JP7438102B2 - 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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- JP7438102B2 JP7438102B2 JP2020513549A JP2020513549A JP7438102B2 JP 7438102 B2 JP7438102 B2 JP 7438102B2 JP 2020513549 A JP2020513549 A JP 2020513549A JP 2020513549 A JP2020513549 A JP 2020513549A JP 7438102 B2 JP7438102 B2 JP 7438102B2
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- polysaccharide
- carrier protein
- protein conjugate
- conjugate
- immunogenic composition
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- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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Description
本発明の血清型(類)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。
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。
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、ストレプトコッカス・ニューモニエ血清型24F由来の非コンジュゲート多糖体または多糖体-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、16F、17F、18B、18C、19A、19F、20、21、22A、22F、23A、23B、23F、24B、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多価多糖体ワクチン。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、それから本質的になるか、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)のような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とコンジュゲートしていない多糖体)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。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。
S.ニューモニエ血清型24Fの主な活性化部位は、アラビニトール側鎖の第2の炭素にあることが分かった。
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24F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、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。最終的な0.2ミクロン濾過の前に、得られたコンジュゲートを、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、0.45ミクロンで濾過した。溶解させた多糖体のサイズを、酢酸を200mMまで加え、92℃で50分間インキュベートし、次いで、冷リン酸カリウムpH7緩衝液を400mMまで加えて中和することによる酸加水分解により縮小した。
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、そして、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。約4℃で、約0.025%(w/v)ポリソルベート20を含む150mM塩化ナトリウムでバッチを希釈した。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、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、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。S.ニューモニエ血清型24Fのバルクコンジュゲートを賦形剤と組み合わせ、滅菌濾過し、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S.ニューモニエ血清型24F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24F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。
一価コンジュゲートマウスチャレンジ試験
S.ニューモニエ血清型24グリココンジュゲートの免疫原性を検証するために、マウスチャレンジモデルを対象にそれらを試験した。0日目、14日目および28日目に0.1mlの24F-CRM197一価コンジュゲートワクチンを用いて、幼若マウス(6~8週齢)を免疫した(n=10/群)。C57BL/6マウスおよびSwiss Websterマウスは、1つの部位に0.1mlを注射して腹腔内(IP)免疫した。CD-1マウスは、2つの部位に0.05mlを注射して筋肉内(IM)免疫した。免疫1回当たり、25μgのリン酸アルミニウムアジュバント(APA)とともに0.4μgのPnPs(CRM197にコンジュゲートされた24F多糖体)の用量で一価肺炎球菌ワクチンを投与した。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マウスを少なくとも連日観察した。マウス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。
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、様々な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)に製剤化した。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させ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7に記載の21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PCV21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およびCovance(Denver,PA)のInstitutional Animal Care and Use Committeesによって承認された。
Claims (34)
- 多糖体-キャリアタンパク質コンジュゲートであって、
ここで、キャリアタンパク質のアミノ基が、以下の構造の活性化された繰り返し単位のアルデヒド基において多糖体とコンジュゲートされ、引き続いて還元されて、-O-P(=O)(OH)-O-CH2CH2-NH-タンパク質部分を形成し、
