JP4795021B2 - 敗血症治療における経口用ラクトフェリン - Google Patents
敗血症治療における経口用ラクトフェリン Download PDFInfo
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- JP4795021B2 JP4795021B2 JP2005508468A JP2005508468A JP4795021B2 JP 4795021 B2 JP4795021 B2 JP 4795021B2 JP 2005508468 A JP2005508468 A JP 2005508468A JP 2005508468 A JP2005508468 A JP 2005508468A JP 4795021 B2 JP4795021 B2 JP 4795021B2
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- lactoferrin
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Description
本出願は、参照によりここに組み込まれる2002年12月6日出願の米国仮出願第60/431,393号および2003年8月27日出願の同第60/498,327号の優先権を主張する。
本発明によるラクトフェリンは、例えば哺乳類の乳等の、しかしこれに限定されない天然源から単離、精製により得ることができる。ラクトフェリンは、好ましくは、ウシまたはヒトのラクトフェリン等、哺乳類のラクトフェリンである。好ましい実施態様において、ラクトフェリンは、遺伝子組み換えが行われた動物、植物、真核生物での組み換え発現または直接の生産等の当該分野でよく知られ、使用される遺伝子工学技術を用いて組み換えて作られるか、または化学合成で作られる。例えば、参照によりここに組み込まれる米国特許第5,571,896号、同5,571,697号および同5,571,691号を参照されたい。
本発明は、薬学的担体に分散したラクトフェリン組成物を含む組成物に関する。本発明の組成物に含まれるラクトフェリンは、ラクトフェリンまたは少なくともN−1末端のグリシン残基が切り取られるか、置換されたN末端ラクトフェリン変異体を含む。さらに具体的には、N‐末端ラクトフェリン変異体は、組成物の少なくとも1%、組成物の少なくとも5%、組成物の少なくとも10%、組成物の少なくとも25%、組成物の少なくとも50%またはこれらの間のいずれかの範囲の組成物を構成する。
本発明に従い、上記の薬学的担体のいずれかの中に供給される組成物は菌血症、敗血症、敗血症性ショックまたは続発症と疑われる、またはそれを有する対象に経口投与する。これらの条件はグラム陰性菌、グラム陽性菌または体の病巣中のカンジダ菌等の他の病原菌により引き起こされ、全身炎症応答症候群となるか、なっっている危険性を有する。当業者は、対象に投与すべき組成物の治療効果および/または予防効果のある量を、局所効果、薬物動態、吸収、代謝、投薬方法、年齢、体重、重症度および治療に対する応答性等、いくつかの考慮事項に基づいて決定できる。組成物の経口投与として、経口、腔口、腸内、直腸または胃内投与が挙げられる。
組成物の有効性を高めるために、これらの組成物と本発明の方法を、菌血症、敗血症、敗血症性ショックおよび関連する状態の治療または予防に効果的な公知の物質、例えば細菌感染治療に公知の物質、抗生物質、敗血症の治療に公知の物質、例えば(活性化)ドロトレコギン アルファ(Drotrecogin alpha)および炎症を治療する物質と組み合わせることが望ましいこともある。いくつかの実施態様において、薬理学的治療剤等の、しかしこれに限定されない慣用の治療または物質を本発明の組成物と併用してよいことが意図される。
マウスにおけるリポ多糖誘導敗血症性ショック−モデルの特性付け
本実験において、LPSの投与量と試験動物の死亡率との関係を調べた。10匹のC57BL/6Jマウス(18±1g)群を用いた。動物には、D(+)ガラクトサミン(20mg/マウス、静脈内(IV))での前処理直後に異なる投与量の大腸菌リポ多糖(LPS、30、20、15および10ng/マウス、静脈内(IV))とビヒクル(生理食塩水、0.2ml/マウス)を与えた。死亡率は3日間にわたって12時間毎に記録した。表2は、20〜30ng/マウスのLPSが100%の死亡率をもたらし、15ng/マウスのLPSが50%の死亡率をもたらしたことを示している。
敗血症のマウスLPSモデルにおける静脈内投与したrhLFの効果
リポ多糖(大腸菌由来LPS、20ng/動物のLD100、静脈内(i.v.))とガラクトサミン(20mg/動物、i.v.)とによる誘発の60分前およびこの誘発の10分後に、ビヒクルと試験物質(rhLF)を18〜20gの体重の8匹のC57BL/6Jのオスマウスに静脈内投与した。表3に示されたように、RhLFは、LPSにより誘導された死亡率を38%低下させた。
敗血症のマウスLPSモデルにおける経口投与したrhLFの効果
リポ多糖とガラクトサミンとによる誘発の1、6および12時間後に、組み換えヒトラクトフェリンを5および1.5mg/マウス(経口、PO)と1.5と0.5mg/マウス(IV)の投与量でそれぞれ経口および静脈内投与した。図1は、経口投与rhLFが静脈内投与rhLFに匹敵する防御をもたらしたことを示す。
