JP5390103B2 - 連鎖球菌性莢膜糖の複合 - Google Patents
連鎖球菌性莢膜糖の複合 Download PDFInfo
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- JP5390103B2 JP5390103B2 JP2007553744A JP2007553744A JP5390103B2 JP 5390103 B2 JP5390103 B2 JP 5390103B2 JP 2007553744 A JP2007553744 A JP 2007553744A JP 2007553744 A JP2007553744 A JP 2007553744A JP 5390103 B2 JP5390103 B2 JP 5390103B2
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- Prior art keywords
- sugar
- galactose
- capsular saccharide
- residue
- modified
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
本発明は、従来技術に開示されている直接還元アミノ化の代わりに使用できる3つの複合方法に基づく。これらの方法は全て、(a)シアル酸残基を従来技術よりも天然多糖に見られる型に近い型で保持すること、及び(b)担体に対する結合を向上させるために、複合化反応においてリンカーの使用を可能にすることを目的とする:
・ 第1の方法では、酸化されたシアル酸残基側鎖の還元アミノ化を使用するが、アルデヒド基を最初にアミノ化し、次いで得られたアミンを担体にリンカーによって結合する。この方法は、図2の「経路A」に示される。
・ 第2の方法では、シアル酸残基及び/又はN−アセチル−グルコサミン残基を脱−N−アセチル化してアミン基を得、アミン基を担体タンパク質にリンカーによって結合する。この方法は、図2の「経路B」に示される。
・ 第3の方法では、結合は、シアル酸残基よりもむしろ莢膜糖のガラクトース残基による。この方法は、シアル酸残基によって形成されるキーエピトープを分解することを回避する。
本発明は、ストレプトコッカス・アガラクティエの莢膜糖に基づく。莢膜多糖は、GBSのペプチドグリカン主鎖に共有結合しており、ペプチドグリカン主鎖に結合している別の糖であるB群抗原と異なる。
β−D−GlcpNAc(1→3)β−D−Galp(1→4)β−D−Glcp
を共有する。
本発明は、担体分子(これは典型的にはタンパク質である)の使用を含む。一般的に、担体に対する糖類の共有結合による複合は、それが糖類をT細胞非依存性抗原からT細胞依存性抗原に転化させることから、糖類の免疫原性を高め、従って免疫記憶を与える(priming)ことを可能にする。複合は、小児用ワクチンに特に有用であり[例えば、参考文献16]、周知の技術である[例えば、参考文献17〜25に記載されている]。
本発明の第1の態様は、アルデヒドを形成するためのシアル酸の酸化を包含し、第3の態様はアルデヒドを形成するためのガラクトースの酸化を包含する。次いで、アルデヒドは、還元アミノ化などの反応に使用することができる。
本発明の第1の態様では、新しいアルデヒド基の還元アミノ化は、リンカーの結合用の基を得るのに使用される。還元アミノ化はまた、リンカーを結合するために又は担体に直接結合させるために、アルデヒド基が生成した後に本発明の第3の態様で使用することもできる。還元アミノ化は、有機化学での標準的な技術であり、ワクチン用途の莢膜糖の複合体の製造に広く使用されている。
本発明の第1及び第2の態様(並びに、場合によっては、第3の態様)は、二官能性リンカーの使用を含む。二官能性リンカーは、修飾された莢膜糖のアミン基に連結するための第1の基及び担体に連結するための(典型的には、担体のアミンに連結するための)第2の基を提供するのに使用される。
