JP2009102344A - 熱ショックタンパク質とオリゴ糖または多糖とから形成されるコンジュゲート - Google Patents
熱ショックタンパク質とオリゴ糖または多糖とから形成されるコンジュゲート Download PDFInfo
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Abstract
【解決手段】少なくとも1つの熱ショックタンパク質または少なくとも1つの免疫刺激ドメインを合有する熱ショックタンパク質の一部と、病原菌の少なくとも1つの莢膜のオリゴ糖または多糖とを含有する、コンジュゲート化合物。
【選択図】なし
Description
本発明は、熱ショックタンパク質と、多糖またはオリゴ糖(特に、病原性微生物の莢膜由来の多糖またはオリゴ糖)とからなるコンジュゲート化合物に関する。本化合物は、抗多糖抗体の形成を誘導し得る。そのため、本化合物は、ヒトおよび動物に使用するワクチンとして有用である。
細菌は、広範囲の疾患状態に対する病原物質である。
クタンパク質に結合した(T−細胞依存性であることが周知の)ペプチドによって示されるT細胞依存効果に関するLussowらに観察された効果は、注目に値する。
本発明は、少なくとも1つの熱ショックタンパク質または少なくとも1つの免疫刺激ドメインを含有する熱ショックタンパク質の一部と、少なくとも1つのオリゴ糖または多糖とを含有するコンジュゲート化合物を提供する。
真核の動物または植物に、最もよく保存されているタンパク質であり、そして、その保存は配列全体にわたっている。
生成され得る。
(項目1) 少なくとも1つの熱ショックタンパク質または少なくとも1つの免疫刺激ドメインを含有する熱ショックタンパク質の一部と、少なくとも1つのオリゴ糖または多糖とを含有する、コンジュゲート化合物。
(I.一般的な方法論)
本発明の実施には、他に示されていなければ、当該分野の分子生物学、微生物学、組換えDNA、および免疫学の従来の方法を使用する。このような方法は、文献に十分に説明されている。例えば、Sambrookら、MOLECULAR CLONING;A LABORATORY MANUAL,第二版(1289):DNA CLONING,VOLUMES IおよびII(D.N Glover編 1985):OLIGONUCLEOTIDE SYNTHESIS(M.J.Gait編 1984):NUCLEIC ACID HYBRIDIZATION(B.D.HamesおよびS.J.Higgins編 1984);TRANSCRIPTION AND TRANSLATION(B.D.HamesおよびS.J.Higgins編 1984);ANIMAL
CELL CULTURE(R.I.Freshney編 1986);IMMOBILIZED CELLS AND ENZYMES(IRL Press,1986);B.Perbal,A PRACTICAL GUIDE TO MOLECULAR CLONIHG(1984);METHODS IN EHZYMOLOGYシリーズ(Academic Press,Inc.);GENE TRANSFER VECTORS FOR MAMMALlAN CELLS(J.H.MillerおよびM.P.Calos編 1987,Cold Spring Harbor Laboratory)、Methods in Enzymology Vol.154およびVol.155(それぞれに、WuおよびGrossman、およびWu編)、MayerおよびWalker編(1987),IMMHNOCHEMICAL METHODS IN CELL AND MOLECULAR BIOLOGY(Academic Press,London)、Scopes,(1987),PROTEIN PURIFICATION:PRINCIPLES AND PRACTICE,第二版(Springer−Verlag,N.Y.)、および、HANDBOOK OF EXPERIMENTAL IMMUNOLOGY,VOLUMES I−IV(D.M.WeirおよびC.C.Blackwell編 1986)を参照のこと。
本発明に使用し得る熱ショックタンパク質には、上記のポリペプチド、および、上記タンパク質の天然のアミノ酸配列から少数のアミノ酸が変異したポリペプチドがあげられ;特に保存的なアミノ酸置換が予期される。
、相補的ポリヌクレオチド鎖を包含する。相補的ポリヌクレオチド結合パートナーの場合には、パートナーは通常、少なくとも約15塩基の長さであり、少なくとも40塩基であり得、さらに、少なくとも約40%から約60%のG+C含有量を有する。ポリヌクレオチドは、DNA、RNAまたは合成ヌクレオチドアナログを含み得る。
るようなポリメラーゼ連鎖反応の技法である。
