JP7144481B2 - Dna配列をコードするポリ(a)配列の安定化 - Google Patents
Dna配列をコードするポリ(a)配列の安定化 Download PDFInfo
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- JP7144481B2 JP7144481B2 JP2020084559A JP2020084559A JP7144481B2 JP 7144481 B2 JP7144481 B2 JP 7144481B2 JP 2020084559 A JP2020084559 A JP 2020084559A JP 2020084559 A JP2020084559 A JP 2020084559A JP 7144481 B2 JP7144481 B2 JP 7144481B2
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Description
(a)プロモーター;
(b)転写可能な核酸配列または転写可能な核酸配列を導入するための核酸配列;および
(c)プロモーター(a)の制御下で転写された場合、転写産物において少なくとも80個の連続するヌクレオチドのヌクレオチド配列をコードする核酸配列であって、転写産物中の少なくとも80個の連続するヌクレオチドの前記ヌクレオチド配列が、ポリアデニル配列内に、Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの配列を含むポリアデニル配列である、核酸配列
を含む核酸分子に関する。
(i)本発明の核酸分子を提供すること、および
(ii)前記核酸分子を大腸菌中で増殖させること
を含む、核酸分子を増殖させる方法に関する。
(i)核酸分子を増殖させる本発明の方法に従って核酸分子を増殖させること、および
(ii)前記核酸分子を鋳型として使用してRNAをインビトロ転写すること
を含む、RNAを得る方法に関する。
(i)RNAを得る本発明の方法に従って前記ペプチドまたはタンパク質をコードするmRNAを得ること、および
(ii)mRNAを翻訳すること
を含む方法に関する。
ポリ(dA:dT)領域を有するプラスミドDNAを担持する96個の大腸菌クローンを採取し、96ウェルプレートの1.4mL中に14~16時間接種した(37℃、225rpm)。細菌培養懸濁液を採取し、Nucleospin 96well kit(Macherey & Nagel)を製造者のプロトコルに従って使用してプラスミドDNAを精製した。プラスミドDNA濃度を紫外分光法(Nanodrop 2000,Thermo Scientific)によって測定した。ポリ(dA:dT)の完全性をSacI制限分析(New England Biolabs)によって判定した。生じたフラグメントを自動キャピラリーゲル電気泳動(Qiagen)で分離した。
5’末端 5’--P-NNNNNNN-OH-3’ 3’末端
3’-HO-NNNNNNN-P--5’
以下、参考形態の例を付記する。
1. 転写の5’→3’方向に、
(a)プロモーター;
(b)転写可能な核酸配列または転写可能な核酸配列を導入するための核酸配列;および
(c)前記プロモーター(a)の制御下で転写された場合、転写産物において少なくとも80個の連続するヌクレオチドのヌクレオチド配列をコードする核酸配列であって、前記転写産物中の少なくとも80個の連続するヌクレオチドの前記ヌクレオチド配列が、ポリアデニル配列内に、Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの配列を含む前記ポリアデニル配列である、核酸配列
を含む核酸分子。
2. Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、2つ以上の連続する、ヌクレオチドの配列、好ましくは恣意的な配列であり、2つ以上の連続するヌクレオチドの前記配列の最初と最後のヌクレオチドがAヌクレオチド以外のヌクレオチドである、1.に記載の核酸分子。
