JP2014525249A - C.ディフィシルの毒素aおよび毒素bタンパク質の単離ポリペプチドならびにその使用 - Google Patents
C.ディフィシルの毒素aおよび毒素bタンパク質の単離ポリペプチドならびにその使用 Download PDFInfo
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- JP2014525249A JP2014525249A JP2014527505A JP2014527505A JP2014525249A JP 2014525249 A JP2014525249 A JP 2014525249A JP 2014527505 A JP2014527505 A JP 2014527505A JP 2014527505 A JP2014527505 A JP 2014527505A JP 2014525249 A JP2014525249 A JP 2014525249A
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Abstract
【選択図】 なし
Description
本発明は、毒素Aの19反復単位(RU)および毒素Bの23反復単位(RU)またはそのペプチド断片もしくは変異体を含む、単離ポリペプチドC−TAB.G5(配列番号2)またはその誘導体、C−TAB.G5.1(配列番号4)の使用を含む、C.ディフィシル毒素AおよびBに対する保護的および/または治療的免疫反応を誘導するための免疫原性組成物を提供する。
単離ポリペプチド
組成物および製剤
C−TAB.G5またはC−TAB.G5.1単離ポリペプチドの使用方法
キット
本実施例は、大腸菌細胞における発現のためのC.ディフィシル毒素A(CTA)およびB(CTB)の一部を含む単離ポリペプチドの調製を説明する。後述の方法は、CTAおよびCTBを含む様々な単離ポリペプチドを作製するために使用され得る。一例として、CTAのC末端ドメインの一部およびCTBのC末端ドメインの一部を含む単離ポリペプチドが説明される。
実施例1.1:C−TAB.G5およびC−TAB.G5.1遺伝子コンストラクトのクローニング。
順方向:5’−caccACTAGTatgaacttagtaactggatggc−3’(配列番号9)および
逆方向:5’−CTCGAGttagccatatatcccaggggc−3’(配列番号10)。
順方向プライマーによる増幅は、SpeI部位を形成し、逆方向プライマーによる増幅は、Xhol部位を形成した。
順方向:5’−caccATGCATatgagtttagttaatagaaaacag−3’(配列番号11)および
逆方向:5’−ggcCTCGAGctattcactaatcactaattgagc−3’(配列番号12)。
順方向プライマーによる増幅は、Nsil部位を形成し、逆方向プライマーによる増幅は、Xhol部位を形成した。
順方向:5’−AGATCTATGCATGAGCTCctcgagcccaaaacgaaaggctcagc−3’(配列番号13)
逆方向:5’−cggtccggggccatatatcccaggggcttttactcc−3’(配列番号14)。
順方向:5’−caccCCATTGatggtaacaggagtatttaaagga(配列番号15)
逆方向:5’−CTCGAGctattcactaatcactaattgagctg(配列番号16)。
