JP6943908B2 - 迅速かつ持続的な免疫学的治療法 - Google Patents
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Description
本願は、2011年3月21日に出願された米国仮特許出願第61/454,819号および2011年12月8日に出願された米国仮特許出願第61/568,054号に対する優先権を主張するものである。
本発明は、一部には、国立衛生研究所(National Institutes of Health)助成金2-R44-AI-068285-02、1-UC1-AI-067198-01および1-UC1-AI-067205-1;国立衛生研究所契約N01-AI-30063;ならびに国立アレルギー感染症研究所(National Institute of Allergy and Infectious Diseases)非臨床的評価協定(Non-Clinical Evaluation Agreement)の支援を受けている。連邦政府は、本発明に対し一定の権利を有し得る。
(a)有糸分裂細胞および有糸分裂後の細胞の両方をin situで形質導入するアデノウイルスベクターの能力、
(b)高い感染効率(MOI)で細胞をin situで形質導入するための、高力価のウイルス[1ml当たり1012ifu(感染単位)を超える]を含有するストックを調製する既存の技術、
(c)アデノウイルスの吸入が、進化的医学(Tang and Van Kampen、2008)に準拠すること、
(d)鼻腔内投与したアデノウイルスベクターの効力が、アデノウイルスに対する先在の免疫に干渉されないと思われること(Hoelscherら、2006;Shiら、2001;Van Kampenら、2005)。理論に制約されることは望まないが、これは、呼吸器における粘膜関門に沿った高効率の遺伝子送達、高レベルの導入遺伝子発現および高度の抗原提示が原因となり得る、
(e)高レベルの導入遺伝子発現(少なくとも、初期バーストとして)を誘導するアデノウイルスの能力ならびに
(f)複製欠損アデノウイルスベクターを生物工学によって作ることができる容易さ
が挙げられる。
(実施例1)
呼吸病原体に対する広域スペクトル薬物としてのアデノウイルス粒子
ワクチン接種は、数週間または数ヶ月前に投与された場合、感染性疾患を予防するための有効なアプローチであるが、これは、即時のリスク下にある動物または人間を保護するには緩慢過ぎる。感染の直前または直後に摂取した場合に感染症の重症度を低下させることのできる薬剤は、公衆衛生において極めて重要である。タミフル(オセルタミビルリン酸塩)およびリレンザ(ザナミビル)は、インフルエンザウイルス感染の予防における有効性を立証した。しかし、これらのノイラミニダーゼ阻害剤は、経時的に薬物耐性インフルエンザウイルス株を生じ得る(Polandら、2009)。ウイルスと同様に、一般に、薬物耐性細菌も薬物の過使用により生じる(Davies and Davies、2010)。よって、使用中のある薬物が薬剤耐性により損なわれた場合、医療従事者は、病原体を抑止するためにパイプライン下の別の薬物を使用するオプションを有するため、追加的な薬物の開発が急がれる。
インフルエンザに対する完璧な保護を付与するための迅速応答ツールとしてのアデノウイルスベクター化薬物・ワクチンデュオ
インフルエンザほどの莫大な損害(toll)を与える他の疾患はほとんどない。本出願人は、本明細書において、E1/E3欠損(ΔE1E3)アデノウイルス血清型5(Ad5)粒子の鼻腔内(i.n.)投与が、マウスにおいて数週間持続する予防療法の手段として抗インフルエンザ状態を迅速に誘導したことを報告する。インフルエンザウイルス(IFV)赤血球凝集素(HA)HA1ドメインをコードすることにより、Ad5-HA1ベクターは、単一パッケージにおける薬物・ワクチンデュオ(DVD)として、予防的薬物として迅速な保護を付与し、続いて、インフルエンザに対して完璧な保護を誘導するためのワクチンとして持続性の防御免疫を誘発した。Ad5粒子は、気道におけるIFV増殖を妨害するための自然免疫の特異的な武器を活性化することによりインフルエンザを抑止することができる、宿主応答の複雑な網(web)を誘導するため、この多方向性の(multi-pronged)インフルエンザDVDは、現在のインフルエンザ薬物を損なう薬剤耐性の運命を回避できると考え得る。
感染性疾患に対する大規模な保護を付与するための潜在的な伝達機構(driver)としてのアデノウイルスベクター化薬物・ワクチンデュオ
