JP5882741B2 - サルアデノウイルスの核酸配列及びアミノ酸配列、それを含有するベクター、並びにその使用 - Google Patents
サルアデノウイルスの核酸配列及びアミノ酸配列、それを含有するベクター、並びにその使用 Download PDFInfo
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- JP5882741B2 JP5882741B2 JP2011546719A JP2011546719A JP5882741B2 JP 5882741 B2 JP5882741 B2 JP 5882741B2 JP 2011546719 A JP2011546719 A JP 2011546719A JP 2011546719 A JP2011546719 A JP 2011546719A JP 5882741 B2 JP5882741 B2 JP 5882741B2
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Description
(a)配列番号14〜配列番号19、配列番号50及び配列番号53のいずれかに記載のアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;
(b)配列番号14〜配列番号19、配列番号50及び配列番号53のいずれかに記載のポリペプチドの機能的誘導体をコードするポリヌクレオチドであって、上記機能的誘導体が1つ又は複数のアミノ酸残基の欠失、挿入及び/又は置換を含む、ポリヌクレオチド;並びに
(c)配列番号14〜配列番号19、配列番号50及び配列番号53のいずれかのアミノ酸配列と、その全長にわたって少なくとも85%同一なアミノ酸配列を有する機能的誘導体をコードするポリヌクレオチド。
(a)配列番号20〜配列番号25、配列番号51及び配列番号54のいずれかに記載のアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;
(b)配列番号20〜配列番号25、配列番号51及び配列番号54のいずれかに記載のポリペプチドの機能的誘導体をコードするポリヌクレオチドであって、上記機能的誘導体が1つ又は複数のアミノ酸残基の欠失、挿入及び/又は置換を含む、ポリヌクレオチド;並びに
(c)配列番号20〜配列番号25、配列番号51及び配列番号54のいずれかのアミノ酸配列と、その全長にわたって少なくとも95%同一なアミノ酸配列を有する機能的誘導体をコードするポリヌクレオチド。
(a)配列番号26〜配列番号31、配列番号52及び配列番号55のいずれかに記載のアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;
(b)配列番号26〜配列番号31、配列番号52及び配列番号55のいずれかに記載のポリペプチドの機能的誘導体をコードするポリヌクレオチドであって、上記機能的誘導体が1つ又は複数のアミノ酸残基の欠失、挿入及び/又は置換を含む、ポリヌクレオチド;並びに
(c)配列番号26〜配列番号31、配列番号52及び配列番号55のいずれかのアミノ酸配列と、その全長にわたって少なくとも85%同一なアミノ酸配列を有する機能的誘導体をコードするポリヌクレオチド。
(i)1つ又は複数の本発明による単離アデノウイルスカプシドポリペプチド;
(ii)本発明による単離ポリヌクレオチド;
(iii)本発明によるベクター;
(iv)本発明による組換えアデノウイルス;及び、
任意で、薬学的に許容可能な賦形剤。
(i)1つ又は複数の本発明による単離アデノウイルスカプシドポリペプチド;
(ii)本発明によるの単離ポリヌクレオチド;
(iii)本発明によるベクター;
(iv)本発明による組換えアデノウイルス。
アデノウイルス(Ad)は、幾つかの鳥類及び哺乳類の宿主において同定された非エンベロープ正20面体ウイルスである。ヒトアデノウイルス(hAd)は、既知の全てのヒトAd及び動物(例えばウシ、ブタ、イヌ、マウス、ウマ、サル及びヒツジ)起源の多くのAdを含むマストアデノウイルス属に属する。ヒトアデノウイルスは概して、ラット赤血球及びアカゲザル赤血球の血球凝集特性、DNA相同性、制限酵素切断パターン、G+C含有率並びに発癌性を含む多数の生物学的、化学的、免疫学的及び構造的基準に基づいて、6つの亜群(A〜F)に分けられる(Straus, 1984, The Adenoviruses中, ed. H.Ginsberg, pps. 451-498, New York: PlenusPress、及びHorwitz, 1990; Virology中, eds. B. N. Fields and D.M. Knipe, pps. 1679-1721)。
(a)配列番号14〜配列番号19、配列番号50及び配列番号53のいずれか、すなわち、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19、配列番号50、又は配列番号53に記載のアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;
(b)配列番号14〜配列番号19、配列番号50及び配列番号53のいずれか、すなわち、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19、配列番号50、又は配列番号53に記載のポリペプチドの機能的誘導体をコードするポリヌクレオチドであって、上記機能的誘導体が1つ又は複数のアミノ酸残基の欠失、挿入及び/又は置換を含む、ポリヌクレオチド;並びに
