JP6230527B2 - サルアデノウイルス及び雑種アデノウイルスベクター - Google Patents
サルアデノウイルス及び雑種アデノウイルスベクター Download PDFInfo
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Description
(a)配列番号1の18302ないし21130番目のヌクレオチドか、これと実質的に同一の配列と、
(b)配列番号1の13891ないし15486番目のヌクレオチドか、これと実質的に同一の配列と、
(c)配列番号1の32290ないし33621番目のヌクレオチドか、これと実質的に同一の配列とからなるグループから選択される、1本以上のヌクレオチド配列を含むことが好ましい。
(a)配列番号2のアミノ酸配列を含むヘクソンタンパク質をコードするヌクレオチド配列又はこれと少なくとも98.2%の同一性がある配列か、配列番号1の18302ないし21130番目のヌクレオチドにコードされるタンパク質と少なくとも98.2%の同一性がある配列を有するヘクソンタンパク質をコードするヌクレオチド配列かと、
(b)配列番号3のアミノ酸配列を含むペントンタンパク質をコードするヌクレオチド配列又はこれと少なくとも98.3%の同一性がある配列か、配列番号1の13891ないし15486番目のヌクレオチドにコードされるタンパク質と少なくとも98.3%の同一性がある配列を有するペントンタンパク質をコードするヌクレオチド配列かと、
(c)配列番号4のアミノ酸配列を含む線維タンパク質をコードするヌクレオチド配列又はこれと少なくとも99.1%の同一性がある配列か、配列番号1の32290ないし33621番目のヌクレオチドにコードされるタンパク質と少なくとも99.1%の同一性がある配列を有する線維タンパク質をコードするヌクレオチド配列かとからなるグループから選択される、1本以上のヌクレオチド配列をも含む場合がある。
(a)配列番号2のアミノ酸配列又はこれと実質的に同一な配列を含むヘクソンタンパク質と、
(b)配列番号3のアミノ酸配列又はこれと実質的に同一な配列を含むペントンタンパク質と、
(c)配列番号4のアミノ酸配列又はこれと実質的に同一な配列を含む線維タンパク質とからなるグループから選択される1種類以上のカプシドタンパク質を含む。
i)前記ウイルスヌクレオチド配列を挟む左右の挟み込み領域(flank)と相同性のある領域を含むBACレスキューベクターを構築するステップと、
ii)前記BACレスキューベクターを線状化するステップと、
iii)前記ウイルスヌクレオチド配列を前記BACレスキューベクターに取り込むために、前記ウイルスヌクレオチド配列と、線状化され前記BACレスキューベクターとの間の相同組換えを宿主細胞内で行わせるステップとを含む。
(a)BAC骨格と
(b)本発明の第5の局面のポリヌクレオチド配列とを含むことが好ましい。
本明細書に説明されるとおり、ベクターAdChOX1は、チンパンジーアデノウイルスY25に由来し、E1領域及びE3領域の欠失と、E4領域の改変と、TIPeGFPモデル抗原のE1遺伝子座への挿入とを有する。前記BACを含む大腸菌はクラスI遺伝子改変生物である。
野生型チンパンジーアデノウイルスAdY25は、スウェーデン、Umea大学のGoran Wadellから入手された。前記ウイルスはHEK293細胞内で高力価で増殖され、ウイルスDNAは、フェノール抽出され、配列決定された。野生型AdY25ウイルスのヌクレオチド配列は配列番号1に示される。配列データにもとづいて、ウイルスゲノムの右側及び左側の挟み込み領域(flanks、ウイルスDNAからPCR法で増幅された)と相同性のある領域を含むBAC「レスキューベクター」が構築された。それから、ウイルスゲノムをBACベクターに取り込むために、相同組換えが、ウイルスDNAと、線状化されたレスキューベクターとの間でBJ5183大腸菌細胞内で実行された。
実施例1にしたがって生成されたΔE1 Ad−BACベクターゲノムは、アデノウイルスE3領域を欠失されて、新規ベクターの挿入容量を約5kb増大させるために、GalK組換えを用いてさらに改変された。
i)E4領域の改変
実施例2にしたがって作製されたΔE1ΔE3Ad−BACベクターゲノムのE4遺伝子座が改変された。E4領域は、ベクターゲノムと、E4遺伝子のいずれかの側に50bpの相同領域により挟まれた、PCR増幅されたGalKカセットとの間の組換えによりSW102大腸菌細胞中で欠失された。組換え細胞はガラクトースのみを含む最小培地を用いて選択された。その後、図3−Cに列挙される5個のコンストラクトを提供するために同様のやり方で、GalK遺伝子はAdHu5及びAdY25由来の必要なE4オープン・リーディング・フレームと置換された。GalK遺伝子のかわりに前記遺伝子を含む組換え細胞は、2−デオキシガラクトース(DOG)を含む培地を用いて選択された(Warmingら、Nuc. Acid. Res, 2005, Vol33;4)。
HEK293細胞は、感染多重度9で以下のウイルスベクターに感染させられ、回収まで37℃48時間インキュベーションされた。
i) AdHu5(Ad5)
ii) AdY25 E4野生型(Y25E4wt)