ワクチンの病気と闘う力は、世界的な死亡率および罹患率低下に高い評価を得る公衆衛生の宝庫であった。ワクチンの適用範囲を強化することによりその威力をさらに増幅するための目標には、低コストで大量生産し、非医療従事者により大量投与することのできる新世代の迅速応答ワクチンの開発が必要とされる。新たなワクチンはまた、従来のワクチンよりも高い安全域に恵まれる必要がある。ベクターは、需要変動に応じて無血清浮遊細胞において迅速に製造し、進化的医学に準拠して鼻内噴霧によりヒト対象に非侵襲的に投与することができるため、非複製的アデノウイルスベクター化ワクチンは、ワクチン適用範囲の強化において期待できる。非経口注射とは対照的に、非侵襲的粘膜ワクチン接種は、全身性炎症を最小化する。さらに、先在のアデノウイルス免疫は、アデノウイルスベクター化経鼻ワクチンの効力に認め得るほど干渉しない。病原体抗原をコードするアデノウイルスベクターの経鼻投与は、恐怖がなく無痛性であるのみならず、導入遺伝子発現なしのアデノウイルス粒子単独は、気道における抗インフルエンザ状態を誘導することができるため、薬物・ワクチンデュオとして粘膜病原体に対する迅速かつ持続性の保護も付与する。人間へのワクチン接種に加えて、このクラスのベクター化ワクチンにより動物を大量免疫化することもできる。
る可能性も回避する必要がある。
免疫応答を誘導することなく、門脈において粘膜病原体に対する局在化された防御免疫を誘発する。
Van Kampen KR、Shi Z、Gao Pら、Safety and immunogenicity of adenovirus-vectored nasal and epicutaneous influenza vaccines in human. Vaccine 23、1029〜1036(2005)。
Toro H、Tang DC、Suarez DL、Sylte MJ、Pfeiffer J、Van Kampen KR. Protective avian influenza in ovo vaccination with nonreplicating human adenovirus vector. Vaccine 25、2886〜2891(2007)。
Zhang J、Tarbet EB、Feng T、Shi Z、Van Kampen KR、Tang DC. Adenovirus-vectored drug-vaccine duo as a rapid-response tool for conferring seamless protection against influenza. PLoS ONE 6、e22605(2011)。
アデノウイルスベクター化インフルエンザの迅速かつ持続的な免疫学的治療法
Ad5ベクター化インフルエンザRAPITの目標は、低コストで大量生産して、非医療従事者により大量投与することができ、インフルエンザに対する迅速/持続性の保護を付与する能力を有するが、薬剤耐性を誘導する可能性および野生のインフルエンザウイルスとの再集合の可能性のない、インフルエンザの迅速かつ持続的な免疫学的治療法(RAPIT)を開発することである。インフルエンザウイルスを繁殖させる必要性はなく、免許を持つ医療従事者による針注射の必要性もない。
呼吸病原体に対する広域スペクトルで迅速かつ持続的な免疫学的治療法(RAPIT)としてのアデノウイルス粒子
図14は、胞子チャレンジ直前のアデノウイルス粒子の鼻腔内滴下注入による予防的炭疽菌療法を描写する。
呼吸病原体に対する広域スペクトルの迅速かつ持続的な免疫学的治療法(RAPIT)としてのアデノウイルス粒子
近年、Ad5ゲノムにコードされた病原体抗原ありまたはなしのΔE1E3アデノウイルス5型(Ad5)粒子の鼻腔内(i.n.)投与が、獲得免疫が誘発される前にインフルエンザに対する予防療法を付与できることが実証された。よって、病原体抗原をコードするAd5ベクターは、薬物・ワクチンデュオ(DVD)として、病原体に対する迅速かつ持続性の完璧な保護を誘導し得る。マウスへのΔE1E3 Ad5粒子の投与が、I型インターフェロン(IFN-αおよびIFN-β)等、多様な炎症性サイトカインおよびケモカインの産生を迅速に誘導し、肺樹状細胞を損ない、ナチュラルキラー細胞を活性化し、抗ウイルス一酸化窒素の産生を誘導し、Ad5と、血液タンパク質、血小板、マクロファージ、内皮細胞およびそれぞれの実質細胞との間に多面的な相互作用を引き起こすことが実証された。ΔE1E3 Ad5粒子により誘導される複数の反応が組み合わされて、気道における抗インフルエンザ状態を確立し、これによりインフルエンザウイルスがほぼ迂回できない多次元的な防御障壁を生じることができることが考え得る。インフルエンザが、Ad5粒子により抑止され得る唯一の疾患である可能性は低い。Ad5粒子が、万能薬としてあらゆる疾患に対抗できる可能性も低い。この知見は、AdE粒子の単一のi.n.投与が、粘膜呼吸病原体の少なくともサブセットに対する予防療法をマウスにおいて何週間も付与でき、AdE粒子は、他のウイルスに突然変異圧を直接的に付与することなく気道における生息環境を変化させるため、DVDの使用が、薬剤耐性を誘導できない筈であることを単に示すものである。DVDのワクチン構成成分によるその後の持続性の防御免疫誘発は、有効性を強化する。DVDプラットフォームの開発は恐らく、多種多様な疾患状況における新規臨床戦略の開発を助成するであろう。