(c)配列番号14〜配列番号19、配列番号50及び配列番号53のいずれか、すなわち、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19、配列番号50、又は配列番号53のアミノ酸配列と、その全長にわたって少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%又は少なくとも99%、より好ましくは少なくとも85%、最も好ましくは少なくとも99%同一なアミノ酸配列を有する機能的誘導体をコードするポリヌクレオチド。
(i)別の異なる塩基性アミノ酸による塩基性アミノ酸の置換;
(ii)別の異なる酸性アミノ酸による酸性アミノ酸の置換;
(iii)別の異なる芳香族アミノ酸による芳香族アミノ酸の置換;
(iv)別の異なる非極性脂肪族アミノ酸による非極性脂肪族アミノ酸の置換;及び
(v)別の異なる極性非荷電アミノ酸による極性非荷電アミノ酸の置換。
(a)配列番号20〜配列番号25、配列番号51及び配列番号54のいずれか、すなわち、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号51、又は配列番号54に記載のアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;
(b)配列番号20〜配列番号25、配列番号51及び配列番号54のいずれか、すなわち、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号51、又は配列番号54に記載のポリペプチドの機能的誘導体をコードするポリヌクレオチドであって、上記機能的誘導体が1つ又は複数のアミノ酸残基の欠失、挿入及び/又は置換を含む、ポリヌクレオチド;並びに
(c)配列番号20〜配列番号25、配列番号51及び配列番号54のいずれか、すなわち、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号51、又は配列番号54のアミノ酸配列と、その全長にわたって少なくとも95%、98%、99%、99.5%、99.9%又は少なくとも99.95%、より好ましくは少なくとも98%、最も好ましくは少なくとも99.95%同一なアミノ酸配列を有する機能的誘導体をコードするポリヌクレオチド。
(a)配列番号26〜配列番号31、配列番号52及び配列番号55のいずれか、すなわち、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号52、又は配列番号55に記載のアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;
(b)配列番号26〜配列番号31、配列番号52及び配列番号55のいずれか、すなわち、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号52、又は配列番号55に記載のポリペプチドの機能的誘導体をコードするポリヌクレオチドであって、上記機能的誘導体が1つ又は複数のアミノ酸残基の欠失、挿入及び/又は置換を含む、ポリヌクレオチド;並びに
(c)配列番号26〜配列番号31、配列番号52及び配列番号55のいずれか、すなわち、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号52、又は配列番号55のアミノ酸配列と、その全長にわたって少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、又は少なくとも99%、より好ましくは少なくとも85%、最も好ましくは少なくとも99%同一なアミノ酸配列を有する機能的誘導体をコードするポリヌクレオチド。
本発明の第1の態様の好ましい実施形態では、単離ポリヌクレオチドは、配列番号14に記載のアミノ酸配列を有するアデノウイルスファイバータンパク質、又はその機能的誘導体をコードし、機能的誘導体は(i)1個、2個、3個、4個、5個、6個、7個、8個、9個、10個、15個、20個、25個、30個、35個、40個、45個、50個、60個、70個、80個、90個若しくは100個を超える、好ましくは10個を超える欠失、挿入、修飾及び/又は置換されたアミノ酸を含まないか、又は(ii)配列番号14のアミノ酸配列と、その全長にわたって少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%若しくは少なくとも99%、より好ましくは少なくとも85%、最も好ましくは少なくとも99%同一なアミノ酸配列を有する。
本発明の第1の態様の好ましい実施形態では、単離ポリヌクレオチドは、配列番号15に記載のアミノ酸配列を有するアデノウイルスファイバータンパク質、又はその機能的誘導体をコードし、機能的誘導体は(i)1個、2個、3個、4個、5個、6個、7個、8個、9個、10個、15個、20個、25個、30個、35個、40個、45個、50個、60個、70個、80個、90個若しくは100個を超える、好ましくは10個を超える欠失、挿入、修飾及び/又は置換されたアミノ酸を含まないか、又は(ii)配列番号15のアミノ酸配列と、その全長にわたって少なくとも98%、99%若しくは少なくとも99.9%、より好ましくは少なくとも99%、最も好ましくは少なくとも99.9%同一なアミノ酸配列を有する。
