JP2005247868A - 免疫原性の解毒変異体E.coliLT−A毒素 - Google Patents
免疫原性の解毒変異体E.coliLT−A毒素 Download PDFInfo
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Abstract
【解決手段】 E.coli熱不安定毒素(LT−A)のサブユニットA、またはそのフラグメントのアミノ酸配列を含む免疫原性解毒タンパク質であって、ここで、該配列またはフラグメントにおけるアミノ酸Ala−72が変異されている、タンパク質であって、1つの実施形態において、Ala−72が置換によって変異を受けており、また、Ala−82が、アルギニン残基で置換され得る、免疫原性解毒タンパク質。
【選択図】 なし
Description
本発明は、免疫原性の解毒された、Escherichia coli(E.coli)の腸毒素産生株によって産生される熱不安定毒素タンパク質(LT)に関する。そのタンパク質では、少なくともAサブユニットのアミノ酸Ala-72が変異している。そして本発明は、腸毒素産生性E.coli感染の予防もしくは処置において有用であるワクチンにおける使用、ならびに他の免疫原性タンパク質のためのアジュバントとしての使用に関する。本発明のトキソイドは、野生型毒素をコードするDNAの部位特異的変異誘発による組換えDNA技術を用いて適切に産生され得る。
熱不安定(heat-labile)腸毒素(LT)(E.coliの腸毒素産生株により産生される)およびコレラ毒素(CT)(V.cholerae株によって産生される)は、それぞれ、旅行者の下痢およびコレラの原因物質である(Spangler(1992)、MicrobiolRev 56:622)。LTおよびCTは、1次構造においては80%の相同性、および同一の3次構造を示す。これらは2つの機能的に異なるドメインから構成されている:酵素的に活性なAサブユニット、およびB5量体であり、B5量体はレセプター結合部位を含む。Aサブユニットは、標的のプロテインG、すなわちGTP結合タンパク質(cAMPの細胞内レベルを制御する)をADP-リボシル化する(RappuoliおよびPizza(1991),Sourcebook of bacterial protein toxins, Academic Press NY)。cAMPレベルの増強はまた、水および塩素イオンの腸への分泌を誘導して、イオン輸送を変更させ得る。
−Harfordら(EurJ Biochem(1989) 183:311)は、Ser-61-PheおよびGly-79-Lys置換を保有するLT-Aを生成した。
本発明の第1の局面によれば、E.coli熱不安定毒素のサブユニットA(LT-A)のアミノ酸配列、もしくはそのフラグメントを含む免疫原性の解毒タンパク質がであって、ここで提供されるタンパク質の中では、上記配列またはフラグメントにおいて少なくともアミノ酸Ala-72が変異している。
本発明の免疫原性の解毒タンパク質は、E.coliの腸毒素産生株による感染の予防および処置に有用なワクチン組成物の活性成分を構成し得る。免疫原性の解毒タンパク質はまた、粘膜アジュバントとしてワクチン組成物に用いられ得る。従って、この組成物は、薬学的産業での使用のために利用可能である。
本発明の実施は、他に示されない限り、分子生物学、微生物学、組換えDNA、および免疫学の従来技術(これらは当該技術内である)を使用する。このような技術は、文献において十分に説明される。例えば、Sambrookら、MOLECULARCLONING;A LABORATORY MANUAL,第2版 (1989);DNA CLONING,第IおよびII巻(D.N Glover編1985);OLIGONUCLEOTIDESYNTHESIS(M.J.Gait編,1984);NUCLEIC ACID HYBRIDIZATION(B.D.HamesおよびS.J.Higgins編1984);TRANSCRIPTIONAND TRANSLATION(B.D.HamesおよびS.J.Higgins編1984);ANIMAL CELL CULTURE(R.I.Freshney編1986);IMMOBILIZEDCELLS AND ENZYMES(IRL Press,1986);B.Perbal,A PRACTICAL GUIDE TO MOLECULARCLONING(1984);シリーズ、METHODS IN ENZYMOLOGY(Academic Press,Inc.);GENE TRANSFERVECTORS FOR MAMMALIAN CELLS(J.H.MillerおよびM.P.Calos編1987,Cold Spring HarborLaboratory)、Methods in Enzymology 第154巻および第155巻(それぞれ、WuおよびGrossmanならびにWu編)、MayerおよびWalker編(1987),IMMUNOCHEMICALMETHODS IN CELL AND MOLECULAR BIOLOGY(Academic Press,London)、Scopes,(1987),PROTEINPURIFICATION:PRINCIPLES AND PRACTICE,第2版(Springer-Verlag,N.Y.)、およびHANDBOOK OFEXPERIMENTAL IMMUNOLOGY,第I-IV巻(D.M.WeirおよびC.C.Blackwell編1986)を参照のこと。
