − 抗TNFアルファ抗体の軽鎖可変領域配列
DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号90 − 抗TNFアルファ抗体の重鎖可変領域配列
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAIISFDGSNKSSADSVKGRFTYSRRNSKNALFLQMNSLRAEDTAVFYCARDRGVSAGGNYYYYGMDVWGQGTTVTVSS
配列番号91 − 抗TNFアルファ抗体の軽鎖可変領域配列
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTRFTLTISSLEPEDFAVYYCQQRSNWPPFTFGPGTKVDIL
配列番号92 − ヒトTNFR‐p75‐Fc二量体融合タンパク質のアミノ酸配列
LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
配列番号93 − GLP‐1アゴニストペプチドアミノ酸配列(エキセナチド)
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
配列番号94 − GLP‐1アゴニストペプチドアミノ酸配列(リラグルチド)
HAEGTFTSDVSSYLEGQAAKEEFIIAWLVKGRG
配列番号95 − ヒト成長ホルモンのアミノ酸配列(ソマトトロピン)
FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGF
配列番号96 − ペプチドリンカーのアミノ酸配列
GGGGS
配列番号97 − ペプチドリンカーのアミノ酸配列
GGGGSGGGGS
配列番号98 − ペプチドリンカーのアミノ酸配列
GGGGSGGGGSGGGGS
配列番号99 − ペプチドリンカーのアミノ酸配列
GGGGSGGG
配列番号100 − ペプチドリンカーのアミノ酸配列
AAPF
配列番号101 − ペプチドリンカーのアミノ酸配列
GGF
配列番号102 − ペプチドリンカーのアミノ酸配列
AAPV
配列番号103 − ペプチドリンカーのアミノ酸配列
GGL
配列番号104 − ペプチドリンカーのアミノ酸配列
AAL
配列番号105 − ペプチドリンカーのアミノ酸配列
FVR
配列番号106 − ペプチドリンカーのアミノ酸配列
VGR
配列番号107 − ペプチドリンカーのアミノ酸配列
RKPR
配列番号108 − ペプチドリンカーのアミノ酸配列
Y V A D Xaa Xaa=任意のアミノ酸
配列番号109 − ペプチドリンカーのアミノ酸配列
D Xaa Xaa D Xaa Xaa=任意のアミノ酸
配列番号110 − ペプチドリンカーのアミノ酸配列
R (Xaa)n R Xaa Xaa=任意のアミノ酸 n=0、2、4、または6
配列番号111 − ペプチドリンカーのアミノ酸配列
K (Xaa)n R Xaa Xaa=任意のアミノ酸 n=0、2、4、または6
配列番号112 − ペプチドリンカーのアミノ酸配列
E R T K R Xaa Xaa=任意のアミノ酸
配列番号113 − ペプチドリンカーのアミノ酸配列
R V R R Xaa Xaa=任意のアミノ酸
配列番号114 − ペプチドリンカーのアミノ酸配列
デカノイル-R V R R Xaa Xaa=任意のアミノ酸
配列番号115 − ペプチドリンカーのアミノ酸配列
P Xaa W V P Xaa Xaa=任意のアミノ酸
配列番号116 − ペプチドリンカーのアミノ酸配列
W V A Xaa Xaa=任意のアミノ酸
配列番号117 − ペプチドリンカーのアミノ酸配列
Xaa F Xaa Xaa Xaa=任意のアミノ酸
配列番号118 − ペプチドリンカーのアミノ酸配列
Xaa Y Xaa Xaa Xaa=任意のアミノ酸 n=0、2、4、または6
配列番号119 − ペプチドリンカーのアミノ酸配列
Xaa W Xaa Xaa Xaa=任意のアミノ酸 n=0、2、4、または6
配列番号120 − ペプチドリンカーのアミノ酸配列
(V、A、またはP)-Y-(S、P、またはA)と組み合わせたD R W I P F H L L
配列番号121 − ペプチドリンカーのアミノ酸配列
GGGGSGGGENLYFQS
配列番号122 − コリックス415−TEV−IL‐10融合分子のアミノ酸配列
MVEEALNIFDECRSPCSLTPEPGKPIQSKLSIPGDVVLDEGVLYYSMTINDEQNDIKDED KGESIITIGEFATVRATRHYVSQDAPFGVINLDITTENGTKTYSFNRKESEFAINWLVPIGEDSPASIKISIDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPIDAIYNYITQQNCTLGDNWFGGSYETVAGTPKAITVKQGIEQKPVEQRIHFSKKNAMEALAAHRVCGVPLETLARSRKPRDLPDDLSCAYNAQQIVSLFLATRILFTHIDSIFTLNLDGQEPEVAERLDDLRRINENNPGMVIQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNSDQANINIESGGGGSGGGENLYFQSPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQA ENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN
配列番号123 − コリックス415−(G4S)3−IL‐10融合分子のアミノ酸配列
MVEEALNIFDECRSPCSLTPEPGKPIQSKLSIPGDVVLDEGVLYYSMTINDEQNDIKDED KGESIITIGEFATVRATRHYVSQDAPFGVINLDITTENGTKTYSFNRKESEFAINWLVPIGEDSPASIKISIDELDQQRNIIEVPKLYSIDLDNQTLEQWKTQGNVSFSVTRPEHNIAISWPSVSYKAAQKEGSRHKRWAHWHTGLALCWLVPIDAIYNYITQQNCTLGDNWFGGSYETVAGTPKAITVKQGIEQKPVEQRIHFSKKNAMEALAAHRVCGVPLETLARSRKPRDLPDDLSCAYNAQQIVSLFLATRILFTHIDSIFTLNLDGQEPEVAERLDDLRRINENNPGMVIQVLTVARQIYNDYVTHHPGLTPEQTSAGAQAADILSLFCPDADKSCVASNSDQANINIESGGGGSGGGGSGGGGSPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQA ENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN
Claims (37)
- 非天然ホモ二量体融合分子、および1つ以上の薬理学的に許容されるキャリアを含む医薬組成物であって、
ここで、前記ホモ二量体融合分子の各単量体は、生物活性カーゴとカップリングされた、配列番号1で示されるアミノ酸配列、またはその変異体、またはその断片を有するコリックス毒素を含み、
ここで、コリックス毒素の変異体または断片は:
(a)ドメインIa、または、前記融合分子の細胞への結合を媒介するドメインIaの能力を除去しない、1乃至10アミノ酸の挿入、欠失および/もしくは置換を含むドメインIa;ならびに
(b)ドメインII、または、ドメインIIのトランスサイト−シス活性を除去しない、1乃至10アミノ酸の挿入、欠失および/もしくは置換を含むドメインII;を含み、
ここで、前記生物活性カーゴが、
(i)配列番号82で示されるアミノ酸配列と少なくとも90%の相同性を有するインターロイキン−10;または
(ii)配列番号82のアミノ酸残基20乃至178を含むインターロイキン−10
であることを特徴とする医薬組成物。 - 請求項1に記載の医薬組成物において、前記インターロイキン−10が、配列番号82で示されるアミノ酸配列と少なくとも95%の相同性を有することを特徴とする医薬組成物。
- 請求項1又は2に記載の医薬組成物において、前記インターロイキン−10が、配列番号82で示されるアミノ酸配列と少なくとも99%の相同性を有することを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、配列番号1で示されるアミノ酸配列の変異体または断片であることを特徴とする医薬組成物。
- 請求項4に記載の医薬組成物において、前記ドメインIaが、前記融合分子の細胞への結合を媒介するドメインIaの能力を除去しない、1乃至10アミノ酸の挿入、欠失および/または置換を含むことを特徴とする医薬組成物。
- 請求項5に記載の医薬組成物において、前記ドメインIaが、前記融合分子の細胞への結合を媒介するドメインIaの能力を除去しない、1乃至10アミノ酸の置換を含むことを特徴とする医薬組成物。
- 請求項4乃至6の何れか1項に記載の医薬組成物において、前記ドメインIaが、Val1−Glu2−Glu3−Ala4を含むことを特徴とする医薬組成物。
- 請求項4乃至7の何れか1項に記載の医薬組成物において、前記ドメインIIが、前記融合分子の細胞への結合を媒介するドメインIaの能力を除去しない、1乃至10アミノ酸の挿入、欠失および/または置換を含むことを特徴とする医薬組成物。
- 請求項4に記載の医薬組成物において、前記コリックス毒素が、解毒されたドメインIIIを含むことを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、配列番号1で示されるアミノ酸配列に対して少なくとも95%の相同性を有することを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、配列番号1で示されるアミノ酸配列に対して少なくとも99%の相同性を有することを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、前記生物活性カーゴに共有結合的にカップリングされていることを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、前記生物活性カーゴに非共有結合的にカップリングされていることを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、前記生物活性カーゴに直接的にカップリングされていることを特徴とする医薬組成物。