Claims (22)
- 異種インフルエンザウイルスに対する免疫応答を、それを必要としている哺乳類対象において誘導するための組成物であって、
前記異種インフルエンザウイルスが、少なくとも、第1抗原を含む第1のインフルエンザ株と、第2抗原を含む第2のインフルエンザ株とを含み、
前記組成物は、前記第1抗原を含み発現するが、前記第2抗原を含まず発現しない、少なくとも107感染単位(ifu)の有効量のE1およびE3欠失アデノウイルスベクターを含み、
前記免疫応答が、前記第2のインフルエンザウイルス株に由来する曝露に対する保護をもたらし、
第1のインフルエンザ株または第2のインフルエンザ株に曝露する1日前から2日前の期間の間に鼻腔内投与される、組成物。 - 異種インフルエンザウイルスに対する保護的免疫応答が、第1抗原および第2抗原に対する抗体応答を少なくとも含む、請求項1に記載の組成物。
- インフルエンザウイルスが、ブタインフルエンザ、季節性インフルエンザ、トリインフルエンザ、H1N1インフルエンザまたはH5N1インフルエンザである、請求項1に記載の組成物。
- インフルエンザウイルス抗原が、インフルエンザ赤血球凝集素、インフルエンザ核タンパク質、またはインフルエンザM2である、請求項1に記載の組成物。
- 有効量が、少なくとも108感染単位(ifu)のE1およびE3欠失アデノウイルス、または少なくとも109感染単位(ifu)のE1およびE3欠失アデノウイルス、または少なくとも1010感染単位(ifu)のE1およびE3欠失アデノウイルスである、請求項1に記載の組成物。
- それを必要としている対象が、成体である、請求項1に記載の組成物。
- それを必要としている対象が、幼体である、請求項1に記載の組成物。
- それを必要としている対象が、免疫力がない患者である、請求項1に記載の組成物。
- 少なくとも2つの投与ステップを介して投与され、前記投与が、約40日間置いて、約41日間置いて、約42日間置いて、約43日間置いて、約44日間置いて、約45日間置いて、約46日間置いて、約47日間置いて、約48日間置いて、約49日間置いて、あるいは約50日間置いて為される、請求項1に記載の組成物。
- アデノウイルスが、ヒトアデノウイルス、ウシアデノウイルス、イヌアデノウイルス、非ヒト霊長類アデノウイルス、ニワトリアデノウイルスまたはブタアデノウイルスである、請求項1に記載の組成物。
- 保護的応答が、24時間以内に誘発される、請求項1に記載の組成物。
- 保護的応答が、約1日間から約47日間持続する、請求項1に記載の組成物。
- 哺乳類対象への鼻腔内への単回投与に適した、インフルエンザウイルスに対する免疫応答を誘導するための医薬処方物であって、
前記哺乳類対象に関してコドン最適化されたインフルエンザウイルス赤血球凝集素抗原を含み発現する、少なくとも107感染単位(ifu)の有効量のE1および/またはE3欠損アデノウイルスベクターであって、前記有効量によって、投与から24時間以内に保護免疫応答が誘導される、E1および/またはE3欠失アデノウイルスベクター;ならびに
医薬的に許容可能な希釈液または担体
を含み、
インフルエンザウイルスに曝露する1日前から2日前の期間の間に鼻腔内投与される、処方物。 - インフルエンザウイルスが、ブタインフルエンザ、季節性インフルエンザ、トリインフルエンザ、A型インフルエンザ、H1N1インフルエンザまたはH5N1インフルエンザである、請求項13に記載の処方物。
- 哺乳類対象が、ヒトである、請求項13に記載の処方物。
- アデノウイルスが、ヒトアデノウイルスである、請求項13に記載の処方物。
- アデノウイルスが、ウシアデノウイルス、イヌアデノウイルス、非ヒト霊長類アデノウイルス、ニワトリアデノウイルスまたはブタアデノウイルスである、請求項13に記載の処方物。
- 保護的応答が、少なくとも47日間持続する、請求項13に記載の処方物。
- 有効量が、少なくとも107感染単位(ifu)のE1およびE3欠失または破壊アデノウイルスである、請求項13に記載の処方物。
- 有効量が、少なくとも108感染単位(ifu)のE1およびE3欠失または破壊アデノウイルスである、請求項13に記載の処方物。
- 有効量が、少なくとも109感染単位(ifu)のE1およびE3欠失または破壊アデノウイルスである、請求項13に記載の処方物。
