JP2019535678A - ExPEC複合糖質ワクチン製剤 - Google Patents
ExPEC複合糖質ワクチン製剤 Download PDFInfo
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- JP2019535678A JP2019535678A JP2019521766A JP2019521766A JP2019535678A JP 2019535678 A JP2019535678 A JP 2019535678A JP 2019521766 A JP2019521766 A JP 2019521766A JP 2019521766 A JP2019521766 A JP 2019521766A JP 2019535678 A JP2019535678 A JP 2019535678A
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- antigen polysaccharide
- polysaccharide
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Abstract
Description
1つの一般的な態様では、本発明は、大腸菌(E.coli)臨床分離株の中で主に見出されるO抗原血清型を含む多価ワクチンに関し、このワクチンはその中に含まれるO抗原血清型を有するExPECによって引き起こされる疾患を予防する能動免疫を提供するために使用することができる。一実施形態では、本発明は、少なくとも1つの大腸菌(E.coli)O抗原を含む組成物に関する。特定の実施形態では、組成物は、大腸菌(E.coli)O25B抗原多糖を含み得る。他の実施形態では、組成物は、大腸菌(E.coli)O1A、O2、および/またはO6A抗原多糖を含む。好ましい実施形態では、組成物は、大腸菌(E.coli)O1A、O2、O6A、およびO25B抗原多糖を含むが、これらは国際公開第WO2015/124769号パンフレットおよび国際公開第2017/035181号パンフレットに記載されている。これらの各参考文献は、参照によりその全体が本明細書に組み込まれる。特定の実施形態では、組成物中に、他の、またはさらなる大腸菌(E.coli)O抗原多糖が含まれる。このような大腸菌(E.coli)O抗原多糖には、限定されないが、大腸菌(E.coli)O1、O2、O4、O6、O7、O8、O15、O16、O18、O21、O25、O73、O75およびO153の血清(亜)型由来のO抗原が含まれ得る。多くの大腸菌(E.coli)血清型に対する免疫防御を提供するために、組成物は、必要に応じて、2つ以上のさらなる大腸菌(E.coli)O抗原、例えば、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20またはそれ以上のさらなる大腸菌(E.coli)O抗原を含み得る。
ここで、式O25B’中のnは、1〜30、1〜20、1〜15、1〜10、1〜5、10〜30、15〜30、20〜30、25〜30、5〜25、10〜25、15〜25、20〜25、10〜20または15〜20の整数である。本発明の一実施形態では、式O25B’中のnは10〜20の整数である。
ここで、式O1A’中のnは、1〜30、1〜20、1〜15、1〜10、1〜5、10〜30、15〜30、20〜30、25〜30、5〜25、10〜25、15〜25、20〜25、10〜20または15〜20の整数である。本発明の一実施形態では、式O1A’中のnは7〜15の整数である。
ここで、式O2’中のnは、1〜30、1〜20、1〜15、1〜10、1〜5、10〜30、15〜30、20〜30、25〜30、5〜25、10〜25、15〜25、20〜25、10〜20または15〜20の整数である。一実施形態では、式O2’中のnは8〜16の整数である。
ここで、β1,2結合はまたβ2結合とも称され、式O6A’中のnは、1〜30、1〜20、1〜15、1〜10、1〜5、10〜30、15〜30、20〜30、25〜30、5〜25、10〜25、15〜25、20〜25、10〜20または15〜20の整数である。一実施形態では、式O6A’中のnは8〜18の整数である。
