JP5956974B2 - パピローマウイルスワクチン組成物 - Google Patents
パピローマウイルスワクチン組成物 Download PDFInfo
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- JP5956974B2 JP5956974B2 JP2013254271A JP2013254271A JP5956974B2 JP 5956974 B2 JP5956974 B2 JP 5956974B2 JP 2013254271 A JP2013254271 A JP 2013254271A JP 2013254271 A JP2013254271 A JP 2013254271A JP 5956974 B2 JP5956974 B2 JP 5956974B2
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- hpv
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- aluminum
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Description
本発明は、HPVに関連した罹患および死亡をなくす最も有効な方法である、患者におけるHPVに対する免疫応答の誘導および患者におけるHPVの感染の予防をもたらしうる医薬組成物および製剤を提供する。本発明は、本発明で提供する組成物および製剤の使用方法も提供する。
本発明において、少なくとも1つのHPV型のHPV VLP、ISCOM型アジュバントおよびアルミニウムアジュバントを含むHPVワクチン製剤が、アルミニウムアジュバントのみを含むVLPワクチンと比較して、該標的化HPV型に対する、より高いAb力価を、動物モデルおよびヒト患者において惹起しうることが示されている。この目的のために、後記で詳細に説明するとおり、ISCOM型アジュバントと組合されたアルミニウムアジュバントに吸着されたHPV VLPを含むHPV VLPワクチン製剤および医薬組成物を本発明において提供する。
HPV VLPに基づくワクチンに対する免疫応答が、アルミニウムアジュバントのみで得られる力価より増大しうるかどうかを判定するために、8価HPV VLPワクチンを、無定形アルミニウムヒドロキシホスファートスルファート(AAHS)+ISCOMATRIX(登録商標)アジュバントと共に、アカゲザルに投与した。
免疫応答を示すために、免疫化されたサルからの血清抽出物を競合Luminexイムノアッセイ(cLIA)により分析した。該HPV cLIAは、HPV 8価ワクチンでの免疫化に対する免疫応答をモニターするために8つの型特異的コンホメーション依存性mAbを使用する。試験サンプル中の複数のHPV型に対する抗体の存在を同時に測定するために粒子に基づくフローサイトメトリー分析を利用する競合Luminexイムノアッセイの、より詳細な説明は、米国特許第7,067,258号およびOpalkaら,Clin Diagn Lab Immunol.10(1):108−15(2003)に記載されている。抗体除去ヒト血清(Antibody Depleted Human Serum)(ADHS)を含有する前スクリーニングアッセイマトリックスにおいて、各HPV型に関して8価参照標準溶液を調製した。該参照標準は、HPV 1価L1 VLP 6、11、16、18、31、45、52、58型で過免疫化されたアカゲザルからの血清サンプルのプールであった。すべての標準、対照およびサンプルを2回重複して試験した。血清サンプルの試験は、1:4、1:40、1:400または1:4000の希釈度で行った。蛍光単位を読取り、2回重複試験のウェルを平均した。各アッセイプレートに関する標準曲線の4パラメータロジスティックフィットに基づいて、希釈度補正mMu/mL血清値を計算した。標準曲線に関する定量の限界を超えたサンプルは、より高い希釈度で再試験した。過剰変動性(extra variability)を満たさなかった重複試験物は表示されておらず、ついで該サンプルは、それらが重複パラメーターを満足するまで再試験した。該アッセイに関する対照仕様を開発し、定量の限界を各HPV型に関して確定した。