も8−10アミノ酸、そしてよりさらに好ましくは少なくとも11−15アミノ酸からなる、または配列にコードされたポリペプチドにより免疫学的に同定され得るポリペプチドのことである。この用語にはまた、示された核酸配列から発現されるポリペプチドも包含される。
ば、直接取り込み、形質導入、f−交配またはエレクトロポーレーション)に関係なく、外因性ポリヌクレオチドの宿主細胞への挿入のことである。外因性ポリヌクレオチドは、非組込みベクター(例えばプラスミド)として維持され得るか、または、宿主細胞ゲノムに組み込まれ得る。
一旦、適切な熱ショックタンパク質のコーディング配列が単離されると、それは種々の異なる発現系、例えば、哺乳類細胞、バキュロウイルス、細菌、および酵母により用いられる発現系、で発現され得る。
哺乳類発現系は当該分野で公知である。哺乳類プロモーターは、哺乳類RNAポリメラーゼを結合し得、コーディング配列(例えば、構造遺伝子)のmRNAへの下流(3’)転写を開始し得る、いずれものDNA配列である。プロモーターは、通常はコーディング配列の5’末端近傍に位置する転写開始領域、および、通常は転写開始部位の上流25−30塩基対(bp)に位置するTATAボックスを有する。TATAボックスは、RNAポリメラーゼIIがRNA合成を適切な部位で開始させるのを導くと考えられている。哺乳類プロモーターはさらに、通常はTATAボックスの上流100から200bp内に位置する上流プロモーターエレメントを有する。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、いずれかの向きに作用し得る(Sambrookら、Molecular Cloning:A Laboratory Manual,第二版(1989))。
761)、および、ラウス肉腫ウイルスの長末端反復(LTR)由来(Gormanら、(1982)Proc.Natl.Acad.Sci.79:6777)およびヒトサイトメガロウイルス由来(Boshartら、(1985)Cell 41:5221)のエンハンサー/プロモーターが含まれる。さらに、いくつかのエンハンサーは、調節可能であり、ホルモンまたは金属イオンのような誘導物質が存在するときのみに活性になる(Sassone−Corsiら、(1986)Trends Genet.2:215;Maniatisら、(1987)Science 236:1237)。
成分は、発現構築物中に組み立てられる。エンハンサー、機能性スプライス供与部位および受容部位を有するイントロン、およびリーダー配列もまた、所望であれば発現構築物中に含まれる。発現構築物は、しばしば、哺乳類細胞または細菌のような宿主中で安定に維持され得る染色体外エレメント(例えば、プラスミド)のような、レプリコン中に維持される。哺乳類複製系には、複製にトランス作用因子が必要とされる動物ウイルス由来のものが含まれる。例えば、SV40のようなパポーバウイルス(Gluzman(1981)Cell 23:175)またはポリオーマウイルスの複製系を含むプラスミドが、適切なウイルスT存在下で、非常に多数のコピーを複製する。哺乳類レプリコンのさらなる例には、ウシパピローマウイルスおよびエプスタイン・バーウイルス由来のものが含まれる。さらに、レプリコンは2つの複製系を有し得、このため、例えば、発現のために哺乳類細胞中に、およびクローニングおよび増幅のために原核生物宿主中に維持される。このような哺乳類−細菌シャトルベクターの例には、pMT2(Kaufmanら(1989)Mol,Cell Biol.9:946)、およびpHEBO(Shimizuら(1986)Mol.Cell,Biol.6:1074)が含まれる。
タンパク質をコードするポリヌクレオチドもまた、適切な昆虫発現ベクターに挿入され得、ベクター内の制御エレメントに作動可能に連結される。ベクター構築には、当該分野で公知の方法が用いられる。
ーター、リーダー(所望であれば)、目的のコーディング配列、および転写終止配列を含む上記の成分が、通常は中間置換構築物(intermediate transplacement construct)(転移ベクター)に組み立てられる。この構築物は、1つの遺伝子および作動可能に連結された調節エレメント;各遺伝子がそれ自身の固有のセットの作動可能に連結された調節エレメントを有する複数の遺伝子;または、同じセットの調節エレメントに調節される複数の遺伝子を含み得る。中間置換構築物はしばしば、細菌のような宿主中で安定して維持され得る染色体外エレメント(例えば、プラスミド)のような、レプリコン中に維持される。レプリコンは1つの複製系を有し、このため、クローニングおよび増幅のために適切な宿主中に維持される。
