JP2019513377A - 安定化された可溶性融合前rsv fタンパク質 - Google Patents
安定化された可溶性融合前rsv fタンパク質 Download PDFInfo
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- A61P31/14—Antivirals for RNA viruses
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
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- C07K16/1027—Paramyxoviridae, e.g. respiratory syncytial virus
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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Abstract
Description
ワクチン製造に有望な1つのアプローチは、精製されたRSV Fタンパク質に基づくサブユニットワクチンである。しかしながら、このアプローチの場合、精製されたRSV Fタンパク質は、RSV Fタンパク質の融合前状態のコンフォメーションに類似したコンフォメーションにあり、経時的に安定であり、かつ十分な量で製造できることが望ましい。加えて、サブユニットベースのワクチンの場合、RSV Fタンパク質を、膜貫通(TM)領域および細胞質領域の欠失により短縮して、可溶性分泌型Fタンパク質(sF)を生成させる必要がある。TM領域は膜アンカリングおよび三量体形成を担うため、アンカーなしの可溶性Fタンパク質は、完全長タンパク質よりもかなり不安定であり、融合後最終状態に容易にリフォールディングするであろう。したがって、高い発現レベルおよび高い安定性を示す安定な融合前コンフォメーションの可溶性Fタンパク質を得るために、融合前コンフォメーションを安定化する必要がある。
いくつかの融合前RSV Fタンパク質変異体を生成し、これを図1に模式的に示す。すべての候補は、RSV A2 F1ドメインのアミノ酸残基495に連結した、フィブリチン三量体化ドメイン(フォルドン)(GYIPEAPRDGQAYVRKDGEWVLLSTFL;配列番号20)を含む。
同種RSV−A2チャレンジコットンラットモデルにおいて、アジュバントの存在下または非存在下での組換えPRPMタンパク質の免疫原性および予防の有効性を決定する実験を行った。0日目および28日目に、2用量のPRPM(5および0.5μg)を、アジュバント非添加、または100μgAdjuphosをアジュバントとして添加して、動物にi.m.により免疫を付与した。49日目に動物に105(pfu)のRSV A2でチャレンジした。チャレンジの5日後に動物を屠殺し、肺および鼻で力価を測定した。
アジュバントを添加したPRPMによる免疫化は、鼻で無効であった1匹の動物を除いて、肺および鼻で完全な防御を誘導した。5および0.5μgのアジュバント非添加PRPMを接種された動物のほとんどは、肺および鼻で無効を示し、アジュバント添加タンパク質およびアジュバント非添加タンパク質を接種された群の間に有意差があった(図8)。アジュバント化タンパク質は、非アジュバント化タンパク質と比較して、免疫から49日後に有意に高いVNA力価を誘導した(図9)。
配列番号1:PRPM
配列番号2 PRQM
配列番号3 PRPM+S46G
CR9501重鎖(配列番号16):
CR9501軽鎖(配列番号17):
CR9502重鎖(配列番号18):
CR9502軽鎖(配列番号19):
PRPM(配列番号20)をコードするヌクレオチド配列:
PRQM(配列番号21)をコードするヌクレオチド配列:
PRPM+S46G(配列番号22)をコードするヌクレオチド配列:
Claims (11)
- 配列番号1、配列番号2および配列番号3からなる群から選択されるアミノ酸配列を含む、組換え融合前呼吸器合胞体ウイルス(RSV)融合(F)タンパク質。
- 前記融合前コンフォメーションFタンパク質に特異的な少なくとも1種のエピトープを含み、前記少なくとも1種のエピトープは、配列番号4の重鎖CDR1領域、配列番号5の重鎖CDR2領域、配列番号6の重鎖CDR3領域および配列番号7の軽鎖CDR1領域、配列番号8の軽鎖CDR2領域、および配列番号9の軽鎖CDR3領域を含む融合前特異的モノクローナル抗体、ならびに/または配列番号10の重鎖CDR1領域、配列番号11の重鎖CDR2領域、配列番号12の重鎖CDR3領域および配列番号13の軽鎖CDR1領域、配列番号14の軽鎖CDR2領域、および配列番号15の軽鎖CDR3領域を含む融合前特異的モノクローナル抗体によって認識される、請求項1に記載の融合前RSV Fタンパク質またはその断片。
- 前記タンパク質は三量体である、請求項1または2に記載の融合前RSV Fタンパク質またはその断片。
- 請求項1、2または3に記載の融合前RSV Fタンパク質またはその断片をコードする核酸分子。
- 前記核酸分子は哺乳動物細胞における発現用にコドン最適化されている、請求項4に記載の核酸分子。
- 配列番号21、配列番号22および配列番号23からなる群から選択されるヌクレオチド配列を含む、請求項4または5に記載の核酸分子。
- 請求項4、5または6に記載の核酸分子を含むベクター。
- 請求項1、2または3に記載の融合前RSV Fタンパク質またはその断片、請求項4、5または6に記載の核酸分子、および/あるいは請求項7に記載のベクターを含む組成物。
- RSV Fタンパク質に対する免疫応答の誘導に使用するための請求項8に記載の組成物。
- RSV感染の予防および/または治療に使用するための請求項8または9に記載の組成物。
- 請求項1、2または3に記載の融合前RSVタンパク質またはその断片、請求項4、5または6に記載の核酸分子、および/あるいは請求項7に記載のベクターを含むRSVワクチン。
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