JP2020533438A - 肺炎球菌多糖体および免疫原性多糖体−キャリアタンパク質コンジュゲートでのその使用 - Google Patents
肺炎球菌多糖体および免疫原性多糖体−キャリアタンパク質コンジュゲートでのその使用 Download PDFInfo
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- JP2020533438A JP2020533438A JP2020513531A JP2020513531A JP2020533438A JP 2020533438 A JP2020533438 A JP 2020533438A JP 2020513531 A JP2020513531 A JP 2020513531A JP 2020513531 A JP2020513531 A JP 2020513531A JP 2020533438 A JP2020533438 A JP 2020533438A
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Abstract
Description
本発明の血清型からのストレプトコッカス・ニューモニエ由来の莢膜多糖体は、当業者に公知の標準的な技術により調製することができる。例えば、多糖体は、細菌から単離することができ、既知の方法によって(例えば、欧州特許番号EP497524および欧州特許番号EP497525を参照)、好ましくは、ホモジナイザーを使用して達成されるマイクロ流動化または化学的加水分解によって、ある程度までサイズ調整され得る。一実施形態では、各多糖体血清型に対応するS.ニューモニエ株を大豆ベースの培地で増殖させる。次いで、遠心分離、沈殿および限外濾過を含む標準的な工程によって個々の多糖体を精製する。例えば、米国特許出願公開番号2008/0286838および米国特許第5,847,112号を参照されたい。多糖体をサイズ調整して、粘度を低下させる、および/またはその後のコンジュゲート生成物の濾過性を改善することができる。化学的加水分解は、酢酸を使用して行われ得る。機械的サイジングは、高圧ホモジナイズ化せん断を使用して行われてもよい。
S.ニューモニエ血清型のうちの1つ以上に由来する多糖体はキャリアタンパク質(「Pr」)にコンジュゲートされ、小児、高齢者および/または免疫不全患者の免疫原性を改善することができる。多価組成物に複数の血清型が使用される場合、同じキャリアタンパク質または異なるキャリアタンパク質を用いて血清型が調製されてもよい。同じ血清型の各莢膜多糖体は、典型的には、同じキャリアタンパク質にコンジュゲートされる。
)、サイトカイン、リンホカイン、増殖因子もしくはホルモン(国際特許出願公開番号WO91/01146を参照)、様々な病原体由来抗原に由来する複数のヒトCD4+T細胞エピトープを含む人工タンパク質(Falugi et al.,2001,Eur J Immunol 31:3816−3824を参照)、例えばN19タンパク質(Baraldoi et al.,2004,Infect Immun 72:4884−7を参照)、鉄取込みタンパク質(国際特許出願公開番号WO01/72337を参照)、C.ディフィシル(C.difficile)の毒素AもしくはB(国際特許公開番号WO00/61761を参照)、およびフラジェリン(Ben−Yedidia et al.,1998,Immunol Lett 64:9を参照)もまたキャリアタンパク質として使用することができる。
コンジュゲーションの前に、精製された多糖体を、糖をキャリアタンパク質と反応させて活性化多糖体を形成させることができるように、化学的に活性化され得る。本明細書で使用される用語「活性化多糖体」は、リンカーまたはキャリアタンパク質へのコンジュゲーションを可能にするために、以下に記載されるように化学的に修飾された多糖体を指す。精製された多糖体は、リンカーに接続されてもよい。活性化されるかリンカーに接続されると、各莢膜多糖体は、キャリアタンパク質に別個にコンジュゲートされてグリココンジュゲートを形成する。多糖体コンジュゲートは、既知のカップリング技術によって調製され得る。
本発明の特定の実施形態では、多価多糖体ワクチンは、多価肺炎球菌ワクチンを提供するために、遊離多糖体、多糖体−タンパク質コンジュゲートの成分またはそれらの組合せとして、非コンジュゲートS.ニューモニエ血清型16F多糖体および/または血清型16F由来の多糖体−タンパク質コンジュゲートと、S.ニューモニエ血清型1、2、3、4、5、6A、6B、6C、6D、7B、7C、7F、8、9N、9V、10A、11A、12F、14、15A、15B、15C、17F、18B、18C、19A、19F、20、21、22A、22F、23A、23B、23F、24B、24F、27、28A、31、33F、34、35A、35B、35Fおよび38のうちの1つ以上に由来する莢膜多糖体とを含む。本発明の特定の実施形態では、免疫原性組成物は、1つ以上のキャリアタンパク質に個々にコンジュゲートされた、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43または44のS.ニューモニエ血清型由来の莢膜多糖体を含むか、それから本質的になるか、それからからなる。好ましくは、特定の血清型に由来する糖は、複数のキャリアタンパク質にはコンジュゲートされていない。
本発明はさらに、薬学的に許容される担体およびアジュバントとともに、上記の多糖体S.ニューモニエ血清型の組合せのいずれかを含むか、本質的にそれからなるか、それからなる医薬、免疫原性およびワクチン組成物を含む組成物を提供する。
(1)アルミニウム塩(ミョウバン)、例えば、水酸化アルミニウム、リン酸アルミニウム、硫酸アルミニウムなど;
(2)(ムラミルペプチド(以下に定義)などの特定の免疫刺激剤または細菌細胞壁成分の有無にかかわらず)水中油型エマルジョン製剤、例えば、(a)モデル110Yマイクロフルイダイザー(Microfluidics,Newton,MA)などのマイクロフルイダイザーを使用してサブミクロン粒子に配合された5%スクアレン、0.5%Tween 80および0.5%Span 85を含有する(様々な量のMTP−PEを含有してもよい)MF59(国際特許出願公開番号WO90/14837)、(b)サブミクロンエマルジョンにマイクロ流動化されるか、大きな粒径のエマルジョンを生成するためにボルテックスされた10%スクアレン、0.4%Tween 80、5%プルロニックブロックポリマーL121およびthr−MDPを含有するSAF、(c)2%スクアレン、0.2%Tween 80、ならびに米国特許第4,912,094号に記載の3−O−脱アシル化モノホスホリルリピドA(MPL(商標))、トレハロースジミコレート(TDM)、および細胞壁骨格(CWS)、好ましくはMPL+CWS(Detox(商標))からなる群からの1つ以上の細菌細胞壁成分を含有するRibi(商標)アジュバント系(RAS)、(Corixa,Hamilton,MT);(d)Montanide ISA;