iii) AdY25 E4 AdHu5 E4Orf6(Y25Ad5E4Orf)
iv) AdY25 E4 AdHu5 E4Orf4、6、6/7(AdChOX1)
ワクチンベクターの免疫原性及び有効性を評価するためには、ウイルスの感染力価を定量する信頼性の高い方法を開発することが必須である。従来は、HEK293細胞におけるプラークアッセイが選択すべき方法であったが、これらは長いインキュベーション期間を要し、力価のつじつまがあわないことがしばしばある。さらに、プラークアッセイは内在的に敏感でなく、全ての感染性ビリオンがプラーク形成を誘導するわけではない。1つの方法は、ウイルス感染した細胞の数を定量することを伴う簡便な、単細胞感染性アッセイである。最初の組換えAdY25由来ウイルスベクターは緑蛍光タンパク質(GFP)を発現し、細胞内で組換え外来遺伝子発現を開始したウイルスを蛍光顕微鏡により直接視覚化できる。しかし、ワクチン抗原コンストラクトが蛍光マーカー遺伝子をもたないとき、例えば、ワクチン抗原コンストラクトが臨床用であるとき、細胞の感染性を評価する代替的な方法が使われなければならない。
TIPeGFPを発現するChAdOX1ウイルスベクターのヘクソン力価に対するマーカー遺伝子の比が、蛍光検出の感度を制御するために、GFP及びmCherry蛍光外来遺伝子を用いて測定された。
AdC63及びAdC68に比肩する免疫原性がAdY25系ベクターを用いてマウスで得ることができたかを決定するために、モデル抗原TIPeGFPを用いて評価された。
i)Adch63
ii)ΔE1ΔE3AdCh68、及び
iii)ChAdOX1
2種類の異なるE4の改変がAdY25系ベクターに及ぼす影響が以下のコンストラクトを用いて評価された。
(i) AdY25 E4野生型(E4wt)
(ii) AdY25 E4 AdHu5 E4Orf6(E4Orf6)
(iii) AdY25 E4 AdHu5 E4Orf4/6/7(E4Orf4/6/7)
英国及びガンビア由来のヒト血清中のAdY25系ベクター及びAdCh63系ベクターに対する中和抗体の陽性率が評価された。
Balb/cマウス(群あたり6匹)が、両方ともTIPeGFPを発現する以下のベクターのいずれかの108感染単位で免疫された。
i)ΔE1ΔE3AdCh68、又は
ii)ChAdOX1
実施例1で説明されたBAC技術を用いて、結核菌タンパク質Ag85Aをコードする外来遺伝子がChAdOX1のE1遺伝子座にヒトサイトメガロウイルス前初期プロモーターの制御下で挿入された。外来遺伝子のヌクレオチド配列(配列番号42)は、前記抗原の1ないし323番目の残基をコードし、ヒトコドン使用頻度に最適化された配列(103ないし1071番目のヌクレオチド)によりコードされ、N末端でt−PA(ヒト組織型プラスミノゲン・アクチベーター由来シグナルペプチドで、1ないし102番目のヌクレオチド)に融合され、C末端でPKタグ(1072ないし1104番目のヌクレオチド)に融合された。Ag85A抗原のアミノ酸配列は配列番号43に提供される。
実施例1で説明されたBAC技術を用いて、インフルエンザA型ウイルスの核タンパク質(NP)及びマトリックスタンパク質1(M1)をコードする外来遺伝子がChAdOX1のE1遺伝子座にヒトサイトメガロウイルス主要前初期プロモーターの制御下で挿入された。前記外来遺伝子(配列番号46)のヌクレオチド配列は、インフルエンザA型マトリックスタンパク質1(1516ないし2274番目のヌクレオチド)に、リンカー(1495ないし1515番目のヌクレオチド)で隔てられて融合された核タンパク質(1ないし1494番目のヌクレオチド)をコードする。NPM1融合タンパク質のアミノ酸配列は配列番号47に提供される。
1.Buchbinder et al, Lancet, Vol 372, Nov 2008
2.Farina et al, J. Virol, Dec 2001, p11603-11613
3.Dudareva et al, Vaccine 27, 2009, 3501-3504
4.R. Wigand et al, Intervirology, Vol30; 1 1989
5.Roy et al, Hum. Gen. Ther., 2004, 15:519-530
6.Warmingら、Nuc. Acid. Res, 2005, Vol33;4
7.http://www.invitrogen.com/gateway
8.Havenga et al, J.G.V., 2006, 87, 2135-214
9.Warming, S. et al. Nucleic Acids Res, 2005, Feb 24; 33(4): e36
Claims (29)
- カプシドを含むアデノウイルスベクターであって、前記カプシドは、野生型チンパンジーアデノウイルスAdY25由来の1種類以上のカプシドタンパク質を含み、かつ核酸分子をカプシド封入しており、該核酸分子は、動物細胞内での翻訳、転写及び/又は発現を制御する発現制御配列に動作可能に連結された目的外来ヌクレオチド配列と、アデノウイルスパッケージングシグナル配列とを含み、前記野生型チンパンジーアデノウイルスAdY25をコードするヌクレオチド配列が配列番号1である、アデノウイルスベクター。