LPS誘導敗血症性ショックにおける経口rhLFの用量依存的防御
実施例1に記載のように、LPSとガラクトサミンを用いてそれぞれ10匹の各マウスからなる4群に敗血症性ショックを誘導した。次に、これらマウスの群に、LPS投与の1時間後、6時間後および12時間後に強制飼養で経口投与するプラシーボまたはrhLF(1投与あたり1.5mg、5mgまたは10mg)の3投与量のいずれかを与えた。表4に示すように、経口rhLFはLPS誘導致死に対して用量依存的防御をもたらした。
LPS誘導敗血症ショックにおける異なる投与計画により投与された経口rhLFの有効性
実施例1に記載のように、LPSとガラクトサミンを用いてそれぞれ8〜10匹の各マウスからなる4群に敗血症性ショックを誘導した。次に、これらマウスの群に、異なる4投与計画の一つにより強制飼養で経口投与するプラシーボまたは5mg/投与のrhLFを与えた。表5に示すように、経口rhLFは、予防的または治療的のいずれかで、試験されたすべての投与計画において投与されたときに、LPS誘導致死に対する防御をもたらした。
菌血症のマウスモデルにおけるrhLFの防御効果
22±2gの体重の10匹のICRのオスとメスのマウスの群を用いた。各動物に、5%ムチンを含有する0.5ml脳−心臓注入培養液に懸濁した大腸菌(ATCC25922; 1〜3×105CFU/マウス)を腹腔内に接種した。
菌血症の亜致死マウスモデルにおけるhrLFの防御効果
22±2g体重の10匹のICRのオスとメスのマウスの群を用いた。各動物に、5%ムチンを含有する0.5ml脳−心臓注入培養液に懸濁した大腸菌(ATCC25922)の亜致死投与量を腹腔内に接種する。
菌血症の亜致死マウスモデルにおける抗生物質と併用したhrLFの防御効果
22±2g体重の10匹のICRのオスとメスのマウスの群を用いた。各動物に、5%ムチンを含有する0.5ml脳−心臓注入培養液に懸濁した大腸菌(ATCC25922)の亜致死投与量を腹腔内に接種する。動物はカナマイシン抗生物質を100mg/kg/日の投与量で処置する。
菌血症のヒヒモデルにおける経口hrLF投与の防御効果
見込みのあるランダム化されたプラシーボ対照研究において、経口rhLFの有効性を、生きた大腸菌を注入した、絶えず機器を取り付けた抗生物質治療下にあるオスのヒヒにおいて72時間にわたって調べる。
菌血症、敗血症および敗血症性ショックにおけるEDTAを共に投与した場合のrhLFの防御効果
リポ多糖とガラクトサミンとの誘発の1時間後、6時間後および12時間後に、組換えヒトラクトフェリンをEDTAと共に1:1の重量比で、経口または静脈内に、それぞれ5および1.5mg/マウスのrhLFと5と1.5mg/マウスのEDTAの投与量で(経口(PO))、およびそれぞれ1.5および0.5mg/マウスのrhLFと1.5と0.5mg/マウスのEDTAの投与量で(静脈内(IV))共に投与する。死亡率は3日間にわたって記録する。ビヒクル処置群に比べて死亡率の50%以上(≧50%)の減少が顕著な防御を示す。
菌血症と敗血症を治療するために投与されたrhLFの安全性に関する臨床研究
研究のために、患者を、菌血症の症状の存在、すなわち熱>華氏101度(38.3℃)、寒気、不快感、腹部の痛み、吐き気、嘔吐、下痢、不安感、息切れおよび困惑に基づいて選択する。ほとんどの細菌感染はスタフィロコッカス、シュードモナス、ヘモフィラスおよび大腸菌による。その後の敗血症性ショックは通常免疫弱体化または慢性病患者で起こる。
敗血症におけるrhLFの防御効果を示す臨床研究−投与量の範囲
研究のために、患者を、菌血症の症状の存在、すなわち熱>華氏101度(38.3℃)、寒気、不快感、腹部の痛み、吐き気、嘔吐、下痢、不安感、息切れおよび困惑に基づいて選択する。ほとんどの細菌感染はスタフィロコッカス、シュードモナス、ヘモフィラスおよび大腸菌による。その後の敗血症性ショックは通常免疫弱体化または慢性病患者で起こる。
菌血症と敗血症におけるrhLFの防御効果を示す臨床研究
フェーズ3研究
研究のために、患者を、菌血症の症状の存在、すなわち熱>華氏101度(38.3℃)、寒気、不快感、腹部の痛み、吐き気、嘔吐、下痢、不安感、息切れおよび困惑に基づいて選択する。ほとんどの細菌感染はスタフィロコッカス、シュードモナス、ヘモフィラスおよび大腸菌による。その後の敗血症性ショックは通常免疫弱体化または慢性病患者で起こる。
菌血症と敗血症におけるrhLF/キシグリス(登録商標)併用の防御効果を示す臨床研究−フェーズ2研究
研究のために、患者を、菌血症の症状の存在、すなわち熱>華氏101度(38.3℃)、寒気、不快感、腹部の痛み、吐き気、嘔吐、下痢、不安感、息切れおよび困惑に基づいて選択する。ほとんどの細菌感染はスタフィロコッカス、シュードモナス、ヘモフィラスおよび大腸菌による。その後の敗血症性ショックは通常免疫弱体化または慢性病患者で起こる。
ARDSにおけるrhLFの防御効果を示す臨床研究−フェーズ2研究
このランダム化され、管理された研究において、各患者はランダムにrhLFの12mL/kgまたは6mL/kgの換気処置群またはプラシーボ群に割り当てられる。rhLF治療群はプラシーボ対照で二重盲検である。