をコードする遺伝子由来のような、非昆虫起源のリーダーもまた、昆虫での分泌を提供するために使用され得る。
4:91。
いる。例えば、組換えバキュロウイノレは、とりわけ、Aedes aegypti、Autographa californica、Bombyx mori、Drosophila melanogaster、Spodoptera frugiperda、およびTrichoplusa niのために開発されている(PCT公開No.WO89/046699;Carbonellら、(1985) J.Virol.56:153;Wright(1986)Nature 321:718;Smithら、(1983)Mol.Cell.Biol.3:2156:および一般的にはFraserら(1989)In Vitro Cell.Dev.Biol.25:225を参照のこと)。
細菌発現法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得、コーディング配列(例えば、構造遺伝子)のmRNAへの下流(3’)転写を開始し得るいずれものDNA配列である。プロモーターは、通常コーディング配列の5’末端近傍に位置す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二ドメインを有し得、これは、RNA合成を開始する位置である隣接RNAポリメラーゼ結合部位に重複し得る。遺伝子リプレッサ一タンパク質はオペレターに結合し得、そのことにより特異遺伝子の転写を阻害し得るので、オペレーターは、負の調節(誘導可能な)転写を行い得る。構成的発現は、オペレーターのような負の調節エレメントの非存在下で起こり得る。さらに、正の調節は、遺伝子活性化タンパク質結合配列により達成され得、これは、存在する場合には、通常RNAポリメラーゼ結合配列(5’)の近くに存在する。遺伝子活性化タンパク質の例は、力タボライト活性化タンパク質(CAP)であり、これは、E.coliでのlacオペロンの転写開始を助ける(Raibaudら(1984)Annu.Rev.Genet.18:173)。従って、調節的発現は正または負のいずれかであり得、そのことにより転写を促進または減退する。
る。さらなる例には、トリプトファン(trp)のような生合成酵素由来のプロモーター配列が含まれる(Goeddelら(1980)Nuc.Acids Res.8:4057;Yelvertonら(1981)Nucl.Acids Res.9:731;米国特許第4,738,921号;EPO公開No.036776およびNo.121775)。g−ラオタマーゼ(g−laotamase)(bla)プロモーター系(Weissmann(1981)「インターフェロンのクローニングおよびその他の誤り(mistakes)」Interferon 3(I.Gresser編)、バクテリオファージλPL(Shimatakeら(1981)Nature 292:128)、およびT5(米国特許第4,689,406号)プロモーター系もまた、有用なプロモーター配列を提供する。
列の5’末端に融合される。発現に際し、この構築物は、2つのアミノ酸配列の融合を提供する。例えば、バクテリオファージλ細胞遺伝子が外来遺伝子の5’末端で連結され得、細菌内で発現され得る。得られた融合タンパク質は、好ましくは、外来遺伝子からバクテリオファージタンパク質を切断するためのプロセッシング酵素(因子Xa)に対する部位を保持している(Nagaiら(1984)Nature 309:810)。融合タンパク質はまたlacZ由来の配列を用いて生成され得る(Jiaら(1987)Gene 60:197,trpE,Allenら(1987)J.Biotechnol.5:93:Makoffら(189)J.Gen.Microbiol.135:11、およびEPO公開No.324647,genes)。2つのアミノ酸配列を接続したDNA配列は、切断部位をコードし得るか、またはコードし得ない。その他の例は、ユビキチン融合タンパク質である。このような融合タンパク質は、好ましくは、外来遺伝子からユビキチンを切断するためのプロセッシング酵素(例えば、ユビキチン特異的プロセッシングプロテアーゼ)に対する部位を保持しているユビキチン領域を用いて生成される。この方法によって、そのままの外来タンパク質が単離され得る(Millerら(1989)Bio/Technology 7:698)。
J.3:2437)およびE.coliアルカリホスファターゼシグナル配列(phoA)(Okaら(1985)Proc.Natl Acad.Sci.82:7212)のような、分泌される細菌タンパク質の遺伝子由来であり得る。さらなる例として、種々のBacillus株由来のα−アミラーゼ遺伝子のシグナル配列は、B.subtilisから異種タンパク質を分泌するために使用され得る(Palvaら(1982)Proc.Natl.Acad.Sci.USA 79:5582:EPO公開No.244042)。