PCR反応は、PCR Super mix(Invitrogen社)を使用して行った。サイクル条件は、95℃で2分、95℃で45秒、55℃で50秒、68℃で4分(30サイクル)および72℃で10分であった。PCR生成物は、迅速遺伝子抽出キット(Invitrogen社)で精製し、PCR2.1−TOPOベクター(Invitrogen社)にライゲーションした。ライゲーション混合物を使用して、大腸菌Mech−1細胞を熱ショックにより形質転換した。形質転換体をImMedia Amp Blue(Invitrogen社)のプレート上に播種した。白色コロニーを採取し、100μg/mlのアンピシリンを含有する4mlのLB培地を有する15ml管内で培養した。培養物を37℃で一晩インキュベートし、プラスミドを迅速プラスミドミニプレップキット(Invitrogen社)で抽出した。PCR 2.1−TOPOTAベクター中のC−TAB.G5融合遺伝子を、NcoIおよびXhoI 制限酵素で分解させた。これらのC−TAB断片を、同じ制限酵素で分解させたpET28発現ベクターにライゲーションした。この得られたコンストラクトは、アミノ酸1851から2366からの毒素BのC末端ドメインに融合した、アミノ酸2272から2710からの毒素AのC末端ドメインをコードする。pET28/C−TAB.G5コンストラクトを、発現のために大腸菌BL21(DE3)に形質転換した。C−TAB.G5融合遺伝子を含有する5つのコロニーを、分析のために選択した。
実施例1.2:大腸菌における組み換えC−TAB.G5またはC−TAB.G5.1融合タンパク質の発現
実施例1.3:組み換えC−TAB.G5またはC−TAB.G5.1融合タンパク質の精製。
C−TAB.G5.1バルク調製物の精製:バイオマスを、処理まで−80℃で保存した。450gの凍結細胞ペースト(2.90Lの発酵槽に相当)を、4体積の溶解緩衝液(20mM Hepes、pH7.5、約0.6mS/cm)で希釈し(例えば450gのペースト+1800mLの緩衝液)、このようにして約1時間±0.5時間、機械的撹拌下で解凍した。随意の残りの塊を、Ultraturraxを使用して(例えば8000rpmで5分間)再懸濁することができる。細胞溶解は、Niro Soavi Panda高ホモジナイザで行う(640±25バール、3サイクル)。熱交換器を使用して溶解物を10℃未満まで冷却し、遠心分離までこの温度で維持する。粗細胞溶解物を、14000rpm(30000g)で4℃で30分間、バッチ遠心分離ステップ(Beckmann Avanti JLA 60.25)に供する。上澄みを回収してプールする。濾過ステップの詰まりのリスクを低減するために、ペレットの半液体部分も廃棄する。次いで、プールされた上澄みをSupercap PDH4 100/5インチ深さのフィルタカプセル(Pall社)(250cm2有効濾過面積)を通して濾過する。フィルタハウジング内の残りの溶解物を、溶解緩衝液で洗い流す。浄化後、1Mトリス原液(pH7.5)の一定量を、25mM.の最終濃度まで溶解物に添加する。最終溶解物の緩衝組成物は、20mM Hepes、25mMトリス(pH7.5、伝導度約6mS/cm)である。溶解物は濾過後もまだ若干混濁している可能性があるが、これはその後の捕捉ステップに影響しない。捕捉ステップは、直径50mm、充填層高さ20cm、充填層体積約400mLの寸法を有するXK50/30カラム(GE Healthcare社)において、DEAE Sepharose FF(GE Healthcare社)で室温で行う。投入密度は、約0.8gから1.2gバイオマス/mLゲルである。プロセスは、Akta Explorerシステム(GE Healthcare社)により行い、280nmで監視する。平衡化は、100cm/時間で、約5CVの25mMトリス、20mM Hepes、25mM NaCl(pH7.5、伝導度約5mS/cm)を用いて、pH、伝導度および280nm吸光度が安定するまで行う。溶解物を75cm/時間でカラムに投入し、通過物を廃棄する。全ての濾過された溶解物を投入したら、280nm吸光度が安定化するまで、流動を約5CVの平衡化緩衝液で再開する。5CVの25mMトリス、175mM NaCl(pH7.5、伝導度19mS/cm)による洗浄ステップ2の間に不純物をカラムから除去する。3CVの25mMトリス、375mM NaCl(pH7.5、伝導度36mS/cm)での段階的溶出により、C−TABタンパク質をカラムから溶出する。