GBS莢膜糖のシアル酸残基は、三糖コア内のグルコサミン残基であるので、N−アセチル化される。本発明の第1の態様がシアル酸のC−8にアルデヒド中間体を介してアミン基を導入するのに対して、本発明の第2の態様は、シアル酸及び/又はN−アセチル−グルコサミン残基の脱−N−アセチル化によって製造されるアミン基を使用する。この方法で製造されるアミンの反応スキームは、概して本発明の第1の態様について記載の反応スキームと同じである。
本発明の複合体は、修飾されたGBS糖類を担体と適当な反応条件下で混合することによって形成される。一般的に、図5に示すように2種類の複合体:すなわち(a)個々の糖が例えばその還元末端によって単一の担体に結合されている複合体;及び(b)個々の糖が、例えば数個の単糖サブユニットが反応性であるという理由で多数の担体に結合されている複合体を調製することができる。両方の状況において、単一の担体タンパク質は、多数の露出したリシン側鎖を有することができることから、多数の糖分子に結合することができる。
− アクロリル化(例えば、アクリロイルクロリドとの反応による)、次いでアミノ酸側鎖のε−NH2又はシステイン側鎖の−SHのいずれかに対するマイケル型の付加[54]。得られるリンカーは、図8に示すような−NH−C(O)−(CH2)2−(プロピオンアミド)であるか、又は存在する−NH2が反応に関与する場合には−C(O)−(CH2)2−である。
− ハロアシルハライドとの反応、次いでアミノ酸側鎖のε−NH2又はシステイン側鎖の−SHとの反応[55]。このリンカーは、存在するか又は添加された−NH2が反応に関与するか否かに応じて、−NH−C(O)−CH2−(図9に示す)又は−C(O)−CH2−である。
同様に、上記の個々の複合体を提供するとともに、本発明は、本発明の複合体及び1種又はそれ以上の別の抗原を含有してなる組成物を提供する。
− 髄膜炎菌(N.meningitidis)血清群B由来のタンパク質抗原、例えば参考文献56〜62に記載のタンパク質抗原。タンパク質「287」(以下を参照)及び誘導体(例えば「ΔG287」)が特に好ましい。
− 髄膜炎菌血清群B由来の外膜小胞(OMV)調製物、例えば参考文献63、64、65、66などに記載のもの。
− 血清群C由来の参考文献67に記載のオリゴ糖又は参考文献68のオリゴ糖等の、髄膜炎菌血清群A、C、W135及び/又はY由来の糖抗原。
− 肺炎連鎖球菌由来の糖抗原[例えば、参考文献69〜71;参考文献78の第22及び23章参照]。
− A型肝炎ウイルス、例えば不活化ウイルス由来の抗原[例えば、参考文献72、73;参考文献78の第15章参照]。
− B型肝炎ウイルス由来の抗原、例えば表面抗原及び/又はコア抗原[例えば、参考文献73、74;参考文献78の第16章参照]。
− C型肝炎ウイルス由来の抗原[例えば、参考文献75参照]。
− 百日咳菌(Bordetella perutussis)由来の抗原、例えば百日咳菌由来の百日咳ホロトキシン(PT)及び繊維状赤血球凝集素(FHA)、場合によってはまた、ペルタクチン並びに/又は凝集原2及び3の組み合わせ[例えば、参考文献76及び77;参考文献78の第21章参照]。
− ジフテリア抗原、例えばジフテリアトキソイド[例えば、参考文献78の第13章参照]。
− 破傷風抗原、例えば破傷風トキソイド[例えば、参考文献78の第27章参照]。
− ヘモフィルス・インフルエンザB由来の糖抗原[例えば、参考文献78の第14章参照]。
− 淋菌(N.gonorrhoeae)由来の抗原[例えば、56、57、58]。
− クラミジア肺炎菌(Chlamydia pneumoniae)由来の抗原[例えば、79、80、81、82、83、84、85]。
− クラミジア・トラコマチス(Chlamydia trachomatis)由来の抗原[例えば、86]。
− ポルフィロモナス・ジンジバリステン(Porphyromonas gingivalis)由来の抗原[例えば、87]。
− IPVなどのポリオ抗原(1種又はそれ以上)[例えば、88、89;参考文献78の第24章]。
− 凍結乾燥不活化ウイルス[例えば、9l、RabAvert(商標)]などの狂犬病抗原(1種又はそれ以上)[例えば、90]。
− はしか、おたふく風邪及び/又は風疹抗原[例えば、文献78の第19、20及び26章]。
− 赤血球凝集素及び/又はノイラミニダーゼ表面タンパク質などのインフルエンザ抗原(1種又はそれ以上)[例えば、文献78の第17及び18章]。
