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大学・研究所にある論文を検索できる 「IL-2受容体α鎖結合性を欠損する新規IL-2変異体MK-6はエフェクター/制御性T細胞バランスを改善することで抗腫瘍活性を発揮する」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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IL-2受容体α鎖結合性を欠損する新規IL-2変異体MK-6はエフェクター/制御性T細胞バランスを改善することで抗腫瘍活性を発揮する

小林 真紀 東北大学

2022.03.25

概要

【背景】
免疫チェックポイント阻害剤は、様々ながん種において優れた臨床効果をもたらしているが、奏効率は充分ではない。抗腫瘍効果を高める新たな免疫賦活薬の開発が期待されている。インターロイキン-2 (IL-2)は、活性化T 細胞を誘導する主たる増殖因子であり、免疫細胞の恒常性維持に必須である。従前、腎細胞がんや悪性黒色腫などの進行がんに対する免疫療法としてリコンビナントヒト IL-2 が臨床応用されてきた。しかしながら、米国 FDA が承認したアルデスロイキン(Aldesleukin)は、血管漏出症候群等の重篤な副作用が頻発し、エフェクターT 細胞よりも制御性T 細胞を優先的に活性化しやすいことなどから、使用頻度が限定されていた。いずれも IL-2 受容体α鎖への結合に起因する現象であると考えられることから、本研究では IL-2 受容体α鎖への結合能を低下させた IL-2 改変体の分子設計を行うことで副反応の制御と抗腫瘍活性の改善を目指した。

【方法】
ヒト IL-2 とIL-2 受容体α鎖の接触面に着目し、IL-2 に種々の変異を加えた。新規 IL-2 改変体(Mutakine, MK)にルシフェラーゼレポーター(NanoLuc)を融合することで、簡便に追跡可能な実験系を構築した。IL-2 受容体α鎖への結合能が低下し、かつT 細胞増殖能を保持するMK-6 を選抜し、細胞生物学的性状および担がんモデルマウスを対する治療効果を検討した。

【結果】
生化学的解析により、MK-6 とIL-2 受容体αとの結合はほぼ完全に欠損した。3 次元構造解析では、4 つのアミノ酸変異(K35A, R38A, K43A, Y45A)によって、野生型 IL-2 とIL-2 受容体α鎖との相互作用に必要な水素結合およびファンデルワールス力の多くが無効化さ
れていることが示された。一方、MK-6 は野生型 IL-2 の全体構造とIL-2 受容体βγへの結合能を保持していた。

MK-6 は制御性T 細胞の増殖能、活性化能およびSTAT5 のリン酸化能を弱めた。アルデスロイキンタイプIL-2(MK-0)を投与した群においては用量依存性に体重増加や肺水腫などの副作用を認めたが、MK-6 を投与した群はプラセボ群と比較しほぼ変わりなかった。同種腫瘍担がんマウスモデル(CT26)に、1 日2 回連続投与したところ、有意な腫瘍増殖抑制効果を示した。MK-6 の体内半減期を改善するため、マウス血清アルブミン(MSA)を付加したところ、1 日1 回・4 日毎の投与でも顕著な抗腫瘍効果を発揮した。さらに、B16F10 を用いた同種腫瘍マウスモデルにおいても抗腫瘍効果が確認された。腫瘍浸潤リンパ球を解析したところ、MSA-MK-6 投与群ではプラセボおよびMK-0 投与群に比較して、1)制御性T細胞の増殖を抑制し、2)CD8 陽性T 細胞/制御性T 細胞比の改善が認められた。

【結語】
MK-6 はIL-2 受容体αへの結合能を欠損することで、高用量IL-2 投与に関連する毒性を抑えながら、エフェクター細胞/制御性T 細胞比を上昇させた。安定性を大幅に改善したアルブミン融合型MK-6 は、臨床応用も視野に入れた有望な抗腫瘍免疫賦活薬であると考えられる。

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