(3)Quil AまたはSTIMULON(商標)QS−21(Antigenics,Framingham,MA)のようなサポニンアジュバント(例えば、米国特許第5,057,540号を参照)が使用されるか、ISCOM(コレステロール、サポニン、リン脂質および両親媒性タンパク質の組合せにより形成された免疫刺激複合体)およびIscomatrix(登録商標)(ISCOMと本質的に同じ構造を有するが、タンパク質を含まない)のようなそれから生成された粒子;
(4)Corixaから入手可能であり、米国特許第6,113,918号に記載されているアミノアルキルグルコサミンホスフェート化合物(AGP)またはその誘導体もしくは類似体などの細菌リポ多糖、合成脂質A類似体;そのようなAGPの1種は、水性形態または安定なエマルジョンとして製剤化されている529としても知られている(以前はRC529として知られていた)2−[(R)−3−テトラデカノイルオキシテトラデカノイルアミノ]エチル2−デオキシ−4−O−ホスホノ−3−O−[(R)−3−テトラデカノイルオキシテトラデカノイル]−2−[(R)−3−テトラデカノイルオキシテトラデカノイルアミノ]−b−D−グルコピラノシドである;
(5)(1または複数の)CpGモチーフを含有するオリゴヌクレオチドなどの合成ポリヌクレオチド(米国特許第6,207,646号);
(6)サイトカイン、例えば、インターロイキン(例えば、IL−1、IL−2、IL−4、IL−5、IL−6、IL−7、IL−12、IL−15、IL−18など)、インターフェロン(例えば、ガンマインターフェロン)、顆粒球マクロファージコロニー刺激因子(GM−CSF)、マクロファージコロニー刺激因子(M−CSF)、腫瘍壊死因子(TNF)、共刺激分子B7−1およびB7−2など;ならびに
(7)補体、例えば、補体成分C3dの三量体。
本発明の組成物および製剤は、全身または粘膜経路を介してワクチンを投与することにより、感染症、例えば肺炎球菌感染症に易感染性のヒトを防御または治療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、S.ニューモニエ莢膜多糖体コンジュゲートに対する免疫応答を誘発する方法であって、本発明の免疫原性組成物の免疫学的有効量をヒトに投与することを含む方法を提供する。別の実施形態では、本発明は、肺炎球菌感染に対してヒトをワクチン化する方法であって、本発明の免疫原性組成物の免疫学的有効量をヒトに投与する工程を含む方法を提供する。
本発明の組成物は、非経口的、経粘膜的、経皮的、筋肉内、静脈内、皮内、鼻腔内、皮下、腹腔内のような当業者に公知の1つ以上の方法によって対象に投与することができ、それに応じて製剤化することができる。
HPSEC/UV/MALS/RIアッセイを使用したコンジュゲートの分子量および濃度分析
高速サイズ排除クロマトグラフィー(HPSEC)によってコンジュゲート試料が注入および分離される。紫外線(UV)、多角度光散乱(MALS)および屈折率(RI)検出器を順次使用して検出が達成される。吸光係数を使用してUV280からタンパク質濃度が計算される。mL/gで報告された溶質濃度の変化を伴う、溶液の屈折率の変化であるdn/dc因子を使用して、RIシグナル(タンパク質および多糖体の両方によってもたらされる)から多糖体濃度がデコンボリューションされる。全試料ピークにわたる測定濃度および光散乱情報を使用するAstraソフトウェア(Wyatt Technology Corporation,Santa Barbara,CA)によって、試料の平均分子量が計算される。多分散分子の分子量の平均値には複数の形態がある。例えば、数平均分子量Mn、重量平均分子量Mwおよびz平均分子量Mz(Molecules,2015,20:10313−10341)である。指定されない限り、本明細書全体にわたって使用される用語「分子量」は、重量平均分子量である。
コンジュゲート試料のコンジュゲーションの程度を測定するためにWaters AccQ−Tagアミノ酸分析(AAA)が使用される。Eldexワークステーションにおいて気相酸加水分解を使用して試料を加水分解して、キャリアタンパク質をそれらの成分のアミノ酸に分解する。6−アミノキノリル−N−ヒドロキシスクシンイミジルカルバメート(AQC)を使用して遊離アミノ酸を誘導体化する。次いで、C18カラム上でのUV検出を伴うUPLCを使用して、誘導体化された試料を分析する。リジン以外の代表的なアミノ酸を使用して平均タンパク質濃度を得る。コンジュゲーション中のリジン消費(すなわちリジン損失)は、コンジュゲート中の平均測定リジン量と出発タンパク質中の予測リジン量との差によって決定される。
コンジュゲート試料中の遊離多糖体(すなわち、CRM197とコンジュゲートされていない多糖体)を、遊離タンパク質、ならびにデオキシコレート(DOC)および塩酸とのコンジュゲートを最初に沈殿させることによって、測定する。次いで、沈殿物を濾過し、濾液を、遊離多糖体濃度について、HPSEC/UV/MALS/RIにより分析する。遊離多糖体は、HPSEC/UV/MALS/RIによって測定された総多糖体の割合として計算される。
ミセル動電クロマトグラフィー(MEKC)モードのキャピラリー電気泳動により、コンジュゲート試料中の遊離多糖体、多糖体‐CRM197コンジュゲートおよび遊離CRM197を分離する。簡潔には、試料を25mMボレート、100mM SDS、pH9.3を含有するMEKCランニング緩衝液と混合し、プレコンディションされた裸溶融シリカキャピラリーで分離する。分離を200nmでモニターし、CRM197標準曲線を用いて遊離CRM197を定量する。遊離タンパク質の結果は、HPSEC/UV/MALS/RI手順によって決定された総タンパク質含有量の割合として報告される。
[実施例1]
S.ニューモニエ莢膜多糖体の調製
肺炎球菌を培養する方法は、当技術分野で周知である。例えば、Chase,1967,Methods of Immunology and Immunochemistry 1:52を参照されたい。肺炎球菌莢膜多糖体を調製する方法も当技術分野で周知である。例えば、欧州特許番号EP0497524B1を参照されたい。以下に説明するプロセスは、一般に、欧州特許番号EP0497524B1に記載された方法に従い、特に変更された場合を除き、あらゆる肺炎球菌血清型に一般に適用可能である。
肺炎球菌多糖体の精製は、いくつかの遠心分離、深層濾過、濃縮/ダイアフィルトレーション操作および沈殿工程からなった。特に指定のない限り、手順はいずれも室温で行った。
多糖体のNMR構造分析
多糖体構造を決定するための戦略には、Abeygunawardana et al.,Determination of the Chemical Structure of Complex Polysaccharides by Heteronuclear NMR Spectroscopy in Advances in Biophysical Chemistry 1993,Vol 3,pages 199−249,JAI Press Inc.に記載されているように実質的に行われる複数工程のプロセスを含めた。標準の1Dおよび2D NMR技術を使用して、精製された多糖体を調査した。S.ニューモニエ16F血清型由来の多糖体がO−アセチルを含むと同定されたため、脱−O−アセチル化多糖体について詳細な分析を行った(塩基加水分解を使用してO−アセテート基を除去した)。最後に、31P NMRを使用して、ホスフェートの存在について多糖体を調査した。
