Holdase/Foldase Mimetic Nanochaperone Improves Antibody‐Based Cancer Immunotherapy
Holdase/Foldase Mimetic Nanochaperone Improves Antibody‐Based Cancer Immunotherapy
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DOI：
10.1002/smtd.202201051
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发表时间：
2022-10
期刊：
影响因子：
12.4
通讯作者：
Yongxin Zhang;Hao Fu;Jiajing Chen;Linlin Xu;Yingli An;Rujiang Ma;Chunlei Zhu;Yang Liu;Feihe Ma;Linqi Shi
中科院分区：
文献类型：
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作者：
Yongxin Zhang;Hao Fu;Jiajing Chen;Linlin Xu;Yingli An;Rujiang Ma;Chunlei Zhu;Yang Liu;Feihe Ma;Linqi Shi
尽管基于抗体的癌症免疫疗法取得了前所未有的成功，但全身给药后的严重副作用和快速清除仍然是实现其全部潜力的巨大挑战。同时，使用多种抗体的联合免疫疗法在癌症治疗中显示出特别有前途。值得注意的是，天然保持酶和折叠酶伴侣的工作机制是克服治疗性抗体的局限性所期望的。Holdase分子伴侣稳定未折叠的客户端，防止其活化和降解，而Foldase分子伴侣则帮助未折叠的客户端恢复其天然状态以发挥功能。在这里，开发了一种保持酶/折叠酶模拟物纳米伴侣（H/F-nChap），用于共同递送两种类型的单克隆抗体（mAb），α CD 16和α PDL 1，以及瑞喹莫特（R848），这显著改善了癌症免疫治疗。H/F-nChap在血液和正常组织中具有保持酶活性，可隐藏和保护mAb免受不必要的靶向活化和降解，从而延长血液循环并降低体内免疫毒性。此外，H/F-nChap在肿瘤微环境中转换为折叠酶活性，暴露mAb并释放R848，以分别增强NK细胞和肿瘤细胞之间的接合并促进免疫激活。H/F-nChap代表了一种安全和时空递送多种mAb的策略，为改善癌症免疫治疗提供了一个有前途的平台。
Despite unprecedented successes of antibody‐based cancer immunotherapy, the serious side effects and rapid clearance following systemic administration remain big challenges to realize its full potential. At the same time, combination immunotherapy using multiple antibodies has shown particularly promising in cancer treatment. It is noticed that the working mechanisms of natural holdase and foldase chaperone are desirable to overcome the limitations of therapeutic antibodies. Holdase chaperone stabilizes unfolded client and prevents it from activation and degradation, while foldase chaperone assists unfolded client to its native state to function. Here a holdase/foldase mimetic nanochaperone (H/F‐nChap) to co‐delivery two types of monoclonal antibodies (mAbs), αCD16 and αPDL1, and resiquimod (R848) is developed, which significantly improves cancer immunotherapy. The H/F‐nChap presents holdase activity in blood and normal tissues that hides and protects mAbs from unnecessary targeted activation and degradation, thereby prolonging blood circulation and reducing immunotoxicity in vivo. Furthermore, H/F‐nChap switches to foldase activity in the tumor microenvironment that exposes mAbs and releases R848 to enhance the engagement between NK cells and tumor cells and promote immune activation, respectively. The H/F‐nChap represents a strategy for safe and spatiotemporal delivery of multiple mAbs, providing a promising platform for improved cancer immunotherapy.