本発明の第1の態様の好ましい実施形態では、単離ポリヌクレオチドは、配列番号16に記載のアミノ酸配列を有するアデノウイルスファイバータンパク質、又はその機能的誘導体をコードし、機能的誘導体は(i)1個、2個、3個、4個、5個、6個、7個、8個、9個、10個、15個、20個、25個、30個、35個、40個、45個、50個、60個、70個、80個、90個若しくは100個を超える、好ましくは10個を超える欠失、挿入、修飾及び/又は置換されたアミノ酸を含まないか、又は(ii)配列番号16のアミノ酸配列を有する。
本発明の第1の態様の好ましい実施形態では、単離ポリヌクレオチドは、配列番号17に記載のアミノ酸配列を有するアデノウイルスファイバータンパク質、又はその機能的誘導体をコードし、機能的誘導体は(i)1個、2個、3個、4個、5個、6個、7個、8個、9個、10個、15個、20個、25個、30個、35個、40個、45個、50個、60個、70個、80個、90個若しくは100個を超える、好ましくは10個を超える欠失、挿入、修飾及び/又は置換されたアミノ酸を含まないか、又は(ii)配列番号17のアミノ酸配列を有する。
本発明の第1の態様の好ましい実施形態では、単離ポリヌクレオチドは、配列番号18に記載のアミノ酸配列を有するアデノウイルスファイバータンパク質、又はその機能的誘導体をコードし、機能的誘導体は(i)1個、2個、3個、4個、5個、6個、7個、8個、9個、10個、15個、20個、25個、30個、35個、40個、45個、50個、60個、70個、80個、90個若しくは100個を超える、好ましくは10個を超える欠失、挿入、修飾及び/又は置換されたアミノ酸を含まないか、又は(ii)配列番号18のアミノ酸配列と、その全長にわたって少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%若しくは少なくとも99%、より好ましくは少なくとも85%、最も好ましくは少なくとも90%同一なアミノ酸配列を有する。
本発明の第1の態様の好ましい実施形態では、単離ポリヌクレオチドは、配列番号19に記載のアミノ酸配列を有するアデノウイルスファイバータンパク質、又はその機能的誘導体をコードし、機能的誘導体は(i)1個、2個、3個、4個、5個、6個、7個、8個、9個、10個、15個、20個、25個、30個、35個、40個、45個、50個、60個、70個、80個、90個若しくは100個を超える、好ましくは10個を超える欠失、挿入、修飾及び/又は置換されたアミノ酸を含まないか、又は(ii)配列番号19のアミノ酸配列と、その全長にわたって少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%若しくは少なくとも99%、より好ましくは少なくとも85%、最も好ましくは少なくとも99%同一なアミノ酸配列を有する。
本発明の第1の態様の好ましい実施形態では、単離ポリヌクレオチドは、配列番号50に記載のアミノ酸配列を有するアデノウイルスファイバータンパク質、又はその機能的誘導体をコードし、機能的誘導体は(i)1個、2個、3個、4個、5個、6個、7個、8個、9個、10個、15個、20個、25個、30個、35個、40個、45個、50個、60個、70個、80個、90個若しくは100個を超える、好ましくは10個を超える欠失、挿入、修飾及び/又は置換されたアミノ酸を含まないか、又は(ii)配列番号50のアミノ酸配列と、その全長にわたって少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%若しくは少なくとも99%、より好ましくは少なくとも85%、最も好ましくは少なくとも99%同一なアミノ酸配列を有する。
本発明の第1の態様の好ましい実施形態では、単離ポリヌクレオチドは、配列番号53に記載のアミノ酸配列を有するアデノウイルスファイバータンパク質、又はその機能的誘導体をコードし、機能的誘導体は(i)1個、2個、3個、4個、5個、6個、7個、8個、9個、10個、15個、20個、25個、30個、35個、40個、45個、50個、60個、70個、80個、90個若しくは100個を超える、好ましくは10個を超える欠失、挿入、修飾及び/又は置換されたアミノ酸を含まないか、又は(ii)配列番号53のアミノ酸配列と、その全長にわたって少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%若しくは少なくとも99%、より好ましくは少なくとも85%、最も好ましくは少なくとも99%同一なアミノ酸配列を有する。
(i)本発明の第1、第2又は第3の態様による1つのポリヌクレオチドを含むポリヌクレオチド;
(ii)本発明の第1の態様によるポリヌクレオチド及び本発明の第2の態様によるポリヌクレオチドを含むポリヌクレオチド;
(iii)本発明の第1の態様によるポリヌクレオチド及び本発明の第3の態様によるポリヌクレオチドを含むポリヌクレオチド;
(iv)本発明の第2の態様によるポリヌクレオチド及び本発明の第3の態様によるポリヌクレオチドを含むポリヌクレオチド;並びに
(v)本発明の第1、第2及び第3の態様によるポリヌクレオチドを含むポリヌクレオチドからなる群から選択されるポリヌクレオチドであり、