3. 前記核酸配列(c)が、前記核酸配列(c)の代わりに、前記プロモーター(a)の制御下で転写された場合、転写産物において少なくとも80個の連続するヌクレオチドの前記ヌクレオチド配列と同じ長さのポリアデニル配列をコードする核酸配列(c)’を含む核酸分子と比較して、大腸菌での前記核酸分子の増殖時により高い安定性を示す、1.または2.に記載の核酸分子。
4. 少なくとも80個の連続するヌクレオチドの前記ヌクレオチド配列が、少なくとも90個のヌクレオチド、好ましくは少なくとも100個のヌクレオチドを含む、1.から3.のいずれか一つに記載の核酸分子。
5. Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、前記ポリアデニル配列の21位から80位まで、好ましくは21位から60位まで、より好ましくは31位から50位までの領域内に位置する、1.から4.のいずれか一つに記載の核酸分子。
6. Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列に、前記ポリアデニル配列中の少なくとも20個のA残基が先行するおよび/または前記ポリアデニル配列中の少なくとも20個のA残基が続く、1.から5.のいずれか一つに記載の核酸分子。
7. Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、少なくとも3個、少なくとも4個、少なくとも5個、少なくとも6個、少なくとも8個、好ましくは少なくとも10個、より好ましくは少なくとも15個のヌクレオチドの長さを有する、1.から6.のいずれか一つに記載の核酸分子。
8. Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、50個未満、好ましくは30個未満、より好ましくは20個未満のヌクレオチドの長さを有する、1.から7.のいずれか一つに記載の核酸分子。
9. Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、3個より多い連続するA残基を含まず、好ましくは2個以下の連続するA残基を含み、好ましくは連続するA残基を全く含まない、1.から8.のいずれか一つに記載の核酸分子。
10. 前記プロモーター(a)の制御下の前記核酸配列(b)および(c)が、転写されて共通の転写産物を与えることができる、1.から9.のいずれか一つに記載の核酸分子。
11. 前記転写産物において少なくとも80個の連続するヌクレオチドの前記ヌクレオチド配列が3’末端に位置する、1.から10.のいずれか一つに記載の核酸分子。
12. 閉環状分子または直鎖状分子である、1.から11.のいずれか一つに記載の核酸分子。
13. 前記転写可能な核酸配列がペプチドまたはタンパク質をコードする核酸配列を含み、および転写可能な核酸配列を導入するための前記核酸配列がマルチクローニングサイトである、1.から12.のいずれか一つに記載の核酸分子。
14. (i)レポーター遺伝子;(ii)選択マーカー;および(iii)複製起点から成る群より選択される1つ以上の成員をさらに含む、1.から13.のいずれか一つに記載の核酸分子。
15. 特に線状化後に、RNA、特にmRNAのインビトロ転写に適する、1.から14.のいずれか一つに記載の核酸分子。
16. 1.から15.のいずれか一つに記載の核酸分子を鋳型として使用して、転写によって、好ましくはインビトロ転写によって得られるRNA。
17. 核酸分子を増殖させる方法であって、
(i)1.から15.のいずれか一つに記載の核酸分子を提供する工程、および
(ii)前記核酸分子を大腸菌中で増殖させる工程
を含む方法。
18. 大腸菌中で前記核酸分子を増殖させる工程が、前記核酸分子で大腸菌を形質転換する工程および前記形質転換した大腸菌を培養する工程を含む、17.に記載の方法。
19. 増殖後に大腸菌から前記核酸分子を単離する工程をさらに含む、17.または18.に記載の方法。
20. RNAを得る方法であって、
(i)17.から19.のいずれか一つに記載の方法に従って核酸分子を増殖させる工程、および
(ii)前記核酸分子を鋳型として使用してRNAをインビトロ転写する工程
を含む方法。
21. ペプチドまたはタンパク質を得る方法であって、
(i)20.に記載の方法に従って前記ペプチドまたはタンパク質をコードするmRNAを得る工程、および
(ii)前記mRNAを翻訳する工程
