Li Mengyu, Mei Sen, Yang Yi, Shen Yuelei, Chen Lei
Department of Postgraduate, Jiangxi University of Traditional Chinese Medicine, Nanchang, China.
Biotherapeutics, Biocytogen Jiangsu Co. Ltd, Nantong, China.
Antib Ther. 2022 Jun 16;5(3):164-176. doi: 10.1093/abt/tbac014. eCollection 2022 Jul.
Targeted cancer therapies using immunotoxins have achieved remarkable efficacy in hematological malignancies. However, the clinical development of immunotoxins is also faced with many challenges like anti-drug antibodies and dose-limiting toxicity issues. Such a poor efficacy or safety ratio is also the major hurdle in the research and development of antibody-drug conjugates. From an antibody engineering perspective, various strategies were summarized or proposed to tackle the notorious on-target off-tumor toxicity issues, including passive strategy (XTENylation of immunotoxins) and active strategies (modulating the affinity and valency of the targeting moiety of immunotoxins, conditionally activating immunotoxins in the tumor microenvironments and reconstituting split toxin to reduce systemic toxicity, etc.). By modulating the functional characteristics of the targeting moiety and the toxic moiety of immunotoxins, selective tumor targeting can be augmented while sparing the healthy cells in normal tissues expressing the same target of interest. If successful, the improved therapeutic index will likely help to address the dose-limiting toxicities commonly observed in the clinical trials of various immunotoxins.
使用免疫毒素的靶向癌症疗法在血液系统恶性肿瘤中已取得显著疗效。然而，免疫毒素的临床开发也面临许多挑战，如抗药抗体和剂量限制性毒性问题。如此低的疗效或安全性比率也是抗体药物偶联物研发的主要障碍。从抗体工程的角度来看，人们总结或提出了各种策略来解决臭名昭著的靶向非肿瘤毒性问题，包括被动策略（免疫毒素的XTENylation）和主动策略（调节免疫毒素靶向部分的亲和力和价态、在肿瘤微环境中有条件地激活免疫毒素以及重组裂解毒素以降低全身毒性等）。通过调节免疫毒素靶向部分和毒性部分的功能特性，可以增强肿瘤靶向的选择性，同时使表达相同目标的正常组织中的健康细胞免受影响。如果成功，改善的治疗指数可能有助于解决各种免疫毒素临床试验中常见的剂量限制性毒性问题。