水溶液中の還元的アミノ化を使用したCRM197へのS.ニューモニエ血清型16F多糖体のコンジュゲーション
多糖体を溶解させ、サイズを縮小し、化学的に活性化し、限外濾過により緩衝液交換した。次いで、反応混合物中の塩化ニッケルを利用して、精製されたCRM197を活性化多糖体にコンジュゲートさせ、そして、得られたコンジュゲートは、最終の0.2ミクロン濾過の前に限外濾過により精製した。pH、温度、濃度および時間のような各工程内のいくつかのプロセスパラメーターを制御して、望ましい属性を有するコンジュゲートを得た。
精製された肺炎球菌莢膜多糖体粉末を水に溶解させ、0.45ミクロンで濾過した。溶解させた多糖体を均質化して、分子量を低下させた。均質化圧力とホモジナイザーを通過する回数とを、200bar/5回通過、続いて500bar/5回通過に制御して、目標分子量までサイズを縮小した。次いで、サイズが縮小された多糖体を濃縮し、そして、10kDa NMWCO接線流限外濾過膜を使用して、水に対してダイアフィルトレーションした。
酸化多糖体溶液を水および1.5Mリン酸カリウムpH7.0と混合した。選択した緩衝液のpHは、コンジュゲーション反応中の活性化多糖体の安定性を改善するためのものであった。前述のように(WO2012/173876A1)シュードモナス・フルオレッセンスでの発現により得られた精製されたCRM197を0.2ミクロンで濾過し、多糖体とCRM197との質量比0.7で緩衝多糖体溶液と組み合わせた。質量比を選択して、得られたコンジュゲート中の多糖体とCRM197との比を制御した。多糖体およびホスフェートの濃度は、それぞれ7.5g/Lおよび100mMであった。多糖体濃度を選択して、得られたコンジュゲートのサイズを制御した。次いで、溶液を0.2ミクロンで濾過した。100mM塩化ニッケル溶液を使用して、塩化ニッケルを約2mMまで加えた。シアノ水素化ホウ素ナトリウム(多糖体繰り返し単位1モル当たり2モル)を加えた。コンジュゲーションを122時間進行させて、多糖体およびタンパク質の消費を最大化させた。
コンジュゲーション反応後、バッチを約3.0g/Lの多糖体濃度に希釈し、2〜8℃に冷却し、そして、1.2ミクロンで濾過した。バッチを、100kDa NMWCO接線流限外濾過膜を使用して、2〜8℃で100mMリン酸カリウム、pH7.0に対してダイアフィルトレーションした。次いで、保持液中に回収したバッチを約2.0g多糖体/Lに希釈し、pH9.4の1.2M重炭酸ナトリウムを加えてpH調整した。水素化ホウ素ナトリウム(多糖体繰り返し単位1モル当たり1モル)を加えた。後に1.5Mリン酸カリウム、pH6.0を加えた。
次いで、バッチを濃縮し、そして、300kDa NMWCO接線流限外濾過膜を使用して、150mM塩化ナトリウムpH7.0中の10mMヒスチジンに対して4℃でダイアフィルトレーションした。保持液バッチに0.05%(w/v)の濃度までポリソルベート20を加え、次いで、バッチを0.2ミクロンで濾過した。
S.ニューモニエ血清型16F多糖体の活性化部位の同定
S.ニューモニエ血清型16F多糖体の活性化部位を、pH5の5mMシトレート緩衝液中で(水和)アルデヒドとチオセミカルバジド(TSC)とを反応させることによって同定した。TSCは、アルデヒド(および水和アルデヒド)と反応してイミン(二次アルジミン)を形成する。形成されたイミンプロトンは多糖体シグナルのダウンフィールドである固有の化学シフトを有し、このイミンプロトンを使用して多糖体の酸化部位を調べた。
ジメチルスルホキシド中の還元的アミノ化を使用したCRM197へのS.ニューモニエ血清型16F多糖体のコンジュゲーション
多糖体を溶解させ、目標分子量にサイズ調整し、化学的に活性化し、限外濾過により緩衝液交換した。活性化多糖体および精製されたCRM197を個別に凍結乾燥させ、そして、ジメチルスルホキシド(DMSO)に再溶解させた。次いで、再溶解させた多糖体およびCRM197溶液を組み合わせ、下記のようにコンジュゲートさせた。得られたコンジュゲートを、最終的な0.2ミクロン濾過の前に、限外濾過により精製した。pH、温度、濃度および時間のような各工程内のいくつかのプロセスパラメーターを制御して、望ましい属性を有するコンジュゲートを得た。
精製された肺炎球菌莢膜Ps粉末を水に溶解させ、そして、0.45ミクロンで濾過した。溶解させた多糖体をホモジナイズして、Psの分子量のサイズを縮小した。均質化圧力とホモジナイザーを通過する回数とを800〜1000bar/5回通過に制御した。
前述のように(WO2012/173876A1)シュードモナス・フルオレッセンスでの発現により得られた精製されたCRM197を、5kDa NMWCO接線流限外濾過膜を使用して、2mMホスフェート、pH7.0緩衝液に対してダイアフィルトレーションし、0.2ミクロンで濾過した。
コンジュゲーション反応に続いて、水素化ホウ素ナトリウム(多糖体繰り返し単位1モル当たり2モル)を加え、22℃で1時間インキュベートした。バッチを、約4℃で、約0.025%(w/v)ポリソルベート20を含む150mM塩化ナトリウムに希釈した。次いで、リン酸カリウム緩衝液を加えてpHを中和した。いくつかのバッチについては、バッチを濃縮し、そして、30kD NMWCO接線流限外濾過膜を使用して、150mM塩化ナトリウム、25mMリン酸カリウムpH7に対して約4℃でダイアフィルトレーションした。
次いで、バッチを濃縮し、そして、300kDa NMWCO接線流限外濾過膜を使用して、0.015%(w/v)ポリソルベート20を含む150mM塩化ナトリウムpH7.0中の10mMヒスチジンに対して4℃でダイアフィルトレーションした。
一価コンジュゲートの製剤化
実施例3に記載されているように、肺炎球菌多糖体−CRM197コンジュゲートを調製した。個々のバルク多糖体濃度のバッチ容量および濃度に基づいて、個々の血清型の目標濃度を得るのに必要なバルクコンジュゲートの必要量を計算した。個々の血清型を賦形剤と組み合わせ、滅菌濾過し、そして、混合条件下でAPAに加えた。20mMヒスチジン、150mM NaCl、0.2%(w/v)PS−20、およびAPAの形態の0.250mg/mL(w/v Al)を含む各一価コンジュゲートワクチンの最終濃度は、4μg/mL(w/v PnPs)であった。
一価コンジュゲートニュージーランド白ウサギ免疫原性試験