アラニン A Ala アルギニン R Arg
アスパラギン N Asn アスパラギン酸 D Asp
システイン C Cys グリシン G Gly
グルタミン酸 E Glu グルタミン Q Gln
ヒスチジン H His イソロイシン I Ile
ロイシン L Leu リジン K Lys
メチオニン M Met フェニルアラニン F Phe
プロリン P Pro セリン S Ser
スレオニン T Thr トリプトファン W Trp
チロシン Y Tyr バリン V Val
上述のように、本発明において使用され得る免疫原性無毒化タンパク質の例は、詳細に述べられた変異部位以外に、タンパク質の天然アミノ酸配列に由来する少数のアミノ酸変化を有するポリペプチドを含む。
哺乳動物発現系は、当該分野で公知である。哺乳動物プロモーターは、哺乳動物RNAポリメラーゼに結合し、そしてコード配列(例えば、構造遺伝子)のmRNAへの下流(3’)転写を開始し得る任意のDNA配列である。プロモーターは転写開始領域を有し、これは通常コード配列の5’末端の近位に置かれ、そしてTATAボックスは、通常、転写開始部位の25〜30塩基対(bp)上流に位置する。TATAボックスは、正しい部位でRNA合成を始めるようにRNAポリメラーゼIIを導くと考えられる。哺乳動物プロモーターはまた、通常TATAボックスの100〜200bp上流内に位置する、上流プロモーターエレメントを含む。上流プロモーターエレメントは、転写が開始される速度を決定し、そしていずれの方向でも作用し得る(Sambrookら(1989)「哺乳動物細胞におけるクローニング遺伝子の発現」MolecularCloning:A Laboratory Manual.第2版)。
タンパク質をコードするポリヌクレオチドはまた、適切な昆虫発現ベクターに挿入され得、そしてそのベクター内の制御エレメントに作動可能に連結される。ベクター構築物は、当該分野で公知の技術を使用する。
細菌発現技術は当該分野で公知である。細菌プロモーターは、細菌RNAポリメラーゼに結合し、そしてコード配列(例えば、構造遺伝子)のmRNAへの下流(3’’)転写を開始し得る任意のDNA配列である。プロモーターは、通常、コード配列の5’末端に隣接して置かれる転写開始領域を有する。この転写開始領域は、通常、RNAポリメラーゼ結合部位および転写開始部位を含む。細菌プロモーターはまた、オペレーターと呼ばれる第2のドメインを有し得、これは近接したRNAポリメラーゼ結合部位(ここでRNA合成が始まる)と重複し得る。オペレーターは、遺伝子リプレッサータンパク質がオペレーターに結合し得、それにより特異的遺伝子の転写を阻害するので、負の調節された(誘導的)転写を可能にする。構成的発現は、負の調節エレメント(例えば、オペレーター)の非存在下で起こり得る。さらに、正の調節は、遺伝子アクチベータータンパク質結合配列(これは、存在する場合、通常RNAポリメラーゼ結合配列に(5’)隣接する)により達成され得る。遺伝子アクチベータータンパク質の例は、カタボライトアクチベータータンパク質(CAP)であり、これはEscherichiacoli(E.coli)におけるlacオペロンの転写を開始するのを助ける(Raibaudら(1984)Annu.Rev.Genet.18:173)。従って、調節される発現は正または負のいずれかであり得、それにより転写を増強または低減させるかのいずれかである。
さらに、天然に存在しない合成プロモーターはまた細菌プロモーターとして機能する。例えば、1つの細菌プロモーターまたはバクテリオファージプロモーターの転写活性化配列は、別の細菌プロモーターまたはバクテリオファージプロモーターのオペロン配列に接合され得、これは合成ハイブリッドプロモーターを創作する(米国特許第4,551,433号)。例えば、tacプロモーターは、trpプロモーターおよびlacリプレッサーにより調節されるlacオペロン配列の両方からなるハイブリッドtrp-lacプロモーターである(Amannら(1983)Gene25:167;de Boerら(1983)Proc.Natl.Acad.Sci.80:21)。さらに、細菌プロモーターは、細菌RNAポリメラーゼに結合し、そして転写を開始する能力を有する、非細菌起源の天然に存在するプロモーターを含み得る。非細菌起源の天然に存在するプロモーターはまた、原核生物においていくつかの遺伝子の高発現レベルを生じるための適合RNAポリメラーゼと対にされ得る。バクテリオファージT7RNAポリメラーゼ/プロモーター系は、対にされたプロモーター系の例である(Studierら(1986)J.Mol.Biol.189:113;Taborら(1985)Proc Natl.Acad.Sci.82:1074)。さらに、ハイブリッドプロモーターはまた、バクテリオファージプロモーターおよびE.coliオペレーター領域からなり得る(EPO公報第267851号)。