− モラクセラ・カタラーリス(Moraxella catarrhalis)由来の抗原[例えば、92]。
− 化膿連鎖球菌(Streptococcus pyrogenes)(A群連鎖球菌)由来の抗原[例えば、93、94、95]。
− 黄色ブドウ球菌(Staphylococcus aureus)由来の抗原[例えば、96]。
本発明は、(a)本発明の複合体と(b)製薬学的に許容し得る担体とを含有する医薬組成物を提供する。典型的な「製薬学的に許容し得る担体」としては、組成物を受け入れる個人に有害な抗体の産生をそれ自体誘発しない担体が挙げられる。適当な担体は、典型的には大きくて、徐々に代謝される巨大分子、例えばタンパク質、多糖類、ポリ乳酸類、ポリグリコール酸類、高分子アミノ酸、アミノ酸共重合体、スクロース[106]、トレハロース[107]、ラクトース、及び脂質凝集体(例えば油滴又はリポソーム)である。このような担体は、当業者には周知である。ワクチンはまた、希釈剤、例えば水、食塩水、グリセロールなどを含有していてもよい。さらに、補助物質、例えば湿潤又は乳化剤、pH緩衝物質などを存在させてもよい。滅菌発熱物質無含有のリン酸緩衝食塩水が典型的な担体である。製薬学的に許容し得る賦形剤に関する詳細な考察は参考文献108において利用できる。
A.無機物含有組成物
本発明でアジュバントとして使用するのに適した無機物含有組成物としては、無機塩、例えばアルミニウム塩及びカルシウム塩が挙げられる。本発明は、無機塩、例えば水酸化物(例えば、オキシ水酸化物)、リン酸塩(例えば、ヒドロキシリン酸塩、オルトリン酸塩)、硫酸塩など[例えば、参考文献117の第8及び9章参照]、又は種々の無機化合物の混合物(例えば、リン酸塩と水酸化物アジュバントと、場合によっては過剰のリン酸塩との混合物)を含有し、化合物は適当な形態(例えば、ゲル、結晶質、無定形など)をとり、塩(1種又はそれ以上)に対する吸着が好ましい。無機物含有組成物は、金属塩の粒子として製剤してもよい[118]。
本発明においてアジュバントとして使用するのに適したオイルエマルジョン組成物としては、スクアレン−水エマルジョン、例えばMF59(5%スクアレン、0.5%Tween80、及び0.5%Span85、ミクロ流動化装置を使用してサブミクロン粒子に製剤される)が挙げられる[参考文献117の第10章;参考文献119〜121も参照]。MF59は、FLUAD(商標)インフルエンザウイルス三価サブユニットワクチンにおいてアジュバントとして使用される。
サポニン製剤もまた、本発明でアジュバントとして使用し得る。サポニンは、種々様々な植物種の樹皮、葉、茎、根及び花に見出される異種群のステロールグリコシド及びトリテルペノイドグリコシドである。Quillaia saponaria Molinaと呼ばれる木の樹皮から単離されるサポニンは、アジュバントとして広く研究されている。サポニンはまた、サルサバリラ(Smilax ornata)、シュッコンカスミソウ(Gypsophilla paniculata)、及びシャボンソウ(Saponaria officianalis)から商業的に得ることもできる。サポニンアジュバント製剤としては、QS21などの精製製剤、及びISCOM類などの脂質製剤が挙げられる。
ビロゾーム及びウイルス様粒子(VLP)もまた、本発明においてアジュバントとして使用することができる。これらの構造は、一般に、場合によりリン脂質と組み合わせられていてもよいし又は製剤されていてもよいウイルス由来の1種又はそれ以上のタンパク質を含有する。これらは、一般に非病原性、非複製性であり、しかも一般に天然ウイルスゲノムを含有していない。ウイルスタンパク質は、ウイルス全体から組換え技術によって製造又は単離し得る。ビロゾーム又はVLPに使用するのに適したこれらのウイルスタンパク質としては、インフルエンザウイルス(例えば、HA又はNA)、B型肝炎ウイルス(例えば、コア又はタンパク質)、E型肝炎ウイルス、麻疹ウイルス、シンドビスウイルス、ロタウイルス、口蹄疫ウイルス、レトロウイルス、ノーウォークウイルス、ヒトパピローマウイルス、HIV、RNA−ファージ、Qβ−ファージ(例えば、コートタンパク質)、GA−ファージ、fr−ファージ、AP205ファージ、及びTy(例えば、レトロトランスポゾンTyタンパク質p1)由来のタンパク質が挙げられる。VLPは、さらに参考文献131〜136で論じられている。ビロゾームは、さらに参考文献137で論じられている。
