JP4510382B2 - ゾンネ赤痢菌から得られるInvaplex50を含む組成物の使用、感染から保護し得る免疫応答を対象体において誘導するための組成物、ゾンネ赤痢菌から得られるInvaplex50を含むワクチン、ワクチンの使用、およびキット - Google Patents
ゾンネ赤痢菌から得られるInvaplex50を含む組成物の使用、感染から保護し得る免疫応答を対象体において誘導するための組成物、ゾンネ赤痢菌から得られるInvaplex50を含むワクチン、ワクチンの使用、およびキット Download PDFInfo
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- JP4510382B2 JP4510382B2 JP2002590911A JP2002590911A JP4510382B2 JP 4510382 B2 JP4510382 B2 JP 4510382B2 JP 2002590911 A JP2002590911 A JP 2002590911A JP 2002590911 A JP2002590911 A JP 2002590911A JP 4510382 B2 JP4510382 B2 JP 4510382B2
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Description
本明細書には、グラム陰性細菌の同種の種(すなわち、当該Invaplexが調製された種)による感染から保護するために効果的であり、かつグラム陰性細菌の異種の種(すなわち、当該Invaplexに寄与しなかった種)による感染に対して効果的であるグラム陰性ワクチンInvaplex50が記載される。
本発明は、天然の構造を形成するために一緒に複合体化したLPSとの組合せでインベイシン類を含み、1つ以上の異種の赤痢菌属の種に対する保護的な免疫原として1つの赤痢菌属の種に由来するInvaplexの使用を記載する。
[実施例]
細菌の増殖および菌株。本研究において使用された赤痢菌属菌株はWRAIRコレクションの一部である。使用された菌株には、フレクスナー赤痢菌(Shigella flexneri)2a(2457T)、ゾンネ赤痢菌(S.sonnei)(Mosley)、およびボイド赤痢菌(S.boydii)2、フレクスナー赤痢菌5(M90T−W、Vir+)、フレクスナー赤痢菌5(M90T−55、Vir−)、フレクスナー赤痢菌2a(M42−43a、Vir−)、志賀赤痢菌(S.dysenteriae)1(Ubon)、そして細胞侵入性大腸菌Q152が含まれる。コンゴーレッドTSA平板で増殖する単離された赤色の赤痢菌属コロニーを使用して、50mlのPenAssay(抗生物質培地#3、Difco Laboratories、Detroit、MI)培養液に37℃で接種した。4時間増殖させた後、10mlの対数期培養物を1リットルの事前に加温(37℃)されたPenAssay培養液のそれぞれに加えた。これらの1リットル培養物を振とうインキュベーターで37℃において一晩インキュベーションした。
2週間の間隔で与えられたゾンネ赤痢菌Invaplex50の3回の鼻腔内用量(25μg)で免疫化されたモルモットから得られた末梢血リンパ球(PBL)を様々な赤痢菌属抗原とインキュベーションして、様々な赤痢菌属抗原に対するIgAを分泌する循環B細胞の数を測定した。血液が最後の免疫化の1週間後に集められた。100万細胞あたりのASC数が示される。PBLを、ゾンネ赤痢菌LPS(Son LPS)、ゾンネ赤痢菌Invaplex50(Son IVP50)、フレクスナー赤痢菌Invaplex50(Flex IVP50)、フレクスナー赤痢菌Invaplex24(Flex IVP24)およびフレクスナー赤痢菌LPS(Flex LPS)を含む5つの異なる赤痢菌属抗原とインキュベーションした。ゾンネ赤痢菌Invaplex50で免疫化されたモルモットは、ゾンネ赤痢菌LPSおよびゾンネ赤痢菌Invaplex50に対する抗体を分泌する抗体分泌細胞(ASC)を産生し、しかしフレクスナー赤痢菌Invaplex50およびフレクスナー赤痢菌Invaplex24に対する抗体を分泌する抗体分泌細胞をも産生するが、フレクスナー赤痢菌LPSに対する抗体を分泌する抗体分泌細胞を産生しない(図14)。このことは、ゾンネ赤痢菌Invaplex50が異種の免疫応答を刺激することを示す本発明者らのデータを裏付けている。
