JP7449246B2 - ウイルス粒子ベースのワクチン - Google Patents
ウイルス粒子ベースのワクチン Download PDFInfo
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- JP7449246B2 JP7449246B2 JP2020567233A JP2020567233A JP7449246B2 JP 7449246 B2 JP7449246 B2 JP 7449246B2 JP 2020567233 A JP2020567233 A JP 2020567233A JP 2020567233 A JP2020567233 A JP 2020567233A JP 7449246 B2 JP7449246 B2 JP 7449246B2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/245—Herpetoviridae, e.g. herpes simplex virus
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
組換えHCMV株は、HCMV株Towneの遺伝子改変バリアントであり、
組換えHCMV株は、機能的なUL130タンパク質をコードし、そして機能的な緑色蛍光タンパク質(GFP)をコードしない、核酸分子を指す。
- 粒子は、その中にウイルス糖タンパク質が埋め込まれている脂質膜によって囲まれており、
- 粒子は、実質的な量のウイルスDNAまたはカプシドを含まず、
- 粒子は、特に上記のような、ウイルスタンパク質gH、gL、UL128、UL130およびUL131からなる5量体複合体を含み、そして
- 粒子は、GFPを含まない。
- 粒子は、その中にウイルス糖タンパク質が埋め込まれている脂質膜によって囲まれており、
- 粒子は、実質的な量のウイルスDNAまたはカプシドを含まず、
- 粒子は、特に上記のような、ウイルスタンパク質gH、gL、UL128、UL130およびUL131からなる5量体複合体を含み、そして
- 粒子は、GFPを含まない。
5量体陽性DB産生株の生成
DBを、ヒト線維芽細胞において、組換えHCMV種ウイルスでの感染に際して産生した。この種ウイルスを、以下に記載するようなHCMV Towne株のゲノムの遺伝子改変型をコードするBACプラスミドでの細胞のトランスフェクションに際して得た。
デンスボディのUV不活化
液体がスポットプレートに固着するので、UV不活化の前に、DBの量を調整する必要があった。DBの必要量を200μlのPBSに添加し、そして不活化の後に10μgのDBが150μlのPBS中に再懸濁されるようにスポットプレート上に滴下した。その後、スポットプレートをUVランプ下に置き、そして254nmの波長のスイッチを2分間作動させた。DBのUV不活化のために、UV-Handランプ(Herolab GmbH Laborgerate, Wiesloch; Type NU-4)を使用した。150μlのPBS/DB懸濁液(150μlのPBS中10μgのDB)を新たなチューブに移した。10cmディッシュ中の5×105個のHFFへのDBの適用のために、1350μlの培養MEMと150μlのDB/PBSとを混合し、そしてDB接種物を1.5時間37℃で吸着させた。次いで、培養MEMを添加し、そして細胞を示した時間インキュベートした。
核内構造体(NB)媒介内在性免疫に対するDBの影響
タンパク質PMLは、核内構造体(NB)としても知られるND10ドメインの形成のために重要であることが以前に示されている(総説については(16、17)を参照のこと)。これらの核内構造は、ヘルペスウイルス感染に対抗する複数の細胞タンパク質の集積を表す。ND10ドメインのインターフェロン誘導性アップレギュレーションを示した以前のデータに基づいて、PMLが細胞の内在性抗ウイルス防御機構に寄与することが示唆された。HCMVは、この抗ウイルス活性に対抗するためのストラテジーを進化させた。HCMV感染の間、前初期タンパク質1(IE1)はPMLボディにおいて集積し、その後PMLの分散を誘導し、それによってNB媒介内在性免疫に拮抗する。PML分散に対するDBの影響を分析した。
インターフェロン誘導遺伝子15(ISG15)発現の誘導に対するDBの影響
インターフェロンは、ウイルス感染に対する自然免疫応答のために重要である。全てのインターフェロンは、数百のインターフェロン誘導遺伝子(ISG)の転写を誘発し、そのタンパク質産物は抗ウイルス活性を示す。インターフェロン誘導遺伝子15は、I型IFNによって誘導されるユビキチン様タンパク質(ISG15)をコードする。ISG15によるタンパク質修飾(ISG化(ISGylation))は多くのウイルスの複製を阻害することが知られている(18)。HCMV誘導ISG15集積は、宿主の、細胞質二本鎖DNA(dsDNA)の検出によって誘発される。しかし、この集積は後にHCMV IE1発現によって抑制される(19、20)
DB適用はオートファジーを誘導する
本発明者らおよび他者は、DBの適用が、ウイルスペプチドの確かな主要組織適合性複合体(MHC)クラスI媒介提示に導くことを示した。本発明者らは、DB由来抗原がオートファジーの誘導を介してMHCクラスI経路に導入されるという仮定を追求する。ここで、本発明者らは、ヒト包皮線維芽細胞へのHCMVのUV不活化DBの適用が実際にオートファジーの誘導をもたらすことを示す。