ニュージーランド白ウサギ(NZWR)モデルにおいて、一価コンジュゲートの免疫原性を評価した。0日目および14日目(交互の体側部)に、各一価コンジュゲートワクチン0.25mlを用いて、成体ニュージーランド白ウサギ(NZWR、n=3/群)を筋肉内(IM)免疫した。免疫1回当たり、62.5μgのリン酸アルミニウムアジュバント(APA)とともに1μgのPnPs(CRM197にコンジュゲートされたS.ニューモニエ血清型16F多糖体)の用量で一価肺炎球菌ワクチンを投与した。試験開始前(免疫前)および14日目(投与後1、PD1)および28日目(投与後2、PD2)に、血清を採取した。病気または苦痛の徴候がないか、訓練を受けた動物ケアスタッフがNZWRを少なくとも連日観察した。NZWRに対するワクチン製剤は、安全で忍容性が高いとみなされた。動物実験はいずれも、国立衛生研究所のGuide for Care and Use of Laboratory Animalsの推奨事項に厳密に従って行った。NZWR実験プロトコルは、Merck&Co.,Inc(Kenilworth,NJ)およびCovance(Denver,PA)のInstitutional Animal Care and Use Committeesによって承認された。
ウサギ多価試験のための肺炎球菌コンジュゲートワクチンの製剤化
肺炎球菌多糖体−CRM197コンジュゲートを使用して、異なるコンジュゲートバルクブレンド調製物(S.ニューモニエ血清型16F、23A、23B、24Fおよび31由来のものを含む)からなる多価肺炎球菌コンジュゲートワクチンを調製し、総多糖体濃度84μg/mLに対して各血清型4μg/mLで、20mMヒスチジンpH5.8および150mM塩化ナトリウムおよび0.1%w/vのポリソルベート−20(PS−20)で製剤化した。肺炎球菌多糖体(PnPs)型(S.ニューモニエ血清型16F、23A、23B、24Fおよび31由来のものを含む)にCRM197タンパク質を個別にコンジュゲートすることによりコンジュゲートを調製した。個々のバルク多糖体濃度のバッチ容量および濃度に基づいて、個々の血清型の目標濃度を得るのに必要なバルクコンジュゲートの必要量を計算した。個々のコンジュゲートを、ヒスチジン、塩化ナトリウムおよびポリソルベート−20(PS−20)の溶液に加えてコンジュゲートブレンドを作製した。磁気撹拌棒を使用して、コンジュゲートブレンドを含む製剤容器を混合し、滅菌濾過して別の容器に入れた。次いで、製剤を、プラスチック製シリンジ、ガラス製シリンジまたはバイアルに充填し、2〜8℃で保存した。
ニュージーランド白ウサギにおける多価肺炎球菌コンジュゲートワクチンの免疫原性
0日目および14日目(交互の体側部)に、実施例8に記載の多価肺炎球菌コンジュゲートワクチン0.5mlを用いて、成体ニュージーランド白ウサギ(NZWR、n=5/群)を筋肉内(IM)免疫した。免疫1回当たり各コンジュゲートPnPs 2μgで、多価肺炎球菌コンジュゲートワクチンを投与した。試験開始前(免疫前)および14日目(投与後1、PD1)および28日目(投与後2、PD2)に、血清を採取した。病気または苦痛の徴候がないか、訓練を受けた動物ケアスタッフがNZWRを少なくとも連日観察した。NZWRに対するワクチン製剤は、安全で忍容性が高いとみなされた。動物実験はいずれも、国立衛生研究所のGuide for Care and Use of Laboratory Animalsの推奨事項に厳密に従って行った。NZWR実験プロトコルは、Merck&Co.,IncおよびCovance(Denver,PA)のInstitutional Animal Care and Use Committeesによって承認された。
Claims (30)
- 前記多糖体が10〜5000の繰り返し単位を有する、請求項1に記載の多糖体。
- 前記多糖体が150〜2000の繰り返し単位を有する、請求項1に記載の多糖体。
- 前記多糖体が、MALSにより決定される50kDa〜4000kDaの平均分子量を有する、請求項1に記載の多糖体。
- 前記多糖体が、MALSにより決定される100kDa〜3500kDaの分子量を有する、請求項1に記載の多糖体。
- xが0.5〜1.0である、請求項1に記載の多糖体。
- xが0.7〜1.0である、請求項6に記載の多糖体。
- 前記活性化が前記グリセロール−1−PO4糖のうちの1つ以上で起こる、請求項8に記載の活性化多糖体。
- 前記多糖体が過ヨウ素酸塩によって活性化される、請求項8に記載の活性化多糖体。
- 前記活性化が、前記グリセロール−1−PO4糖のうちの1つ以上の炭素2位で起こる、請求項10に記載の活性化多糖体。
- 活性化の程度が前記グリセロール−1−PO4糖の各々でほぼ等しく生じる、請求項11に記載の活性化多糖体。
- 前記キャリアタンパク質が、CRM197、ジフテリア毒素フラグメントB(DTFB)、DTFB C8、ジフテリアトキソイド(DT)、破傷風トキソイド(TT)、TTのフラグメントC、百日咳トキソイド、コレラトキソイド、E.coli LT、E.coli ST、またはシュードモナス・エルギノーサ由来の外毒素Aである、請求項13に記載の多糖体−タンパク質コンジュゲート。
- 前記キャリアタンパク質がCRM197である、請求項14に記載の多糖体−タンパク質コンジュゲート。
- 前記多糖体−タンパク質コンジュゲートが1,000kDa〜10,000kDaの分子量を有する、請求項15に記載の多糖体−タンパク質コンジュゲート。
- 前記多糖体−タンパク質コンジュゲートが、0.4〜2.0の多糖体対タンパク質比を有する、請求項15に記載の多糖体−タンパク質コンジュゲート。
- 前記タンパク質が、グリセロール−1−PO4糖の炭素2位を介して前記多糖体にコンジュゲートされている、請求項13に記載の多糖体−タンパク質コンジュゲート。
- 請求項13から18のいずれか一項に記載の多糖体−タンパク質コンジュゲートと、薬学的に許容される担体とを含む免疫原性組成物。
- 更に、CRM197にコンジュゲートされた、ストレプトコッカス・ニューモニエの血清型1、2、3、4、5、6A、6B、6C、6D、7B、7C、7F、8、9N、9V、10A、11A、12F、14、15A、15B、15C、17F、18C、19A、19F、20、21、22A、22F、23A、23B、23F、24F、27、28A、31、33F、34、35A、35B、35Fおよび38のうちの少なくとも1つに由来する莢膜多糖体を含む多糖体−タンパク質コンジュゲートを含む、請求項19に記載の免疫原性組成物。
- 存在する場合0.8〜8μg/mLの多糖体を含有する血清型6B多糖体を除いて、0.4〜4μg/mLの各多糖体と、多糖体の総量の約0.5倍〜3倍の量のCRM197キャリアタンパク質とを含有するように製剤化される、請求項20に記載の免疫原性組成物。
- 150mM塩化ナトリウムと、20mM L−ヒスチジン緩衝液と、0.05〜2%w/vの界面活性剤とをさらに含む、請求項21に記載の免疫原性組成物。
- アジュバントをさらに含む、請求項22に記載の免疫原性組成物。
- 前記アジュバントがアルミニウムベースのアジュバントである、請求項23に記載の免疫原性組成物。
- 前記アジュバントが、リン酸アルミニウム、硫酸アルミニウムおよび水酸化アルミニウムからなる群から選択される、請求項24に記載の免疫原性組成物。