ー数を有する。高コピー数のプラスミドを含有する宿主は、好ましくは少なくとも約10、より好ましくは少なくとも約20のプラスミドを含有する。高コピー数または低コピー数のいずれかのベクターが、宿主でのベクターの効果および外来タンパク質に依存して選択され得る。
ドによるE.coli形質転換のための改良法」,Genetic Enineerings:Proceeding of the International Symposium on Genetic Engineering(H.W.BoyerおよびS.Nicosia編);Mandelら(1970)J.Mol.Biol.53:159;Taketo(1988)Biochim.Biophys.Acta 949:318、Escherichiaに関する;Chassyら(1987)FEMS Microbiol.Lett.44:173、Lactobacillusに関する;Fiedlerら(1988)Anal.Biochem 170:38、Pseudomonsに関する;Augustinら(1990)FEMS Microbiol.Lett.66:203、Staphylococcusに関する;Baranyら(1980)J.Bacteriol.144:698:Harlander(1987)「エレクトロポーレーションによるStretococcus lactisの形質転換」,Streptococcal Genetics(J.FerrettiおよびR.Curtiss III編);Perryら(1981)Infec.Immun.32:1295;Powellら(1988)Appl.Environ.Microbiol.54:655:Somkutiら(1987)Proc.4th Evr.Cong.Biotechnology 1:412、Stretococcusに関する、を参照のこと。
酵母発現系も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得、コーディング配列(例えば、構造遺伝子)のmRNAへの下流(3’)転写を開始し得る、いずれものDNA配列である。プロモーターは、コーディング配列の5’末端近傍に通常位置す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さらに、上流活性化配列(UAS)と呼ばれる第二ドメインを有し得、これは、存在する場合には通常構造遺伝子の遠位に存在する。UASにより、調節(誘導可能な)発現が行われる。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、そのことにより転写を促進または減退する。
、Cohenら(1980)Proc.Natl.Acad.Sci.USA 77:1078;Henikoffら(1981)Nature 283:835:Hollenbergら(1981)Curr.Topics Microbiol.Immunol.96:119:Hollenbergら(1978)「酵母Saccharomyces cerevisiaeでの細菌抗生物質耐性遺伝子の発現」:Plasmids of Medical,Environmental and Commercial Imortance(K.N.TimmisおよびA.Puhler編);Mercerau−Puigalonら(1980)Gene 11:163;Panthierら(1980)Curr.Genet.2:109が、含まれる。
/02463を参照のこと)。
Microbiol.25:141、Candidaに関する;Gleesonら(1986)J.Gen.Microbioy.132:3459;Roggenkampら(1986)Mol.Gen.Genet.202:302、Hansenulaに関する;Dasら(1984)J.Bacteriol.158:1165;De Louvencourtら(1983)J.Bacteriol.154:1165:Van den Bergら(1990)Bio/Technology 8:135、Kluyveromycesに関する;Creggら(1985)Mol.Cell.Biol.5:3376;Kunzeら(1985)J.Basic Microbiol.25:141;米国特許第4,837,148号および米国特許第4,929,555号、Pichiaに関する;Hinnenら(1978)Proc.Natl.Acad.Sci.USA 75;1929;Itoら(1983)J.Bacteriol.153:163、Saccharomycesに関する;Beachら(1981)Nature 300:706、Schizosaccharomycesに関する;Davidowら(1985)Curr.Genet.10:39;Gaillardinら(1985)Curr.Genet.10:49、Yarrowiaに関する;参照のこと。
