JP6166533B2 - ピロリ菌リポ多糖類の外殻エピトープ - Google Patents
ピロリ菌リポ多糖類の外殻エピトープ Download PDFInfo
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- C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
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- A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
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- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- 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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- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/02—Dextran; Derivatives thereof
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- A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
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Description
本出願は、2009年7月31日に出願され米国仮特許出願第61/230,315号の利益を主張し、その全体は引用によって本明細書に組み入れられる。
本発明は新しいヘリコバクター・ピロリLPS外殻エピトープに関する。より具体的には、本発明は、新しいピロリ菌(H.pylori)外殻エピトープ、その合成、特徴づけ、および、複合体に関する。
ヘリコバクター・ピロリ菌株26695は、R.Alm博士(マイアミ州ボストンのアストラゼネカ)から入手し、ピロリ菌(O):3分離株はJ.Penner博士から、J99は、D.Taylor博士(カナダ・エドモントンのアルバータ大学)から入手し、SS1はA.Lee博士(オーストラリア・シドニーのニューサウスウェールズ大学)から、PJ1とPJ2の臨床分離株は、W.Conlan博士(IBS、NRC)からの新鮮な臨床分離株であり、および、M6はK.Eaton博士(ミシガン州のミシガン州立大学)から入手した。
実施例1で得られた生成した26695 HP0826::Kan LPS(20mg)を、0.1Mの酢酸ナトリウム緩衝液(pH4.2)において100°Cで2時間加水分解し、先に記載したように(Altman et al,2003)Bio−GelP−2カラムでのゲルろ過によって分画することで、脱脂したLPS(dLPS)を生成した。3つの分画(分画1−3)を集めて、キャピラリー電気泳動質量分析法(CE−MS;表1)によって分析した。
(実施例1の)26695 HP0826::Kan LPSのO−脱アシル化は、幾つかの修正をしたHolst et al.に従って実行された(1991)。手短にいえば、LPS(4mg)を4時間、37°Cで無水ヒドラジン(0.2ml)中で撹拌した。反応混合物を冷却し、冷たいアセトン(2ml)をゆっくりと加えることで超過ヒドラジンを破壊した。30分後、沈殿したO−脱アシル化したLPS(LPS−OH)を、遠心分離(4°C、9300×g、10分)によって集めた。ペレットを冷たいアセトンで2度洗浄し、水に溶解させ、凍結乾燥させることでLPS−OH(3.5mg)を得た。
PEtN置換基のアルカリ加水分解がアグリコンを含まない還元末端を残すため(Holst et al.,1991)、(実施例1の)ピロリ菌株26695 HP0826::KanからのLPSの分解は、脂質A GlcNの即時還元のためのNaBH4の存在下で、4M KOHによる完全な脱アシル化で始まった。ゲルクロマトグラフィーによる生成物の分離は、クロマトグラムのオリゴ糖領域で溶出された、2つの分画をもたらした。更なる分析によって、これらの分画は、グルカン鎖の長さによって明らかに異なる、類似する化合物を含むことが示された。低分子量分画(Lower molecular mass fraction)は、質量分析法によって同定された化合物1−3を含み、両方の分画は、グルカン部分の異なる長さの化合物4を含んでいた(図3)。