280nm吸光度が増加し始めたら(通常1CV後)、C−TAB含有分画の回収を開始し、約0.5CVから1.0CVの間継続する。C−TABを含有するプールされた分画は、2〜8℃で一晩保存することができる。中間精製ステップは、直径50mm、充填層高さ20cm、充填層体積約400mLの寸法を有するXK50/30カラム(GE Healthcare社)において、SP−Sepharose FF(GE Healthcare社)で室温で行う。最大投入密度は、約4〜5mg C−TAB/mLゲルである。プロセスは、Akta Explorerシステム(GE Healthcare社)により行い、280nmで監視する。平衡化、洗浄および線形勾配溶出ステップを、過度の背圧(>4バール)により妨げられない限り、200cm/時間(65mL/分)の最大流速で行う。pH、伝導度および280nm吸光度が安定となるまで、約5〜10CVの緩衝液Gで200cm/時間で平衡化を行う。投入前に、SP−FF樹脂上へのC−TABの結合を可能とするようにDEAEプールを調節する必要がある。最終伝導度が3.5mS/cm(pH5.5±0.1)以下となるまで、SP−FF平衡化緩衝液(10mMクエン酸、2mM EDTA(pH5.5±0.1、伝導度約2mS/cm))でDEAEプールを25倍希釈する。必要な場合は、所望の伝導度を達成するために追加のMilliQ水を添加する。SP−FF上へのC−TABの結合を可能とするためには、低い伝導度が極めて重要であることに留意されたい。試料を150cm/時間でカラムに投入し、通過物を廃棄する。試料の投入後、280nm吸光度が安定化するまで、流動を約5CVの平衡化緩衝液で200cm/時間で再開する。0%平衡化緩衝液から、10CVを超える30% 20mMリン酸ナトリウム、500mM NaCl(pH7.0)まで、100cm/時間の線形勾配により溶出を行う。分画を回収し、UV280nm吸光度によりプールを行う。プールは、ピーク最大値の15%で開始し、ピーク最大値の15%で終了する。1.5Mクエン酸原液(pH8.0)を使用して、プールをすぐに400mMのクエン酸(最終pH7、約49mS/cm)まで調節する。調節されたSPFFプールは、pH7および約49mS/cmを有するべきであり、2〜8℃で一晩保存される。
実施例2:マウスにおけるalumの存在下および非存在下での組み換えC−TAB.G5融合タンパク質の用量力価測定。
・群1:PBSのみ
・群2:100(154)ngのC−TAB.G5
・群3:300(462)ngのC−TAB.G5
・群4:1,000(1,540)ngのC−TAB.G5
・群5:3,000(4,620)ngのC−TAB.G5
・群6:10,000(15,400)ngのC−TAB.G5
・群7:50μgのalumを含むPBS
・群8:50μgのalum OHを含む10.0(15.4)ngのC−TAB.G5
・群9:50μgのalum OHを含む30.0(46.2)ngのC−TAB.G5
・群10:50μgのalum OHを含む100(154)ngのC−TAB.G5
・群11:50μgのalum OHを含む300(462)ngのC−TAB.G5
・群12:50μgのalum OHを含む1,000(1,540)ngのC−TAB.G5
実施例3:マウスにおけるC−TAB.G5の免疫原性および保護効果
・群1:PBSのみ
・群2:3μgのC−TAB.G5
・群3:10μgのC−TAB.G5
・群4:30μgのC−TAB.G5
・群5:3μgのC−TAB.G5+50μgのalum OH
・群6:10μgのC−TAB.G5+50μgのalum OH
・群7:30μgのC−TAB.G5+50μgのalum OH
・群8:PBSのみ
・群9:3μgのC−TAB.G5
・群10:10μgのC−TAB.G5
・群11:30μgのC−TAB.G5
・群12:3μgのC−TAB.G5+50μgのalum OH
・群13:10μgのC−TAB.G5+50μgのalum OH