酵母発現系はまた当業者に公知である。酵母プロモーターは、酵母RNAポリメラーゼに結合し、そしてコード配列(例えば、構造遺伝子)のmRNAへの下流(3’)転写を開始し得る任意のDNA配列である。プロモーターは、通常コード配列の5’末端に隣接して置かれる転写開始領域を有する。この転写開始領域は、通常、RNAポリメラーゼ結合部位(「TATAボックス」)および転写開始部位を含む。酵母プロモーターはまた、上流アクチベーター配列(UAS)と呼ばれる第2のドメインを有し得、これは、存在する場合、通常、構造遺伝子に対して遠位である。UASは、調節的(誘導的)発現を可能にする。構成的発現はUASの非存在下で起こる。調節的発現は正または負のいずれかであり得、それにより転写を増強または低減させるかのいずれかである。
a.LTDNA供給源
プラスミドpEWD299に由来する1.5kbSmaI-EcoRIフラグメント(LT-A遺伝子およびLTプロモーター領域を含む)(Pronkら(1985)J.Biol.Chem.260:13580;Spicerら(1981)Proc.Natl.Acad.Sci.USA78:50)を、Bluescript KSベクター(Stratagene)にサブクローニングした。得られたベクター(BS-LT-Aと命名された)を、部位特異的変異誘発(ZollerおよびSmith(1982)Nucl.Acid.Res.10:6487)に使用した。
部位特異的変異誘発を、BS-LT-Aベクターの一本鎖DNA上で、ZollerおよびSmith(前出)の方法に従って行った。使用したオリゴヌクレオチド:
5’GCTCACTTACGTGGACAGTCT3’(オリゴLTA72R)
は、Ala-72のコドン(GCA)をArgコドン(CGT)に変異する。
c.LTA72R変異体の発現および精製
E.coliをBS-LTA72Rベクターで形質転換し、そして5リットル発酵槽においてLBブロス中で増殖させた。変異タンパク質LTA72Rを、制御孔ガラス(CPG350、Serva)およびA5Mアガロースカラムを用いて、次いでSephacryl S-200TMを用いるゲル濾過により、ペリプラズム(Pronkら;Magagnoliら(1996)InfectImmun 64:5434)から精製した。
a.トリプシン消化
45μg毒素(LT、LTA72R、LTK63)を、37℃の最終容量150μlの10mMTris(pH7.5)において、9μgのトリプシンで処理した。30μlのサンプルを、5分間および30分間のインキュベーション後に収集し、そして反応を、3.6μgのトリプシンインヒビターを用いて停止させた。10μlの4×濃縮電気泳動サンプル緩衝液を、各サンプルに添加し、そして混合物を10分間95℃に加熱した。タンパク質を、15%SDSミニゲルにロードし、そしてクーマシーブリリアントブルーR-250で染色するか、またはニトロセルロース膜に移し、続いて膜を1:300希釈のウサギ抗LTポリクローナル血清とインキュベートした。
b.ポリアルギニンのADPリボシル化
LT(野生型および変異体)を、Laiら(BBRC102:1021、1981)により記載されるように分析し、そして結果を図3に示す。
インビトロ毒性を、Y1副腎細胞(Dontaら(1973)Science 183:334)において、LTにより引き起こされる以下の形態変化により評価した。このアッセイを、マイクロタイタープレートにおいて、2倍希釈のLT、LT-A72R、およびLTK63で、50000細胞/ウェルを使用して行い、野生型については80pg/ウェル、そして変異体については40μg/ウェルから始めた。形態変化を、48時間のインキュベーション後に読み取った。
a.粘膜アジュバント活性
LT-A72Rのアジュバント活性を、Douceら(PNAS 92:1644-1648(1995))のプロトコルを用いて試験した。10匹のBALB/cマウス(雌、4〜6週齢)のグループを、1μgの毒素(LT、LT-A72R、LTBまたはLK-K63)および10μgのOVAで鼻腔内的に免疫した。動物を軽く麻酔し、そして0、21および35日目に鼻孔あたり15μl容量で免疫した。免疫応答を、0、20、34および52日目に採取された血清サンプルにおいて追跡した。動物を屠殺し、そして鼻洗浄を、反復流水式洗浄および0.1%BSAを含む1mlPBSの吸引により行った。
OVA+LT(野生型または変異体)での2または3回の鼻腔内免疫の14〜20日後、グループあたり2または3匹のマウスを屠殺し、そして脾臓を取り出した。脾臓細胞懸濁物を得、そして完全DMEM(10%FCS、2mML-グルタミン、15mM Hepes、100Uペニシリン/ストレプトマイシン、50mM 2-メルカプトエタノール)に再懸濁した。2×105脾臓細胞/ウェルを、U底96ウェルプレートに播種し、そして異なる濃度のOVAの存在下で5日間培養した。[3H]チミジンを、培養終了の16時間前に添加した(1μCi/ウェル)。次いで、細胞を細胞採集機で採集し、そして[3H]チミジン取り込みを、液体シンチレーション計数により評価した(図10)。
c.インビボ抗原投与
