Abstract 2718: A novel TROP2-targeted immune stimulating antibody conjugate (ISAC) with potent anti-tumoral activtiy and accpetable safety

Abstract Immune stimulating antibody conjugates (ISACs) are a unique class of ADC in which antibodies recognizing tumor antigens are conjugated with immune agonists. ISACs target tumor tissue and specifically activate intra-tumoral myeloid cells, unleashing downstream immune response. Like the other immune agonists, balance between efficacy and safety remains a challenge for ISACs. Here we describe a potential first-in-class TROP2 ISAC with rationally selected antibody and TLR7/8 agonist linker-payload. The anti-TROP2 antibody elicited robust ADCP of TROP2+ tumor cells by macrophages. In-vitro, TROP2 ISAC mildly activated myeloid cells only in the presence of TROP2+ tumor cells. In-vivo, the molecule potently suppressed tumor growth in different TROP2+ xenograft tumors, and effectively enhanced killing of an ADC. In terms of safety, the ISAC was tolerated in both WT and hTROP2KI mice, and, importantly, in monkeys. Taken together, our data demonstrate a novel TROP2 ISAC with outstanding efficacy and manageable safety profile, which may benefit patients with TROP2+ tumors. Citation Format: Ye Chen, Fei You, Chenchen Zhu, Yao Xiong, Li Li, Nana Luo, Shuaixiang Zhou, Fushuai Wang, Chenyang Xu, Fan Fei, Chang Li, Jianglu Wang, Jinling Xu, Huizhong Xiong. A novel TROP2-targeted immune stimulating antibody conjugate (ISAC) with potent anti-tumoral activtiy and accpetable safety abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2718.