(i)〜(v)によるポリヌクレオチド中に含まれる上記ポリヌクレオチドが、同じアデノウイルス分離株から選択される、例えばファイバータンパク質、ヘキソンタンパク質及びペントンタンパク質又はその機能的誘導体をそれぞれコードする3つ全てのポリヌクレオチドが、以下のアデノウイルスのうち1つのみに由来することが好ましい:ChAd55、ChAd73、ChAd83、ChAd146、ChAd147、PanAd1、PanAd2又はPanAd3。さらに、本発明の第4の態様又はその好ましい実施形態において、例えば上記に概説されるように、各々の「機能的誘導体」が、10個、5個又は3個を超えるアミノ酸変化(すなわち欠失、挿入、修飾及び/又は置換されたアミノ酸)を含まないことが好ましい。
(i)配列番号14と、その全長にわたって少なくとも85%同一なアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;
(ii)配列番号20と、その全長にわたって少なくとも95%同一なアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;及び
(iii)配列番号26と、その全長にわたって少なくとも98%同一なアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド。
(i)配列番号32と、その全長にわたって少なくとも98%同一なポリヌクレオチド;
(ii)配列番号38と、その全長にわたって少なくとも98%同一なポリヌクレオチド;及び
(iii)配列番号44と、その全長にわたって少なくとも98%同一なポリヌクレオチド。
(a)アデノウイルス5’逆方向末端反復(ITR);
(b)アデノウイルスE1a領域、又は13S領域、12S領域及び9S領域の中から選択されるその断片;
(c)アデノウイルスE1b領域、又はスモールT領域、ラージT領域及びIX領域からなる群の中から選択されるその断片;
(d)アデノウイルスE2b領域、又はスモールpTP領域、ポリメラーゼ領域及びIVa2領域からなる群の中から選択されるその断片;
(e)アデノウイルスL1領域、又は28.1kDタンパク質、ポリメラーゼ、アグノタンパク質、52/55kDaタンパク質及びIIIaタンパク質からなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(f)アデノウイルスL2領域、又は本発明のペントンタンパク質をコードするポリヌクレオチドを含むL2領域、又はペントンタンパク質若しくは本発明のペントンタンパク質、VIIタンパク質、Vタンパク質及びMuタンパク質からなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(g)アデノウイルスL3領域、又は本発明のヘキソンタンパク質をコードするポリヌクレオチドを含むL3領域、又はVIタンパク質、ヘキソンタンパク質若しくは本発明のヘキソンタンパク質、及びエンドプロテアーゼからなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(h)アデノウイルスE2a領域;
(i)アデノウイルスL4領域、又は100kDタンパク質、33kDホモログ及びVIIIタンパク質からなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(j)アデノウイルスE3領域、又はE3 ORF1、E3 ORF2、E3 ORF3、E3 ORF4、E3 ORF5、E3 ORF6、E3 ORF7、E3 ORF8及びE3 ORF9からなる群から選択されるその断片;
(k)アデノウイルスL5領域、又は本発明のファイバータンパク質をコードするポリヌクレオチドを含むL5領域、ファイバータンパク質又は本発明のファイバータンパク質をコードするその断片;
(l)アデノウイルスE4領域、又はE4 ORF7、E4 ORF6、E4 ORF5、E4 ORF4、E4 ORF3、E4 ORF2及びE4 ORF1からなる群から選択されるその断片;特に、上記E4領域のORF6、及び/又は
(m)アデノウイルス3’−ITR。
(a)配列番号13、配列番号62、配列番号63又は配列番号65のいずれか1つの5’−逆方向末端反復(ITR)領域;
(b)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスE1a領域、又は13S領域、12S領域及び9S領域の中から選択されるその断片;
(c)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスE1b領域、又はスモールT領域、ラージT領域及びIX領域からなる群の中から選択されるその断片;
(d)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスE2b領域、又はスモールpTP領域、ポリメラーゼ領域及びIVa2領域からなる群の中から選択されるその断片;