・群14:30μgのC−TAB.G5+50μgのalum OH
実施例4:幼若および老齢マウスにおける、C−TAB.G5の免疫原性および保護効果の評価。
−群1:幼若マウスへのPBS
−群2:老齢マウスへのPBS
−群3:幼若マウスへの10μgのC−TAB.G5
−群4:幼若マウスへの30μgのC−TAB.G5
−群5:老齢マウスへの10μgのC−TAB.G5
−群6:老齢マウスへの30μgのC−TAB.G5
−群7:幼若マウスへの10μgのC−TAB.G5+50μgのalum OH
−群8:幼若マウスへの30μgのC−TAB.G5+50μgのalum OH
−群9:老齢マウスへの10μgのC−TAB.G5+50μgのalum OH
−群10:老齢マウスへの30μgのC−TAB.G5+50μgのalum OH
−群11:幼若マウスへのPBS
−群12:老齢マウスへのPBS
−群13:幼若マウスへの10μgのC−TAB.G5
−群14:幼若マウスへの30μgのC−TAB.G5
−群15:老齢マウスへの10μgのC−TAB.G5
−群16:老齢マウスへの30μgのC−TAB 5th
−群17:幼若マウスへの10μgのC−TAB.G5+50μgのalum OH
−群18:幼若マウスへの30μgのC−TAB.G5+ 50μgのalum OH
−群19:老齢マウスへの10μgのC−TAB.G5+50μgのalum OH
−群20:老齢マウスへの30μgのC−TAB.G5+50μgのalum OH
実施例5:C−TAB.G5.1ならびにとトキソイドAおよびBの免疫原性および保護効果の比較。
−群1:PBSのみ
−群2:10μgのC−TAB.G5.1
−群3:30μgのC−TAB.G5.1
−群4:10μgのC−TAB.G5.1+50μgのalum OH
−群5:10μgのC−TAB.G5.1+50μgのalum OH
−群6:30μgのトキソイドA/B
−群7:10μgのトキソイドA/B
−群8:30μgのトキソイドA/B+50μgのalum OH
−群9:30μgのトキソイドA/B+50μgのalum OH
−群10:PBS
−群11:10μgのC−TAB.G5.1
−群12:30μgのC−TAB.G5.1
−群13:10μgのC−TAB.G5.1+50μgのalum OH
−群14:30μgのC−TAB.G5.1+50μgのalum OH
−群15:10μgトキソイドA/B
−群16:30μgのトキソイドA/B
−群17:10μgのトキソイドA/B+50μgのalum OH
−群18:30μgのトキソイドA/B+50μgのalum OH
実施例5.1:異なる免疫化計画におけるC−TAB.G5.1の抗体力価および保護効果の比較。
実施例6:ハムスターにおける組み換えC−TAB.G5.1融合タンパク質の免疫原性および保護効果の評価。
・群1:製剤緩衝液のみ
・群2:10μgのC−TAB.G5.1
・群3:10μgのC−TAB.G5.1+100μgのalum OH
・群4:30μgのC−TAB.G5.1
・群5:30μgのC−TAB.G5.1+100μgのalum OH
・群6:100μgのC−TAB.G5.1
・群7:100μgのC−TAB.G5.1+100μgのalum OH
・群10:製剤緩衝液のみ
・群11.10μgのC−TAB.G5.1
・群12.10μgのC−TAB.G5.1+100μgのalum OH
・群13.30μgのC−TAB.G5.1
・群14.30μgのC−TAB.G5.1+100μgのalum OH
・群15.100μgのC−TAB.G5.1
・群16.100μgのC−TAB.G5.1+100μgのalum OH
実施例7:クリンダマイシン処理ハムスターにおけるC.ディフィシル芽胞負荷に対するC−TAB.G5.1融合タンパク質の保護効果。
群1:PBSのみ+102芽胞負荷
群2:C−TAB.G5.1+102芽胞負荷
群3:PBSのみ+103芽胞負荷
群4:C−TAB.G5.1+102芽胞負荷
群5:PBSのみ+104芽胞負荷