- 前記多糖体が、50kDa~1000kDaの分子量を有する、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 前記多糖体が、100kDa~800kDaの分子量を有する、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 前記多糖体が、100kDa~300kDaの分子量を有する、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 多糖体-キャリアタンパク質コンジュゲートのコンジュゲーションの程度が、2~15である、請求項1に記載の多糖体-タンパク質コンジュゲート。
- 多糖体-キャリアタンパク質コンジュゲートのコンジュゲーションの程度が、3~10である、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 多糖体-キャリアタンパク質コンジュゲートのコンジュゲーションの程度が、5~10である、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 前記多糖体-キャリアタンパク質コンジュゲートが、0.5~3.0の多糖体対タンパク質質量比を有する、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 前記多糖体-キャリアタンパク質コンジュゲートが、0.8~1.2の多糖体対タンパク質質量比を有する、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 前記多糖体-キャリアタンパク質コンジュゲートが、0.94の多糖体対タンパク質質量比を有する、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 前記多糖体-キャリアタンパク質コンジュゲートが、0.81の多糖体対タンパク質質量比を有する、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 前記多糖体-キャリアタンパク質コンジュゲートが、多糖体の総量と比較して30%未満の遊離多糖体を更に含む、
請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。 - 前記多糖体-キャリアタンパク質コンジュゲートが、多糖体の総量と比較して25%未満の遊離多糖体を含む、請求項12に記載の多糖体-キャリアタンパク質コンジュゲート。
- 前記多糖体-キャリアタンパク質コンジュゲートが、多糖体の総量と比較して20%未満の遊離多糖体を含む、請求項12に記載の多糖体-キャリアタンパク質コンジュゲート。
- 前記多糖体-キャリアタンパク質コンジュゲートが、多糖体の総量と比較して15%未満の遊離多糖体を含む、請求項12に記載の多糖体-キャリアタンパク質コンジュゲート。
- 多糖体-キャリアタンパク質コンジュゲートのコンジュゲーションの程度が、5~10であり、
前記多糖体-キャリアタンパク質コンジュゲートが、0.8~1.2の多糖体対タンパク質質量比を有し、そしてここで、
前記多糖体-キャリアタンパク質コンジュゲートが、多糖体の総量と比較して15%未満の多糖体を更に含む、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。 - キャリアタンパク質が、少なくとも50%の繰り返し単位が、アルデヒド基において多糖体とコンジュゲートされている、請求項1に記載の多糖体-キャリアタンパク質コンジュゲート。
- 多糖体-キャリアタンパク質コンジュゲートであって、
キャリアタンパク質のアミノ基は、以下の構造の活性化された繰り返し単位のアルデヒド基において多糖体とコンジュゲートされ、引き続いて還元されて、-O-P(=O)(OH)-O-CH2CH2-NHタンパク質部分を形成し、
ここで、多糖体-キャリアタンパク質コンジュゲートのコンジュゲーションの程度が、5~10であり、
ここで、前記多糖体-キャリアタンパク質コンジュゲートが、0.8~1.2の多糖体対タンパク質質量比を有する、多糖体-キャリアタンパク質コンジュゲートであり、
更に、前記多糖体-キャリアタンパク質コンジュゲートが、多糖体の総量と比較して15%未満の遊離多糖体を含む、
多糖体-キャリアタンパク質コンジュゲート。 - 請求項1に記載の多糖体-キャリア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。
- 1以上の追加の多糖体-キャリアタンパク質コンジュゲートをさらに含む請求項19に記載の免疫原性組成物であって、ここで、各コンジュゲートは、CRM197にコンジュゲートされた、特定のストレプトコッカス・ニューモニエの血清型の多糖体を含み、そしてここで、ストレプトコッカス・ニューモニエの血清型は、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よりなる群から選択される、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有するように製剤化される、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。
- 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ための、請求項20に記載の免疫原性組成物。
- 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、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28に記載の免疫原性組成物。
- 請求項18に記載の多糖体-キャリア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。
- 1以上の追加の多糖体-キャリアタンパク質コンジュゲートをさらに含む請求項30に記載の免疫原性組成物であって、ここで、各コンジュゲートは、CRM197にコンジュゲートされた、特定のストレプトコッカス・ニューモニエの血清型の多糖体を含み、そしてここで、ストレプトコッカス・ニューモニエの血清型は、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よりなる群から選択される、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ための、請求項30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ための、請求項31に記載の免疫原性組成物。
- 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、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33に記載の免疫原性組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11951165B2 (en) | 2016-12-30 | 2024-04-09 | Vaxcyte, Inc. | Conjugated vaccine carrier proteins |
CN116870144A (zh) | 2017-01-31 | 2023-10-13 | 默沙东有限责任公司 | 制备多糖-蛋白缀合物的方法 |
WO2018156491A1 (en) | 2017-02-24 | 2018-08-30 | Merck Sharp & Dohme Corp. | Enhancing immunogenicity of streptococcus pneumoniae polysaccharide-protein conjugates |
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WO2019050814A1 (en) | 2017-09-07 | 2019-03-14 | Merck Sharp & Dohme Corp. | ANTI-PNEUMOCOCCAL POLYSACCHARIDES AND THEIR USE IN IMMUNOGENIC CONJUGATES POLYSACCHARIDE-PROTEIN CARRIER |