本明細書中で考察されている各コンジュゲート化合物は、単一ワクチン候補物として、または他の病原由来の1つ以上のその他の抗原との組み合わせで使用され得る。これらのワクチンは、予防剤(感染を予防するため)または治療剤(感染後に疾患を治療するため)のいずれかであり得る。
ア」との組合せで含有し、このキャリアは、この組成物が与えられる個体に対して有害な抗体の産生をそれ自身が誘導しないいずれものキャリアを含む。適切なキャリアは、典型的には、タンパク質、多糖類、ポリ乳酸、ポリグリコール酸、アミノ酸ポリマー、アミノ酸コポリマー、脂質凝集体(例えば、油滴またはリボソーム)、および不活性ウイルス粒子のような、大きくて徐々に代謝される高分子である。このようなキャリアは、当業者に周知である。さらに、これらのキャリアは、免疫刺激剤(「アジュバント」)として機能し得る。さらに、抗原は、ジフテリア、破傷風などのような細菌トキソイドにコンジュゲートされ得る。
ト効果を増強するために、エマルジョンにされるか、またはリボソームにカプセル化され得る。
Meningococci C群の多糖類ならびに熱ショックタンパク質hspR70およびhsp65を含有するコンジュゲート化合物を構築し、ワクチンの効力について試験した。
C群髄膜炎菌の多糖を、Frasc C.E3.の「バイオテクノロジープロセスの進歩:バクテリアワクチン」(A.Mizrahi編),vol.13,pp.123−145,Wiley−Liss Inc.,New York(1990)に記載されているように精製した。精製多糖類(10mg/ml)を、pH5の0.01M酢酸緩衝液中で、100℃で8時間加水分解して解重合した。得られた生産物を、分析用クロマトグラフィー(Sephadex 6−50)で分析し、0.27のKd(分布係数)を示した。
0.5Mの塩化アンモニウムおよび0.15Mのシアノボロヒドリドナトリウムを加水分解から得られた溶液に加えた。pHを7に上げて、得られた溶液を35℃で1週間置いた。次に、オリゴ糖をクロマトグラフィー(Sephadex 6−15)により、収集したアミン基およびカルボハイドレート基に関して化学活性を含有するボイド容量画分を精製した。一方、単糖および過剰の試薬を含有する画分は廃棄した。得られたMenCオリゴ糖は、アミン基、シアル酸基、およびO−アセチル基を測定することによって特徴付けられた。次のモル比が得られた:シアル酸/アミン基=20、O−アセチル/シアル酸=0.84。
M.bovis BCG GroEL−型 65kDa hsp(hspR65)をプラスミドpRIB1300を宿した組換えE.coli K12株から発現し(Tholeら、Infect.Immun.1985,50,800:Van Edenら、Nature,1989,331,171)、そして、Tholeら、Infect.Immune.,1987,55.1466に記述されたように精製した。
MenCアミノ−オリゴ糖を、H2Oを10%含むジメチルスルホキシドに溶解し、それから(アミン基について)12倍過剰のアジピン酸のN−ヒドロキシスクシンイミドエステル[Hillら、「FEBS LETT.」102:282(1979)に従って調製した]と反応させた。ジオキサン(1〜4倍量)で沈澱させて精製した後、活性化オリゴ糖を真空中で乾燥し、N−ヒドロキシスクシンイミドエステルの含有量について分析した。次いで、pH7の0.1Mリン酸緩衝液中で5mg/mlの量のhspR65およびhspR70を、300倍モル過剰の活性化オリゴ糖と反応させた。それぞれ得られた糖コンジュゲートは、クロマトグラフィーにより未反応オリゴ糖から遊離し、濾過し、そして4℃で保存した。開始物質のMenC多糖中のシアル酸の割合に対する糖コンジュゲートのシアル酸含有量の比は、カップリングしたオリゴ糖の量を表す。調製したタンパク質の含有量は、Lowry「J.Biol.Chem.」193:265(1951)の方法により確認した。特に、hspR70とのコンジュゲートは、310μg/mlのタンパク質含有量および76μg/mlの糖含有量を有し、一方、hspR65とのコンジュゲートは、180μg/mlのタンパク質含有量および97μg/mlの糖含有量を有する。
BALB/c(H−2d)、C567BL/6(H−2b)およびCBA/J(H−2k)の雌のマウス(8〜12週齢)を本発明者らの飼育施設で飼育した。
