JP2011502521A - Hiv−1外被糖タンパク質オリゴマー及び使用方法 - Google Patents
Hiv−1外被糖タンパク質オリゴマー及び使用方法 Download PDFInfo
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Abstract
【選択図】なし
Description
本発明は、以下の連邦政府の助成金:AI37438及びAI64070を得た研究から一部生じたものである。米国政府は本発明の特定の権利を有する。
また、本発明は、抗体の生産を誘導するのに充分な量で本発明の1又は複数のタンパク質、ポリペプチド及び核酸を投与することを含む、対象において抗体を生成する方法も提供する。好ましい実施態様において、方法は、高い効力のある、迅速な交差中和抗体反応を生じる。方法は、HIV−1による感染の治療または予防に用いてもよい。
本発明は、切断していない、膜に結合していない、カルボキシル末端の先端を切り取ったHIV−1のR2Env由来のgp160(すなわちR2gp140)の三量体ドメインへの融合を含む融合ポリペプチド(すなわちR2gp140−三量体ドメイン融合ポリペプチド)を提供する。いくつかの実施態様において、三量体ドメインは、R2gp140のカルボキシル末端に融合している。他の実施態様において、三量体ドメインは、アミノ末端に融合している。
本発明は、R2gp140−三量体ドメイン融合ポリペプチドを含むオリゴマーを提供する。オリゴマーは、2又は3以上のサブユニットで構成されているタンパク質複合体である。オリゴマーは、をタンパク質−タンパク質相互作用によって会合するサブユニットからなる。オリゴマーの各々のサブユニットは、独立して生じたポリペプチドである。オリゴマーは、各々のサブユニットが同じポリペプチドであるサブユニットからなっていてもよい。オリゴマーは、各々のサブユニットが異なるポリペプチドであるサブユニットからなっていてもよい。オリゴマーは、すべてではない、いくつかのサブユニットが、同じポリペプチドであるサブユニットからなっていてもよい。
また、本発明は、R2gp140−三量体ドメイン融合ポリペプチドのアミノ酸配列をコードする核酸も提供する。核酸としては、単一の又は二重鎖の形態のデオキシリボヌクレオチド又はリボヌクレオチド又はそのポリマーが挙げられる。該核酸は、さらに、匹敵する結合特性を有し、天然に存在するヌクレオチドと同様に代謝される天然のヌクレオチドの既知のアナログを含む。当業者であれば、生じるアミノ酸を変化させずにヌクレオチド配列において置換を行うことができることを理解するだろう。核酸は、分子の一次及び二次構造のみを指し、いずれの特定の第3級の形態に制限される。特定の二重鎖DNA分子の構造を論じる場合、配列は、転写されないDNA鎖(例えば、mRNAと相同である配列を有する鎖)に沿って5’〜3’方向での配列のみを与える通常の慣習に従って、本明細書に記載されている。転写及び翻訳の制御配列は、プロモーター、エンハンサー、ポリアデニル化シグナル、ターミネーター、及びそれらと同様のものなどの核酸制御配列である宿主細胞においてコード配列の発現をもたらす。
本明細書における「融合タンパク質」という用語は、gp120及びgp41の動作可能なように結合したコード配列の発現から生じるタンパク質を指す。これらの融合タンパク質は、gp120のC末端の部分が、介在性のインフレームのリンカー配列を介してgp41のN末端の部分に融合しているコンストラクトを含む。
また、本発明は、R2gp140−三量体ドメイン融合ポリペプチドを含む免疫原性の組成物も提供する。免疫原性の組成物は、免疫反応を生じることが可能な組成物である。免疫反応は、組成物の特定の免疫優性の領域に向けられていてもよい。いくつかの実施態様において、R2gp140−三量体ドメイン融合ポリペプチドの会合は、抗体結合のための1の新規のエピトープ又は複数の新規のエピトープを示す。本発明の一実施態様において、R2gp140の免疫優性のV3領域が遮蔽されている。
また、本発明は、HIV−1に対する交差反応を有する免疫反応を誘導する方法も提供する。いくつかの実施態様において、交差反応を有する免疫反応を誘導する方法は、対象に、本発明の融合ポリペプチドを投与することを含む。いくつかの実施態様において、交差反応を有する免疫反応を誘導する方法は、対象に、本発明の免疫原性の組成物を投与することを含む。他の実施態様において、交差反応を有する免疫反応を誘導する方法は、対象に、本発明の融合ポリペプチドをコードする核酸を投与することを含む。更なる実施態様において、本発明の融合ポリペプチドをコードする核酸からなるベクターを投与する。他の実施態様において、本発明の融合ポリペプチドをコードするネイキッドな核酸を投与する。対象への投与の経路は、本技術分野において既知である。例えば、そのような経路としては、経口、直腸、経鼻、局所、非経口、皮下、筋肉内、静脈内及び/又は皮内の経路が挙げられる。