を含む方法。
22. 前記核酸分子の転写の前に、前記核酸分子の切断をさらに含む工程を特徴とする、20.または21.に記載の方法。
23. 宿主細胞をトランスフェクトするための、16.に記載のRNAの使用。
24. 前記宿主細胞が抗原提示細胞、特に樹状細胞、単球またはマクロファージである、23.に記載の使用。
25. ワクチン接種のための、16.に記載のRNAの使用。
ポリ(dA:dT)安定性に関する半自動スクリーニング
個々の大腸菌クローンによって担持されるプラスミド上にコードされる重要なポリ(dA:dT)配列領域の完全性に関して多数の大腸菌クローンをスクリーニングするため、半自動工程を確立した。1つの特定のポリ(dA:dT)構築物のスクリーニングのために、96個の大腸菌クローンを96ウェルプレート中37℃で接種し、インキュベートした。細胞を遠心分離によって採取し、96ウェルプレートの減圧に基づく精製プラットフォームでプラスミドを精製した。試験したプラスミドDNAは3つのSacI制限部位を含み、ベクターを3-UTR(3’非翻訳領域)内で2回およびポリ(dA:dT)配列の下流で1回切断した。SacI制限は、常に142bpと270bpのサイズの2つの特異的バンドをもたらし、ポリ(dA:dT)の長さの計算を可能にした。3番目のバンドは、ベクター骨格および挿入された抗原(GOI=対象とする遺伝子)に依存するサイズの抗原を表した。制限部位の位置およびフラグメントの長さを含む例示的なベクターマップを図1Bに示す。
種々のポリ(dA:dT)構築物の安定性試験
モデル抗原としてSIINFEKLペプチドを選択した。その理由は、以前の実験でこの抗原のポリ(dA:dT)不安定性が再現可能に50~60%と測定され、それゆえ安定性試験のために大きな実験ウィンドウを提供するからである。10個の異なるポリ(dA:dT)構築物を設計し、SIINFEKLペプチドの後に直接融合した。10個のヌクレオチドリンカー(L)をポリ(dA:dT)配列の異なる位置でポリ(dA:dT)ストレッチに挿入した。リンカー配列(GCATATGACT)は、4個すべてのヌクレオチド(2×G、2×C、3×Tおよび3×A)のバランスの取れた寄与を含むように選択した。4つの構築物を、ポリ(dA:dT)の中央にリンカーを配置し、各々の側で45個のアデノシン残基(45×A)から出発して(A45L45)、両側に5×Aを段階的に増加し、リンカーの各々の側の60×Aで終了する(それぞれA50L50、A55L55およびA60L60)ように設計した。
種々の大腸菌株におけるポリ(dA:dT)構築物の安定性
さらなる実験では、構築物A30L70およびA40L60の卓越した安定性の特異性と機能性を試験した。安定性試験で認められた結果が試験した大腸菌株TOP10に限定されるという可能性を、他の2つの大腸菌株を試験に含めることによって評価した。A30L70およびA40L60についての試験を、DH5α、XL1-blueおよびTOP10を対照として用いてそれぞれ反復した。これらの菌株は、i)高い遺伝的多様性を有する(表2参照)およびii)分子生物学研究室において広く使用されている大腸菌株を代表する、として選択した。
種々のポリ(A)尾部の機能的インビトロ特徴付け
同定された安定化ポリ(A)尾部A30L70およびA40L60の、RNA分子の機能性への影響を明らかにするため、ルシフェラーゼレポーターに基づく実験を実施した。構築物A30L70、A40L60およびA120をホタルルシフェラーゼレポーター遺伝子に融合し、それぞれのメッセンジャーRNAをインビトロ転写によって作製した。RNA分子は同等の完全性を示し、これらを細胞電気穿孔に使用した(表3参照)。RNAを、関連のmRNA腫瘍ワクチンアプローチの標的細胞である、ヒト血液から単離したヒト未熟樹状細胞に電気穿孔した。ルシフェラーゼ翻訳を72時間にわたって観測した。3つの異なるmRNA分子はごくわずかの差で等しく発現された(図4A)。一般的なmRNAの機能性がポリ(A)尾部の性質によって影響されないことを証明するため、ヒト線維芽細胞株(CCD細胞)およびマウス筋芽細胞株(C2C12)において実験を反復した(図4Bおよび図4C)。mRNA翻訳の細胞型特異的パターンを経時的に観測したが、ヒトまたはマウス細胞株のいずれもが、異なるポリ(A)尾部を含むmRNAによるタンパク質発現の相違を示さなかった。