群6:C−TAB.G5.1+104芽胞負荷
実施例8:サルにおけるC−TAB.G5.1の免疫原性および保護効果。
実施例9:C−TAB.G5およびC−TAB.G5.1の免疫原性の比較。
群1:1μgのPBS中のC−TAB.G5
群2:3μgのPBS中のC−TAB.G5
群3:10μgのPBS中のC−TAB.G5
群4:30μgのPBS中のC−TAB.G5
群5:1μgのヒスチジン緩衝液中のC−TAB.G5
群6:3μgのヒスチジン緩衝液中のC−TAB.G5
群7:10μgのヒスチジン緩衝液中のC−TAB.G5
群8:30μgのヒスチジン緩衝液中のC−TAB.G5
群9:1μgのヒスチジン緩衝液中のC−TAB.G5.1
群10:3μgのヒスチジン緩衝液中のC−TAB.G5.1
群11:10μgのヒスチジン緩衝液中のC−TAB.G5.1
群12:30μgのヒスチジン緩衝液中のC−TAB.G5.1
実施例10:代替C−TABNCTBおよびC−TADCTB融合タンパク質の調製および評価。
実施例10.1:マウスにおけるC−TAB.G5、C−TABNCTBおよびC−TADCTBの免疫原性および保護効果の比較。
実施例10.2:ハムスターにおけるC−TAB.G5.1およびC−TADCTBの免疫原性および保護効果の比較。
実施例11:C−TAB.G5.1を含む薬学的組成物の安全性、免疫原性および用量反応を評価する非盲検第1相試験
試験目的
主目的:
・第3のワクチン接種から6か月後までの、C−TAB.G5.1を含む薬学的組成物の安全性および忍容性を調査すること。
副次的目的:
・最適な用量および製剤の第1の指標を得るための、第1のワクチン接種後0、7、14、21、28、113、201日目における、3つの異なる用量および2種の製剤に対するワクチン抗原C−TAB.G5.1ならびにC.ディフィシルの天然毒素AおよびBに対して測定される免疫反応を調査すること。
・C.ディフィシル毒素AおよびBをin vitroで中和するC−TAB.G5.1ワクチン誘導IgG抗体の能力を調査すること。
試験デザイン
試験のパートBは、高齢集団における用量確定を探求するものである。したがって、パートBは、群当たり20名の高齢健常対象の5つの治療群において行う。0、7および21日目のワクチン接種スケジュールを適用する。本試験デザインにより、成人および高齢者の両方における用量反応の比較が可能となる。後者の年齢群は、C.ディフィシルワクチンの主要な標的集団であり、年齢に基づく、または年齢−リスクに基づく予防ワクチン接種手法において、C.ディフィシルワクチンの発達経路における2つの標的指標、すなわち再発性C.ディフィシル下痢の予防および原発性C.ディフィシル感染症の予防に対し最も脆弱な集団を示す。しかしながら、高齢対象は、若年成人よりもワクチン接種に対し反応性が低い可能性があり、したがって、早期発達段階からの高齢標的集団における用量確定が必要である。パートAからの全ての成人がワクチン接種された後の中間解析によって、高齢群内の対象を、ワクチンの潜在的に安全でない、または効果のない用量(例えば最低用量)および/または製剤(例えば非アジュバント製剤)に暴露するリスクを軽減するために、安全でない、または成人において有意なIgG反応を誘導しない用量/製剤を中止することができる。
C−TAB.G5.1ワクチンは、標準的方法により生成された、20mM L−ヒスチジン、75mM NaCl、5%スクロース、0.025% Tween(登録商標)80(pH6.5)中のC−TAB.G5.1の水溶液である。
配列:
好ましいポリペプチドおよびその使用:
1.配列番号2に記載のアミノ酸配列に対して少なくとも85%、より好ましくは少なくとも90%、さらにより好ましくは少なくとも95%、最も好ましくは99%の配列同一性を有するアミノ酸配列を含む単離ポリペプチド。
2.配列番号4に記載のアミノ酸配列に対して少なくとも85%、より好ましくは少なくとも90%、さらにより好ましくは少なくとも95%、最も好ましくは99%の配列同一性を有するアミノ酸配列を含む単離ポリペプチド。