(e)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスL1領域、又は28.1kDタンパク質、ポリメラーゼ、アグノタンパク質、52/55kDaタンパク質及びIIIaタンパク質からなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(f)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスL2領域、又は配列番号31、配列番号52若しくは配列番号55のアミノ酸配列を有するペントンタンパク質、VIIタンパク質、Vタンパク質及びMuタンパク質からなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(g)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスL3領域、又はVIタンパク質、配列番号25、配列番号51若しくは配列番号54のアミノ酸配列を有するヘキソンタンパク質、及びエンドプロテアーゼからなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(h)配列番号13、配列番号62、配列番号63又は配列番号65のいずれか1つのアデノウイルスE2a領域;
(i)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスL4領域、又は100kDタンパク質、33kDホモログ及びVIIIタンパク質からなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(j)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスE3領域、又はE3 ORF1、E3 ORF2、E3 ORF3、E3 ORF4、E3 ORF5、E3 ORF6、E3 ORF7、E3 ORF8及びE3 ORF9からなる群から選択されるその断片;
(k)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスL5領域、又は配列番号19、配列番号50若しくは配列番号53のアミノ酸配列を有するファイバータンパク質をコードするその断片;
(l)配列番号13、配列番号62、配列番号63若しくは配列番号65のいずれか1つのアデノウイルスE4領域、又はE4 ORF7、E4 ORF6、E4 ORF5、E4 ORF4、E4 ORF3、E4 ORF2及びE4 ORF1からなる群から選択されるその断片、又はAd5 E4領域のORF6(配列番号64);並びに
(m)配列番号13、配列番号62、配列番号63又は配列番号65のいずれか1つの3’−ITR。
(i)本発明による単離タンパク質;
(ii)本発明による単離ポリヌクレオチド;
(iii)本発明によるベクター;
(iv)本発明による組換えアデノウイルス;及び、
任意で、薬学的に許容可能な賦形剤。
(i)本発明による単離タンパク質;
(ii)本発明による単離ポリヌクレオチド;
(iii)本発明によるベクター;
(iv)本発明による組換えアデノウイルス。
a)ラクトース、マンニトール、結晶性ソルビトール、リン酸水素二カリウム(dibasic phosphates)、リン酸カルシウム、糖類、微結晶性セルロース、カルボキシメチルセルロース、ヒドロキシエチルセルロース、ポリビニルピロリドン等の結合剤;
b)ステアリン酸マグネシウム、タルク、ステアリン酸カルシウム、ステアリン酸亜鉛、ステアリン酸、硬化植物油、ロイシン、グリセリド及びフマル酸ステアリルナトリウム等の滑剤;
c)デンプン、クロスカルメロースナトリウム、メチルセルロース、寒天、ベントナイト、アルギン酸、カルボキシメチルセルロース、ポリビニルピロリドン等の崩壊剤。
ChAd55、ChAd73、ChAd83、ChAd146、ChAd147は、欧州及び米国の様々な施設に収容された健常な動物から得られたチンパンジーアデノウイルスの群である。ChAd55、ChAd73、ChAd83、ChAd146、ChAd147には、ヒト血清との検出可能な反応性を有しないという性質がある。PanAd1、PanAd2及びPanAd3は、欧州及び米国の様々な施設に収容された健常なボノボ(Pan Paniscus)から単離した新たなアデノウイルスである。PanAd1、PanAd2及びPanAd3には、ヒト血清との検出可能な反応性を有しないという性質がある。
PanAd1、PanAd2及びPanAd3、並びにChAd55、ChAd73、ChAd83、ChAd146、ChAd147ウイルスゲノムを、下記に詳述する戦略に従ってプラスミドベクターにクローニングした。ベクターゲノムの全ての操作は、標準的な技法に従って大腸菌において行った。ベクター系は、ChAd及びPanAdの骨格からE1領域及びE3領域を欠失させることによって開発した。E1領域を、動物モデルにおける免疫学的効力の評価のために、ヒトCMV IEプロモーター及びBGHpAシグナル含有HCV非構造領域(HCV NS)及びHIV gag(配列番号1)遺伝子に基づく発現カセットに置換した。加えて、分泌型アルカリフォスファターゼ遺伝子(SEAP)を発現するChAdベクター及びPanAdベクターを、中和アッセイのために構築した。ベクターを293細胞中で増殖させて、標準的なプロトコルに従ったCsCl勾配によって精製した。
PanAd1ゲノムを使用して、PanAd1、PanAd2及びPanAd3の全ゲノムの相同組換えによるクローニングのためのシャトルベクターを構築した。簡潔に述べると、ボノボアデノウイルス1のクローニングに使用されるシャトルベクター(本明細書中でpBAd1RLD_EGFPと称される)を以下のように構築した:
PanAd1左端(nt 1〜nt 450)を、SpeI及びEcoRIで消化したオリゴヌクレオチド5’−ATCTGGAATTCGTTTAAACCATCATCAATAATATACCTTATTTTG−3’(配列番号7)及び5’−TCAGGAACTAGTTCCGTATACCTATAATAATAAAACGGAGACTTTG−3’(配列番号8)を用いたPCRによって増幅した後、pBAd1−Lを生成することによってHCMV−EGFP−bgh polyAカセットを既に含有するプラスミドベクターにライゲーションした。次いで、PanAd1右端(nt 37362〜nt 37772)を、オリゴヌクレオチド5’−TCCAGCGGCGCGCCAGACCCGAGTCTTACCAGGA−3’(配列番号9)及び5’−ATTCAGGATCCGAATTCGTTTAAACCATCATCAATAATATACCTTATTTTG−3’(配列番号10)を用いたPCRによって増幅し、pBAd1−Lにクローニングすることにより、プラスミドpBAd1−RLを作製した。
PanAd1、PanAd2及びPanAd3ベクターを、大腸菌株BJ5183における相同組換えによって構築した。BJ5183細胞を、PanAd1、PanAd2及びPanAd3の精製ウイルスDNA及びpBAd1RLD−EGFP又はpBAd1RLD−Gagによって同時形質転換させた。pIX遺伝子、線状化pBAd1RLD−EGFP又はpBAd1RLD−Gagの末端に存在する右側のITR DNA配列、及びウイルスゲノムDNAの間の相同組換えでは、発現カセットにより置換されたE1領域を同時に欠失させることによってプラスミドベクターへのその挿入が可能となった。この戦略によって、EGFP又はHIV gag形質導入遺伝子を発現するプレアデノプラスミドpPanAd1、pPanAd2及びpPanAd3の構築が可能となった。次いで、SEAP又はHCV−NS発現カセットを、EGFP又はGag発現カセットを置き換えることによってpPanAd1、pPanAd2及びpPanAd3ベクターにクローニングした。
E3領域の欠失を、大腸菌におけるクローニング及び相同組換えの幾つかの工程を含む戦略を用いることによって、PanAd1、PanAd2及びPanAd3ベクター骨格に導入した。PanAd1 E3欠失は、ゲノムPanAd1配列のヌクレオチド28636からヌクレオチド32596までにわたり(配列番号13)、PanAd2 E3欠失は、ゲノムPanAd2配列のヌクレオチド28653からヌクレオチド32599までにわたり(配列番号62)、PanAd3 E3欠失は、ゲノムPanAd3配列のヌクレオチド28684からヌクレオチド32640までにわたる(配列番号63)。
PanAd1、PanAd2及びPanAd3の固有のE4領域を欠失させ、Ad5 E4 ORF6コード配列(配列番号64)と置き換えた。PanAd1、PanAd2及びPanAd3骨格中に導入されたE4欠失の座標は以下である:
PanAd1 E4欠失は、ヌクレオチド34690から37369までにわたり(配列番号13);
PanAd2 E4欠失は、ヌクレオチド34696から37400までにわたり(配列番号62);
PanAd3 E4欠失は、ヌクレオチド34690から37369までにわたる(配列番号63)。
ChAd55のクローニングのためのシャトルベクターの構築
ChAd55シャトルを、PanAdベクターについて上記で記載したものと同じ戦略に従うことによって構築した後、ChAd55ウイルスゲノムのクローニングに使用した。この目的で、ウイルスゲノムの右端及び左端を含有するシャトルベクターpARS ChAd55(ITR遺伝子からpIX遺伝子までの左端からE1領域を欠失させ、発現カセットで置換した)を、AscI制限酵素で線状化し、ChAd55精製ウイルスDNAと共に大腸菌株BJ5183に同時形質転換した。pIX遺伝子から、線状化pARS ChAd55及びChAd55、ChAd73、ChAd83、ChAd146及びChAd147精製ウイルスゲノムDNAの末端に存在する右側のITRまでのDNA配列間の相同組換えによって、E1領域を同時に欠失させることによるプラスミドベクターへのそれらの挿入が可能となった。チンパンジーアデノウイルス55(ChAd55)ゲノムのクローニング戦略の図を図4に提示する。
ChAd55、ChAd73、ChAd83、ChAd146、ChAd147、PanAd1、PanAd2及びPanAd3ベクターの潜在的組換えワクチンとしての有効性を、マウスにおいてHIV gag形質導入遺伝子を発現するベクターを用いて評価した。ChAd55 gagのベクター効力を、並行して行った免疫化実験においてヒトAd5 gagと比較した。10匹の動物の群について、大腿四頭筋に108vp/マウスのベクター用量でAd5 gag又はChAd55 gagを注射した(図5A)。別個の実験においては、5匹の動物の群に、108vp/マウスのベクター用量でAd5 gag又はPanAd1 gag、PanAd2 gag及びPanAd3 gagを注射した(図5B)。ChAd73 gag、ChAd83 gag、ChAd146 gag及びChad147 gagの効力を、ChAd55 gagと並行して、5匹のマウスの群を108vp/マウスのベクター用量で免疫化することによって同様に決定した(図5C)。HIV gagに対して引き起こされる免疫応答を、脾細胞に対するインターフェロン−γ Elispotアッセイによって測定した。ヒトAd5 gagベクターと比較した、ChAd55、ChAd73、ChAd83、ChAd146、ChAd147、並びにPanAd1、PanAd2及びPanAd3を用いた免疫化実験の結果から、本発明の新規のアデノウイルスが、特異的免疫応答を引き起こす上で、従来技術の組換えアデノウイルスAd5と少なくとも同程度効果的であることが示される。