種々のポリ(A)尾部の機能的インビボ特徴付け
ワクチン接種のためのmRNAの全身的インビボ適用のために、RNAを脂質と共に製剤することによってRNAリポプレックスを作製し、静脈内投与した。RNAリポプレックスは、脾臓を標的とし、それぞれのmRNAを翻訳する未熟樹状細胞によって取り込まれるように作製されている。インビボでの機能性タンパク質発現を確実にするためにマウス実験において2つの安定化ポリ(A)尾部、すなわちA30L70とA40L60を試験することを目的とした。A120を有するRNAを発現対照として使用した。各5匹の動物のBALB/cマウスの3つの群に、種々のポリ(A)尾部(A30L70、A40L60およびA120)を有する機能的インビトロ試験に使用したRNA(表3)をコードするホタルルシフェラーゼを含有するRNA-リポプレックスを静脈内注射した。インビボ生物発光イメージングシステムを用いて48時間にわたってホタルルシフェラーゼ発現を観測した(図5A)。累積ルシフェラーゼシグナルの定量化を図5Bに示す。ルシフェラーゼシグナルの位置または強度のいずれもが、異なるポリ(A)尾部を有するRNAの間で有意に異ならず、両方の安定化ポリ(A)尾部が全身的インビボ適用に適することを証明した。
種々のポリ(A)尾部に対する免疫学的応答
最後のセットの実験では、安定化ポリ(A)尾部、A30L70およびA40L60が、mRNAワクチンによって誘導される特異的免疫応答に影響を及ぼすかどうかを評価した。それゆえ、安定化ポリ(A)尾部および対照A120を先の安定性試験に関してのSIINFEKLペプチドに融合した。ポリ(A)尾部A30L70、A40L60およびA120を含む3つのRNAをインビトロ転写によって作製し、これらのRNAは同等の品質と完全性を示した(表4)。C57/BL6マウスの3つの群に、各々5匹の動物で2回、0日目と3日目に種々のSIINFEKL RNAを含むRNA-リポプレックスを2組ずつ静脈注射した。抗原特異的CD8+ T細胞の頻度を最後の免疫の5日後(8日目)にSIINFEKL-MHC四量体染色によって測定することにより、RNA誘導性免疫応答を分析した。FACS分析によるそれぞれのゲーティング戦略を図6Aに示す。抗原特異的CD8+ T細胞頻度の比較は、試験したすべてのポリ(A)尾部を有するRNAが免疫応答を誘導することを示した。それにより、同じ群内(各RNAについて2×5匹の動物)または異なるIVT RNAを摂取した3つの群間のいずれにおいても有意差は検出されず、安定化ポリ(A)尾部がmRNAによって誘導される特異的免疫応答に影響を及ぼさないことが実証された(図6B)。
Claims (23)
- 転写の5’→3’方向に、
(a)プロモーター;
(b)転写可能な核酸配列または転写可能な核酸配列を導入するための核酸配列;および
(c)前記プロモーター(a)の制御下で転写された場合、転写産物において少なくとも80個の連続するヌクレオチドのヌクレオチド配列をコードする核酸配列であって、前記転写産物中の少なくとも80個の連続するヌクレオチドの前記ヌクレオチド配列が、ポリアデニル配列内に、Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの配列を含む前記ポリアデニル配列である、核酸配列を含み、
3個から50個のヌクレオチドの長さを有するAヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列に、前記ポリアデニル配列中の少なくとも20個のA残基が先行する、および前記ポリアデニル配列中の少なくとも20個のA残基が続き、
前記核酸配列(c)が、前記核酸配列(c)の代わりに、前記プロモーター(a)の制御下で転写された場合、転写産物において少なくとも80個の連続するヌクレオチドの前記ヌクレオチド配列と同じ長さのポリアデニル配列をコードする核酸配列(c)’を含む核酸分子と比較して、大腸菌での前記核酸分子の増殖時により高い安定性を示す、