- 組成物が、液体、エマルジョン、固体、エアロゾルまたはガスの形態である、請求項13に記載の処方物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161454819P | 2011-03-21 | 2011-03-21 | |
US61/454,819 | 2011-03-21 | ||
US201161568054P | 2011-12-07 | 2011-12-07 | |
US61/568,054 | 2011-12-07 | ||
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US10183069B2 (en) * | 2011-03-21 | 2019-01-22 | Altimmune Inc. | Rapid and prolonged immunologic-therapeutic |
KR20160049010A (ko) * | 2013-09-06 | 2016-05-04 | 알티뮨 인크. | 바이러스 벡터화된 백신을 위한 방법 및 조성물 |
WO2015189425A1 (en) | 2014-06-13 | 2015-12-17 | Glaxosmithkline Biologicals Sa | Immunogenic combinations |
TWI801377B (zh) | 2017-04-18 | 2023-05-11 | 美商阿尼拉製藥公司 | 治療具有b型肝炎病毒(hbv)感染之個體之方法 |
CN111315407B (zh) * | 2018-09-11 | 2023-05-02 | 上海市公共卫生临床中心 | 一种广谱抗流感疫苗免疫原及其应用 |
BR112021018086A2 (pt) * | 2019-03-14 | 2021-11-23 | Univ Arizona | Método de tratamento e/ou prevenção de asma, exacerbações de asma, asma alérgica e/ou condições associadas com microbiota relacionadas a distúrbios respiratórios |
CN114096675A (zh) * | 2020-02-14 | 2022-02-25 | 艾天穆股份有限公司 | 冠状病毒免疫原性组合物和其用途 |
KR20230132816A (ko) * | 2021-01-15 | 2023-09-18 | 더 유나이티드 스테이츠 오브 어메리카, 애즈 리프리젠티드 바이 더 세크러테리, 디파트먼트 오브 헬쓰 앤드 휴먼 서비씨즈 | 복제-능력 있는 아데노바이러스 타입 4 sars-cov-2백신 및 이의 용도 |
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ES2645156T3 (es) | 2017-12-04 |
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EP3763385A1 (en) | 2021-01-13 |
JP2014513067A (ja) | 2014-05-29 |
JP2017186369A (ja) | 2017-10-12 |
CA2829916C (en) | 2019-08-20 |
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ES2861576T3 (es) | 2021-10-06 |
CA2829916A1 (en) | 2012-09-27 |
JP2019081806A (ja) | 2019-05-30 |
EP2688588B1 (en) | 2017-08-09 |
KR102104650B1 (ko) | 2020-04-24 |
MX2013010794A (es) | 2014-03-12 |
KR20220047790A (ko) | 2022-04-19 |
WO2012129295A1 (en) | 2012-09-27 |
US9175310B2 (en) | 2015-11-03 |
EP3205353A1 (en) | 2017-08-16 |
JP6075734B2 (ja) | 2017-02-08 |
EP2688588A1 (en) | 2014-01-29 |
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JP2017008100A (ja) | 2017-01-12 |
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