JP6381147B2 - 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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- JP6381147B2 JP6381147B2 JP2016250262A JP2016250262A JP6381147B2 JP 6381147 B2 JP6381147 B2 JP 6381147B2 JP 2016250262 A JP2016250262 A JP 2016250262A JP 2016250262 A JP2016250262 A JP 2016250262A JP 6381147 B2 JP6381147 B2 JP 6381147B2
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- Prior art keywords
- glucan
- lps
- pylori
- heptane
- residue
- Prior art date
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
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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 (6)
- 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・ピロリ化合物と、特異的に結合するモノクローナル抗体であって、
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モノクローナル抗体。 - 前記モノクローナル抗体は、カナダの国際預託機関であるカナダ国立微生物学研究所に受け入れ番号300709−01として寄託された細胞株によって産生されるモノクローナル抗体1C4F9であることを特徴とする請求項1に記載のモノクローナル抗体。
- 処置を必要としている個体において、α1,6−グルカンを発現するピロリ菌株の補体を媒介とした溶菌を引き起こすために使用されることを特徴とする、請求項1に記載のモノクローナル抗体。
- 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哺乳動物を免疫化することによって作製される免疫抗血清であって、
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、
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、式I中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、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複合体である、ことを特徴とする免疫抗血清。 - 免疫抗血清は、同種及び異種の、分類可能な及び分類不可能な、ピロリ菌の変異株および野生株における、α1,6−結合グルカンエピトープに特異的に結合するIgGを含むことを特徴とする、請求項4に記載の免疫抗血清。
- カナダの国際預託機関であるカナダ国立微生物学研究所に受け入れ番号300709−01として寄託された細胞株によって産生されるモノクローナル抗体1C4F9。
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JP2013501080A (ja) | 2013-01-10 |
CA2762366C (en) | 2017-09-19 |
KR101616599B1 (ko) | 2016-04-28 |
US9328158B2 (en) | 2016-05-03 |
EP2459708B1 (en) | 2016-06-22 |
JP2017101036A (ja) | 2017-06-08 |
CN102482646B (zh) | 2015-09-16 |
JP6166533B2 (ja) | 2017-07-19 |
RU2558257C2 (ru) | 2015-07-27 |
CA2762366A1 (en) | 2011-02-03 |
KR20120041235A (ko) | 2012-04-30 |
EP2459708A1 (en) | 2012-06-06 |
CN102482646A (zh) | 2012-05-30 |
US20150284449A1 (en) | 2015-10-08 |
WO2011011879A1 (en) | 2011-02-03 |
US20170129941A1 (en) | 2017-05-11 |
MX2012001312A (es) | 2012-06-01 |
RU2012107480A (ru) | 2013-09-10 |
US20120164145A1 (en) | 2012-06-28 |
US20120301480A1 (en) | 2012-11-29 |
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