核酸分子。 - Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、2つ以上の連続するヌクレオチドの配列であり、2つ以上の連続するヌクレオチドの前記配列の最初と最後のヌクレオチドがAヌクレオチド以外のヌクレオチドである、請求項1に記載の核酸分子。
- 少なくとも80個の連続するヌクレオチドの前記ヌクレオチド配列が、少なくとも90個のヌクレオチド、又は少なくとも100個のヌクレオチドを含む、請求項1または2に記載の核酸分子。
- Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、前記ポリアデニル配列の21位から80位まで、21位から60位まで、又は31位から50位までの領域内に位置する、請求項1から3のいずれか一項に記載の核酸分子。
- Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、少なくとも3個、少なくとも4個、少なくとも5個、少なくとも6個、少なくとも8個、少なくとも10個、又は少なくとも15個のヌクレオチドの長さを有する、請求項1から4のいずれか一項に記載の核酸分子。
- Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、30個未満、又は20個未満のヌクレオチドの長さを有する、請求項1から5のいずれか一項に記載の核酸分子。
- Aヌクレオチド以外のヌクレオチドを含有する1つ以上の連続するヌクレオチドの前記配列が、3個より多い連続するA残基を含まず、2個以下の連続するA残基を含まず、又は連続するA残基を全く含まない、請求項1から6のいずれか一項に記載の核酸分子。
- 前記プロモーター(a)の制御下の前記核酸配列(b)および(c)が、転写されて共通の転写産物を与えることができる、請求項1から7のいずれか一項に記載の核酸分子。
- 前記転写産物において少なくとも80個の連続するヌクレオチドの前記ヌクレオチド配列が3’末端に位置する、請求項1から8のいずれか一項に記載の核酸分子。
- 閉環状分子または直鎖状分子である、請求項1から9のいずれか一項に記載の核酸分子。
- 前記転写可能な核酸配列がペプチドまたはタンパク質をコードする核酸配列を含み、および転写可能な核酸配列を導入するための前記核酸配列がマルチクローニングサイトである、請求項1から10のいずれか一項に記載の核酸分子。
- (i)レポーター遺伝子;(ii)選択マーカー;および(iii)複製起点から成る群より選択される1つ以上の成員をさらに含む、請求項1から11のいずれか一項に記載の核酸分子。
- RNA、又はmRNAのインビトロ転写に適する、請求項1から12のいずれか一項に記載の核酸分子。
- 請求項1から13のいずれか一項に記載の核酸分子を鋳型として使用して、転写によって、又はインビトロ転写によって得られるRNA。
- 核酸分子を増殖させる方法であって、
(i)請求項1から13のいずれか一項に記載の核酸分子を提供する工程、および
(ii)前記核酸分子を大腸菌中で増殖させる工程
を含む方法。 - 大腸菌中で前記核酸分子を増殖させる工程が、前記核酸分子で大腸菌を形質転換する工程および前記形質転換した大腸菌を培養する工程を含む、請求項15に記載の方法。
- 増殖後に大腸菌から前記核酸分子を単離する工程をさらに含む、請求項15または16に記載の方法。
- RNAを得る方法であって、
(i)請求項15から17のいずれか一項に記載の方法に従って核酸分子を増殖させる工程、および
(ii)前記核酸分子を鋳型として使用してRNAをインビトロ転写する工程
を含む方法。 - ペプチドまたはタンパク質を得る方法であって、
(i)請求項18に記載の方法に従って前記ペプチドまたはタンパク質をコードするmRNAを得る工程、および
(ii)前記mRNAを翻訳する工程
を含む方法。 - 前記核酸分子の転写の前に、前記核酸分子の切断をさらに含む工程を特徴とする、請求項18または19に記載の方法。
- 宿主細胞をトランスフェクトするための、請求項14に記載のRNA。
- 前記宿主細胞が抗原提示細胞、樹状細胞、単球またはマクロファージである、請求項21に記載のRNA。
- ワクチン接種に使用される、請求項14に記載のRNA。
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