ゾンネ赤痢菌Invaplex50で免疫化され、続いてゾンネ赤痢菌で攻撃されたモルモットから得られた免疫血清(GP6LH)が、フレクスナー赤痢菌2a、ゾンネ赤痢菌(Mosley)、志賀赤痢菌1、ボイド赤痢菌2および細胞侵入性大腸菌に由来するInvaplex24調製物およびInvaplex50調製物をプローブするためにウエスタンブロットにおいて使用された(図15)(レーンは抗原含有物により表示される)。このウエスタンブロットの各レーンには、15μgの示されたInvaplexが負荷された。GP6LH抗血清には、IpaB、IpaC、84kDa、72kDa、70kDa、64kDaおよび58kDaのタンパク質を含むいくつかの赤痢菌属タンパク質に対する抗体が含有される。フレクスナー赤痢菌5Vir+およびフレクスナー赤痢菌5Vir−の全細胞溶解物がブロットの左側の2つのレーンに示される。最も左側のレーンには、事前に染色された分子サイズ標準物(MWマーカー)が含まれる。タンパク質サンプルは9%アクリルアミドゲルで最初に分離され、その後、ブロットされた。赤痢菌属抗原がブロットの右手側に矢印により示される。
フレクスナー赤痢菌Invaplex50で免疫化され、続いてフレクスナー赤痢菌2aで攻撃されたモルモットから得られた免疫血清(GP6RS)が、フレクスナー赤痢菌2a、ゾンネ赤痢菌(Mosley)、志賀赤痢菌1、ボイド赤痢菌2および細胞侵入性大腸菌に由来するInvaplex24調製物およびInvaplex50調製物をプローブするためにウエスタンブロットにおいて使用された(図16)(レーンは抗原含有物により表示される)。このウエスタンブロットの各レーンには、15μgの示されたInvaplexが負荷された。GP6RS抗血清には、IpaB、IpaC、84kDa、72kDa、70kDa、64kDaおよび58kDaのタンパク質を含むいくつかの赤痢菌属タンパク質に対する抗体が含有される。フレクスナー赤痢菌5Vir+およびフレクスナー赤痢菌5Vir−の全細胞溶解物がブロットの左側の2つのレーンに示される。最も左側のレーンには、事前に染色された分子サイズ標準物(MWマーカー)が含まれる。タンパク質サンプルは9%アクリルアミドゲルで最初に分離され、その後、ブロットされた。赤痢菌属抗原がブロットの右手側に矢印により示される。
ゾンネ赤痢菌Invaplex50で免疫化され、続いてゾンネ赤痢菌で攻撃されたモルモットから集められた血清が、84kDaおよび72kDaのタンパク質の存在について赤痢菌属の様々な菌株をプローブするためにウエスタンブロットにおいて使用された(図17)。全細胞溶解物(WCL)を電気泳動し、ニトロセルロースにブロットし、その後、抗血清と反応させた。各レーンには、レーンの上部に示されるような赤痢菌属の異なる菌株が含まれる。毒性(Vir+)および無毒性(Vir−)の両方の赤痢菌属菌株が使用された。Vir+プラス株は、IpaB、IpaCおよびIpaDを発現する。Vir−株はこれらのIpaタンパク質を発現しない。分子量マーカーのすぐ左側のレーンには、フレクスナー赤痢菌2aに由来する精製されたInvaplex24およびInvaplex50が含まれる。ゲルの最も右手側の2つのレーン(フレクスナー赤痢菌5Vir+WCLおよびフレクスナー赤痢菌5Vir−WCL)が、IpaBおよびIpaCを特異的に認識するモノクローナル抗体混合物でプローブされた。これらのコントロールにより、これらのゲルにおけるIpaBおよびIpaCの存在位置が明瞭に示される。分子量標準物が、97kDa、43kDa、30kDaおよび18kDaのサイズによって示される。矢印により、84kDa、72kDa、IpaBおよびIpaCの特異的なタンパク質が示される。
フレクスナー赤痢菌2aのInvaplex50で免疫化され、その後、フレクスナー赤痢菌2aで攻撃されたモルモットから集められた血清が、84kDaおよび72kDaのタンパク質の存在について赤痢菌属の様々な菌株をプローブするためにウエスタンブロットにおいて使用された(図18)。全細胞溶解物(WCL)を電気泳動し、ニトロセルロースにブロットし、その後、抗血清と反応させた。各レーンには、レーンの上部に示されるような赤痢菌属の異なる菌株が含まれる。毒性(Vir+)および無毒性(Vir−)の両方の赤痢菌属菌株が使用された。Vir+プラス株は、IpaB、IpaCおよびIpaDを発現する。Vir−株はこれらのIpaタンパク質を発現しない。分子量マーカーのすぐ左側のレーンには、フレクスナー赤痢菌2aに由来する精製されたInvaplex24およびInvaplex50が含まれる。ゲルの最も右手側の2つのレーン(フレクスナー赤痢菌5Vir+WCLおよびフレクスナー赤痢菌5Vir−WCL)が、IpaBおよびIpaCを特異的に認識するモノクローナル抗体混合物でプローブされた。これらのコントロールにより、これらのゲルにおけるIpaBおよびIpaCの存在位置が明瞭に示される。分子量標準物が、97kDa、43kDa、30kDaおよび18kDaのサイズによって示される。矢印により、84kDa、72kDa、IpaBおよびIpaCの特異的なタンパク質が示される。