本発明の組成物は、例えば、それを必要としている対象へExPECに対する免疫応答を誘導する方法に使用することができる。免疫応答は、それを必要としている対象におけるExPECに関連する疾患を予防または治療するのに有効であることが好ましい。方法は、本発明による組成物を対象に投与することを含む。
実施形態1は、大腸菌(E.coli)O25B抗原多糖、大腸菌(E.coli)O1A抗原多糖、大腸菌(E.coli)O2抗原多糖、および大腸菌(E.coli)O6A抗原多糖の1つ以上、好ましくは大腸菌(E.coli)O25B、O1A、O2およびO6A抗原多糖の4つ全て(ここで、各抗原多糖は緑膿菌(Pseudomonas aeruginosa)エキソトキシンA(EPA)担体タンパク質に共有結合している);3%(w/v)〜8%(w/v)(好ましくは、4%(w/v)〜6%(w/v))のソルビトール;5〜15mM(好ましくは、8〜12mM)のメチオニン;5〜20mM(好ましくは8〜15mM)のリン酸カリウム/ナトリウム緩衝液(pH6.5〜7.5);ならびに0.01%(w/v)〜0.2%(w/v)界面活性剤を含む免疫原性組成物である。
a.大腸菌(E.coli)O25B抗原多糖、大腸菌(E.coli)O1A抗原多糖、大腸菌(E.coli)O2抗原多糖、および大腸菌(E.coli)O6A抗原多糖(ここで、各抗原多糖は緑膿菌(Pseudomonas aeruginosa)エキソトキシンA(EPA)担体タンパク質に共有結合している);
b.5%(w/v)のソルビトール;
c.10mMのメチオニン;
d.6.19mMのKH2PO4および3.81mMのNa2HPO4緩衝液(pH7.0);ならびに
e.0.02%(w/v)のPS80
を含む免疫原性組成物である。
a.大腸菌(E.coli)O25B抗原多糖、大腸菌(E.coli)O1A抗原多糖、大腸菌(E.coli)O2抗原多糖、および大腸菌(E.coli)O6A抗原多糖(ここで、各抗原多糖は緑膿菌(Pseudomonas aeruginosa)エキソトキシンA(EPA)担体タンパク質に共有結合している);
b.8%(w/v)のスクロース;
c.1mMのEDTA;
d.10mMのリン酸カリウム/ナトリウム(例えば、6.19mMのKH2PO4および3.81mMのNa2HPO4)緩衝液(pH7.0);ならびに
e.0.02%(w/v)のPS80
を含む免疫原性組成物である。
どのような組み合わせの賦形剤を、それぞれ独立して、別個の緑膿菌(Pseudomonas aeruginosa)のエキソトキシンA(EPA)に共有結合した大腸菌(E.coli)O25B、O1A、O2、O6A抗原多糖(すなわち、合計4つの別個の複合糖質)(以下、ExPEC複合糖質と呼ぶ)に添加して、凍結/融解、撹拌、熱誘発ストレス、および金属誘発酸化ストレスに対する安定化を助けることができるかを決定するために、異なる賦形剤を、最初のExPEC複合糖質製剤(ExPEC複合糖質、25mMトリス、pH7.4、137mM NaCl、2.7mM KCl)(以下、「旧」ExPEC複合糖質と呼ぶ。これは、ExPEC複合糖質の第2相臨床試験、ClinicalTrials.gov 識別名:NCT02546960において現在使用されている製剤である)に添加し、得られた製剤の安定化の増加を、適切な方法によって試験した。
界面活性剤がExPEC複合糖質の凍結/融解誘発凝集を抑制できることを実証した後、製剤に好適な緩衝液、pH、および浸透圧調節剤を調べた。追跡実験において、浸透圧調節剤としてのNaCl(150mM)または5%(w/v)のソルビトールの存在下、および全てがPS80(0.01%(w/v)を含有する、異なる緩衝液−pHの組み合わせをカバーするいくつかの製剤を調べた。旧製剤(25mMトリス、pH7.4、137mM NaCl、2.7mM KCl)を対象として使用した。多くの濃度のExPEC複合糖質(例えば、各多糖について16または8μg/mL)を試験したが、試験した製剤の安定化に、濃度差の影響は観察されなかった(データは示さず)。
