JP2018505861A - インフルエンザ後の細菌重感染を処置するための方法及び医薬組成物 - Google Patents
インフルエンザ後の細菌重感染を処置するための方法及び医薬組成物 Download PDFInfo
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Abstract
Description
Streptococcus pneumoniae血清型1(臨床分離株E1586)は、National Reference Laboratory - Ministry of Health, Uruguayから入手された。作業ストックを以下のように調製した。Todd Hewitt Yeast Broth(THYB)(Sigma-Aldrich - Saint-Louis, MO)を、血液−寒天板で成育された新鮮なコロニーで接種し、37℃で0.7〜0.9単位のOD600nmまでインキュベーションした。培養物は、THYB+グリセロール12%(容量/容量)中、−80℃で上限3カ月まで保存された。マウス感染のためには、作業ストックを解凍して、滅菌Dulbecco's Phosphate-Buffered Saline(DPBS;Gibco - Grand Island, NY)で洗浄し、適切な濃度に希釈した。ストック中の細菌の数を、血液寒天板上での平板培養段階希釈によって確認した。
雌性BALB/c(6〜8週齢)マウスは、Janvier laboratories(St. Berthevin, France)から得られた。動物を個々に換気されたケージ内で維持し、垂直層流キャビネット(クラスII A2, ESCO - Hatboro, PA)において取り扱った。実験はすべて、現行の国内及び施設内規制及び倫理ガイドライン(B59-350009 - Institut Pasteur de Lille)に適合するものであった。マウスは、250μl DPBS中1.25mgケタミン(Imalgene、Merial - Lyon、フランス)プラス0.25mgキシラジン(Rompun, Bayer HealthCare - Loos, France)の腹腔内(i.p.)注射によって麻酔された。マウスを、30PFUの高病原性マウス馴化H3N2インフルエンザAウイルス株Scotland/20/74.7を含有する50μl D−PBSで鼻腔内感染させた。ウイルスチャレンジ後7日又は14日に、103CFUのS. pneumoniaeを含有するD−PBS30μlでマウスを鼻腔内感染させた。
リコンビナントフラジェリン類FliCΔ174-400(カルボキシ末端ヒスチジンTagを保持)及びrFliC(アミノ末端ヒスチジンTagを保持)をエンコードする構築体をによってPCR生成し、発現ベクターpET22b+へとクローニングした。リコンビナントフラジェリン類は、以下のとおりに生成された。プラスミドをEscherichia coli BL21(DE3)に導入し、IPTG 1mMを添加することによってタンパク質生成を誘導した。フレンチプレスにて崩壊させた後、可溶性画分は、これまでに記載されたとおりTriton X-114抽出を用いてリポ多糖(LPS)を涸渇させた。タンパク質を、ニッケル親和性クロマトグラフィー、陰イオン交換クロマトグラフィー及びFastタンパク質液体クロマトグラフィー(GE Healthcare)によるゲル濾過にて連続的に精製した。最後に、タンパク質はここでもまた、ポリミキシンBカラム(Pierce, USA)を用いてLPSを涸渇させた。Limulusアッセイ(Associates of Cape Cod Inc., USA)を用いて、残存LPS濃度がリコンビナントフラジェリンμgあたり20pgLPS未満であることを確認した。使用前にフラジェリン類を65℃で10分間加熱し、タンパク質がほとんど単量体であるとの確証を得た。麻酔非再呼吸システム(DRE-Compact 150, DRE Veterinary - Louisville, KY)を用い、軽度の麻酔下にイソフルラン(Axience - Pantin, France)の吸入によって、30μl DPBS中フラジェリン類を鼻腔内投与した。プラスチックチューブフィード(V0104030, ECIMED - Boissy-St-Leger, France)を用い、アモキシシリン(AMX)の胃内(i.g.)最適以下用量(200μl水中5μg;アモキシシリンVERTANAL(商標)、Sigma-Aldrich - Saint-Louis, MO)により、感染させたマウスを処置した。これは、6〜8週齢マウスに対して、250μg/kgのAMXの用量を表す。
マウスを100μl DPBS中5.47mgのペントバルビタールナトリウム(CEVA Sante animale, Libourne, France)の腹腔内注射により感染後の異なる時点で屠殺した。感染後の選択された時点で肺及び脾臓を収集し、UltraTurraxホモジナイザー(IKA-Werke, Staufen, Germany)でホモジナイズした。生菌数は、血液寒天板上での平板培養段階希釈によって確認した。
肺の総RNAをNucleospin RNA IIキット(Macherey Nagel - Hoerdt, France)で抽出し、High-Capacity cDNA Archiveキット(Applied Biosystems - Foster city, Canada)で逆転写させた。7300 Real Time PCR System(Applied Biosystems)のSYBR Green-basedリアルタイムPCRを用いて、得られたcDNAを増幅させた。参照遺伝子ActB、並びにケモカインをエンコードしている遺伝子Ccl20及びCxcl1に特異的なプライマーは、これまでに報告されたものである[20]。第1に、関心対象の遺伝子とActb(ΔCt)とに対するPCRサイクル閾値(Ct)、第2に、処置群と参照群(ΔΔCt)に対するΔCt値を、これまでに記載されたとおりに[20]比較することにより、相対的なmRNAレベル(2−ΔΔCt)を求めた。
