JP6639077B2 - β−プロピオラクトン処理による低レベルの残存細胞DNAを含む細胞由来のウイルスワクチン - Google Patents
β−プロピオラクトン処理による低レベルの残存細胞DNAを含む細胞由来のウイルスワクチン Download PDFInfo
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- JP6639077B2 JP6639077B2 JP2014149517A JP2014149517A JP6639077B2 JP 6639077 B2 JP6639077 B2 JP 6639077B2 JP 2014149517 A JP2014149517 A JP 2014149517A JP 2014149517 A JP2014149517 A JP 2014149517A JP 6639077 B2 JP6639077 B2 JP 6639077B2
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Description
本発明は、減少された不純物を伴う、改善された細胞培養プロダクトおよびプロセスを提供する。具体的には、本発明は、細胞培養で作製されたプロダクトと関連する残存しているいかなる残存機能性細胞培養物DNAをも分解する改善された方法を提供する。本発明によれば、残存機能性細胞培養物DNAは、DNAアルキル化剤、例えばβ−プロピオラクトン(BPL)での処理によって分解される。このプロセスは、ワクチンおよび組換えタンパク質を含む一連の細胞培養プロダクトを処理するために使用され得る。
この危険性を低下させるための現在の努力は、残存宿主細胞DNAの総濃度を低下させることに注目してきた。本発明の目的は、いかなる残存宿主細胞DNAの機能性をも排除することによって、さらに危険性を低下させることである。
本発明は、減少された不純物を伴う、改善された細胞培養プロダクトおよびプロセスを提供する。具体的には、本発明は、細胞培養で作製されたプロダクトと関連する残存しているいかなる残存機能性細胞培養物DNAをも分解する改善された方法を提供する。本発明によれば、残存機能性細胞培養物DNAは、DNAアルキル化剤、例えばβ−プロピオラクトン(BPL)での処理によって分解される。このプロセスは、ワクチンおよび組換えタンパク質を含む一連の細胞培養プロダクトを処理するために使用され得る。
本発明は、例えば、以下の項目を提供する:
(項目1)
細胞培養物において増殖されたウイルスから誘導された免疫原性タンパク質を含むワクチンであって、該ワクチンが残存機能性細胞培養物DNAを実質的に含まない、ワクチン。
(項目2)
あらゆる残存細胞培養物DNAがアルキル化剤での処理によって分解される、項目1に記載のワクチン。
(項目3)
前記アルキル化剤がβ−プロピオラクトン(BPL)である、項目2に記載のワクチン。
(項目4)
前記分解された残存細胞培養物DNAの長さが500塩基対未満である、項目1に記載のワクチン。
(項目5)
前記分解された残存細胞培養物DNAの長さが200塩基対未満である、項目1に記載のワクチン。
(項目6)
前記残存細胞培養物DNAが0.1%未満のβ−プロピオラクトン(BPL)での処理によって分解される、項目3に記載のワクチン。
(項目7)
前記ワクチンが低下したレベルの凝集を示す、項目1に記載のワクチン。
(項目8)
細胞培養物において増殖されたウイルスから誘導された免疫原性タンパク質を含むワクチンであって、残存細胞培養物DNAの長さが500塩基対未満である、ワクチン。
(項目9)
前記残存細胞培養物DNAがアルキル化剤での処理によって分解される、項目8に記載のワクチン。
(項目10)
前記アルキル化剤がβ−プロピオラクトン(BPL)である、項目9に記載のワクチン。
(項目11)
前記残存細胞培養物DNAの長さが300塩基対未満である、項目8に記載のワクチン。
(項目12)
前記残存細胞培養物DNAの長さが200塩基対未満である、項目8に記載のワクチン。
(項目13)
前記残存細胞培養物DNAが0.1%未満のβ−プロピオラクトン(BPL)での処理によって分解される、項目8に記載のワクチン。