- 機能のあるE1遺伝子座を欠く、請求項1記載のベクター。
- 前記ベクターはE3遺伝子座を欠く、請求項1又は2記載のベクター。
- 別のアデノウイルス血清型由来の少なくとも1個の異種E4オープン・リーディング・フレームを含む、請求項1から3いずれか1項記載のベクター。
- 原種E4遺伝子座を欠き、別のアデノウイルス血清型由来の異種E4遺伝子座又はそのオープン・リーディング・フレームを含む、請求項1記載のベクター。
- 原種E4遺伝子座を欠き、AdHu5由来のE4Orf6のコーディング領域を含む、請求項5記載のベクター。
- 前記E4遺伝子座は、原種E4Orf1、E4Orf2及びE4Orf3のコーディング領域と、AdHu5由来の異種E4Orf4、E4Orf6及びE4Orf6/7のコーディング領域とを含む、請求項4記載のベクター。
- 前記目的外来ヌクレオチド配列は、タンパク質又はポリペプチドをコードする、請求項1から7いずれか1項記載のベクター。
- 前記タンパク質又はポリペプチドは、抗原、分子アジュバント、免疫刺激性タンパク質及びリコンビナーゼを含む群から選択される、請求項8記載のベクター。
- 前記目的外来ヌクレオチド配列は、miRNA又は免疫刺激性RNA配列である、請求項1から9いずれか1項記載のベクター。
- 前記カプシドは、
(a)配列番号2のアミノ酸配列を含むAdY25ヘクソンタンパク質、
(b)配列番号3のアミノ酸配列を含むAdY25ペントンタンパク質、および
(c)配列番号4のアミノ酸配列を含むAdY25線維タンパク質、
よりなる群から選択される1種類以上のカプシドタンパク質を含む、請求項1から9いずれか1項記載のベクター。 - 請求項1から11いずれか1項記載のアデノウイルスベクター、ならびに、任意的に、1種類以上の追加の活性成分、薬学的に許容される担体、希釈剤、賦形剤又はアジュバントを含む、免疫原組成物。
- 医学で使用するための請求項12記載の免疫原組成物。
- 医学で使用するための薬剤の製造における、請求項12記載の免疫原組成物の使用。
- 前記医学での使用は、外来遺伝子を宿主細胞内に送達することを含む、請求項13記載の免疫原組成物又は請求項14記載の使用。
- 前記医学での使用は、動物における免疫応答を誘発することを含む、請求項13記載の免疫原組成物又は請求項14記載の使用。
- 前記医学での使用は、動物において免疫応答をブーストすることを含む、請求項13記載の免疫原組成物又は請求項14記載の使用。
- 前記医学での使用は、少なくとも1つの疾患を治療又は予防することを含む、請求項13記載の免疫原組成物又は請求項14記載の使用。
- 前記医学での使用は、自己抗原に対するトレランスを破る免疫応答を動物において誘導することを含む、請求項13記載の免疫原組成物又は請求項14記載の使用。
- 前記医学での使用は遺伝子治療を含む、請求項13記載の免疫原組成物又は請求項14記載の使用。
- 請求項1から11いずれか1項記載のウイルスベクターをコードする配列を有するポリヌクレオチド。
- 請求項1から11いずれか1項記載のウイルスベクターで形質導入された宿主細胞。
- 請求項1から11いずれか1項記載のウイルスベクターを製造する方法。
- 請求項21記載のポリヌクレオチドを、細菌人工染色体(BAC)に組み込んで、Ad−BACベクターを作製するステップを含む、請求項23記載の方法。
- 請求項21記載のポリヌクレオチド配列を含む、細菌人工染色体(BAC)クローン。
- 請求項1から11いずれか1項記載のウイルスベクターを製造するパッケージング細胞株。
- 請求項1から11いずれか1項記載のウイルスベクターにおいて機能的に欠失する遺伝子の相補体を含む、請求項26記載のパッケージング細胞株。
- 配列番号1の全長にわたってその配列と少なくとも98%同一の配列を有する、単離核酸分子。
- 請求項28記載の配列と相補的な配列を有する単離核酸分子。
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GB201108879D0 (en) | 2011-07-06 |
EP3321367B1 (en) | 2021-09-29 |
BR112013030222A2 (pt) | 2016-12-06 |
CN103930551A (zh) | 2014-07-16 |
JP2014516536A (ja) | 2014-07-17 |
EP2714916A1 (en) | 2014-04-09 |
RU2013152648A (ru) | 2015-06-27 |
EP3321367A2 (en) | 2018-05-16 |
CN103930551B (zh) | 2017-05-24 |
FR21C1026I1 (fr) | 2021-08-06 |
US20240181078A1 (en) | 2024-06-06 |
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CA2837274A1 (en) | 2012-12-20 |
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