材料及び方法。R2gp140−GCN4をコードする遺伝子をプロモーター改変哺乳類の発現ベクターpcDNA 3.1 Hygro(+) (Invitrogen)に構築した。トランス遺伝子発現レベルを増加させるために、phCMVlベクター(Gelantis)由来の増大させたCMVプロモーターをpcDNA 3.1 Hygro(+)へ導入した。ハイグロマイシン選択マーカーは、通常用いられるジェネテシン(G418)抗生物質に対し耐性があるトランスフェクトした293T細胞の選択を可能にする。変異した切断部位を有するヒトコドンに最適化したR2gp140を、三量体のコイルコイルドGCN4モチーフとC末端で融合した(図5)。この構築は、QuikChange Mutagenesis(Strategene)によって、R2gp140の停止コドンの上流にHind III制限部位を生成することによって、プライマー:フォワード 5’− CTGTGGTACATCAAGAAGCTTTAATAATCTAGAGGG(配列番号7)及びリバース 5 ’ −CCCTCTAGATTATTAAAGCTTCTTGATGTACCACAG (配列番号8) ( Hind III部位を下線で示す)を用いて行った。Hind III部位の横に配置したGCN4断片を、Hind III で消化した R2gp140に連結した。GCN4の正確な方向を、酵素による消化及びDNA配列決定の両方によって確認した。次に、生じたR2gp140−GCN4(配列番号3)を、プロモーター改変pcDNA3.1Hygro(+)にクローン化した。このプラスミドを、pLY−1と称す。図5は、構築されたR2gp140−GCN(配列番号4)の概略を示す。
材料及び方法。精製したR2gp140±GCN4(実施例1に記載されているように製造されたもの)のSuperdex 200 (GE healthcare) column用いるサイズ排除クロマトグラフィーを行った。約1.5mgのタンパク質を、分子量スタンダードでキャリブレーションした Superdex 200 10/300 columで分析して、オリゴマーの種を観測し、異なる種のおよその分子量を評価した。400μlの画分を回収した。10μl及び1μlの各画分を、クーマシーブルーにおけるBNゲルシステム(Invitrogen)及びwestern blot detection (図7及び8)を用いて、製造業者の説明書に従って分析した。ウエスタンブロッティングにおける免疫検出のために、 ポリクローナルウサギ抗gp140血清R2143を用いた。次に、残存するタンパク質を、HiLoad 16/60 Superdex 200 prep grade gel filtration columnにアプライした。
材料及び方法。推定上の三量体及び二量体の画分(実施例2から得られた)をゲルろ過の後に回収した。サンプルの一部を−80°Cで4日間貯蔵し、次いで凍結融解した。凍結融解したサンプルを、BN−PAGE上に、比較のために4℃で貯蔵したサンプルと並べて流した(図9)。
材料及び方法。可溶性オリゴマーのR2gp140糖タンパク質を、減少した(optiMEM、Invitrogen)血清条件の下で安定したHEK293T細胞株培養における発現によって製造した。タンパク質を、レンチルレクチン親和性クロマトグラフィー、Capto−DEAE adsorption及びSuperdex−200 prep grade gel filtration columnを用いるサイズ排除クロマトグラフィーによる最終の分離を用いて、順次精製した。3つのバージョンのR2gp140オリゴマーを示し(図10)、すべて変異している切断部位を有する。WT:野生型の先端を切り取ったgp140;+GCN:C末端にGCN4三量体ドメインを付加したgp140;+リンカー−GCN:gp120及びgp41外部ドメインの間の切断部位の場所にて15aaの可動性リンカーを有し、C末端にGCN4三量体ドメインを付加したgp140。3μgの各々の精製したタンパク質を各レーンにロードした。パネルA(図10):サンプルを還元SDS−PAGEサンプルバッファーで処理し、煮沸し、SDS−PAGEによって分離し、クーマシーで染色した。パネルB(図10):サンプルを処理し、3−12%ブルー・ネイティブPAGE(Invitrogen)を用いて分離した。
材料及び方法。各タイプのR2gp140タンパク質、(WT)R2gl40、R2gp140−GCN(三量体)及びR2gp140−リンカー−GCN(を有する三量体)を、モノクローナル抗体のパネルに加えてCD4についての結合コンピテンスを用いて分析した。R2gp140調製物の質を計測するために、精製したR2gp140調製物を、CD4結合コンピテンス及び立体構造依存的な及び独立したmabsに加えてR2gp140と反応することが知られ、特定のプロフィール(CD4i)mabsを示す特定のmAbsを含むモノクローナル抗体(mAbs)のパネルに対する反応性について調べた。R2gp140オリゴマーは、CD4結合を有するおよび有さないCD4i mabsによって認識される独自の能力を示す一方で、他のgp140株は、CD4i mAbsがgp140(Env)に結合するために、CD4結合を必要とする。
Claims (17)