DB曝露後の細胞プロテオームの質量分析
細胞に対するDBの影響のより包括的な描写を得るために、ラベルフリー質量分析をDB処理HFF細胞に対して実施した。
試薬還元サンプル 19.5μL(min. 20μg)
NuPAGE(登録商標)LDSサンプル緩衝液(4×) 7.5μL
1Mジチオスレイトール(DTT) 3μL
総体積 30μL
Human_cytomegalovirus_(HCMV)_Uniprot_20180108.fasta
Human_cytomegalovirus_(HCMVA)Uniprot(strain_AD169)_20180108.fasta
Human_cytomegalovirus_(HCMVT)Uniprot(strain_Towne)_20180108.fasta
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Claims (21)
- 組換えHCMV株のゲノムをコードする核酸分子であって、
前記組換えHCMV株は、HCMV株Towneの遺伝子改変バリアントであり、前記核酸分子は、GenBankアクセッション番号AY315197.2(配列番号6)の下で寄託されているTowne-BAC中に存在する、前記HCMV株Towneのヌクレオチド配列と、UL130遺伝子および緑色蛍光タンパク質(GFP)遺伝子をコードする配列以外で、その全長にわたって少なくとも90%の同一性を有し、
前記組換えHCMV株は、HCMV株Towneとは異なるHCMV株由来の機能的なUL130タンパク質をコードし、かつ機能的な緑色蛍光タンパク質(GFP)をコードしない、核酸分子。 - 少なくとも99%の同一性を有する、請求項1に記載の核酸分子。
- GFP遺伝子が欠失されており、かつ異種遺伝子が挿入されている、請求項1または2に記載の核酸分子。
- 異種遺伝子が、細菌ガラクトキナーゼ遺伝子である、請求項3に記載の核酸分子。
- 組換えHCMV株Towne-UL130repΔGFPのゲノムをコードする、請求項1~4のいずれか1項に記載の核酸分子。
- ベクター上に配置されている、請求項1~5のいずれか1項に記載の核酸分子。
- ベクターが、BACベクターである、請求項6に記載の核酸分子。
- 請求項1~7のいずれか1項に記載のゲノムを有するHCMV株での哺乳動物標的細胞の感染によって産生されるデンスボディであって、前記デンスボディは、ウイルスタンパク質gH、gL、UL128、UL130およびUL131Aからなる5量体複合体を含み、かつGFPを含まない、デンスボディ。
- 前記ウイルスタンパク質gH、gL、UL128およびUL131AはHCMV株Towneに由来し、前記ウイルスタンパク質UL130はHCMV株TB40/Eに由来する、請求項8に記載のデンスボディ。
- 薬学的に許容されるキャリア中の請求項8または9に記載のデンスボディの調製物。
- 不活化されている、請求項10に記載の調製物。
- 不活化されていない、請求項10に記載の調製物。
- 医薬における使用のための、請求項10~12のいずれか1項に記載の調製物。
- ヒト医薬による使用のための、請求項13に記載の調製物。
- HCMVに対するワクチンとしての使用のための、請求項13または14に記載の調製物。
- ワクチン接種されたヒト対象におけるHCMV関連障害の発生を予防および/または改善するための、ならびに/あるいはさらなるヒト対象へのHCMV感染の伝播を阻害するための方法における使用のための、請求項10~12のいずれか1項に記載の調製物。
- 請求項13~16に記載の使用のため、およびワクチン接種されたヒト対象の内在性免疫を維持するための、請求項10~12のいずれか1項に記載の調製物。
- 請求項13~16に記載の使用のため、およびワクチン接種されたヒト対象においてインターフェロン反応を刺激するための、請求項10~12のいずれか1項に記載の調製物。
- 請求項13~16に記載の使用のため、およびワクチン接種されたヒト対象においてウイルスタンパク質のオートファジーを促進するための、請求項10~12のいずれか1項に記載の調製物であって、自己貪食されるタンパク質は分解され、MHC分子によって提示される、調製物。
- MHC分子が、MHCクラスIおよびMHCクラスII分子である、請求項19に記載の調製物。
- 不活化が、紫外線(UV)照射によるものである、請求項11に記載の調製物。
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US20210228711A1 (en) | 2021-07-29 |
US11986521B2 (en) | 2024-05-21 |
JP2021525535A (ja) | 2021-09-27 |
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AU2019280899A1 (en) | 2020-10-08 |
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