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Nanoparticles Targeting Macrophages for Enhancement of Macrophage Phagocytosis in Cancer Immunotherapy

李, 昊 大阪大学 DOI:10.18910/82349

2021.03.24

概要

【背景】
 マクロファージは様々な疾患に関与する細胞であるため、治療標的として極めて重要である。マクロファージへ特異的に薬物を送達するドラッグデリバリーシステム(DDS)として、マクロファージのファゴサイトーシスを誘導して細胞内に取り込ませるナノキャリアが有効であると考えられる。一方、現在、免疫システムを利用したがん治療(抗体医薬、PD-1 阻害剤など)は、画期的に進展し、大いに注目を集めている中、腫瘍微小環境が如何に免疫治療の効果に影響を及ぼしているかを解明することが課題となっている。腫瘍随伴マクロファージ(TAM)は、種々のがん組織に豊富に存在する免疫系細胞であり、各種がん免疫療法における重要なエフェクター細胞となる。しかし、TAM は腫瘍細胞によって免疫抑制型の M2 タイプへ誘導されており、がん免疫療法において十分に働かないと考えられる。

【目的】
 マクロファージを標的化して、ファゴサイトーシスを誘導して細胞内に取り込まれるナノキャリアを創製する。また、TAM を免疫活性化型の M1 タイプに再教育して、現在臨床応用されている様々な抗体医薬のADCP(抗体依存性細胞貪食)効果とADCC(抗体依存性細胞傷害)効果が上昇できるかを検討する。さらに、全身投与では生体利用率が低いため腫瘍内局所投与に限られている免疫賦活剤を、マクロファージ標的化ナノ粒子に封入し、in vivo で効率的なTAM のM1 タイプ化再教育による抗体医薬の治療効果増強を実証する。

【位置づけ】
 TAM 標的化能、TAM 再教育能、ADCC/ADCP 活性化能を全て達成するナノ粒子は前例がなく、本技術が実用化すれば、手術など侵襲的な治療法しかない腫瘍における新たな治療法となる。また、今まで免疫治療において軽視されてきた TAMの中心的な役割が判明すれば、免疫治療の新しい研究方向を開拓することができる。

【意義】
 腫瘍随伴マクロファージ(TAM)は抗体医薬によるがんの免疫治療に極めて重要であり、治療標的として非常に重要な細胞と考えられている。本研究は基盤技術となる抗体医薬、DDS、小分子免疫賦活剤の融合的な挑戦であり、達成時に大きなインパクトがあると予想される。

【新規性】
 ①TAM の免疫治療における重要性を実証する点。
 ②これまでTAM のM1タイプ化再教育による治療研究、および抗体医薬による ADCP や ADCC を介した治療研究は、それぞれ独立して盛んに行われているが、両立させた研究は数例しか存在しない点。
 ③従来の免疫賦活剤は主に T 細胞を活性化するのに対し、TAM の活性化については検討例が少なく、TAM が免疫抑制状態では免疫治療をうまく達成できない主要因であることを証明する点。
 ➃免疫賦活剤のデリバリーに関する研究は、TAMの M1 タイプ化再教育までしか達成されておらず、免疫賦活剤の TAM へのデリバリーによるTAM M1 タイプ化再教育、その後の抗体医薬のエフェクター細胞としての抗腫瘍効果(ADCC/ADCP)増強の実証を目指している点。
 ⑤単独投与では副作用の大きい免疫賦活剤を TAM へピンポイントに送達することによって副作用が軽減できる点。
 ⑥In vivo のTAM 再教育の効果を、画像認識技術でマクロファージの細胞形態から判別する点。

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参考文献

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Chapter 4

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[22] Engel JE, Chade AR. Macrophage polarization in chronic kidney disease: a balancing act between renal recovery and decline? American Journal of Physiology-Renal Physiology. 2019;317:F1409-F13.

[23] Lavine KJ, Pinto AR, Epelman S, Kopecky BJ, Clemente-Casares X, Godwin J, et al. The Macrophage in Cardiac Homeostasis and Disease: JACC Macrophage in CVD Series (Part 4). J Am Coll Cardiol. 2018;72:2213-30.

[24] Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. Journal of hepatology. 2014;60:1090-6.

[25] Mammana S, Fagone P, Cavalli E, Basile MS, Petralia MC, Nicoletti F, et al. The Role of Macrophages in Neuroinflammatory and Neurodegenerative Pathways of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis: Pathogenetic Cellular Effectors and Potential Therapeutic Targets. International journal of molecular sciences. 2018;19:831.

[26] Na YR, Stakenborg M, Seok SH, Matteoli G. Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nature Reviews Gastroenterology & Hepatology. 2019;16:531-43.

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