本発明で使用するのに適したアジュバントとしては、細菌又は微生物誘導体、例えば腸内細菌リポ多糖(LPS)の無毒誘導体、脂質A誘導体、免疫賦活オリゴヌクレオチド及びADP−リボシル化毒素及びその解毒誘導体が挙げられる。LPSの無毒誘導体としては、モノホスホリル脂質A(MPL)及び3−O−脱アシル化MPL(3dMPL)が挙げられる。3dMPLは、3脱−O−アシル化モノホスホリル脂質Aと、4、5又は6アシル化鎖との混合物である。3脱−O−アシル化モノホスホリル脂質Aの好ましい「小粒子」形態は、参考文献138に記載されている。このような3dMPLの「小粒子」は、0.22μm膜を通して滅菌濾過するのに十分に小さい[138]。他の無毒LPS誘導体としては、モノホスホリル脂質A模倣体(mimics)、例えばアミノアルキルグルコサミンリン酸誘導体、例えばRC−529が挙げられる[139、140]。
本発明においてアジュバントとして使用するのに適したヒト免疫調節剤としては、サイトカイン類、例えばインターロイキン類(例えば、IL−1、IL−2、IL−4、IL−5、IL−6、IL−7、IL−12[170]、など)[171]、インターフェロン類(例えば、インターフェロン−γ)、マクロファージコロニー刺激因子、及び腫瘍壊死因子が挙げられる。
生体接着剤及び粘膜接着剤もまた、本発明においてアジュバントとして使用し得る。適当な生体接着剤としては、エステル化ヒアルロン酸微小球[172]又は粘膜接着剤、例えばポリ(アクリル酸)の架橋誘導体、ポリビニルアルコール、ポリビニルピロリドン、多糖類及びカルボキシメチルセルロースが挙げられる。キトサン及びその誘導体もまた、本発明においてアジュバントとして使用し得る[173]。
微粒子もまた、本発明においてアジュバントとして使用し得る。ポリ(ラクチド−コ−グリコリド)を用いて、生分解性であり且つ無毒である材料(例えば、ポリ(α−ヒドロキシ酸)、ポリヒドロキシ酪酸、ポリオルトエステル、ポリ酸無水物、ポリカプロラクトンなど)から形成される微粒子(すなわち、〜100nmから〜150nmの直径、さらに好ましく〜200nmから〜30μmの直径、最も好ましくは〜500nmから〜10μmの直径を有する粒子)が好ましくは、場合によって(例えば、SDSを用いて)負に帯電させた表面を有するか又は(例えば、陽イオン性洗浄剤、例えばCTABを用いて)正に帯電させた表面を有するために処理される。
アジュバントとして使用するのに適したリポソーム製剤は、参考文献174〜176に記載されている。
本発明で使用するのに適したアジュバントとしては、ポリオキシエチレンエーテル及びポリオキシエチレンエステル類が挙げられる[177]。このような製剤としてはまた、オクトキシノールと組み合わせたポリオキシエチレンソルビタンエステル界面活性剤[178]及び少なくとも1種の追加の非イオン性界面活性剤、例えばオクトキシノールと組み合わせたポリオキシエチレンアルキルエーテル又はエステル界面活性剤[179]が挙げられる。好ましいポリオキシエチレンエーテルは、次の群:ポリオキシエチレン−9−ラウリルエーテル(laureth9)、ポリオキシエチレン−9−ステオリルエーテル、ポリオキシエチレン−8−ステオリルエーテル、ポリオキシエチレン−4−ラウリルエーテル、ポリオキシエチレン−35−ラウリルエーテル、及びポリオキシエチレン−23−ラウリルエーテルから選択される。
PCPP製剤は、例えば参考文献180及び181に記載されている。
本発明においてアジュバントとして使用するのに適したムラミルペプチドの例としては、N−アセチル−ムラミル−L−スレオニル−D−イソグルタミン(thr−MDP)、N−アセチル−ノルムラミル−L−アラニル−D−イソグルタミン(nor−MDP)、及びN−アセチルムラミル−L−アラニル−D−イソグルタミニル−L−アラニン−2−(1’−2’−ジパルミトイル−sn−グリセロ−3−ヒドロキシホスホリルオキシ)−エチルアミンMTP−PE)が挙げられる。