- 請求項14に記載の医薬組成物において、前記生物活性カーゴが、前記コリックス毒素のC末端に直接的にカップリングされていることを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、前記生物活性カーゴに化学的にカップリングされていることを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、前記生物活性カーゴに非開裂性リンカーによってカップリングされていることを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記融合分子が、配列番号96、配列番号97、配列番号98、または配列番号99で示されるアミノ酸配列をさらに含むことを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、前記生物活性カーゴに開裂性リンカーによってカップリングされていることを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、前記生物活性カーゴを特定の細胞へと標的化することを特徴とする医薬組成物。
- 請求項20に記載の医薬組成物において、前記特定の細胞が、免疫細胞を含むことを特徴とする医薬組成物。
- 請求項21に記載の医薬組成物において、前記免疫細胞が、マクロファージ、抗原提示細胞、樹状細胞、またはこれらの組み合わせを含むことを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記融合分子が、配列番号97または配列番号98で示されるアミノ酸配列をさらに含むことを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記医薬組成物が、経口送達のための経口製剤の形態であることを特徴とする医薬組成物。
- 請求項24に記載の医薬組成物において、前記経口製剤が、タブレットまたはカプセルであることを特徴とする医薬組成物。
- 請求項24に記載の医薬組成物において、前記経口製剤が、腸溶性コートされていることを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記融合分子が、N末端メチオニンをさらに含むことを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記細胞が、極性上皮細胞であることを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物において、前記コリックス毒素が、配列番号1の変異体または断片であり、前記コリックス毒素の変異体または断片が、配列番号3で示されるアミノ酸配列の変異体であることを特徴とする医薬組成物。
- 請求項29に記載の医薬組成物において、ドメインIaが、前記融合分子の極性上皮細胞への結合を媒介するドメインIaの能力を除去しない、1乃至10アミノ酸の置換を含むことを特徴とする医薬組成物。
- 請求項29又は30に記載の医薬組成物において、前記ドメインIaが、Val1−Glu2−Glu3−Ala4を含むことを特徴とする医薬組成物。
- 請求項29乃至31の何れか1項に記載の医薬組成物において、前記インターロイキン−10が、配列番号82のアミノ酸残基20乃至178からなることを特徴とする医薬組成物。
- 対象における炎症性疾患の治療、予防および/または防止のための医薬の製造における、請求項1乃至32の何れか1項に記載の医薬組成物の使用であって、前記医薬が、経口送達のための経口製剤であることを特徴とする使用。
- 請求項33に記載の使用において、前記炎症性疾患が、炎症性腸疾患、乾癬、または細菌性敗血症から選択されることを特徴とする使用。
- 請求項34に記載の使用において、前記炎症性腸疾患が、クローン病、潰瘍性大腸炎、コラーゲン形成大腸炎、リンパ球性大腸炎、虚血性大腸炎、便流変更性大腸炎、ベーチェット症候群、または非定型的大腸炎から選択されることを特徴とする使用。
- 対象における自己免疫疾患の治療、予防および/または防止のための医薬の製造における、請求項1乃至32の何れか1項に記載の医薬組成物の使用であって、前記医薬が、経口送達のための経口製剤であることを特徴とする使用。
- 請求項36に記載の使用において、前記自己免疫性疾患が、全身性エリテマトーデス(SLE)、尋常性天疱瘡、重症筋無力症、溶血性貧血、血小板減少性紫斑病、グレーブス病、シェーグレン病、皮膚筋炎、橋本病、多発性筋炎、炎症性腸疾患、多発性硬化症(MS)、真性糖尿病、関節リウマチ、または強皮症から選択されることを特徴とする使用。
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