毎週、マウスの後眼窩叢から血液を採取し、抗体はELISAで力価測定した。
ともに4℃で一晩インキュベートした。洗浄を繰り返した後、プレートを再び、ペルオキシダーゼにコンジュゲートしたIgG抗マウス抗血清を適切に希釈したものの100μlとともに37℃で3時間インキュベートした。
HspR65およびhspR70−MenCオリゴ糖コンジュゲートを、予めBCGで感作したまたは感作していないBALB/cおよびC57BL/6マウスの免疫に使用した。
新規のH.pylori熱ショックタンパク質が同定され、組換えDNA法を用いて産生された。
(6.1.1. H.pylori株および増殖条件)
使用したH.pylori株は:CCUG 17874、G39およびG33(Grosseto病院,Italy,で胃生検より単離)、Pylo 2U+およびPylo 2U−(F.Megraud,Pellegzin病院,Bordeaux,Franceにより供与)、BA96(Siena大学,Italy,で胃生検により単離)であった。Pylo 2U+株は非細胞毒性であり;Pylo 2U−株は非細胞毒性およびウレアーゼ陰性である。全ての株は、0.2%のシクロデキストリン、5μg/mlのセフスロジン、および5μg/mlのアムホテリシンBを含むコロンビアアガー上で、微好気性の条件下で、37^℃5〜6日間通常的に増殖した。細胞を採取し、PBSで洗浄した
。ペレットをLaemmliサンプル緩衝液に再懸濁して、そして煮沸して細胞を溶解した。
λgt11 H.pylori DNA発現ライブラリーの50万個のプラークを、0.2%マルトースおよび10mM MgSO4を含むLB中で一晩増殖したE.coli
Y1090株の懸濁液5mlと混和し、そして0.5 O.D.になるように10mM
MgSO4に両懸濁した。37℃で10分インキュベーションした後、溶かした75mlのTopAgaroseを、細菌/ファージ混合物に注ぎ、そして全部をBBLプレート上で平板培養した(50,000プラーク/プレート)。42℃で平板培養したライブラリーを3.5時間インキュベーションした後、10mM IPTGで予め湿らせたニトロセルロース濾紙(SchleicherおよびSchuell,Dassel,Germany)をプレート上に載せ、そしてさらに37℃3.5時間、次いで4℃で一晩インキュベーションした。λタンパク質を有する濾紙を持ち上げてPBSで洗浄し、そしてTBST(10mM TRIS pH8、100mM NaCl、5M MgCl2)に溶解した5%脱脂乾燥乳で20分間飽和させた。最初のハイブリダイゼーション工程は、患者血清で行った;陽性プラークを呈色および可視化するために、製造者の指示に従って、AP緩衝液(100mM Tris pH9.5、100mM NaCl,5mM MgCl2)中でアルカリホスファターゼをコンジュゲートした抗ヒトIg抗体(Cappel,West Chester,PA)およびNBT/BCIPキット(Promega,Madison,WI)を用いた。
使用した試薬および制限酵素は、Sigma(St.Louis,MO)およびBoehringer Mannheim(Germany)から得た。分子クローニング、一本鎖DNA精製、E、coliでの形質転換、プローブの放射標識化、H.pylori
DNA遺伝子ライブラリーのコロニースクリーニング、サザンブロット分析、PAGE、ウェスタンブロット分析については、標準的技法を用いた。
DNAフラグメントをBluescriptSK+(Stratagene,San Diego,CA)でサブクローニングした。一本鎖DNA配列決定を、製造者の指示に従って、[33P]αdATP(New England Nuclear,Boston,MA)およびSequenaseキット(U.S.Biochemical Corp.,Cleveland,OH)を用いて行った。配列は両鎖について決定し、そして各鎖は平均2回配列決定した。コンピュータによる配列分析はGCGパッケージを用いて行った。
MS2ポリメラーゼ融合タンパク質をpEX34A(pEX31の誘導体)ベクターを用いて生成した。挿入Hp67(図3のヌクレオチド445からヌクレオチド1402)およびEcoRIリンカーを、ベクターのEcoRI部位にフレーム内でクローニングした。停止コドンの位置を確認するために、HpG3’HindIIIフラグメントを、pEX34AのHindIII部位にフレーム内でクローニングした。組換えプラスミドをE.coli K12 H1△trpに形質転換した。誘導後の両方の場合で、予測した分子量の融合タンパク質を生成した。EcoRI/EcoRIフラグメントの場合は、誘
導後に得られた融合タンパク質をウサギに免疫するために、標準プロトコルを用いて電気浴出した。
