JP2005068131A - 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
従来使用されてきたキャリアで達成されたよりも良好な免疫原的特性をコンジュゲートに与える新規なタンパク質キャリアを同定し、オリゴ糖および多糖に対する免疫原性応答を高める、確実に高力価のワクチン接種を可能にすること。
【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。
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。
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。
(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。
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))。
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。
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。
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。
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。
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。
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。
Claims (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。
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ITFI920058A IT1262896B (it) | 1992-03-06 | 1992-03-06 | Composti coniugati formati da proteine heat shock (hsp) e oligo-poli- saccaridi, loro uso per la produzione di vaccini. |
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JP51533393A Division JP3641483B2 (ja) | 1992-03-06 | 1993-03-08 | 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 |
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JP2008312770A Division JP4840745B2 (ja) | 1992-03-06 | 2008-12-08 | 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 |
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JP51533393A Expired - Lifetime JP3641483B2 (ja) | 1992-03-06 | 1993-03-08 | 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 |
JP2004137928A Withdrawn JP2005068131A (ja) | 1992-03-06 | 2004-05-06 | 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 |
JP2004216652A Withdrawn JP2004346083A (ja) | 1992-03-06 | 2004-07-23 | 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 |
JP2008312770A Expired - Lifetime JP4840745B2 (ja) | 1992-03-06 | 2008-12-08 | 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 |
JP2010239145A Withdrawn JP2011052000A (ja) | 1992-03-06 | 2010-10-25 | 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 |
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JP51533393A Expired - Lifetime JP3641483B2 (ja) | 1992-03-06 | 1993-03-08 | 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 |
Family Applications After (3)
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JP2004216652A Withdrawn JP2004346083A (ja) | 1992-03-06 | 2004-07-23 | 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 |
JP2008312770A Expired - Lifetime JP4840745B2 (ja) | 1992-03-06 | 2008-12-08 | 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 |
JP2010239145A Withdrawn JP2011052000A (ja) | 1992-03-06 | 2010-10-25 | 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 |
Country Status (8)
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US (1) | US6403099B1 (ja) |
EP (1) | EP0632727B1 (ja) |
JP (5) | JP3641483B2 (ja) |
AT (1) | ATE161425T1 (ja) |
CA (1) | CA2131551C (ja) |
DE (1) | DE69315993T2 (ja) |
IT (1) | IT1262896B (ja) |
WO (1) | WO1993017712A2 (ja) |
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1992
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2008
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WO1993017712A3 (en) | 1993-11-11 |
WO1993017712A2 (en) | 1993-09-16 |
JPH07504423A (ja) | 1995-05-18 |
IT1262896B (it) | 1996-07-22 |
JP2004346083A (ja) | 2004-12-09 |
CA2131551C (en) | 2003-05-20 |
ITFI920058A1 (it) | 1993-09-06 |
EP0632727B1 (en) | 1997-12-29 |
DE69315993D1 (de) | 1998-02-05 |
US6403099B1 (en) | 2002-06-11 |
EP0632727A1 (en) | 1995-01-11 |
JP3641483B2 (ja) | 2005-04-20 |
JP2009102344A (ja) | 2009-05-14 |
ATE161425T1 (de) | 1998-01-15 |
CA2131551A1 (en) | 1993-09-16 |
DE69315993T2 (de) | 1998-07-02 |
JP4840745B2 (ja) | 2011-12-21 |
ITFI920058A0 (it) | 1992-03-06 |
JP2011052000A (ja) | 2011-03-17 |
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