赤痢菌属細菌の表面に局在化する抗原と反応し得る抗体を精製するために抗体の表面アフィニティー精製を使用して、細菌の表面において接近可能なエピトープを有するとしてゾンネ赤痢菌およびフレクスナー赤痢菌のInvaplex50に見出される新しく記載される抗原を同定することが可能である。そのような表面露出抗原は、感染宿主における細菌の抗体媒介による殺傷または除去のための標的であると考えられる。
Claims (6)
- 無傷の毒性赤痢菌属細菌を水で抽出し、その後、水抽出物のアニオン交換クロマトグラフィーによって調製され、0.24MのNaClおよび0.5MのNaClのステップグラジエントで溶出されたピーク部分に含有される、LPS、IpaB、IpaC、およびIpaDに加え、VirG * 、並びに72kDaおよび84kDaのポリペプチドを含むさらなる抗原性タンパク質を含有する、ゾンネ赤痢菌から得られるInvaplex50を含む組成物の使用であって、フレクスナー赤痢菌2a、ボイド赤痢菌、志賀赤痢菌、及び腸管組織侵入大腸菌(EIEC)から選ばれる細菌による感染に対する治療用および/または病気予防用薬剤の製造のためのゾンネ赤痢菌から得られるInvaplex50を含む組成物の使用。
- 無傷の毒性赤痢菌属細菌を水で抽出し、その後、水抽出物のアニオン交換クロマトグラフィーによって調製され、0.24MのNaClおよび0.5MのNaClのステップグラジエントで溶出されたピーク部分に含有される、LPS、IpaB、IpaC、およびIpaDに加え、VirG * 、並びに72kDaおよび84kDaのポリペプチドを含むさらなる抗原性タンパク質を含有する、ゾンネ赤痢菌から得られるInvaplex50の高分子量タンパク質(72KDaおよび84KDa)を含む、フレクスナー赤痢菌2a、ボイド赤痢菌、志賀赤痢菌、及び腸管組織侵入大腸菌(EIEC)から選ばれる細菌による感染から保護し得る免疫応答を対象体において誘導するための組成物。
- フレクスナー赤痢菌2a、ボイド赤痢菌、志賀赤痢菌、及び腸管組織侵入大腸菌(EIEC)から選ばれる細菌による感染から保護するためのワクチンであって、無傷の毒性赤痢菌属細菌を水で抽出し、その後、水抽出物のアニオン交換クロマトグラフィーによって調製され、0.24MのNaClおよび0.5MのNaClのステップグラジエントで溶出されたピーク部分に含有される、LPS、IpaB、IpaC、およびIpaDに加え、VirG * 、並びに72kDaおよび84kDaのポリペプチドを含むさらなる抗原性タンパク質を含有する、ゾンネ赤痢菌から得られるInvaplex50を含むワクチン。
- フレクスナー赤痢菌2a、ボイド赤痢菌、志賀赤痢菌、及び腸管組織侵入大腸菌(EIEC)から選ばれる細菌による感染に対する免疫性を提供する薬剤の製造のための請求項3に記載されるワクチンの使用。
- 前記ワクチンが、経口的、直腸的、皮下、皮内または筋肉内、鼻腔内および経皮からなる群から選択される投与様式に調製される、請求項4の使用。
- 請求項3のワクチンを保持するための容器手段を含むキット。
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US29215401P | 2001-05-18 | 2001-05-18 | |
US29249301P | 2001-05-21 | 2001-05-21 | |
PCT/US2002/016029 WO2002094190A2 (en) | 2001-05-18 | 2002-05-17 | Heterologous protection induced by immunization with invaplex vaccine |
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JP2009139527A Expired - Fee Related JP5149242B2 (ja) | 2001-05-18 | 2009-06-10 | Invaplexワクチンを用いた免疫化により誘導される異種保護 |
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DE602004025144D1 (de) | 2003-11-25 | 2010-03-04 | Us Gov Sec Army | Verwendung von shigella invaplex für den transportven nukleinsäuren durch säugetier-zellmembranen in vitro und in vivo |