(6.2.1. 発現ライブラリーのスクリーニングおよびH.pylori hspのクローニング)
H.pylori DNA発現ライブラリーのスクリーニングに適切な血清を見つけるために、H.pylori CCUG 17874株の超音波処理抽出物を、異種の胃炎によって冒された患者の血清に対するウェスタンブロット分析で試験した。異なった血清による抗原認識パターンは多岐にわたり、おそらく、個体の免疫応答の差異、および感染物に含まれる株により発現する抗原の差異のためであった。
ヌクレオチド配列分析で、開始ATGの6塩基対上流の推定リボゾーム結合部位を有する1638塩基対のオープンリーディングフレームが明らかになった。図3に、H.pylori hspのヌクレオチド配列およびアミノ酸配列を示す。推定リボゾーム結合部位および中間HindIII部位を下線で示す。フラグメントHp67の445位のシトシンおよび1402位のグアニンは、それぞれ最初および最後のヌクレオチドである。チミジン1772を、独立因子ターミネーター領域の局在化に関する演算法を用いて、転写された最後の推定のヌクレオチドとして同定した。オープンリーディングフレームは、58.3KDaの予測分子量、および5.37の予測pIを有する546アミノ酸のタンパク質をコードしていた。この遺伝子のコドンの選択は、H.pyloriコドンの用法と一致する。
アミノ酸配列分析で、全ての生物に存在するメンバーである熱ショックタンパク質hsp60ファミリーと非常に高い相同性が示された。異種のhsp60タンパク質問での相同の程度に基づいて、H.pylori hspは、グラム陰性細菌のhsp60タンパク質のサブグループに属する;しかし、hsp60ファミリーの他のタンパク質に対する相同の程度はかなり高い(少なくとも54%の一致)。
クローンHp67およびクローンHpG3’の挿入物を、MS2ポリメラーゼのアミノ末端に融合したこれらのオープンリーディングフレームを発現するために、発現ベクターpEX34Aにサブクローンした。クローンは予測したサイズの組換えタンパク質を生成し、そして最初のスクリーニングで用いたヒト血清により認識された。クローンHp67由来の融合タンパク質を電気浴出し、そして抗hsp特異的ポリクローナル抗血清を得るためにウサギの免疫に用いた。得られた抗血清は、融合タンパク質と、ウレアーゼ陰性株および非細胞毒性株を含有する、試験したいくつかのH.pylori株の全細胞抽出物の58KDaのタンパク質との両方を認識した。
以下の材料は、1992年12月15日および1993年1月22日に、本発明の譲渡人であるBiocine Sclavo,S.p.A.により、特許手続き上の微生物の寄託の国際的承認に関するブダペスト条約のもとに、アメリカンタイプカルチャーコレクション(ATCC)、メリーランド州,ロックビル,パークローンドライブ12301,電話(301)231−5519に寄託された。
ATCC No.69155 プラスミドpHp60G2を含むE.coli TG1
ATCC No.69156 プラスミドpHp605を含むE.coli TG1。
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EP0632727A1 (en) | 1995-01-11 |
CA2131551A1 (en) | 1993-09-16 |
JP4840745B2 (ja) | 2011-12-21 |
CA2131551C (en) | 2003-05-20 |
JP2004346083A (ja) | 2004-12-09 |
WO1993017712A2 (en) | 1993-09-16 |
IT1262896B (it) | 1996-07-22 |
ITFI920058A0 (it) | 1992-03-06 |
JP2011052000A (ja) | 2011-03-17 |
JP2005068131A (ja) | 2005-03-17 |
DE69315993D1 (de) | 1998-02-05 |
JPH07504423A (ja) | 1995-05-18 |
JP3641483B2 (ja) | 2005-04-20 |
ITFI920058A1 (it) | 1993-09-06 |
US6403099B1 (en) | 2002-06-11 |
DE69315993T2 (de) | 1998-07-02 |
ATE161425T1 (de) | 1998-01-15 |
EP0632727B1 (en) | 1997-12-29 |
WO1993017712A3 (en) | 1993-11-11 |
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