ヒト患者においてHPVに対する免疫応答を増強するISCOMATRIX(登録商標)(IMX)の能力を臨床治験において評価した。無定形アルミニウムヒドロキシホスファートスルファート(MAA)でアジュバント化された8価HPV VLPワクチンを試験する2相無作為化二重盲検多施設IMX用量増加対照研究を開始した。被験者を2つの別々の研究相に無作為化した。MAA(281mcg)で製剤化された一定濃度のHPV VLPを含有する実験用8価ワクチンの場合において、各0.5mL用量当たり15または30mcg(相A)および60または120mcg(相B)のIMX濃度を評価し、GARDASIL(登録商標)と比較した。該8価ワクチンは、6型(20mcg)、11型(40mcg)、16型(40mcg)、18型(20mcg)、31型(20mcg)、45型(20mcg)、5型(20mcg)および58型(20mcg)のHPV VLPを含有していた。GARDASIL(登録商標)は、高精製L1 VLPから製造された4価HPV(6、11、16、18型)組換えワクチンである。VLPに加えて、各ワクチン用量はMAA(225mcg)、塩化ナトリウム、L−ヒスチジン、ポリソルベート80、ホウ酸ナトリウムおよび水を含有していた。
4つの異なる8価HPVサンプル、±MAAおよび±IMXを製剤化した。すべての製剤はHPV VLPを以下の量で含有していた:40μg/mL HPV6、80μg/mL HPV11、80μg/mL HPV16、ならびにHPV18、31、45、52および58 VLPのそれぞれ40μg/mL。また、0.32M NaCl、10mM ヒスチジン(pH6.2)および0.01% ポリソルベート80(PS80)が該製剤のそれぞれに含まれていた。第1製剤はIMXアジュバントもMAAアジュバントも含有していたなかった。第2製剤は240μg/mLのIMXを含有し、MAAを含有していなかった。試験した第3製剤はIMXを含有せず、562.5μg/mL(1.25×)のMAAを含有していた。試験した第4製剤は240μg/mLのIMXおよび562.5μg/mL(1.25×)MAAの両方を含有していた。
サンプルを、Invitrogen 4から20%または14%、1.5mm、10ウェルTris−グリシンゲルを使用するSDS−PAGEにより分析した。サンプルを還元性サンプルバッファー(0.25M Tris PH6.8、8% SDS、40% グリセロール、0.008% ブロモフェノールブルー、ジチオトレイトール)中で調製し、70℃で10分間加熱する。アルミニウムアジュバントを含有するサンプルをサンプル調製前に762μg/mLまで濃縮し、該アルミニウムを溶解するために0.5M EDTA(pH8.0)を加えた。
インビトロ相対効力(IVRP)試験により、参照標準と比較して、HPV6、11、16、18、31、45および52型VLPサンプルの効力を定量した。IVRPアッセイは、捕捉および検出のために別々のモノクローナル抗体を使用するサンドイッチ型イムノアッセイである。
IVRP=(ED50サンプル/ED50標準)×参照標準効力
を用いて、最終IVRPを計算した。ついで該結果を、タンパク質濃度で割り算してIVRP対タンパク質比を得ることにより正規化した。該IVRP対タンパク質比は単位質量当たりの機能性エピトープの尺度となる。
抗微生物試験(抗微生物有効性(AME)試験)を用いて、候補HPVワクチン製剤における種々の保存剤の有効性を評価した。産物の取り出し後にバイアル内に導入されうる微生物を減少させ又は排除する保存剤の能力を決定するために、AME試験を用いた。該アッセイの説明は、米国薬局方(USP)<51>、欧州薬局方5.1.3およびMeyerら,J.Pharm.Sci.96(12):3155−3167(2007)(これを参照により本明細書に組み入れることとする。)を参照されたい。簡潔に説明すると、AME試験はEPA、EPBおよびUSP基準を含み、それらは、時間0の時点で容器当たり105から106 CFU/mLの微生物(例えば、細菌および真菌)を接種し、経時的な対数減少を評価することよりなる(Meyerら,前掲)。
示差走査熱量測定法(DSC)を用いて、タンパク質の構造的および熱的安定性に対する保存剤の影響を評価した。VP−Capillary DSC Platform(MicroCal,LLC,Northampton,MA)を用いて、抗原熱安定性の分析を行った。用いた条件の詳細な説明はIonescuら(2007)(J.Pharm.Sci 97(4):1414−1426(2008))に開示されている。