3.クロストリジウム・ディフィシルの毒素AのC末端ドメインから得られる19反復単位、およびクロストリジウム・ディフィシルの毒素BのC末端ドメインから得られる23反復単位を含む、態様1または2に記載の単離ポリペプチド。
4.配列番号2に記載のアミノ酸配列を有する、態様1に記載の単離ポリペプチド。
5.配列番号4に記載のアミノ酸配列を有する、態様1に記載の単離ポリペプチド。
6.配列番号4に記載のアミノ酸配列に対して少なくとも85%、より好ましくは少なくとも90%、さらにより好ましくは少なくとも95%、最も好ましくは99%の配列同一性を有するアミノ酸配列を含むポリペプチド。
7.前記単離ポリペプチドをワクチン接種されたハムスターは、全ての芽胞用量(102、103および104)において、致死用量のC.ディフィシル芽胞の胃内投与に対し生存する、態様6に記載のポリペプチド。
8.クロストリジウム・ディフィシルの毒素AのC末端ドメインから得られる19反復単位を含む、態様6または7に記載のポリペプチド。
9.クロストリジウム・ディフィシルの毒素BのC末端ドメインから得られる23、33または47反復単位を含む、態様6から8のいずれか1つに記載のポリペプチド。
10.配列番号2、配列番号4、配列番号18、配列番号20および配列番号2、配列番号4、配列番号18または配列番号20のいずれかと95%、96%、97%、98%、99%同一であるポリペプチドからなる群から選択される、態様6から9のいずれか1つに記載のポリペプチド。
11.単離されている、態様6から10のいずれか1つに記載のポリペプチド。
12.医薬品における使用のための、態様6から11のいずれか1つに記載のポリペプチド。
13.CDADの予防および治療のための、態様6から11のいずれか1つに記載のポリペプチド。
14.CDADのリスクを有する対象におけるCDADの予防のための、態様6から11のいずれか1つに記載のポリペプチド。
15.CDADのリスクを有する対象におけるCDADの予防のための、態様6から11のいずれか1つに記載のポリペプチドであって、CDADのリスクを有する前記対象は、i)65歳を超える対象、もしくは2歳未満の対象;ii)AIDSを有する対象;iii)免疫抑制薬を投与されている、もしくは投与される予定がある対象;iv)入院の予定がある対象、もしくは入院している対象;v)集中治療を受けている、もしくは受ける予定がある対象;vi)消化管手術を受けている、もしくは受ける予定がある対象;vii)養護施設等の長期介護を受けている、もしくは受ける予定がある対象;viii)頻繁な、および/もしくは長期的な抗生物質の使用を必要とする共存症を有する対象;またはix)再発性CDADを有する対象である、ポリペプチド。
16.医薬品における使用のための医薬の製造のための、態様6から11のいずれか1つに記載のポリペプチドの使用。
17.CDADの予防および治療のための医薬の製造のための、態様6から11のいずれか1つに記載のポリペプチドの使用。
18.CDADのリスクを有する対象におけるCDADの予防のための医薬の製造のための、態様6から11のいずれか1つに記載のポリペプチドの使用。
19.CDADのリスクを有する対象におけるCDADの予防のための医薬の製造のための、態様6から11のいずれか1つに記載のポリペプチドの使用であって、CDADのリスクを有する前記対象は、i)65歳を超える対象、もしくは2歳未満の対象;ii)AIDSを有する対象;iii)免疫抑制薬を投与されている、もしくは投与される予定がある対象;iv)入院の予定がある対象、もしくは入院している対象;v)集中治療を受けている、もしくは受ける予定がある対象;vi)消化管手術を受けている、もしくは受ける予定がある対象;vii)養護施設等の長期介護を受けている、もしくは受ける予定がある対象;viii)頻繁な、および/もしくは長期的な抗生物質の使用を必要とする共存症を有する対象;またはix)再発性CDADを有する対象である、使用。