- 第1のポリペプチドと第2のポリペプチドとを含むHIV−1多数の株に対する交差反応性の中和抗血清の生産を誘導することが可能な融合ポリペプチドであって、第1のポリペプチドが、配列番号2と少なくとも92%の配列同一性を有するアミノ酸配列を含み、第2のポリペプチドが三量体ドメインを含む、融合ポリペプチド。
- 第1のポリペプチドが、配列番号2を含む、請求項1記載の融合ポリペプチド。
- 第1のポリペプチドが、配列番号2を含み、第2のポリペプチドが配列番号6を含む、請求項1記載の融合ポリペプチド。
- 融合ポリペプチドが三量体を形成することが可能である、請求項1記載の融合ポリペプチド。
- 三量体ドメインが配列番号6を含む、請求項1記載の融合ポリペプチド。
- 請求項1記載の融合ポリペプチドを含む、オリゴマーポリペプチド。
- オリゴマーが三量体である、請求項6記載のオリゴマーポリペプチド。
- オリゴマーポリペプチドが相同ポリペプチドを含む、請求項6記載のオリゴマーポリペプチド。
- 融合ポリペプチドがさらに第3のポリペプチドを含む、請求項1記載の融合ポリペプチド。
- 第3のポリペプチドがポリペプチド切断部位を含む、請求項9記載の融合ポリペプチド。
- 融合ポリペプチドが少なくとも1つのリンカー配列を含む、請求項1記載の融合ポリペプチド。
- 請求項1記載の融合ポリペプチドをコードするヌクレオチド配列を含む、核酸分子。
- ヌクレオチド配列が配列番号3を含む、請求項12記載の核酸分子。
- 請求項1記載の融合ポリペプチドと薬剤として受容可能な担体とを含む、免疫原性の組成物。
- さらにアジュバントを含む、請求項14記載の免疫原性の組成物。
- 請求項14記載の組成物を、有効量投与することを含む、ヒト対象においてHIV−1に対する交差反応を有する免疫反応を誘導する方法。
- 請求項1記載の融合ポリペプチドに特異的に結合する抗体又はその抗原結合断片。
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JP2018138581A (ja) * | 2012-07-26 | 2018-09-06 | ザ・ヘンリー・エム・ジャクソン・ファンデイション・フォー・ジ・アドヴァンスメント・オヴ・ミリタリー・メディシン、インコーポレイテッド | 多量体融合タンパク質ワクチン及び免疫療法 |
JP2019522626A (ja) * | 2016-05-02 | 2019-08-15 | ザ スクリプス リサーチ インスティテュート | Hiv−1免疫原に関連した組成物および方法 |
JP2020503839A (ja) * | 2017-11-17 | 2020-02-06 | グリフォルス ダイアグノステック ソリューションズ インコーポレーテッド | 哺乳類で発現した新規なヒト免疫不全ウイルスエンベロープタンパク質抗原 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2018138581A (ja) * | 2012-07-26 | 2018-09-06 | ザ・ヘンリー・エム・ジャクソン・ファンデイション・フォー・ジ・アドヴァンスメント・オヴ・ミリタリー・メディシン、インコーポレイテッド | 多量体融合タンパク質ワクチン及び免疫療法 |
JP2019522626A (ja) * | 2016-05-02 | 2019-08-15 | ザ スクリプス リサーチ インスティテュート | Hiv−1免疫原に関連した組成物および方法 |
JP7046832B2 (ja) | 2016-05-02 | 2022-04-04 | ザ スクリプス リサーチ インスティテュート | Hiv-1免疫原に関連した組成物および方法 |
JP2020503839A (ja) * | 2017-11-17 | 2020-02-06 | グリフォルス ダイアグノステック ソリューションズ インコーポレーテッド | 哺乳類で発現した新規なヒト免疫不全ウイルスエンベロープタンパク質抗原 |
JP2022022308A (ja) * | 2017-11-17 | 2022-02-03 | グリフォルス ダイアグノステック ソリューションズ インコーポレーテッド | 哺乳類で発現した新規なヒト免疫不全ウイルスエンベロープタンパク質抗原 |
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AU2008350273B2 (en) | 2014-04-10 |
WO2009102357A3 (en) | 2009-10-22 |
EP2235065A2 (en) | 2010-10-06 |
US20100316661A1 (en) | 2010-12-16 |
CA2705373A1 (en) | 2009-08-20 |
AU2008350273A1 (en) | 2009-08-20 |
US8597658B2 (en) | 2013-12-03 |
EP2235065A4 (en) | 2011-09-28 |
WO2009102357A2 (en) | 2009-08-20 |
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