- 前記アジュバントがリン酸アルミニウムである、請求項25に記載の免疫原性組成物。
- 前記リン酸アルミニウムアジュバントが0.05〜0.5mg/mLの濃度で存在する、請求項26に記載の免疫原性組成物。
- 150mM塩化ナトリウムと、20mM L−ヒスチジン緩衝液と、0.05〜2%w/vの界面活性剤とをさらに含む、請求項27に記載の免疫原性組成物。
- ストレプトコッカス・ニューモニエ莢膜多糖体に対する免疫応答を誘発する方法であって、請求項19から28のいずれか一項に記載の免疫原性組成物の免疫学的有効量をヒトに投与することを含む方法。
- 前記免疫原性組成物が、存在する場合4μgである血清型6B多糖体を除いて、2μgの各多糖体と、約32μgのCRM197キャリアタンパク質と、0.125mgのリン酸アルミニウムアジュバントと、150mM塩化ナトリウムと、20mM L−ヒスチジン緩衝液と、0.2%w/vのPS−20とを含有するように製剤化された単一の0.5mL用量である、請求項29に記載の方法。
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US11160855B2 (en) | 2014-01-21 | 2021-11-02 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
AU2017388891A1 (en) | 2016-12-30 | 2019-07-04 | Vaxcyte, Inc. | Polypeptide-antigen conjugates with non-natural amino acids |
US11951165B2 (en) | 2016-12-30 | 2024-04-09 | Vaxcyte, Inc. | Conjugated vaccine carrier proteins |
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US11400162B2 (en) | 2017-02-24 | 2022-08-02 | Merck Sharp & Dohme Llc | Processes for the formulation of pneumococcal polysaccharides for conjugation to a carrier protein |
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US10729763B2 (en) | 2017-06-10 | 2020-08-04 | Inventprise, Llc | Mixtures of polysaccharide-protein pegylated compounds |
WO2019050813A1 (en) | 2017-09-07 | 2019-03-14 | Merck Sharp & Dohme Corp. | ANTI-PNEUMOCOCCAL POLYSACCHARIDES AND THEIR USE IN IMMUNOGENIC CONJUGATES POLYSACCHARIDE-PROTEIN CARRIER |
BR112020004509A8 (pt) * | 2017-09-07 | 2023-01-31 | Merck Sharp & Dohme | Conjugado polissacarídeo-proteína carreadora, composição imunogênica compreendendo o mesmo e uso do referido conjugado |
CN117018172A (zh) | 2017-09-07 | 2023-11-10 | 默沙东有限责任公司 | 肺炎球菌多糖及其在免疫原性多糖-载体蛋白缀合物中的用途 |
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US11524076B2 (en) | 2017-09-07 | 2022-12-13 | Merck Sharp & Dohme Llc | Pneumococcal polysaccharides and their use in immunogenic polysaccharide-carrier protein conjugates |
WO2019070994A1 (en) * | 2017-10-04 | 2019-04-11 | Liffey Biotech Limited | SACCHARIDE-POLYPEPTIDE CONJUGATE COMPOSITIONS AND METHODS OF USE |
CN111683678B (zh) | 2017-12-06 | 2024-01-26 | 默沙东有限责任公司 | 包含肺炎链球菌多糖蛋白缀合物的组合物及其使用方法 |
AU2019215216A1 (en) | 2018-02-05 | 2020-07-23 | Sk Bioscience Co., Ltd. | Multivalent pneumococcal polysaccharide-protein conjugate composition |
CN111989114A (zh) | 2018-04-18 | 2020-11-24 | Sk生物科学株式会社 | 肺炎链球菌的荚膜多糖以及其免疫原性缀合物 |
JP7397000B2 (ja) | 2018-04-30 | 2023-12-12 | メルク・シャープ・アンド・ドーム・エルエルシー | 凍結乾燥変異ジフテリア毒素のジメチルスルホキシド中均一溶液を提供する方法 |
JP7506605B6 (ja) | 2018-04-30 | 2024-07-16 | メルク・シャープ・アンド・ドーム・エルエルシー | 肺炎球菌莢膜多糖類担体タンパク質複合体の製造方法 |
JP7275277B2 (ja) | 2018-12-19 | 2023-05-17 | メルク・シャープ・アンド・ドーム・エルエルシー | ストレプトコッカス・ニューモニエ多糖-タンパク質コンジュゲートを含む組成物およびその使用方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000077254A1 (en) * | 1999-06-11 | 2000-12-21 | The Government Of The United States Of America As Represented By The Secretary, Of The Department Of Health And Human Services | Detection of streptococcus pneumoniae and immunization against streptococcus pneumoniae infection |
