(1) Background: Cytoplasmic delivery of antigens is crucial for the induction of cellular immunity, which is an important immune response for the treatment of cancer and infectious diseases. To date, fusogenic protein-incorporated liposomes and pH-responsive polymer-modified liposomes have been used to achieve cytoplasmic delivery of antigen via membrane rupture or fusion with endosomes. However, a more versatile cytoplasmic delivery system is desired for practical use. For this study, we developed pH-responsive micelles composed of dilauroyl phosphatidylcholine (DLPC) and deoxycholic acid and investigated their cytoplasmic delivery performance and immunity-inducing capability. (2) Methods: Interaction of micelles with fluorescence dye-loaded liposomes, intracellular distribution of micelles, and antigenic proteins were observed. Finally, antigen-specific cellular immune response was evaluated in vivo using ELIspot assay. (3) Results: Micelles induced leakage of contents from liposomes via lipid mixing at low pH. Micelles were taken up by dendritic cells mainly via macropinocytosis and delivered ovalbumin (OVA) into the cytosol. After intradermal injection of micelles and OVA, OVA-specific cellular immunity was induced in the spleen. (4) Conclusions: pH-responsive micelles composed of DLPC and deoxycholic acid are promising as enhancers of cytosol delivery of antigens and the induction capability of cellular immunity for the treatment of cancer immunotherapy and infectious diseases.
1 .背 景 日本では新薬へのアクセスの向上のため,海外で承認さ れた医薬品が日本で承認されるまでの時間差(ドラッグラ グ)の解消を課題として,さまざまな施策が行われてき た 1) .その結果,新薬の審査期間は短縮されてきたが,いま だ新薬の多くは米国または欧州で先行して開発され,承認 されている 2) .今後,世界で最初の承認国が日本となる医 薬品を増加させていくことは,新薬へのアクセスのさらな る向上のため重要な課題であると考える. それと並行して,今後新たに登場する医薬品について, そのリスク管理を適正に行っていくことも重要である.海 外で先行して承認された医薬品では,日本で承認されるま でに当該医薬品の実臨床での安全性情報が海外で集積さ れ,これらの情報を参考に市販後安全対策を立案し,実施 することが可能である.一方,世界で最初の承認国が日本 である医薬品または海外と同時期に日本で承認された医薬 品では,承認までに得られた情報に基づき市販後安全対策 を立案し,実施していくことが求められる. 本研究では,近年日本で承認された新薬について,その 承認が世界で最初のものであったか否かに着目し,その シーズ創出や開発に関する地域的な状況との関係を調査す るとともに, 承認時に特定された安全性検討事項を比較し, 新薬を世界に先駆けて日本で実用化するためのより良い開 発環境および市販後安全対策のあり方について検討するこ とを目的とした. 2 .方 法 2. 1.研究対象品目の選定および分類2008 年 1 月から 2014 年 12 月の期間に日本で承認され た新有効成分含有医薬品(ワクチンおよび診断用医薬品を 臨床薬理 Jpn J Clin Pharmacol Ther 2017 ; 48(1): 9-14 9 * 北里大学大学院薬学研究科臨床医学(医薬開発学) 著者連絡先:還田悠平 北里大学大学院薬学研究科臨床医学(医薬開発学) 〒 108-8641 東京都港区白金 5-9-1 detailed information including the regions where the new drugs were developed and the countries of first global approval were identified. We also collected information about safety concerns that were identified before approval.Result : Two hundred and thirty-nine NASs obtained Japanese approval during the study period. Of the 239 NASs, 44 (18.4%) were approved in Japan before the rest of the world. Drugs that obtained Japanese approval first in the world were more often developed in Japan from the early stage. Furthermore, the data suggested that these drugs were launched with relatively limited safety information.
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