敗血症における死亡率と主要サイトカインの減少
LPS誘導敗血症における経口rhLFの防御効果は公知のサイトカインモジュレーターに関連付けられた。マウスはLPS(20ng IV)+ガラクトサミンで処置した。動物は、LPS誘発時を基準にして、プラシーボ(−1、+1、+6、+12時間)または強制飼養によりrhLF(5mg/投与)を経口的に与えた。死亡率は72時間まで測定したが、すべての死は24時間以内に起こった。循環するサイトカインはLPS誘発の45分後にELISAで測定した。サイトカイン群は一群あたり4匹の動物であった。全28匹(12匹のプラシーボ、16匹のrhLF)を生存に関して追跡調査を行った。片側p値でプラシーボ動物とrhLF動物とを比較した。個々のサイトカインに関する値は平均として示す。初期の実験に一致して、rhLF処置動物は死亡率の顕著な59%の減少を示した。さらに、IL−4、IL−6およびIL−10の循環レベルの減少が観察され(図2)、すべてのTh2サイトカインは敗血症の病態生理学で一定の役割を果たしていることが報告されている。
L005対L006の抗敗血症活性
N−1端切除物の比率が異なるrhLFの3バッチの生物学的活性をLPS誘導敗血症のマウスモデルを用いて比較した。LPS(20ng/動物IV)とガラクトサミン(20mg/動物IV)との誘発の1時間後、6時間後および12時間後に、18〜20g体重の10匹のC57BL/6Jのオスマウス群にプラシーボまたはrhLF(5mg/投与)を経口投与した。死亡率は72時間にわたって12時間毎に監視した。表7に示されるように、広範に変化する濃度のN−1端切除物を有するrhLFの異なるバッチはすべて、LPS誘導致死に対して同様な防御を示した。
経口rhLFのマウスにおける生物学的利用能の欠如
特別に合成した14C標識rhLF(Perkin−Elmer Life Sciences)をCD−1マウスに経口投与してタンパク質吸収の程度を決定した。マウスに14C−rhLFを接種し、血液と組織試料を下記の表8に示すように集めた。
ヒトにおける経口rhLFの生物学的利用能の欠如
組換えヒトラクトフェリンは健康なヒト対象の別々の5群に経口投与された。これらの5群は、(合計35対象者を用いた)rhLFとプラシーボに関して6:1の比率でダンダム化した。投与量を下記の表10に示す。
本明細書に示したすべての特許と刊行物は本発明に関する当業者のレベルを示すものである。すべての特許と刊行物は、それぞれ個々の刊行物が編入されるように具体的にかつ個々に示されているのと同じ程度に参照によりここに組み込まれる。
米国特許第5,571,691号
米国特許第5,571,697号
米国特許第5,571,896号
米国特許第5,629,001号
Kruzel ML, et al. Clin Exp Immunol 2002; 130:25-31
Heyman M and Desjeux J-F, J Pediatr Gastroenterol Nutr 1992; 15:48-57
Fransson GB, et al., Nutr Res 1983; 3:373-84
Holloway NM, et al., Am J Vet Res 2002 Apr; 63(4):476-8
Mojaverian P. et al. Proceedings of the Annual Meeting of the American Association of Pharmaceutical Scientists, 2003.
Claims (6)
- 敗血症性ショックの治療および/または予防の為の経口剤であって、N末端ラクトフェリン変異体のみからなるラクトフェリン成分を含有し、
該N末端ラクトフェリン変異体が、N末端アミノ酸残基の1個から16個までの欠失、置換、あるいはそれらの組み合わせの状態である経口剤。 - 前記敗血症性ショックの治療および/または予防が、敗血症性ショックを減弱すること、器官不全を減弱すること、罹患率を減少させること、および死亡率を減少させること、からなる群より選択される1またはそれ以上である、請求項1記載の経口剤。
- 前記ラクトフェリン成分がヒトまたはウシのラクトフェリンを含む請求項1または2記載の経口剤。
- 前記ラクトフェリン成分が組換えラクトフェリンを含む請求項1から3までのいずれか1項記載の経口剤。
- 前記N末端ラクトフェリン変異体の量が1日当たりの投与量が約10mg〜約10gになるように調整される請求項1から4までのいずれかに記載の経口剤。
- 前記N末端ラクトフェリン変異体が、N末端アミノ酸残基の1個の欠失体(N−1端切除物)である、請求項1から5までのいずれか1項記載の経口剤。
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ITRM20080163A1 (it) * | 2008-03-26 | 2009-09-27 | Maurizio Acri | Uso della lattoferrina per la prevenzione delle sepsi neonatali in neonati prematuri |
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