結果は、中央値±範囲として表される。統計学的差異を、マンホイットニー検定(GraphPad Prism 5.0)を用いて解析し、p値<0.05に対して有意であると考えられた。
本発明者らは、IAV感染動物に対する、フラジェリン+抗生物質からなる併用療法の有効性を検討した。先ず本発明者らは、IAV感染動物においてフラジェリンがシグナリングを促進することができるか否かを明確にした。本発明者らは、FliCΔ174-400での鼻腔内処置が、急性期及び消散期の両方、たとえば感染後7及び14日でのIAV感染に関連して、免疫メディエーターの転写をさらに増加できることを見出した(図1)。本発明者らは、急性感染の動物における併用療法を評価することを選択した。この目的のために、IAVで7日間感染させた動物にS. pneumoniaeを感染させて、AMX及びフラジェリンで処置した(図2)。我々のデータは、肺及び脾臓の両方でAMXの治療指数を高めるのに、かかる併用療法が非常に効果的であることを示した。
本出願全体をとおして、種々の参照文献で本発明の属する技術分野の水準を記載している。これらの参照文献の本開示は、参照により本開示に組み入れられる。
Claims (15)
- インフルエンザ後の細菌重感染を処置する必要のある被検者における処置方法であって、被検者に治療上有効量のフラジェリンポリペプチドを、場合により少なくとも1つの抗生物質と組み合わせて投与することを含む方法。
- 前記細菌重感染が、肺炎連鎖球菌(Streptococcus pneumoniae);黄色ブドウ球菌(Staphylococcus aureus);インフルエンザ菌(Haemophilus influenza)、マイコプラズマ種(Myoplasma species)及びモラクセラ カタラーリス(Moraxella catarrhalis)からなる群より選択される少なくとも1つの生物により媒介される、請求項1に記載の方法。
- 前記被検者が、少なくとも50歳である被検者、長期療養施設に滞在する被検者、肺若しくは心臓脈管系の慢性障害を有する被検者、慢性代謝病、腎機能不全、異常ヘモグロビン症、又は免疫抑制のために前年、定期的な医療経過観察又は入院が必要であった被検者、14歳未満の年齢の小児、長期のアスピリン治療を受けている6カ月から18歳の間の年齢の患者、及びインフルエンザの季節の間に妊娠の第二期又は第三期を迎える女性からなる群より選択される、請求項1に記載の方法。
- 前記フラジェリンポリペプチドが、配列番号:1、配列番号:2又は配列番号:3と少なくとも70%の同一性を有する、請求項1に記載の方法。
- 前記フラジェリンポリペプチドが、a)配列番号:3の第1位に位置するアミノ酸残基から始まり、配列番号:3の第99〜173位に位置するアミノ酸残基のいずれか1つからなる群より選択されるアミノ酸残基で終わるアミノ酸配列と少なくとも90%のアミノ酸同一性を有するN末端ペプチド;及びb)配列番号:3の第401〜406位に位置するアミノ酸残基のいずれか1つからなる群より選択されるアミノ酸残基で始まり、配列番号:3の第494位に位置するアミノ酸残基で終わるアミノ酸配列と少なくとも90%のアミノ酸同一性を有するC末端ペプチドを含み、前記N末端ペプチドは前記C末端ペプチドに直接連結されているか、又は前記N末端ペプチドと前記C末端ペプチドとが間接的に、スペーサー鎖を介して互いに連結されている、請求項1に記載の方法。
- 前記N末端ペプチドが、配列番号:3のアミノ酸配列1〜99、1〜137、1〜160及び1〜173からなる群より選択される、請求項5に記載の方法。
- 前記C末端ペプチドが、配列番号:3のアミノ酸配列401〜494及び406〜494からなる群より選択される、請求項5に記載の方法。
- 前記N末端及びC末端ペプチドが、それぞれ配列番号:3のアミノ酸配列1〜173及び401〜494からなる、請求項5に記載の方法。
- 前記N末端及びC末端ペプチドが、それぞれ配列番号:3のアミノ酸配列1〜160及び406〜494からなる、請求項5に記載の方法。
- 前記N末端及びC末端ペプチドが、それぞれ配列番号:3のアミノ酸配列1〜137及び406〜494からなる、請求項5に記載の方法。
- 前記N末端ペプチドと前記C末端ペプチドとが間接的に、NH2-GIy-AIa-AIa-GIy-COOH(配列番号:4)ペプチド配列からなる中間スペーサー鎖を介して互いに連結されている、請求項5に記載の方法。
- 配列番号:3の第488位に位置するアスパラギンアミノ酸残基が、セリンで置換されている、請求項5に記載の方法。
- 前記抗生物質が、アミノグリコシド類、βラクタム類、キノロン類又はフルオロキノロン類、マクロライド類、スルホンアミド類、スルファメトキサゾール類(sulfamethaxozoles)、テトラサイクリン類、ストレプトグラミン類、オキサゾリジノン類、リファマイシン類、糖ペプチド、ポリミキシン類、リポペプチド抗生物質からなる群より選択される、請求項1に記載の方法。
- 前記抗生物質が、アモキシシリンである、請求項1に記載の方法。
- 前記抗生物質が、スルファメトキサゾール及びトリメトプリム双方を含む、請求項1に記載の方法。
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