EP3678652A4 (en) | 2017-09-07 | 2021-05-19 | Merck Sharp & Dohme Corp. | ANTIPNEUMOCOCCAL POLYSACCHARIDES AND THEIR USE IN POLYSACCHARIDE-CARRIER PROTEIN IMMUNOGENIC CONJUGATES |
BR122021023687A8 (pt) | 2017-12-06 | 2023-02-07 | Merck Sharp & Dohme | Usos de composições imunogênicas multivalentes compreendendo conjugados de proteína carreadora e polissacarídeo de s. pneumoniae |
IL276230B2 (en) | 2018-02-05 | 2024-01-01 | Sanofi Pasteur Inc | A multivalent pneumococcal protein-polysaccharide conjugate preparation |
TW202011985A (zh) | 2018-04-18 | 2020-04-01 | 韓商Sk生物科學股份有限公司 | 肺炎鏈球菌的莢膜多醣類以及其免疫原性接合體 |
EP3788143B1 (en) | 2018-04-30 | 2023-06-28 | Merck Sharp & Dohme LLC | Methods for providing a homogenous solution of lyophilized mutant diptheria toxin in dimethylsulfoxide |
US20220296695A1 (en) | 2018-12-19 | 2022-09-22 | Merck Sharp & Dohme Corp. | Compositions comprising streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
WO2022035816A1 (en) * | 2020-08-10 | 2022-02-17 | Inventprise, Llc | Multivalent pneumococcal glycoconjugate vaccines containing emerging serotype 24f |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996034609A1 (en) | 1994-12-05 | 1996-11-07 | The Biomembrane Institute | Myeloglycan |
US20170021006A1 (en) | 2015-07-21 | 2017-01-26 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof |
Family Cites Families (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0027888B1 (en) | 1979-09-21 | 1986-04-16 | Hitachi, Ltd. | Semiconductor switch |
US4673574A (en) | 1981-08-31 | 1987-06-16 | Anderson Porter W | Immunogenic conjugates |
US4902506A (en) | 1983-07-05 | 1990-02-20 | The University Of Rochester | Immunogenic conjugates |
US4950740A (en) | 1987-03-17 | 1990-08-21 | Cetus Corporation | Recombinant diphtheria vaccines |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
US4912094B1 (en) | 1988-06-29 | 1994-02-15 | Ribi Immunochem Research Inc. | Modified lipopolysaccharides and process of preparation |
ES2055785T3 (es) | 1989-01-17 | 1994-09-01 | Eniricerche Spa | Peptidos sinteticos y su uso como vehiculos universales para la preparacion de conjugados inmunogenos aptos para el desarrollo de vacunas sinteticas. |
HU212924B (en) | 1989-05-25 | 1996-12-30 | Chiron Corp | Adjuvant formulation comprising a submicron oil droplet emulsion |
US5334379A (en) | 1989-07-14 | 1994-08-02 | American Cyanamid Company | Cytokine and hormone carriers for conjugate vaccines |
IT1237764B (it) | 1989-11-10 | 1993-06-17 | Eniricerche Spa | Peptidi sintetici utili come carriers universali per la preparazione di coniugati immunogenici e loro impiego per lo sviluppo di vaccini sintetici. |
SE466259B (sv) | 1990-05-31 | 1992-01-20 | Arne Forsgren | Protein d - ett igd-bindande protein fraan haemophilus influenzae, samt anvaendning av detta foer analys, vacciner och uppreningsaendamaal |
ATE128628T1 (de) | 1990-08-13 | 1995-10-15 | American Cyanamid Co | Faser-hemagglutinin von bordetella pertussis als träger für konjugierten impfstoff. |
NZ239643A (en) | 1990-09-17 | 1996-05-28 | North American Vaccine Inc | Vaccine containing bacterial polysaccharide protein conjugate and adjuvant (c-nd-che-a-co-b-r) with a long chain alkyl group. |
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 |
EP1958646A1 (en) | 1992-02-11 | 2008-08-20 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Dual carrier immunogenic construct |
IT1262896B (it) | 1992-03-06 | 1996-07-22 | Composti coniugati formati da proteine heat shock (hsp) e oligo-poli- saccaridi, loro uso per la produzione di vaccini. | |