US20140050741A1 (en) * | 2011-03-10 | 2014-02-20 | Universiteit Leiden | Synthetic lta mimetics and use thereof as vaccine component for therapy and/or prophylaxis against gram-positive infections |
Family Cites Families (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2059692C (en) | 1991-01-28 | 2004-11-16 | Peter J. Kniskern | Pneumoccoccal polysaccharide conjugate vaccine |
CA2059693C (en) | 1991-01-28 | 2003-08-19 | Peter J. Kniskern | Polysaccharide antigens from streptococcus pneumoniae |
GB0220198D0 (en) | 2002-08-30 | 2002-10-09 | Chiron Spa | Modified saccharides,conjugates thereof and their manufacture |
US7709001B2 (en) * | 2005-04-08 | 2010-05-04 | Wyeth Llc | Multivalent pneumococcal polysaccharide-protein conjugate composition |
CN113198012A (zh) | 2005-04-08 | 2021-08-03 | 惠氏有限责任公司 | 多价肺炎球菌多糖-蛋白质缀合物组合物 |
US20070184072A1 (en) | 2005-04-08 | 2007-08-09 | Wyeth | Multivalent pneumococcal polysaccharide-protein conjugate composition |
US7955605B2 (en) | 2005-04-08 | 2011-06-07 | Wyeth Llc | Multivalent pneumococcal polysaccharide-protein conjugate composition |
EP3466982B1 (en) | 2005-04-08 | 2020-06-17 | Wyeth LLC | Separation of contaminants from streptococcus pneumoniae polysaccharide by ph manipulation |
AR058707A1 (es) | 2005-12-22 | 2008-02-20 | Glaxosmithkline Biolog Sa | Vacuna, procedimiento para fabricarla y su uso |
JP5285431B2 (ja) | 2005-12-28 | 2013-09-11 | ザ ユーエイビー リサーチ ファウンデイション | 肺炎球菌血清型 |
WO2007087064A2 (en) | 2005-12-28 | 2007-08-02 | The Uab Research Foundation | Pneumococcal serotypes |
TW200806315A (en) | 2006-04-26 | 2008-02-01 | Wyeth Corp | Novel formulations which stabilize and inhibit precipitation of immunogenic compositions |
US8808707B1 (en) | 2006-05-08 | 2014-08-19 | Wyeth Llc | Pneumococcal dosing regimen |
DK2074221T3 (da) | 2006-10-10 | 2010-09-06 | Wyeth Llc | Forbedrede fremgangsmåder til separation af streptococcus pneumoniae type 3 polysakkarider |
KR20150021127A (ko) | 2007-03-23 | 2015-02-27 | 와이어쓰 엘엘씨 | 스트렙토코커스 뉴모니아 협막 다당류를 제조하기 위한 단축 정제 방법 |
DK2162546T3 (en) | 2007-05-29 | 2019-01-21 | Uab Res Found | PNEUMOKOK SEROTYPE 6D |
US8540955B2 (en) | 2007-07-10 | 2013-09-24 | Wyeth Llc | Process for producing aluminum phosphate |
US20100160622A1 (en) | 2008-12-18 | 2010-06-24 | Wyeth Llc | Method for controlling streptococcus pneumoniae polysaccharide molecular weight using carbon dioxide |
KR20110091546A (ko) | 2008-12-18 | 2011-08-11 | 와이어쓰 엘엘씨 | 스트렙토코커스 뉴모니에 혈청형 19a 폴리사카라이드 분자량을 조절하는 방법 |
CA2757620C (en) | 2009-04-30 | 2016-04-26 | Coley Pharmaceutical Group, Inc. | Pneumococcal vaccine and uses thereof |
CA2766418C (en) | 2009-06-22 | 2016-03-29 | Wyeth Llc | Compositions and methods for preparing staphylococcus aureus serotype 5 and 8 capsular polysaccharide conjugate immunogenic compositions |
TW201136603A (en) | 2010-02-09 | 2011-11-01 | Merck Sharp & Amp Dohme Corp | 15-valent pneumococcal polysaccharide-protein conjugate vaccine composition |
PL3170508T3 (pl) | 2010-06-04 | 2020-04-30 | Wyeth Llc | Preparaty szczepionek |
GB201101665D0 (en) | 2011-01-31 | 2011-03-16 | Novartis Ag | Immunogenic compositions |