ExPEC複合糖質の安定性に関して最良の候補製剤を特定するために、さらなる製剤を設計した。緩衝液およびpHについては、ヒスチジンをpH6.5および7.0で評価し、純粋なリン酸カリウムの代わりに、リン酸カリウム/ナトリウム緩衝液(KH2PO4/Na2HPO4)をpH6.5および7.0で評価した。カリウムとナトリウムの組み合わせは、最初の結果に基づいて選択され、凍結/融解時の局所pH緩衝能をより良くカバーする。緩衝系の調製においては、ナトリウムよりもカリウムが優勢である(例えば、pH=7.0の10mMリン酸緩衝液では、6.19mMのKH2PO4および3.81mMのNa2HPO4を使用した)。浸透圧調節剤として、スクロース(8%(w/v))およびソルビトール(5%(w/v))を評価した。さらに、抗酸化剤のEDTA(1mM)またはメチオニン(10mM)を評価した。また、NaClの非存在またはソルビトールの存在が、実施例2で観察された保護効果をもたらすか否かを、これらの組み合わせを含む製剤(それぞれ半分の濃度を、これらの成分を実施例2のように個々に使用した場合と比較)を含めることによって試験した。製剤は全て、PS80を0.02%(w/v)の濃度で含有した。
製剤26および28を、金属誘発生成物酸化のモデルとして、タングステンの存在下でのExPEC複合糖質に対するそれらの安定化効果をさらに評価した。タングステン残渣は、通常、タングステンピンを用いたチップ形成プロセスの結果である、ガラスプレフィルドシリンジ(PFS)のチップに存在する。PFS中のタングステン残渣の堆積は製造プロセスに依存し、PFS製造業者間で250〜1250ナノグラム/バレルの範囲で変化し得る。タングステンは、PFSにおけるタンパク質凝集と関連している(Jiang et al.,J.Pharmaceutical Sci.98(12):4695−710(2009);Seidl et al.,Pharmaceutical Res.29:1454−67(2012))。したがって、酸化ストレスおよびExPEC複合糖質の凝集傾向をモニターしながら、異なる濃度のタングステンに曝露したときの製剤26および28ならびに旧製剤の安定性を調べた。この評価では、現在市販されているPFS中に存在するタングステン残渣の全てのレベルをカバーする3つのレベルのタングステン(高(HW)、中(MW)、および低(LW))を調べた。製剤に適用したストレス条件を表4に要約する。
ポリカーボネート(PC)およびポリエチレンテレフタレートグリコール(PETG)などの様々なプラスチック材料と接触させたExPEC複合糖質原薬(O25B複合体、多糖の試験濃度227〜242μg/mLおよびタンパク質の試験濃度952〜1048μg/mL)に対する製剤26および28の安定化効果をさらに評価した。プラスチック材料は、例えば、プラスチック材料を照射によって滅菌した場合に、タンパク質分解に関係している。PETGおよびPC容器中、過酷な撹拌ストレス(室温で200rpmで24時間)下で、製剤の安定性を試験した。旧製剤は、PETG容器中、これらの条件下で完全な分解を示した。対照的に、SEC−HPLC分析が示しているように(図4を参照、不安定性の指標としてプレピーク1を使用)、製剤26および28は、試験したPETGおよびPC容器において同じ条件下で安定なままであった。さらに、25℃でPCおよびPETG容器に7日間保存したこれらの製剤中の原薬の安定性が観察された(データは示さず)。
Claims (17)
- a.大腸菌(E.coli)O25B抗原多糖、大腸菌(E.coli)O1A抗原多糖、大腸菌(E.coli)O2抗原多糖、および大腸菌(E.coli)O6A抗原多糖(ここで、各抗原多糖は緑膿菌(Pseudomonas aeruginosa)エキソトキシンA(EPA)担体タンパク質に共有結合している);
b.3%(w/v)〜8%(w/v)のソルビトール;
c.5〜15mMのメチオニン;
d.5〜20mMのリン酸カリウム/ナトリウム緩衝液(pH6.5〜7.5);ならびに
e.0.01%(w/v)〜0.2%(w/v)の界面活性剤
を含む免疫原性組成物。 - 前記ソルビトールの濃度は5%(w/v)である、請求項1に記載の免疫原性組成物。