本発明においてアジュバントとして使用するのに適したイミダゾキノロン化合物としては、参考文献182及び183に記載されているImiquamod及びその同族体(例えば、「Resiquimod 3M」)が挙げられる。
本発明においてアジュバントとして使用するのに適したチオセミカルバゾン化合物、並びに化合物全てを製剤し、製造し、選別する方法の例としては、参考文献184に記載の化合物及び方法が挙げられる。チオセミカルバゾン類は、サイトカイン、例えばTNF−αの製造用のヒト末梢血単核細胞の刺激に特に有効である。
本発明においてアジュバントとして使用するのに適したトリンプタントリン化合物、並びに化合物全てを製剤し、製造し、選別する方法の例としては、参考文献185に記載の化合物及び方法が挙げられる。トリンプタントリン化合物は、サイトカイン、例えばTNF−αの製造用のヒト末梢血単核細胞の刺激に特に有効である。
本発明はまた、医薬本発明の組成物を哺乳動物に投与することを含む、哺乳動物において免疫応答を高める方法も提供する。免疫応答は、好ましくは保護的であり、好ましくは抗体を伴う。本発明の方法は追加免疫応答を高め得る。
上述のように、GBSタンパク質は、本発明の組成物に含有させることができる。これらのタンパク質は、本発明の複合体用の担体タンパク質、その他の複合体用の担体タンパク質、又は非複合タンパク質抗原として使用し得る。
血清型V菌株2603V/Rから配列決定されたGBS67のヌクレオチド及びアミノ酸配列は、参考文献93に配列番号3745及び3746として示される。アミノ酸配列は、本明細書では配列番号1:
GBS80とは、推定される細胞壁表面アンカーファミリータンパク質を指す。血清型V分離株2603V/Rから配列決定されたGBS80のヌクレオチド及びアミノ酸配列は、参考文献93に配列番号8779及び8780として示される。アミノ酸配列は、本明細書では配列番号2として以下に示す:
GBS104とは、推定される細胞壁表面アンカーファミリータンパク質を指す。それはemaAと呼ばれている。血清型V分離株2603V/Rから配列決定されたGB104のヌクレオチド及びアミノ酸配列は、参考文献93に配列番号8777及び8778として示される。アミノ酸配列を、本明細書では配列番号3として以下に示す:
GBS276とは、C5aペプチダーゼを指す。GBS276の別の説明は、参考文献214〜217に見出すことができる。血清型V分離株2603V/Rから配列決定されたGBS276のヌクレオチド及びアミノ酸配列は、参考文献93に配列番号8941及び8942として示される。アミノ酸配列を、本明細書では配列番号4として以下に示す:
GBS322は、表面免疫原性タンパク質を指し、「sip」とも呼ばれる。血清型V分離株2603V/Rから配列決定されたGBS322のヌクレオチド及びアミノ酸配列は、参考文献93に配列番号8539及び8540として示される。アミノ酸配列を、本明細書では配列番号5として以下に示す:
複合体の製造及び特定
GBS血清型Ib由来の莢膜糖は、参考文献15に記載のようにして精製し、次いで上記のように再アセチル化した。この糖を脱−N−アセチル化して、結合用のアミン基を得た。これらのアミン基を使用して、糖をモノマー破傷風トキソイド(TT)に、直接還元アミノ化(シアル酸のC−8上で、従来技術に記載のようにして)によるか又はSIDEAスペーサーによる(参考文献218に髄膜炎菌糖について記載のようにして)かいずれかで共有結合により複合させた。
Claims (28)
- ストレプトコッカス・アガラクティエ莢膜糖と担体分子との複合体の製造方法であって、該方法は、
(a)該莢膜糖の全ガラクトース単糖単位の5%〜50%にアルデヒド基を導入するために、ストレプトコッカス・アガラクティエ莢膜糖を酸化して、修飾されたガラクトース残基を得る工程であって、ここで、該修飾されたガラクトース残基が、ガラクトースのガラクトヘキソジアロースへの変換によって修飾され、そして、該莢膜糖のシアル酸残基が保持される、工程;そして
(b)少なくとも1個の修飾されたガラクトース残基を担体分子に連結する工程、
を包含する、方法。 - ストレプトコッカス・アガラクティエ莢膜糖と担体分子との複合体の製造方法であって、該方法は、