AU2011338723A1 (en) | 2010-12-10 | 2013-05-30 | Merck Sharp & Dohme Corp. | Novel formulations which mitigate agitation-induced aggregation of immunogenic compositions |
KR102057217B1 (ko) | 2012-06-20 | 2020-01-22 | 에스케이바이오사이언스 주식회사 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
KR20140075201A (ko) | 2012-12-11 | 2014-06-19 | 에스케이케미칼주식회사 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
SI3363806T1 (sl) | 2012-12-20 | 2023-04-28 | Pfizer Inc. | Postopek glikokonjugacije |
MX2020001138A (es) | 2014-01-21 | 2021-09-30 | Pfizer | Polisacaridos capsulares de streptococcus pneumoniae y conjugados de los mismos. |
US11160855B2 (en) | 2014-01-21 | 2021-11-02 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
DK3096785T3 (da) | 2014-01-21 | 2020-09-21 | Pfizer | Immunogene sammensætninger omfattende konjugerede kapsel-saccharid-antigener og anvendelser deraf |
PL3096783T3 (pl) | 2014-01-21 | 2021-12-13 | Pfizer Inc. | Polisacharydy otoczkowe streptococcus pneumoniae i ich koniugaty |
US10307474B2 (en) | 2014-08-08 | 2019-06-04 | Glaxosmithkline Biologicals S.A. | Modified host cells and hybrid oligosaccharides for use in bioconjugate production |
ES2945312T3 (es) | 2015-01-15 | 2023-06-30 | Pfizer | Composiciones inmunogénicas para su uso en vacunas antineumocócicas |
MX368897B (es) | 2015-05-04 | 2019-10-21 | Pfizer | Conjugados proteina-polisacarido de estreptococo grupo b, metodos para producir conjugados, composiciones inmunogenas que comprenden conjugados y sus usos. |
PE20180657A1 (es) | 2015-07-21 | 2018-04-17 | Pfizer | Composiciones inmunogenas que comprenden antigenos de sacarido capsular conjugados, kits que las comprenden y sus usos |
MX2018006063A (es) | 2015-11-17 | 2018-09-17 | Pfizer | Medios y metodos de fermentacion para producir polisacarido en cultivo celular bacteriano. |
EP3377098A1 (en) | 2015-11-20 | 2018-09-26 | Pfizer Inc | Immunogenic compositions for use in pneumococcal vaccines |
EP3436061A4 (en) | 2016-03-31 | 2019-12-04 | Liffey Biotech Limited | Saccharide-polypeptide-conjugate compositions and methods of use thereof |
WO2018027126A1 (en) | 2016-08-05 | 2018-02-08 | Sanofi Pasteur, Inc. | Multivalent pneumococcal polysaccharide-protein conjugate composition |
AU2017388891A1 (en) | 2016-12-30 | 2019-07-04 | Vaxcyte, Inc. | Polypeptide-antigen conjugates with non-natural amino acids |
DK3570879T3 (da) | 2017-01-20 | 2022-04-11 | Pfizer | Immunogene sammensætninger til anvendelse i pneumokokvacciner |
EP3576759A4 (en) | 2017-01-31 | 2020-11-11 | Merck Sharp & Dohme Corp. | PROCESS FOR THE PREPARATION OF CAPSULE POLYSACCHARIDE PROTEIN CONJUGATES FROM STREPTOCOCCUS PNEUMONIAE SEROTYPE 19F |
KR20190108583A (ko) | 2017-01-31 | 2019-09-24 | 머크 샤프 앤드 돔 코포레이션 | 다당류-단백질 접합체 제조 방법 |
EP3585427A4 (en) | 2017-02-24 | 2020-12-30 | Merck Sharp & Dohme Corp. | METHODS FOR IMPROVING THE FILTRABILITY OF POLYSACCHARIDE CONJUGATE WITH PROTEIN REACTIONS |
KR20190119108A (ko) | 2017-02-24 | 2019-10-21 | 머크 샤프 앤드 돔 코포레이션 | 폐렴구균 접합체 백신 제제 |
US11219680B2 (en) | 2017-02-24 | 2022-01-11 | Merck Sharp & Dohme Corp. | Polysaccharide-protein conjugates utilizing diphtheria toxin fragment B as a carrier |