(項目14)
前記ワクチンが低下したレベルの凝集を示す、項目8に記載のワクチン。
(項目15)
組み合わされた0.01%未満の遊離プロピオン酸およびβ−プロピオラクトン(BPL)を含有する、項目10に記載のワクチン。
(項目16)
細胞培養物において増殖されたウイルスから誘導された免疫原性タンパク質を含むワクチンを調製する方法であって、以下:
(i)残存機能性細胞培養物DNAを分解する工程;および
(ii)該免疫原性タンパク質を単離する工程
を包含する、方法。
(項目17)
前記残存機能性細胞培養物DNAを分解する工程が、アルキル化剤での機能性細胞培養物DNAの処理を含む、項目16に記載の方法。
(項目18)
前記アルキル化剤がβ−プロピオラクトン(BPL)である、項目17に記載の方法。
(項目19)
前記細胞培養物DNAが0.1%未満のβ−プロピオラクトン(BPL)での処理によって分解される、項目18に記載の方法。
(項目20)
前記ワクチンが低下したレベルの凝集を示す、項目16に記載の方法。
(項目21)
工程(ii)が、ビリオンからDNAを分離することを含む、項目16〜20のいずれか1項に記載の方法。
(項目22)
前記ウイルスがインフルエンザウイルスである、項目1または8に記載のワクチン。
(項目23)
前記細胞培養物が、MDCK細胞、Vero細胞、およびPER.C.6細胞からなる群より選択される、項目1または8に記載のワクチン。
(項目24)
細胞培養物中において発現された組換えタンパク質を含む製剤であって、該製剤が残存機能性細胞培養物DNAを実質的に含まない、製剤。
(項目25)
あらゆる残存細胞培養物DNAがアルキル化剤での処理によって分解されている、項目24に記載の製剤。
(項目26)
前記アルキル化剤がβ−プロピオラクトン(BPL)である、項目25に記載の製剤。
(項目27)
前記分解された残存細胞培養物DNAの長さが500塩基対未満である、項目24に記載の製剤。
(項目28)
前記分解された残存細胞培養物DNAの長さが200塩基対未満である、項目24に記載の製剤。
(項目29)
前記残存細胞培養物DNAが0.1%未満のβ−プロピオラクトン(BPL)での処理によって分解される、項目26に記載の製剤。
(項目30)
前記製剤が低下したレベルの凝集を示す、項目24に記載の製剤。
(項目31)
細胞培養物中において発現された組換えタンパク質を含む製剤であって、残存機能性細胞培養物DNAの長さが500塩基対未満である、製剤。
(項目32)
前記細胞培養物が、MDCK細胞、Vero細胞、およびPER.C6細胞からなる群より選択される、項目24または31に記載の製剤。
本発明は、減少された不純物を伴う、改善された細胞培養プロダクトおよびプロセスを提供する。具体的には、本発明は、細胞培養で作製されたプロダクトと関連する残存しているいかなる残存機能性細胞培養物DNAをも分解する改善された方法を提供する。本発明によれば、残存機能性細胞培養物DNAは、DNAアルキル化剤、例えばβ−プロピオラクトン(BPL)での処理によって分解される。このプロセスは、ワクチンおよび組換えタンパク質を含む一連の細胞培養プロダクトを処理するために使用され得る。
本発明は、細胞培養物において増殖されたウイルスから誘導された免疫原性タンパク質を含むワクチンであって、該ワクチンが残存機能性細胞培養物DNAを実質的に含まないワクチンを含む。さらに、本発明は、細胞培養物中において発現された組換えタンパク質であって、最終組換えタンパク質製剤が残存機能性細胞培養物DNAを実質的に含まない組換えタンパク質に関する。
本発明における使用のためのアルキル化剤としては、アルキル基を化合物中に導入する物質が挙げられる。好ましくは、アルキル化剤は、モノアルキル化剤、例えばBPLである。BPLは、多くのワクチンの調製においてウイルス不活性化のために広く使用されるモノアルキル化剤である。BPLは、核酸を含む種々の生物学的分子と反応し、ここで、それは、アルキル化および脱プリン反応によって構造的修飾を引き起こす。BPLは、一般的に、下記の構造によって表される:
本発明における使用に好適な免疫原性タンパク質は、ワクチンの標的である任意のウイルスから誘導され得る。免疫原性タンパク質は、不活性化(または死滅)ウイルス、弱毒化ウイルス、分割された(split)ウイルス製剤、精製されたサブユニット製剤、ウイルスから単離、精製または誘導されるウイルスタンパク質、およびウイルス様粒子(VLP)として製剤化され得る。
1991)に記載されるウイルス抗原がさらに提供され、これらは、本発明の組成物と共に考慮される。
本発明のワクチン組成物は、免疫原性タンパク質の単離および残存機能性宿主細胞DNAの分解によって調製され得る。同様に、組換えタンパク質製剤は、組換えタンパク質の単離または精製および残存機能性宿主細胞DNAの分解によって調製され得る。これらの工程は、連続的にまたは同時に行われ得る。残存機能性細胞培養物DNAを分解する工程は、アルキル化剤(例えば、BPL)の添加によって行われる。
本発明のワクチンは、細胞培養物において増殖されるウイルスから調製される。さらに、本発明は、細胞培養物中において発現された組換えタンパク質の製剤を含む。哺乳動物細胞培養物が、ウイルス複製および組換えタンパク質発現の両方について好ましい。
4CDM(BioWhittaker)またはSMIF 7(Gibco/BRL Life Technologies)のような化学的に規定される培地、およびPrimactone、PepticaseもしくはHyPepTM(全てQuest International製)マイトジェンペプチドまたはラクトアルブミン加水分解物(Gibcoおよび他の製造業者)もまた、当該分野において十分に公知である。植物加水分解物に基づく培地添加物は、ウイルス、マイコプラズマまたは未知の感染性因子での汚染が排除され得るという特別な利点を有する。
本発明の組成物は、薬学的に許容される。それらは、通常、抗原に加えて、成分を含み、例えば、それらは、典型的に、1以上の薬学的担体および/または賦形剤を含む。このような成分の完全な議論は、Remington:The Science and Practice of Pharmacy(Gennaro,2000;第20版,ISBN:0683306472)において入手可能である。
本発明の組成物は、動物(および、特に、ヒト)患者への投与に好適であり、そして本発明は、本発明の組成物を患者へ投与する工程を含む、患者における免疫応答を引き起こす方法を提供する。
残存宿主細胞DNAの測定は、当業者の通常の能力内である。本発明の組成物中の残存DNAの総量は、好ましくは、20ng/ml未満、例えば、≦10ng/ml、≦5ng/ml、≦1ng/ml、≦100pg/ml、≦10pg/ml等である。上述されるように、このDNAの実質的に全てが、好ましくは、500塩基対未満の長さである。
34:195−197)。公認されたアッセイの性能特徴は、数学的および定量化可能な用語で記載され得、そしてエラーのその可能性のある供給源が同定された。アッセイは、一般的に、精度、正確さ、特異性等の特徴について試験された。アッセイが(例えば、既知の標準量の宿主細胞DNAに対して)較正されそして試験されると、定量DNA測定が規定通りに行われ得る。DNA定量についての3つの原理技術が使用され得る:ハイブリダイゼーション法、例えば、サザンブロットまたはスロットブロット(slot blots)(Jiら(2002)Biotechniques.32:1162−7);免疫学的決定法、例えば、ThresholdTMシステム(Briggs(1991)J
Parenter Sci Technol.45:7−12.;および定量PCR(Lahijaniら(1998)Hum Gene Ther.9:1173−80)。これらの方法は全て当業者によく知られているが、各方法の正確な特徴は、問題の宿主細胞、例えば、ハイブリダイゼーションについてのプローブの選択、増幅についてのプライマーおよび/またはプローブの選択等に依存し得る。Molecular Devices製のThresholdTMシステムは、ピコグラムレベルのトータルDNAについての定量アッセイであり、そして生物薬剤中のコンタミDNAのレベルをモニタリングするために使用されてきた(Briggs(1991)、上記参照)。