- 前記メチオニンの濃度は10mMである、請求項1または2に記載の免疫原性組成物である。
- 前記リン酸カリウム/ナトリウム緩衝液の濃度は10mMであり、かつ前記リン酸カリウム/ナトリウム緩衝液のpHは7.0である、請求項1〜3のいずれか一項に記載の免疫原性組成物。
- 前記界面活性剤は非イオン性界面活性剤であり、好ましくは、前記界面活性剤はF−68、PS20およびPS80からなる群から選択される、請求項1〜4のいずれか一項に記載の免疫原性組成物。
- 前記界面活性剤はPS80であり、好ましくは、前記PS80の濃度は0.02%(w/v)である、請求項5に記載の免疫原性組成物。
- a.大腸菌(E.coli)O25B抗原多糖、大腸菌(E.coli)O1A抗原多糖、大腸菌(E.coli)O2抗原多糖、および大腸菌(E.coli)O6A抗原多糖(ここで、各抗原多糖は緑膿菌(Pseudomonas aeruginosa)エキソトキシンA(EPA)担体タンパク質に共有結合している);
b.5%(w/v)のソルビトール;
c.10mMのメチオニン;
d.10mMのKH2PO4/Na2HPO4緩衝液(pH7.0);
e.0.02%(w/v)のPS80;ならびに
f.水
からなる免疫原性組成物。 - a.大腸菌(E.coli)O25B抗原多糖、大腸菌(E.coli)O1A抗原多糖、大腸菌(E.coli)O2抗原多糖、および大腸菌(E.coli)O6A抗原多糖(ここで、各抗原多糖は緑膿菌(Pseudomonas aeruginosa)エキソトキシンA(EPA)担体タンパク質に共有結合している);
b.3%(w/v)〜12%(w/v)のスクロース;
c.0.1〜1.5mMのEDTA;
d.5〜20mMのリン酸カリウム/ナトリウム緩衝液(pH6.5〜7.5);ならびに
e.0.01%(w/v)〜0.2%(w/v)の界面活性剤
を含む免疫原性組成物。 - 前記スクロースの濃度は8%(w/v)である、請求項8に記載の免疫原性組成物。
- 前記EDTAの濃度は1mMである、請求項8または9の記載の免疫原性組成物。
- 前記リン酸カリウム/ナトリウム緩衝液の濃度は10mMであり、かつ前記リン酸カリウム/ナトリウム緩衝液のpHは7.0である、請求項8〜10のいずれか一項に記載の免疫原性組成物。
- 前記界面活性剤は非イオン性界面活性剤であり、好ましくは、前記界面活性剤はF−68、PS20およびPS80からなる群から選択される、請求項8〜11のいずれか一項に記載の免疫原性組成物。
- 前記界面活性剤はPS80であり、好ましくは、前記PS80の濃度は0.02%(w/v)である、請求項12に記載の免疫原性組成物。
- a.大腸菌(E.coli)O25B抗原多糖、大腸菌(E.coli)O1A抗原多糖、大腸菌(E.coli)O2抗原多糖、および大腸菌(E.coli)O6A抗原多糖(ここで、各抗原多糖は緑膿菌(Pseudomonas aeruginosa)エキソトキシンA(EPA)担体タンパク質に共有結合している);
b.8%(w/v)のスクロース;
c.1mMのEDTA;
d.10mMのKH2PO4/Na2HPO4緩衝液(pH7.0);
e.0.02%(w/v)のPS80;ならびに
f.水
からなる免疫原性組成物。 - 2〜8℃の温度で保存した場合に、少なくとも6ヶ月間、好ましくは少なくとも12ヶ月間、より好ましくは少なくとも18ヶ月間安定である、請求項1〜14のいずれか一項に記載の免疫原性組成物。
- 前記各O抗原多糖の濃度は約1〜200μg/mL、例えば約2〜100μg/mL、例えば約8〜48μg/mLであり、好ましくは、前記多糖:担体タンパク質比は、各O抗原多糖について、約1:10〜約1:2、好ましくは約1:5〜約1:2である、請求項1〜15のいずれか一項に記載の免疫原性組成物。
- EPA担体タンパク質に共有結合した大腸菌(E.coli)O抗原を含む液体免疫原性組成物を安定に保持する方法であって、請求項1〜16のいずれか一項に記載の組成物を、2〜8℃の温度で少なくとも6ヶ月間保存することを含む方法。
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