US7481997B1 (en) | 2004-02-12 | 2009-01-27 | Montana State University | Snow mountain virus genome sequence, virus-like particles and methods of use |
US20080124355A1 (en) | 2006-09-22 | 2008-05-29 | David Gordon Bermudes | Live bacterial vaccines for viral infection prophylaxis or treatment |
CA2563214A1 (en) * | 2006-10-12 | 2008-04-12 | Institut Pasteur | Shigella ipad protein and its use as a potential vaccine against shigella infection |
CN101711165B (zh) * | 2007-03-27 | 2016-02-24 | 以沃尔特里德军事研究所的名义,由美国陆军部部长为代表的美国政府 | 人造侵袭素复合物 |
EP2197421A1 (en) * | 2007-08-31 | 2010-06-23 | Amgen, Inc | Solid-state protein formulation |
US8241623B1 (en) | 2009-02-09 | 2012-08-14 | David Bermudes | Protease sensitivity expression system |
US9597379B1 (en) | 2010-02-09 | 2017-03-21 | David Gordon Bermudes | Protease inhibitor combination with therapeutic proteins including antibodies |
US8771669B1 (en) | 2010-02-09 | 2014-07-08 | David Gordon Bermudes | Immunization and/or treatment of parasites and infectious agents by live bacteria |
US8524220B1 (en) | 2010-02-09 | 2013-09-03 | David Gordon Bermudes | Protease inhibitor: protease sensitivity expression system composition and methods improving the therapeutic activity and specificity of proteins delivered by bacteria |
JP6045499B2 (ja) * | 2010-10-27 | 2016-12-14 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | 赤痢菌リポ多糖及び外膜タンパク質を含む免疫原性組成物 |
US9593339B1 (en) | 2013-02-14 | 2017-03-14 | David Gordon Bermudes | Bacteria carrying bacteriophage and protease inhibitors for the treatment of disorders and methods of treatment |
US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
US11180535B1 (en) | 2016-12-07 | 2021-11-23 | David Gordon Bermudes | Saccharide binding, tumor penetration, and cytotoxic antitumor chimeric peptides from therapeutic bacteria |
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AU1199900A (en) * | 1998-09-30 | 2000-04-17 | Walter Reed Army Institute Of Research | Use of purified invaplex from gram negative bacteria as a vaccine |
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