典型的なアッセイは、ビオチン化ssDNA結合タンパク質と、ウレアーゼ結合体化抗ssDNA抗体と、DNAとの間の反応複合体の非配列特異的形成を含む。全てのアッセイ成分は、前記製造業者から入手可能な完全なトータルDNAアッセイキット中に含まれる。種々の商業製造業者が、残存宿主細胞DNAを検出するための定量PCRアッセイ、例えば、AppTecTM Laboratory Services、BioRelianceTM、Althea Technologies等を提供している。ヒトウイルスワクチンの宿主細胞DNA汚染を測定することについてのトータルDNA ThresholdTMシステムおよび化学発光ハイブリダイゼーションアッセイの比較が、Lokteffら(2001)
Biologicals.29:123−32に見られ得る。
本発明の組成物は、該組成物を受容する患者において誘発される免疫応答(液性および/または細胞性)を増強するように機能し得る、アジュバントを含み得る。ウイルスワクチンと共のアジュバントの使用は、例えば、肝炎ワクチン、ポリオワクチン等において、周知である。FLUADTMインフルエンザワクチンは、水中油型エマルジョンアジュバントを含む。
Adjuvants:Preparation Methods and Research Protocols,volume 42 of Methods in Molecular Medicine series,ISBN:1−59259−083−7)において、より詳細に開示されている。
●スクアレン、Tween 80、およびSpan 85のサブミクロンエマルジョン。体積での前記エマルジョンの組成は、約5%スクアレン、約0.5%ポリソルベート80、および約0.5% Span 85であり得る。重量表現では、これらの比は、4.3%スクアレン、0.5%ポリソルベート80、および0.48% Span 85となる。このアジュバントは、Powell & Newmanの第10章およびO’Haganの第12章により詳細に記載されるように、「MF59」として公知である。MF59エマルジョンは、有利には、クエン酸イオン、例えば10mMクエン酸ナトリウム緩衝液を含む。
80を溶解して2%溶液を提供し、次いでこの溶液90mlを(5gのDL−α−トコフェロールおよび5mlスクアレン)の混合物と混合し、次いで該混合物をマイクロフルイダイズすることによって、作製され得る。得られるエマルジョンは、例えば100〜250nm、好ましくは約180nmの平均直径を有する、サブミクロン油滴を有し得る。
本発明は、インフルエンザウイルスワクチンを調製するために特に好適である。種々の形態のインフルエンザウイルスワクチンが、現在入手可能である;例えば、Plotkin & Orenstein(Vaccines,第4版,2004,ISBN:0−7216−9688−0)の第17および18章を参照のこと。それらは、一般的に、生ウイルスまたは不活性化ウイルスのいずれかに基づく。不活性化ワクチンは、全ビリオン、「分割された」ビリオン、または精製された表面抗原(血球凝集素を含む)に基づき得る。インフルエンザ抗原はまた、ビロソーム(virosome)(核酸フリーのウイルス様リポソーム粒子)の形態で提示され得る。組換え宿主(例えば、バキュロウイルスベクターを使用して昆虫細胞株中)から精製された抗原もまた使用され得る。
用語「含む(comprising)」は「包含する(including)」および「からなる(consisting)」を含み、例えば、Xを「含む」組成物は、Xのみからなってもよく、または追加のもの、例えばX+Yを含んでもよい。
Eur 一般章5.2.3におけるように、好ましくは、ヒトワクチン製造における使用について認可されたものである。
