JP2019167369A - 新規な免疫賦活法 - Google Patents
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- JP2019167369A JP2019167369A JP2019105433A JP2019105433A JP2019167369A JP 2019167369 A JP2019167369 A JP 2019167369A JP 2019105433 A JP2019105433 A JP 2019105433A JP 2019105433 A JP2019105433 A JP 2019105433A JP 2019167369 A JP2019167369 A JP 2019167369A
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Abstract
Description
本明細書を通して、文脈が他のことを要求していない限り、「含む(comprise)」という語又は「含む(comprises)」若しくは「含んでいる(comprising)」などの変化形は、述べられている要素若しくは整数又は要素若しくは整数の群の組み入れを意味し、任意の他の要素若しくは整数又は要素若しくは整数の群の除外を意味するものではないと理解されるものとする。
ペプチド及びリポペプチドの合成、精製及び確証。リポペプチド及びペプチドの合成を、従来の固相合成により、全体にわたって、Fmoc(9−フルオレニルメトキシ カルボニル)化学を使用して実施した。ペプチドを、Symphony Multiplex synthesiser(Protein Technologies Inc、Arizona、USA)又はマイクロ波技術を使用して高忠実性ペプチド配列の作製を容易にするLiberty synthesiser(CEM、North Carolina、USA)使用して、自動的にアセンブリさせた。ペプチド及びリポペプチドを、逆相高性能液体クロマトグラフィーにより精製し、生成物の信頼性を、質量分析により決定した。ペプチドのアセンブリ、精製及び特徴付けに使用した手順は、他に詳細に記載されている(参考文献1、2、3)。Pam2Cysの可溶性形態を、O−(N−Fmoc−2−アミノエチル)−O’−(2−カルボキシエチル)−ウンデカエチレングリコール(Fmoc−PEG11−OH、Merck Ltd)のPam2Cysへの付加により調製した。これにより、脂質のペグ化形態、Pam2Cys−PEG11が形成された。リポペプチド構築体及び個別のリポペプチド組成物に含まれるエピトープを表1に示す。
Pam2Cysに基づくリポペプチド接種が、肺細胞集団を拡大する。肺細胞環境に対するPam2Cysに基づくリポペプチドの効果を、ヘルパーTエピトープ(Th)OT2及び単純ヘルペスウイルス1由来CD8+T細胞エピトープを含有するリポペプチドOT2−P2C−gB498−505(gB498−505;表1を参照されたい)を鼻腔内接種されたC57BL/6マウスにおいて検査した。PBSで還流された肺における肺常在細胞集団を、細胞フローサイトメトリを使用して特徴付けた。
先天性免疫応答が感染症の制御において果たすきわめて重要な役割は、感染前の先天性免疫系の早期活性化が、感染因子、例えばウイルス又は細菌によるチャレンジに対する保護強化を提供できることを示唆している。この研究の結果は、TLR2アゴニストを含む可溶性TLR2部分の投与が、投与された対象において先天性免疫応答を高め、免疫応答が非抗原特異的であることを明示した。さらに、本発明に従った組成物の鼻腔内予防投与により誘発される肺の変化がウイルス及び細菌への続く曝露に対する抵抗性の増加に関係した。このような組成物が、ウイルス感染症及び細菌感染症に対する予防薬として、特に流行又はパンデミックの発生の高い危険性がある場合、適切であることを示唆している。本発明に従った予防方法及び治療方法はまた、感染因子(又はその抗原成分若しくは特定の菌株)の予備知識を必要としないという有利性を有し、したがって、例えばインフルエンザのパンデミックの期間に特に有用であり得る。凍結乾燥でき、室温において安定である、本発明に従った組成物の安定性は、パンデミックの状況に対する備蓄に非常に適切であることもまた意味する。
Claims (20)
- 対象において先天性免疫応答を高めることにより疾患を治療又は予防する方法であって、
溶液中にTLR2部分を含む有効量の組成物を対象に投与するステップを含み、
TLR2部分がTLR2アゴニストを含み、
疾患が、TLR2部分に対する液性免疫応答又は細胞性免疫応答により治療又は予防されない、方法。 - 対象において先天性免疫応答を高めることによりがんを治療又は予防する方法であって、
溶液中にTLR2部分を含む治療有効量の組成物を対象に投与するステップを含み、
TLR2部分がTLR2アゴニストを含み、
TLR2部分が、がんに対する特異的細胞性免疫応答又は液性免疫応答を誘導しない、方法。 - 感染因子により引き起こされる疾患を治療又は予防する方法であって、
溶液中にTLR2部分を含む有効量の組成物を、それを必要とする対象に投与するステップを含み、
TLR2部分がTLR2アゴニストを含み、
TLR2部分が感染因子に対する特異的な細胞性免疫応答又は液性免疫応答を誘導しない、方法。 - TLR2部分が、可溶化剤にコンジュゲートされたTLR2アゴニストを含む、請求項1〜3のいずれか一項に記載の方法。
- TLR2アゴニストが、Pam2Cys、Pam3Cys、Ste2Cys、Lau2Cys及びOctCysからなる群から選択される、請求項1〜4のいずれか一項に記載の方法。
- TLR2アゴニストがPam2Cysである、請求項5に記載の方法。
- 可溶化剤がPEG(ポリエチレングリコール)又は極性ポリペプチドである、請求項4〜6のいずれか一項に記載の方法。
- 極性ポリペプチドが、R4、H4、E8及びH8からなる群から選択される、請求項7に記載の方法。
- 可溶化剤がPEGである、請求項7に記載の方法。
- 可溶化剤が、PEG並びにR4、H4、H8、EB8及びE8のいずれか1つを含む、請求項7に記載の方法。
- 組成物が対象に鼻腔内投与される、請求項1〜10のいずれか一項に記載の方法。
- 感染因子がウイルスである、請求項3〜11のいずれか一項に記載の方法。
- ウイルスがインフルエンザAウイルス(IAV)である、請求項12に記載の方法。
- 感染因子が、マイコバクテリウム・ツベルクローシス又はレジオネラ・ニューモフィラである、請求項3〜11のいずれか一項に記載の方法。
- がんが感染因子により引き起こされる、請求項2に記載の方法。
- がんが、ヒトパピローマウイルス(HPV)、C型肝炎ウイルス(HCV)又はエプスタイン・バーウイルス(EBV)により引き起こされる、請求項15に記載の方法。
- 溶液中の有効量のTLR2部分を、薬学的に許容される担体又は賦形剤と一緒に含む、対象において先天性免疫応答を高めることにより疾患を治療又は予防するための医薬組成物であって、
TLR2部分がTLR2アゴニストを含み、
疾患が、TLR2部分に対する液性免疫応答又は細胞性免疫応答により治療又は予防されない、医薬組成物。 - 対象において疾患を治療又は予防するための医薬品の製造のための、溶液中の有効量のTLR2部分の使用であって、
TLR2部分がTLR2アゴニストを含み、
TLR2アゴニストが対象において先天性免疫応答を高め、
疾患が、TLR2部分に対する液性免疫応答又は細胞性免疫応答により治療又は予防されない、使用。 - 組成物がTLR9アゴニストを含まない、請求項1〜16のいずれか一項に記載の方法又は請求項17に記載の組成物。
- 医薬品がTLR9アゴニストを含まない、請求項18に記載の使用。
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