20.態様1から11のいずれか1つに記載のポリペプチドを含む、対象におけるC.ディフィシル感染を検出するための診断キット。
好ましい核酸:
1a.態様1から11のいずれか1つに記載のポリペプチドのいずれかをコードするヌクレオチド配列を含む核酸。
2a.態様1から11のいずれか1つのポリペプチドをコードするヌクレオチド配列から本質的になる、態様1aに記載の核酸。
3a.配列番号1、配列番号3、配列番号17および配列番号19の群から選択されるヌクレオチド配列を含む、態様1aまたは2aに記載の核酸。
4a.配列番号1、配列番号3、配列番号17および配列番号19の群から選択されるヌクレオチド配列から本質的になる、態様1aまたは2aに記載の核酸。
好ましい薬学的組成物:
1c.態様1から11のいずれか1つに記載のポリペプチドまたは態様1aから4aのいずれか1つに記載の核酸、および薬学的に許容される担体または賦形剤を含む、薬学的組成物。
2c.C.ディフィシル毒素AおよびBの両方を中和する抗体を惹起する、態様1cに記載の薬学的組成物。
3c.C.ディフィシル毒素AおよびBに対する、対象における防御免疫反応を惹起する、態様1cまたは態様2cに記載の薬学的組成物。
4c.アジュバントをさらに含む、態様1cから3cのいずれか1つに記載の薬学的組成物。
5c.アジュバントが、alumを含む、態様4cに記載の薬学的組成物。
6c.追加的な抗原または薬物をさらに含む、態様1cから5cのいずれか1つに記載の薬学的組成物。
好ましい抗体:1d.態様1から11のいずれか1つに記載のポリペプチドに対する抗体であるが、C.ディフィシル毒素A(配列番号6)およびB(配列番号8)のいずれかまたは両方を認識しない抗体。
好ましい方法
1e.態様1から10のいずれか1つに記載のポリペプチドを生成するための方法であって、宿主細胞内に、ポリペプチドをコードする核酸を導入することと、ポリペプチドの発現を可能とする条件下で宿主細胞を培養することと、ポリペプチドを単離することとを含む方法。
2e.宿主細胞は、大腸菌である、態様1eに記載の方法。
3e.対象におけるC.ディフィシル関連疾患(CDAD)を治療および/または予防する方法であって、それを必要とする対象に、態様1から11のいずれか1つに記載の単離ポリペプチドを投与することを含む方法。
4e.対象においてC.ディフィシルの毒素AおよびBの両方に対する特異的免疫反応を誘導する方法であって、態様1から11のいずれか1つに記載のポリペプチドを対象に、または態様1cから6cのいずれか1つに記載の薬学的組成物を投与することを含む方法。
5e.対象におけるC.ディフィシル感染により引き起こされる原発性疾患を予防する方法であって、態様1から11のいずれか1つに記載のポリペプチドを対象に、または態様1cから6cのいずれか1つに記載の薬学的組成物を投与することを含む方法。
6e.C.ディフィシル関連疾患(CDAD)のリスクを有する対象における C.ディフィシル感染により引き起こされる原発性疾患を予防する方法であって、CDADのリスクを有する前記対象は、i)65歳を超える対象、もしくは2歳未満の対象;ii)AIDSを有する対象;iii)免疫抑制薬を投与されている、もしくは投与される予定がある対象;iv)入院の予定がある対象、もしくは入院している対象;v)集中治療を受けている、もしくは受ける予定がある対象;vi)消化管手術を受けている、もしくは受ける予定がある対象;vii)養護施設等の長期介護を受けている、もしくは受ける予定がある対象;viii)頻繁な、および/もしくは長期的な抗生物質の使用を必要とする共存症を有する対象;またはix)再発性CDADを有する対象であり、前記方法は、態様1から11のいずれか1つに記載のポリペプチドを前記対象に、または態様1cから6cのいずれか1つの薬学的組成物を投与することを含む方法。 7e.ポリペプチドまたは薬学的組成物は、対象に、筋肉内、皮内、皮下、経口、経鼻、または経直腸投与、好ましくは筋肉内投与される、態様1eから6eのいずれか1つに記載の方法。