(a)該莢膜糖の少なくとも1個のガラクトース残基にアルデヒド基を導入するために、ストレプトコッカス・アガラクティエ莢膜糖を酸化して、修飾されたガラクトース残基を得る工程であって、ここで、該修飾されたガラクトース残基が、ガラクトースのガラクトヘキソジアロースへの変換によって修飾され、そして、該莢膜糖のシアル酸残基が保持される、工程;
(b)該修飾されたガラクトース残基を担体分子に連結する工程;そして
(c)複合後に、遊離糖と複合糖とを分離する工程
を包含する、方法。 - ストレプトコッカス・アガラクティエ莢膜糖と担体分子との複合体の製造方法であって、該方法は、
(a)該莢膜糖の少なくとも1個のガラクトース残基にアルデヒド基を導入するために、ストレプトコッカス・アガラクティエ莢膜糖を酸化して、修飾されたガラクトース残基を得る工程であって、ここで、該修飾されたガラクトース残基が、ガラクトースのガラクトヘキソジアロースへの変換によって修飾され、そして、該莢膜糖のシアル酸残基が保持される、工程;そして
(b)該修飾されたガラクトース残基を担体分子に連結する工程
を包含し、ここで、該複合体が、1:5〜5:1の糖:タンパク質比(w/w)を有する、方法。 - ストレプトコッカス・アガラクティエ莢膜糖と担体分子との複合体の製造方法であって、該方法は、
(a)該莢膜糖の少なくとも1個のガラクトース残基にアルデヒド基を導入するために、ストレプトコッカス・アガラクティエ莢膜糖を酸化して、修飾されたガラクトース残基を得る工程であって、ここで、該修飾されたガラクトース残基が、ガラクトースのガラクトヘキソジアロースへの変換によって修飾され、そして、該莢膜糖のシアル酸残基が保持される、工程;そして
(b)該修飾されたガラクトース残基を担体分子に連結する工程、
を包含し、ここで、該糖が>30kDaの分子量を有する、方法。 - ストレプトコッカス・アガラクティエ莢膜糖と担体分子との複合体を含む凍結乾燥医薬組成物の製造方法であって、該方法は、
(a)該莢膜糖の少なくとも1個のガラクトース残基にアルデヒド基を導入するために、ストレプトコッカス・アガラクティエ莢膜糖を酸化して、修飾されたガラクトース残基を得る工程であって、ここで、該修飾されたガラクトース残基が、ガラクトースのガラクトヘキソジアロースへの変換によって修飾され、そして、該莢膜糖のシアル酸残基が保持される、工程;
(b)該修飾されたガラクトース残基を担体分子に連結して、該複合体を提供する工程;そして
(c)該複合体および製薬学的に許容し得る担体を含む凍結乾燥医薬組成物を提供する工程
を包含する、方法。 - アルデヒド基が全ガラクトース単糖単位の5%〜50%に導入される、請求項2〜5のいずれか1項に記載の方法。
- 複合後に、遊離糖及び複合糖が分離される、請求項1および3〜5のいずれか1項に記載の方法。
- 前記複合体が1:5〜5:1の糖:タンパク質比(w/w)を有する、請求項1、2、4および5のいずれか1項に記載の方法。
- 前記糖が>30kDaの分子量を有する、請求項1〜3および5のいずれか1項に記載の方法。
- (c)前記複合体および製薬学的に許容し得る担体を含む凍結乾燥医薬組成物を提供する工程
をさらに包含する、請求項1〜4のいずれか1項に記載の方法。 - 前記糖がGBS血清型Ia、Ib、II、III又はVの1つに由来する、請求項1〜10のいずれか1項に記載の方法。
- 前記糖がその天然型を有する、請求項1〜11のいずれか1項に記載の方法。
- 前記糖が弱酸中での加水分解によって処理される、請求項1〜11のいずれか1項に記載の方法。
- 前記糖が、脱−O−アセチル化、脱−N−アセチル化またはN−プロピオン化される、請求項1〜11のいずれか1項に記載の方法。
- 前記糖が完全に脱−O−アセチル化される、請求項14に記載の方法。
- 前記糖が完全に脱−N−アセチル化される、請求項14に記載の方法。
- 前記担体が細菌毒素またはトキソイドである、請求項1〜16のいずれか1項に記載の方法。
- 前記担体が前記糖に該担体の−NH2基によって結合される、請求項1〜17のいずれか1項に記載の方法。
- 工程(a)が前記アルデヒドを化学的に導入する、請求項1〜18のいずれか1項に記載の方法。
- 工程(a)が近接ヒドロキシドを酸化するために過ヨウ素酸塩の使用を含む、請求項19に記載の方法。