KR20240011879A (ko) | 2017-02-24 | 2024-01-26 | 머크 샤프 앤드 돔 엘엘씨 | 스트렙토코쿠스 뉴모니아에 폴리사카라이드-단백질 접합체의 면역원성의 증진 |
KR20200040812A (ko) | 2017-08-16 | 2020-04-20 | 머크 샤프 앤드 돔 코포레이션 | 폐렴구균 접합체 백신 제제 |
BR112020004509A8 (pt) | 2017-09-07 | 2023-01-31 | Merck Sharp & Dohme | Conjugado polissacarídeo-proteína carreadora, composição imunogênica compreendendo o mesmo e uso do referido conjugado |
WO2019050813A1 (en) | 2017-09-07 | 2019-03-14 | Merck Sharp & Dohme Corp. | ANTI-PNEUMOCOCCAL POLYSACCHARIDES AND THEIR USE IN IMMUNOGENIC CONJUGATES POLYSACCHARIDE-PROTEIN CARRIER |
CN117018172A (zh) | 2017-09-07 | 2023-11-10 | 默沙东有限责任公司 | 肺炎球菌多糖及其在免疫原性多糖-载体蛋白缀合物中的用途 |
CN111065388A (zh) | 2017-09-07 | 2020-04-24 | 默沙东公司 | 肺炎球菌多糖及其在免疫原性多糖-载体蛋白缀合物中的用途 |
MX2020002558A (es) | 2017-09-07 | 2020-07-13 | Merck Sharp & Dohme | Procesos para la formulacion de polisacaridos neumococicos para la conjugacion a una proteina transportadora. |
US20200325020A1 (en) | 2017-10-25 | 2020-10-15 | Merck Sharp & Dohme Corp. | Adjuvanted vaccines |
CN111683678B (zh) | 2017-12-06 | 2024-01-26 | 默沙东有限责任公司 | 包含肺炎链球菌多糖蛋白缀合物的组合物及其使用方法 |
JP7506605B6 (ja) | 2018-04-30 | 2024-07-16 | メルク・シャープ・アンド・ドーム・エルエルシー | 肺炎球菌莢膜多糖類担体タンパク質複合体の製造方法 |
JP7397000B2 (ja) | 2018-04-30 | 2023-12-12 | メルク・シャープ・アンド・ドーム・エルエルシー | 凍結乾燥変異ジフテリア毒素のジメチルスルホキシド中均一溶液を提供する方法 |
CN112074294A (zh) | 2018-04-30 | 2020-12-11 | 默沙东公司 | 从冻干球生产肺炎链球菌荚膜多糖载体蛋白缀合物的方法 |
EP3801469A4 (en) | 2018-06-07 | 2022-03-09 | Merck Sharp & Dohme Corp. | KIT OF CRITICAL REAGENTS IN THE FORM OF LYOSPHERES |
WO2020121159A1 (en) | 2018-12-12 | 2020-06-18 | Pfizer Inc. | Immunogenic multiple hetero-antigen polysaccharide-protein conjugates and uses thereof |
JP7275277B2 (ja) | 2018-12-19 | 2023-05-17 | メルク・シャープ・アンド・ドーム・エルエルシー | ストレプトコッカス・ニューモニエ多糖-タンパク質コンジュゲートを含む組成物およびその使用方法 |
EP3952906A1 (en) | 2019-04-10 | 2022-02-16 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof |
JP2022535063A (ja) | 2019-06-05 | 2022-08-04 | メルク・シャープ・アンド・ドーム・コーポレーション | 免疫原性血清型35b肺炎球菌多糖類-タンパク質コンジュゲート及びそれを作成するためのコンジュゲーションプロセス |
BR112021024491A8 (pt) | 2019-06-05 | 2023-04-11 | Merck Sharp & Dohme | Composição imunogênica, e, método para prevenir, tratar ou melhorar uma infecção, doença ou condição |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000077254A1 (en) * | 1999-06-11 | 2000-12-21 | The Government Of The United States Of America As Represented By The Secretary, Of The Department Of Health And Human Services | Detection of streptococcus pneumoniae and immunization against streptococcus pneumoniae infection |
US20140050741A1 (en) * | 2011-03-10 | 2014-02-20 | Universiteit Leiden | Synthetic lta mimetics and use thereof as vaccine component for therapy and/or prophylaxis against gram-positive infections |
Non-Patent Citations (1)
Title |
---|
"Radical serotype rearrangement of carried pneumococci in the first 3 years after intensive vaccinati", EUROPEAN JOURNAL OF PEDIATRICS, JPN6022034745, 2014, pages 1 - 9, ISSN: 0004854352 * |
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US20220323564A1 (en) | 2022-10-13 |
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