インフルエンザウイルス(A/ニューカレドニア/20/99(H1N1)、A/パナマ/2007/99(H3N2);B/江蘇(Jiangsu)/10/2003;A/ワイオミング/3/2003(H3N2))を、WO97/37000、WO03/23025およびWO04/92360の教示に従って、懸濁培養中においてMDCK細胞において増殖した。最終培養培地を浄化し、ビリオンが得られ、次いでこれをクロマトグラフィーおよび限外濾過/ダイアフィルトレーションに供した。得られた材料中のビリオンを、β−プロピオラクトンを使用して不活性化した(最終濃度0.05% v/v;2〜8℃で16〜20時間インキュベートし、そして次いで37℃で2〜2.5時間インキュベートすることによって加水分解した)。次いで、CTABを使用してビリオンを分割し、そして種々のさらなる処理工程によって、精製された表面抗原を含有する最終一価バルクワクチンが得られた。
上述されるように、残存宿主細胞DNAのサイズを、段階(A)、(B)および(C)において、キャピラリーゲル電気泳動によって分析した。分析を5つの別個のウイルス培養物について行った。
新生物性細胞形質転換は、しばしば修飾されたプロトオンコジーンおよび/または修飾された腫瘍抑制遺伝子と関連する現象である。いくつかのこのようなイヌ遺伝子由来の配列を、BPL処理前および後に、即ち、時点(A)および(B)において、PCRによって分析した。さらに、非感染MDCK細胞由来のDNAを処理し、そして試験した。試験したプロトオンコジーンは、以下であった:H−rasおよびc−myc。試験した腫瘍抑制遺伝子は、以下であった:p53;p21/waf−l;およびPTEN。さらに、反復SINE配列をPCRによって分析した。SINEについての高コピー数は、高感度な検出を促進する。
ウイルス不活性化の間のBPL処理は、2つの独立した工程を有した:(1)2〜8℃でビリオン含有混合物へBPLを添加し;次いで(2)温度を37℃へ上げ、BPLを加水分解する。MDCK DNA不活性化およびフラグメント化に対する前記2つのBPL工程の効果を研究した。
さらなる実験において、BPLを、先ず、4℃で16時間細胞と共にインキュベートした。第1集団において、温度を2時間37℃へ上昇させ;第2集団において、BPLを遠心濾過機によって除去し、そして次いで温度を上昇させた。遥かに低い(>2ログより低い)残存DNAレベルが、第1集団において見られた。
したがって、BPL処理の間に観察されるDNAフラグメント化は、2〜8℃でのウイルス不活性化工程の間よりはむしろ、37℃でのBPL加水分解工程の間に主に生じるようである。
Claims (9)
- 細胞培養物において増殖された2つ以上のインフルエンザウイルス株から誘導された免疫原性タンパク質を含むインフルエンザワクチンであって、該免疫原性タンパク質がインフルエンザ血球凝集素であり、該ワクチンが20ng/mL未満の残存細胞培養物DNAを含み、該残存細胞培養物DNAの長さが200塩基対未満であり、該ワクチンが、約0.5mlの単一投薬容量において1株当たり約10μgまたは約15μgの該インフルエンザ血球凝集素を含み、該細胞培養物が、哺乳動物細胞培養物または鳥類細胞培養物から選択される、インフルエンザワクチン。
- 0.1%未満のβ−プロピオラクトン(BPL)を含むワクチンである、請求項1に記載のワクチン。
- 前記細胞培養物が、MDCK細胞、Vero細胞、およびPER.C6細胞からなる群より選択される、請求項1または2に記載のワクチン。
- 水中油型エマルジョンアジュバントをさらに含む、請求項1〜3のいずれかに記載のワクチン。
- 前記水中油型エマルジョンアジュバントがサブミクロン径の油滴を有する、請求項4に記載のワクチン。
- 前記水中油型エマルジョンアジュバントが、スクアレン、ポリオキシエチレン(20)ソルビタンモノオレエートおよびソルビタントリオレエートを含む、請求項5に記載のワクチン。
- 前記水中油型エマルジョンアジュバントが、スクアレン、トコフェロールおよびポリオキシエチレン(20)ソルビタンモノオレエートを含む、請求項4または5に記載のワクチン。
- 前記ワクチンが、1株当たり約15μgのインフルエンザ血球凝集素を含む、請求項1〜7のいずれかに記載のワクチン。
- 前記ワクチンが、細胞培養物において増殖された3つ以上のインフルエンザウイルス株から誘導された免疫原性タンパク質を含む、請求項1〜8のいずれかに記載のワクチン。
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