ヒト血清におけるナミチンパンジーアデノウイルス55、73、83、146、147並びにボノボアデノウイルス1型、2型及び3型に対する中和抗体の陽性率を評価するために中和アッセイを行った。このアッセイによって、分泌型アルカリフォスファターゼ(SEAP)遺伝子を運搬して、ヒト293細胞に形質導入するChAd55、ChAd73、ChAd83、ChAd146、ChAd147、PanAd1、PanAd2及びPanAd3の能力に対する血清プレインキュベーションの影響を評価した。中和力価は、血清の非存在下でウイルスを有する陽性対照において観察される、SEAP活性の50%の低減をもたらす血清の希釈率として定義される。各々の血清試料を様々な希釈率(18倍希釈から始め、4倍ずつ増加させて4608倍までの5つ)で試験した。試料を37℃で1時間プレインキュベートした後、96ウェルプレートに播種した293細胞(3×104細胞/ウェル)に添加した。ヒト血清パネルを中和活性について試験した。並行して、同じパネルをAd5、並びにチンパンジー及びボノボAd SEAPベクターについて試験した。結果を図6に提示する。この結果から、チンパンジーアデノウイルスに対する血清陽性率が、ヒトアデノウイルスAd5よりも低いことが示される。しかしながら、概して、既に記載されたChAd(CV−68)に対する中和抗体の存在を、被験体のサブセットにおいて検出することができる。対照的に、これまでに試験された全てのヒト血清は、ChAd55、並びにPanAd1、PanAd2及びPanAd3を非常に低い力価であっても中和することができなかった。同じことがChAd73、ChAd83、ChAd146及びChAd147についても観察された。したがって、新規のアデノウイルス分離株ChAd55、ChAd73、ChAd83、ChAd146、ChAd147、並びにPanAd1、PanAd2及びPanAd3は、一般的なヒトAd血清型(Ad5等)ベースのウイルスベクターの投与を制限する、既存の抗ヒトAd免疫の問題に対する理想的な解決策を示す。
PanAd1ベクター及びPanAd3ベクターの潜在的な組換えワクチンとしての有効性を、BALB/cマウスにおいて単純ヘルペスウイルス(HSV)抗原を発現するベクター及び癌抗原を発現するベクターを用いて評価した。HSV Ag及び癌Agを発現するPanAd1及びPanAd3のベクター効力を、ヒトAd5ベースの対応するベクターと比較した。
3匹のカニクイザルの2つの群を、異種プライム/ブースト計画でCsCl精製PanAd1及びPanAd3を筋肉内注射することによって免疫化した。群1の各々の動物には108vpの用量、群2の動物には1010vpの用量のPanAd3 Gagベクターを、0週目に三角筋に注射した。次いで、13週目に両群の全ての動物を、1010vpのPanAd1 Gagの単回投与によってブーストした。
Claims (21)
- (i)アデノウイルスファイバータンパク質をコードし、かつ以下のものからなる群から選択される単離ポリヌクレオチド:
(a)配列番号53に記載のアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;および
(b)配列番号53のアミノ酸配列と、その全長にわたって少なくとも85%同一なアミノ酸配列を有する機能的誘導体をコードするポリヌクレオチド、
(ii)アデノウイルスヘキソンタンパク質をコードし、かつ以下のものからなる群から選択される単離ポリヌクレオチド:
(c)配列番号54に記載のアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;および
(d)配列番号54に記載のアミノ酸配列と、その全長にわたって少なくとも95%同一なアミノ酸配列を有する機能的誘導体をコードするポリヌクレオチド、ならびに
(iii)アデノウイルスペントンタンパク質をコードし、かつ以下のものからなる群から選択される単離ポリヌクレオチド:
(e)配列番号55に記載のアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド;および
(f)配列番号55のアミノ酸配列と、その全長にわたって少なくとも85%同一なアミノ酸配列を有する機能的誘導体をコードするポリヌクレオチド
を含んでなる、ポリヌクレオチド。 - 以下のものをさらに少なくとも1つ含む、請求項1に記載のポリヌクレオチド:
(a)アデノウイルス5’末端;
(b)アデノウイルスE1a領域、又は13S領域、12S領域及び9S領域の中から選択されるその断片;
(c)アデノウイルスE1b領域、又はスモールT領域、ラージT領域及びIX領域からなる群の中から選択されるその断片;
(d)アデノウイルスE2b領域、又はスモールpTP領域、ポリメラーゼ領域及びIVa2領域からなる群の中から選択されるその断片;