DE69324487T2 (de) | 1992-05-06 | 1999-08-12 | Harvard College | Rezeptorbindende region des diphtherietoxius |
IL102687A (en) | 1992-07-30 | 1997-06-10 | Yeda Res & Dev | Conjugates of poorly immunogenic antigens and synthetic pepide carriers and vaccines comprising them |
ATE280235T1 (de) | 1993-03-05 | 2004-11-15 | Wyeth Corp | Plasmid zur herstellung von crm-protein und diphtherie-toxin |
ES2210262T3 (es) | 1993-09-22 | 2004-07-01 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Procedimiento que permite activar un glucido soluble con la ayuda de nuevos reactivos cianilantes para producir estructuras inmunogenas. |
US5866135A (en) | 1994-04-21 | 1999-02-02 | North American Vaccine, Inc. | Group A streptococcal polysaccharide immunogenic compositions and methods |
US5917017A (en) | 1994-06-08 | 1999-06-29 | President And Fellows Of Harvard College | Diphtheria toxin vaccines bearing a mutated R domain |
US6455673B1 (en) | 1994-06-08 | 2002-09-24 | President And Fellows Of Harvard College | Multi-mutant diphtheria toxin vaccines |
US6207646B1 (en) | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
NZ304715A (en) | 1995-03-22 | 1999-07-29 | Jackson H M Found Military Med | Production of immunogenic constructs using organic cyanylating reagents to activate carbohydrates and then coupling the carbohydrate to a protein, peptide or hapten |
US6299881B1 (en) | 1997-03-24 | 2001-10-09 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Uronium salts for activating hydroxyls, carboxyls, and polysaccharides, and conjugate vaccines, immunogens, and other useful immunological reagents produced using uronium salts |
US6113918A (en) | 1997-05-08 | 2000-09-05 | Ribi Immunochem Research, Inc. | Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors |
GB9713156D0 (en) | 1997-06-20 | 1997-08-27 | Microbiological Res Authority | Vaccines |
HUP0100623A3 (en) | 1997-12-23 | 2003-11-28 | Baxter Healthcare S A Wallisel | Procedures for the extraction and isolation of bacterial capsular polysaccharides for use as vaccines or linked to proteins as conjugates vaccines |
US6146902A (en) | 1998-12-29 | 2000-11-14 | Aventis Pasteur, Inc. | Purification of polysaccharide-protein conjugate vaccines by ultrafiltration with ammonium sulfate solutions |
JP2002541808A (ja) | 1999-04-09 | 2002-12-10 | テクラブ, インコーポレイテッド | ポリサッカリド結合体ワクチンのための組換えトキシンaタンパク質キャリア |
GB0007432D0 (en) | 2000-03-27 | 2000-05-17 | Microbiological Res Authority | Proteins for use as carriers in conjugate vaccines |
EP1303612A2 (en) | 2000-06-20 | 2003-04-23 | Shire Biochem Inc. | Streptococcus antigens |
JP4445200B2 (ja) | 2000-12-28 | 2010-04-07 | ワイス エルエルシー | $i(streptococcuspneumoniae)由来の組換え保護タンパク質 |
CN1636062A (zh) | 2001-04-16 | 2005-07-06 | 惠氏控股公司 | 编码多肽抗原的新肺炎链球菌可读框及其应用 |
US20030035806A1 (en) | 2001-05-11 | 2003-02-20 | D'ambra Anello J. | Novel meningitis conjugate vaccine |
AU2002351623A1 (en) | 2001-12-20 | 2003-07-09 | Shire Biochem Inc. | Streptococcus antigens |
NZ541969A (en) | 2003-03-13 | 2008-01-31 | Glaxosmithkline Biolog Sa | Purifying pneumolysin from Streptococcus pneumoniae in a single chromatographic step by binding it to a hydrophobic interaction column in the presence of detergent and high salt |
CA2519511A1 (en) | 2003-03-17 | 2004-09-30 | Wyeth Holdings Corporation | Mutant cholera holotoxin as an adjuvant and an antigen carrier protein |
US20070184072A1 (en) | 2005-04-08 | 2007-08-09 | Wyeth | Multivalent pneumococcal polysaccharide-protein conjugate composition |
