细胞毒性T细胞
癌症研究
肿瘤微环境
抗体
抗原
癌症
体内
细胞毒性
免疫系统
毒性
免疫学
医学
生物
体外
内科学
生物化学
生物技术
作者
Leila M. Boustany,Sherry L. LaPorte,Laurie Wong,Clayton White,Veena Vinod,Joel Shen,Wendy Yu,David Koditek,Michael B. Winter,Stephen James Moore,Li Mei,Linnea Diep,Yuanhui Huang,Shouchun Liu,Olga Vasiljeva,Jim West,Jennifer Richardson,Bryan Irving,Marcia Belvin,W Michael Kavanaugh
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2022-09-16
标识
DOI:10.1158/0008-5472.can-21-2483
摘要
T-cell-engaging bispecific antibodies (TCB) are highly potent therapeutics that can recruit and activate cytotoxic T cells to stimulate an anti-tumor immune response. However, the development of TCBs against solid tumors has been limited by significant on-target toxicity to normal tissues. Probody® therapeutics have been developed as a novel class of recombinant, protease-activated antibody prodrugs that are "masked" to reduce antigen binding in healthy tissues but can become conditionally unmasked by proteases that are preferentially active in the tumor microenvironment (TME). Here, we describe the preclinical efficacy and safety of CI107, a Probody TCB targeting EGFR and CD3. In vitro, the protease-activated, unmasked CI107 effectively bound EGFR and CD3 expressed on the surface of cells and induced T-cell activation, cytokine release, and cytotoxicity towards tumor cells. In contrast, dually masked CI107 displayed a >500-fold reduction in antigen binding and >15,000-fold reduction in cytotoxic activity. In vivo, CI107 potently induced dose-dependent tumor regression of established colon cancer xenografts in mice engrafted with human peripheral blood mononuclear cells. Furthermore, the maximum tolerated dose of CI107 in cynomolgus monkeys was more than 60-fold higher than that of the unmasked TCB, and much lower levels of toxicity were observed in animals receiving CI107. Therefore, by localizing activity to the TME and thus limiting toxicity to normal tissues, this Probody TCB demonstrates the potential to expand clinical opportunities for TCBs as effective anti-cancer therapies for solid tumor indications.
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