- 前記担体への結合が、前記糖中の酸化されたガラクトースと、リンカー中のアミンが関与する還元的アミノ化に基づいており、そこからアルデヒドが形成される、請求項1〜20のいずれか1項に記載の方法。
- 前記担体への結合が、前記糖中の酸化されたガラクトースと、該担体中のアミンが関与する還元的アミノ化に基づいており、そこからアルデヒドが形成される、請求項1〜20のいずれか1項に記載の方法。
- 前記糖が還元的アミノ化の前に再−N−アセチル化される、請求項21または22に記載の方法。
- 前記糖が、ガラクトースの酸化の前に、再−N−アセチル化される、請求項21または22に記載の方法。
- 個々の糖が、複数の担体に結合される、請求項1〜24のいずれか1項に記載の方法。
- 請求項1〜4、ならびに、請求項1〜4に従属する場合の請求項6〜9および11〜25のいずれか1項に記載の方法によって得られる、複合体。
- 請求項5および10、ならびに、請求項5および10に従属する場合の請求項6〜9および11〜25のいずれか1項に記載の方法によって得られる医薬組成物、または、a)請求項26に記載の複合体およびb)製薬学的に許容し得る担体を含む医薬組成物。
- 前記糖が60%脱−N−アセチル化される、請求項14に記載の方法。
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GB201101665D0 (en) * | 2011-01-31 | 2011-03-16 | Novartis Ag | Immunogenic compositions |
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MX2007009277A (es) | 2007-09-19 |
EP3498302A1 (en) | 2019-06-19 |
US20090043077A1 (en) | 2009-02-12 |
CN101304765A (zh) | 2008-11-12 |
JP2013079285A (ja) | 2013-05-02 |
EP1846038A2 (en) | 2007-10-24 |
IL184981A0 (en) | 2007-12-03 |
GB0502095D0 (en) | 2005-03-09 |
CN103349780A (zh) | 2013-10-16 |
JP5818826B2 (ja) | 2015-11-18 |
JP2008532930A (ja) | 2008-08-21 |
CN103349780B (zh) | 2016-05-04 |
US10188719B2 (en) | 2019-01-29 |
US20130295132A1 (en) | 2013-11-07 |
ZA200706969B (en) | 2008-11-26 |
US9040055B2 (en) | 2015-05-26 |
IL184981A (en) | 2016-06-30 |
JP2015147806A (ja) | 2015-08-20 |
US20170246285A1 (en) | 2017-08-31 |
CA2596683A1 (en) | 2006-08-10 |
US9675691B2 (en) | 2017-06-13 |
WO2006082530A2 (en) | 2006-08-10 |
CA2596683C (en) | 2013-12-31 |
AU2006211052A1 (en) | 2006-08-10 |
CA2830588A1 (en) | 2006-08-10 |
WO2006082530A3 (en) | 2008-07-03 |
NZ560432A (en) | 2010-12-24 |
AU2006211052B2 (en) | 2012-03-29 |
CN101304765B (zh) | 2013-03-27 |
US8513392B2 (en) | 2013-08-20 |
US20150231231A1 (en) | 2015-08-20 |
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