8e.ポリペプチドまたは薬学的組成物は、短い間隔(1週間毎または2週間毎)に少なくとも2回以内の投薬で対象に投与される、態様1eから7eのいずれか1つに記載の方法。
9e.生体試料中のC.ディフィシルを検出する方法であって、生体試料を態様1から11のいずれか1つに記載のポリペプチドと接触させることと、生体試料に対するポリペプチドの結合を検出することとを含み、ポリペプチドの結合は、生体試料中のC.ディフィシルの存在を示す方法。
Claims (15)
- 配列番号4に記載のアミノ酸配列に対して少なくとも85%、より好ましくは少なくとも90%、さらにより好ましくは少なくとも95%、最も好ましくは99%の配列同一性を有するアミノ酸配列を含むポリペプチド。
- 前記単離ポリペプチドをワクチン接種されたハムスターは、全ての芽胞用量(102、103および104)において、致死用量のC.ディフィシル芽胞の胃内投与に対し生存する、請求項1に記載のポリペプチド。
- クロストリジウム・ディフィシルの毒素AのC末端ドメインから得られる19反復単位を含む、請求項1または2に記載のポリペプチド。
- クロストリジウム・ディフィシルの毒素BのC末端ドメインから得られる23、33または47反復単位を含む、請求項1から3のいずれか一項に記載のポリペプチド。
- 配列番号2、配列番号4、配列番号18、配列番号20および配列番号2、配列番号4、配列番号18または配列番号20のいずれかと95%同一であるポリペプチドからなる群から選択される、請求項1から4のいずれか一項に記載のポリペプチド。
- 単離されている、請求項1から5のいずれか一項に記載のポリペプチド。
- 医薬品における使用のための、請求項1から6のいずれか一項に記載のポリペプチド。
- C.ディフィシル関連疾患(CDAD)の予防および治療のための、請求項1から6のいずれか一項に記載のポリペプチド。
- CDADのリスクを有する対象におけるCDADの予防のための、請求項1から6のいずれか一項に記載のポリペプチド。
- CDADのリスクを有する対象におけるCDADの予防のための、請求項1から6のいずれか一項に記載のポリペプチドであって、CDADのリスクを有する前記対象は、i)65歳を超える対象、もしくは2歳未満の対象;ii)AIDSを有する対象;iii)免疫抑制薬を投与されている、もしくは投与される予定がある対象;iv)入院の予定がある対象、もしくは入院している対象;v)集中治療を受けている、もしくは受ける予定がある対象;vi)消化管手術を受けている、もしくは受ける予定がある対象;vii)養護施設等の長期介護を受けている、もしくは受ける予定がある対象;viii)頻繁な、および/もしくは長期的な抗生物質の使用を必要とする共存症を有する対象;またはix)再発性CDADを有する対象である、ポリペプチド。
- 請求項1から6のいずれか一項に記載のポリペプチドを含む、対象におけるC.ディフィシル感染を検出するための診断キット。
- 請求項1から6のいずれか一項に記載のポリペプチドのいずれかをコードするヌクレオチド配列を含む核酸。
- 請求項1から6のいずれか一項に記載のポリペプチドを生成するための方法であって、宿主細胞内に、前記ポリペプチドをコードする核酸を導入することと、前記ポリペプチドの発現を可能とする条件下で前記宿主細胞を培養することと、前記ポリペプチドを単離することとを含む、前記方法。
- 請求項1から6のいずれか一項に記載のポリペプチドまたは請求項12に記載の核酸、および薬学的に許容される担体または賦形剤を含む、医薬組成物。
- 請求項1から6のいずれか一項に記載のポリペプチドに対する抗体であるが、C.ディフィシル毒素A(配列番号6)またはC.ディフィシル毒素B(配列番号8)を認識しない抗体。
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