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 |
US7955605B2 (en) | 2005-04-08 | 2011-06-07 | Wyeth Llc | Multivalent pneumococcal polysaccharide-protein conjugate composition |
SI2436700T1 (sl) | 2007-03-23 | 2018-09-28 | Wyeth Llc | Skrajšan postopek čiščenja za proizvodnjo kapsularnih polisaharidov streptococcusa pneumoniae |
TW201136603A (en) | 2010-02-09 | 2011-11-01 | Merck Sharp & Amp Dohme Corp | 15-valent pneumococcal polysaccharide-protein conjugate vaccine composition |
KR20140038517A (ko) | 2011-06-13 | 2014-03-28 | 머크 샤프 앤드 돔 코포레이션 | 천연 또는 돌연변이 형태의 디프테리아 독소의 정제 방법 |
KR101980989B1 (ko) | 2012-12-20 | 2019-05-21 | 화이자 인코포레이티드 | 당접합 방법 |
EP2829612A1 (en) * | 2013-07-25 | 2015-01-28 | Technische Universität München | Method for producing exopolysaccharides, products and uses thereof |
PT3096783T (pt) * | 2014-01-21 | 2021-08-16 | Pfizer | Polissacáridos capsulares de streptococcus pneumoniae e conjugados dos mesmos |
ES2820824T3 (es) * | 2014-01-21 | 2021-04-22 | Pfizer | Composiciones inmunogénicas que comprenden antígenos sacáridos capsulares conjugados y usos de las mismas |
MY186844A (en) * | 2014-07-09 | 2021-08-25 | Cadena Bio Inc | Oligosaccharide compositions and methods for producing thereof |
US20180235987A1 (en) * | 2015-08-25 | 2018-08-23 | Kaleido Biosciences, Inc. | Glycan compositions and uses thereof |
WO2017083520A1 (en) * | 2015-11-13 | 2017-05-18 | Cadena Bio, Inc. | Animal therapeutic and feed compositions and methods of use |
WO2017173415A2 (en) * | 2016-03-31 | 2017-10-05 | Liffey Biotech Limited | Saccharide-polypeptide conjugate compositions and methods of use thereof |
WO2019050814A1 (en) * | 2017-09-07 | 2019-03-14 | Merck Sharp & Dohme Corp. | ANTI-PNEUMOCOCCAL POLYSACCHARIDES AND THEIR USE IN IMMUNOGENIC CONJUGATES POLYSACCHARIDE-PROTEIN CARRIER |
CA3074703A1 (en) * | 2017-09-07 | 2019-03-14 | Merck Sharp & Dohme Corp. | Pneumococcal polysaccharides and their use in immunogenic polysaccharide-carrier protein conjugates |
EP3678652A4 (en) * | 2017-09-07 | 2021-05-19 | Merck Sharp & Dohme Corp. | ANTIPNEUMOCOCCAL POLYSACCHARIDES AND THEIR USE IN POLYSACCHARIDE-CARRIER PROTEIN IMMUNOGENIC CONJUGATES |
AU2018328040A1 (en) * | 2017-09-07 | 2020-03-19 | Merck Sharp & Dohme Llc | Processes for the formulation of pneumococcal polysaccharides for conjugation to a carrier protein |
BR122021023687A8 (pt) * | 2017-12-06 | 2023-02-07 | Merck Sharp & Dohme | Usos de composições imunogênicas multivalentes compreendendo conjugados de proteína carreadora e polissacarídeo de s. pneumoniae |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996034609A1 (en) | 1994-12-05 | 1996-11-07 | The Biomembrane Institute | Myeloglycan |
US20170021006A1 (en) | 2015-07-21 | 2017-01-26 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof |
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AU2024201518A1 (en) | 2024-03-28 |
AU2018328037A1 (en) | 2020-03-19 |
KR20200051004A (ko) | 2020-05-12 |
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JP2020533439A (ja) | 2020-11-19 |
EP3678654A4 (en) | 2021-04-21 |
BR112020004509A8 (pt) | 2023-01-31 |
WO2019050815A1 (en) | 2019-03-14 |
RU2020112308A (ru) | 2021-10-07 |
CA3074708A1 (en) | 2019-03-14 |
CN111093650A (zh) | 2020-05-01 |
MX2020002555A (es) | 2020-09-25 |
JP2024056835A (ja) | 2024-04-23 |
AU2018328037B2 (en) | 2024-03-07 |
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BR112020004509A2 (pt) | 2020-09-15 |
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