LTのLD50を、10匹のBALB/cマウス(雌、9週齢)グループを、LT(12.5μg、25μg、50μg、または100μg)またはPBSで腹腔内的に接種することにより決定した。観察の7日後、LD50を20.4μgとして決定した。
ADPリボシル化活性は、LTのアジュバント活性に必要ではないが、低いレベルの酵素活性の存在は、同時投与された抗原に対してより早くかつより高い免疫応答を誘導するのに有用であり得る。
Claims (1)
- E.coli熱不安定毒素(LT−A)のサブユニットA、またはそのフラグメントのアミノ酸配列を含む免疫原性解毒タンパク質であって、ここで、該配列またはフラグメントにおけるアミノ酸Ala−72が変異されている、タンパク質。
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1996
- 1996-10-31 GB GBGB9622660.0A patent/GB9622660D0/en active Pending
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1997
- 1997-10-30 DK DK97910583T patent/DK0941333T3/da active
- 1997-10-30 CA CA002268758A patent/CA2268758C/en not_active Expired - Fee Related
- 1997-10-30 EP EP97910583A patent/EP0941333B1/en not_active Expired - Lifetime
- 1997-10-30 WO PCT/IB1997/001440 patent/WO1998018928A1/en active IP Right Grant
- 1997-10-30 JP JP52024098A patent/JP3715326B2/ja not_active Expired - Fee Related
- 1997-10-30 ES ES97910583T patent/ES2247622T3/es not_active Expired - Lifetime
- 1997-10-30 US US09/297,171 patent/US20030113338A1/en not_active Abandoned
- 1997-10-30 DE DE69734110T patent/DE69734110T2/de not_active Expired - Lifetime
- 1997-10-30 EP EP05076163A patent/EP1571214A3/en not_active Withdrawn
- 1997-10-30 AT AT97910583T patent/ATE303441T1/de active
-
2002
- 2002-11-25 US US10/304,496 patent/US7291588B2/en not_active Expired - Fee Related
-
2005
- 2005-05-13 JP JP2005141923A patent/JP2005247868A/ja not_active Withdrawn
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022196816A1 (ja) * | 2021-03-19 | 2022-09-22 | 国立大学法人三重大学 | 急性肺障害および肺線維症の急性増悪を改善するための医薬組成物 |
Also Published As
Publication number | Publication date |
---|---|
WO1998018928A1 (en) | 1998-05-07 |
ES2247622T3 (es) | 2006-03-01 |
CA2268758A1 (en) | 1998-05-07 |
EP1571214A3 (en) | 2006-03-29 |
US20030170262A1 (en) | 2003-09-11 |
EP1571214A2 (en) | 2005-09-07 |
US7291588B2 (en) | 2007-11-06 |
ATE303441T1 (de) | 2005-09-15 |
EP0941333A1 (en) | 1999-09-15 |
JP3715326B2 (ja) | 2005-11-09 |
DE69734110T2 (de) | 2006-06-29 |
EP0941333B1 (en) | 2005-08-31 |
DE69734110D1 (de) | 2005-10-06 |
JP2001508286A (ja) | 2001-06-26 |
CA2268758C (en) | 2007-05-29 |
US20030113338A1 (en) | 2003-06-19 |
DK0941333T3 (da) | 2006-01-02 |
GB9622660D0 (en) | 1997-01-08 |
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