ウシ血清アルブミン(BSA)および/または破傷風トキソイド(TT)に対する、LPS−OH(実施例3を参照)およびdLPS(実施例2を参照)のKdo結合複合体を調製した。
実施例5の複合体(LPS−OH−TT、dLPS−BSA、dLPS−TT、および、dLPS(PJ2)−TT)の免疫性をマウスとウサギで試験した。
%阻害=100×[(インヒビターを含むOD−インヒビターを含まないOD)/インヒビターを含まないOD]
ワクチン接種前またはワクチン接種後のウサギの血清(実施例6)を使用して、殺菌アッセイを行なった。
候補ワクチンとしてのdLPS−TT複合体の潜在性を、非近交系のCD−1マウスにて評価した。
250μLの0.2Mのホウ酸塩緩衝液(pH9.0)中に、10mgのデキストランT5(MW 5 KDa,Pharmacosmos A/S,Holbaek,Denmark)を溶解させることにより、デキストラン−BSA複合体を調製した。これを、0.2Mのホウ酸塩緩衝液(pH9.0)中の1,8−ジアミノ−3,6−ジオキサオクタン(25mL)およびシアノヒドリドほう酸ナトリウム(10mg)を含む溶液(250μl)に加えた(「Roy et al.,1984」に記載の通り)。反応を55°Cで5日間行なった。LPSベースの複合体の調製に関して上述されたように、反応生成物を精製した。
ピロリ菌株O:3 HP0826::Kanに対して特異的なモノクローナル抗体を生成し、その特異性を研究した。
抗グルカンmAbsは、間接型のIF顕微鏡観察法研究によって実証されるように、代表的なピロリ菌株から生存する細菌の表面に容易に接触可能であった(表21)。α1,6−グルカンおよびCagAの両方を、細菌の表面上で同時に識別する。
すべての特許、特許出願および出版物は、本明細書を指し、本明細書により出願の全体にわたって引用文に組み込まれる。
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Claims (11)
- 式Iの構造を含み、α1,6−グルカンを備えた、精製されたヘリコバクター・ピロリ化合物の有効な量、及び有効な量のアジュバントを含む組成物であって、
α1,3−DD−ヘプタンの最後のDD−Hep残基は、β−GlcNAc残基でキャッピングされることを特徴とする組成物。 - ヘプタン部分が2から6のα1,3−結合ヘプトース残基を含むことを特徴とする請求項1に記載の組成物。
- Rが以下を含み、
- n=9であることを特徴とする請求項3に記載の組成物。
- m=2であることを特徴とする請求項3に記載の組成物。
- 式Iの構造がKdo残基Cに共有結合している脂質A部分をさらに含むことを特徴とする請求項1に記載の組成物。
- 脂質A部分は、O−脱アシル化するか、または、Kdo残基のケトシド結合の加水分解によって開裂することを特徴とする請求項6に記載の組成物。
- リンカー分子、タンパク質担体、または、その組み合わせに共役した、ほぼ線形のα1,6−グルカンを含む化合物を含む複合体であって、
ほぼ線形のα1,6−グルカンを含む化合物は、請求項1に記載の化合物であり、
該化合物は、リンカー分子、タンパク質担体、またはその組み合わせにKdo残基を介して共役されることを特徴とする、複合体。 - タンパク質担体が、破傷風トキソイドまたはウシ血清アルブミン、CRM、または、CRM197であることを特徴とする請求項8に記載の複合体。
- 分離されたヘリコバクター・ピロリ化合物又は複合体を含む組成物であって、
該ヘリコバクター・ピロリ化合物は、式Iの構造を含み、α1,6−グルカンを備え、
α1,3−DD−ヘプタンの最後のDD−Hep残基は、β−GlcNAc残基でキャッピングされた、ヘリコバクター・ピロリ化合物であって、
該複合体は、式Iの構造を含み、α1,6−グルカンを備えた、分離されたヘリコバクター・ピロリ化合物を含み、Rは、α1,3−DD−ヘプタンに結合した、α1,6−グルカンで置換したα−DDHep−3−α−L−Fuc−3−β−GlcNAc三糖類であり、
α1,3−DD−ヘプタンの最後のDD−Hep残基は、β−GlcNAc残基でキャッピングされ、
リンカー分子、タンパク質担体、またはその組み合わせに共役される複合体であって、
該ヘリコバクター・ピロリ化合物はKdo残基を介してリンカー分子、タンパク質担体、またはその組み合わせに共役されることを特徴とする、組成物。 - 個体内でピロリ菌に対する免疫反応を誘発するための製剤を製造するための、請求項10に記載の組成物の使用。
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