HPV18 VLPおよび種々の保存剤を含むHPVワクチン製剤のインビトロ抗原性を、中和抗体結合アッセイ(Biacore,表面プラズモン共鳴)を用いて評価した。Biacore 2000(VPR 332)およびBiacore 3000(VPR 696)(Biacore,Inc.,Piscataway,NJ)を用いて、抗原生物活性の分析を行った。用いた条件は、Machら(J.Pharm.Sci.95: 2195−2206 (2006))に記載されているものに修飾を施したものであった。
Dunnら(J.Pharm Sci 72:277−80(1983))に記載されているとおりに逆相(RP)−高圧液体クロマトグラフィー(HPLC)を用いて、保存剤安定性の分析を行った。この方法を用いて、アルミニウムアジュバント、ガラス容器および栓との保存剤の可能な相互作用を評価した。
AME、DSCおよびBiacore分析から得られた初期データ(実施例7から9)に基づいて、5つの保存剤含有製剤(1.2%および0.9% ベンジルアルコール、0.5% クロロブタノール、0.3% m−クレーゾールおよび0.5% フェノール)を、長期安定性研究における更なる分析のために選択した。IMXアジュバントの存在下または非存在下に種々の用量および組合せの保存剤を含有する幾つかのHPVワクチン製剤を試験した。
まず、即時研究(2から8℃)からの製剤を、AME試験を用いて、保存剤有効性に関して時間0の時点で評価した。IMXの存在下または非存在下に0.5% クロロブタノールおよび0.3% m−クレーゾールを含有する製剤はUSP、EP−BおよびEP−A試験に合格した。1.2% ベンジルアルコールを含有する製剤はIMXの非存在下ではUSP、EP−BおよびEP−Aに合格したが、IMX含有製剤においてはEP−Aに合格しなかった。IMXの存在下または非存在下でEP−Aに合格しなかった製剤は0.9% ベンジルアルコールおよび0.5% フェノールをも含んでいた。
多用量保存剤含有サンプルの安定性を、HPV VLPに関してはインビトロ抗原性(Biacore)を用いて、そして保存剤およびIMXの安定性に関してはRP−HPLCを用いて評価した。
多用量HPVワクチンにおける保存剤の安定性を、既に記載されているとおりに(実施例10)、RP−HPLC分析によりモニターした。結果は、全5種の保存剤が、IMXの存在下または非存在下、多用量ワクチン製剤中で安定であったことを示している(図9)。保存温度または期間にかかわらず、この研究中に試験した全ての製剤に関して、保存剤の喪失は観察されなかった。
Claims (2)
- (a)少なくとも1つのHPV型のHPVウイルス様粒子(VLP)であって、前記HPV VLPは、HPVの組換えL1または組換えL1+L2タンパク質を含むHPVウイルス様粒子、
(b)アルミニウムアジュバント、及び
(c)m−クレゾール、フェノールおよびベンジルアルコールよりなる群から選ばれる抗微生物保存剤であって、該抗微生物保存剤が、0.15から0.31%の濃度のm−クレゾール、0.25から0.55%の濃度のフェノールまたは0.75から1.2%の濃度のベンジルアルコールよりなる群から選ばれる、
を含んでなる多用量HPVワクチン製剤であって、
前記HPV VLPは、前記アルミニウムアジュバント上に吸着されている、2〜8℃において8か月安定な多用量HPVワクチン製剤。 - 抗微生物保存剤が、0.3%の濃度のm−クレゾール、0.5%の濃度のフェノールまたは0.9%の濃度のベンジルアルコールよりなる、請求項1に記載の多用量ワクチン製剤。
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CN102229660B (zh) | 2011-05-25 | 2015-04-22 | 厦门大学 | 截短的人乳头瘤病毒33型l1蛋白 |
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AU2008226974B2 (en) | 2013-08-15 |
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