(e)アデノウイルスL1領域、又は28.1kDタンパク質、ポリメラーゼ、アグノタンパク質、52/55kDaタンパク質及びIIIaタンパク質からなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(f)アデノウイルスL2領域、又はVIIタンパク質、Vタンパク質及びMuタンパク質からなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(g)アデノウイルスL3領域、又はVIタンパク質およびエンドプロテアーゼからなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(h)アデノウイルスE2a領域;
(i)アデノウイルスL4領域、又は100kDタンパク質、33kDホモログ及びVIIIタンパク質からなる群から選択されるアデノウイルスタンパク質をコードするその断片;
(j)アデノウイルスE3領域、又はE3 ORF1、E3 ORF2、E3 ORF3、E3 ORF4、E3 ORF5、E3 ORF6、E3 ORF7、E3 ORF8及びE3 ORF9からなる群から選択されるその断片;
(k)アデノウイルスL5領域;
(l)アデノウイルスE4領域、又はE4 ORF7、E4 ORF6、E4 ORF5、E4 ORF4、E4 ORF3、E4 ORF2及びE4 ORF1からなる群から選択されるその断片;及び/又は
(m)アデノウイルス3’末端。 - ポリヌクレオチドが、アデノウイルス5’逆方向末端反復である前記a)アデノウイルス5’末端及び/又はアデノウイルス3’逆方向末端反復である前記(m)アデノウイルス3’末端を含む、請求項2に記載のポリヌクレオチド。
- 配列番号63からなる配列と、又は配列番号63からなるが、配列番号63のゲノム領域E1A、E1B、E2A、E2B、E3及び/又はE4を欠いている配列と、その全長にわたって少なくとも90%同一なポリヌクレオチドからなるか、又はそれらを含む、請求項1に記載のポリヌクレオチド。
- 請求項1に記載の単離ポリヌクレオチドによってコードされる単離アデノウイルスカプシドポリペプチド。
- 請求項1〜4のいずれか一項に記載のポリヌクレオチドを含むベクター。
- ベクターがE1A、E1B、E2A、E2B、E3及びE4からなるゲノム領域の群から選択されるゲノム領域に遺伝子を含まないか、及び/又はE1A、E1B、E2A、E2B、E3及びE4の群から選択されるゲノム領域の少なくとも1つの遺伝子を含み、前記少なくとも1つの遺伝子が、該少なくとも1つの遺伝子を非機能的にする欠失及び/又は突然変異を含む、請求項6に記載のベクター。
- 請求項1〜4のいずれか一項に記載のポリヌクレオチド、及び/又は請求項1の単離ポリヌクレオチド(i)、(ii)または(iii)のいずれかに記載の少なくとも1つのアデノウイルスカプシドポリペプチドを含む組換えアデノウイルスであって、
組換えアデノウイルスが標的細胞への送達のための分子を含む、組換えアデノウイルス。 - 組換えアデノウイルスが複製不全アデノウイルスである、請求項8に記載の組換えアデノウイルス。
- ヒト被験体における血清陽性率が5%未満であり、および/または、哺乳動物細胞に感染することが可能である、請求項8または9に記載の組換えアデノウイルス。
- アデノウイルスがヒト被験体において血清陽性率を有しない、請求項10に記載の組換えアデノウイルス。
- 標的細胞への送達のための分子が、抗原タンパク質又はその断片をコードするポリヌクレオチドである、請求項8〜11のいずれか一項に記載の組換えアデノウイルス。
- アジュバント及び以下の(i)〜(iv)の少なくとも1つを含む組成物:
(i)請求項5に記載のアデノウイルスカプシドポリペプチド;
(ii)請求項1〜4のいずれか一項に記載のポリヌクレオチド;
(iii)請求項6又は7に記載のベクター;
(iv)請求項8〜12のいずれか一項に記載の組換えアデノウイルス。 - 薬学的に許容可能な賦形剤をさらに含んでなる、請求項13に記載の組成物。
- アジュバントが、I型サイトカイン受容体、II型サイトカイン受容体、TNF受容体、転写因子として作用するビタミンD受容体、並びにToll様受容体1(TLR1)、TLR−2、TLR3、TLR4、TLR5、TLR−6、TLR7及びTLR9からなる群から選択される受容体の作動薬である、請求項13または14に記載の組成物。
- アジュバントがToll様受容体4又は9の作動薬である、請求項15に記載の組成物。
- 以下のものの少なくとも1つを含む細胞:
(i)請求項5に記載のアデノウイルスカプシドポリペプチド;
(ii)請求項1〜4のいずれか一項に記載のポリヌクレオチド;
(iii)請求項6又は7に記載のベクター;
(iv)請求8〜12のいずれか一項に記載の組換えアデノウイルス。 - E1a、E1b、E2a、E2b、E4、L1、L2、L3、L4及びL5からなる群から選択されるアデノウイルス遺伝子を少なくとも1つ発現する宿主細胞である、請求項17に記載の細胞。
- 疾患の治療又は予防に用いるための、請求項5に記載の単離アデノウイルスカプシドポリペプチド;請求項1〜4のいずれか一項に記載のポリヌクレオチド;請求項6又は7に記載のベクター;請求項8〜12のいずれか一項に記載の組換えアデノウイルス;及び/又は請求項15または16に記載の組成物を含んでなる、医薬組成物。
- 疾患の治療又は予防がワクチン接種である、請求項19に記載の医薬組成物。
- 疾患の治療が遺伝子療法である、請求項20に記載の医薬組成物。
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