Abstract 4891: Ifinatamab deruxtecan (I-DXd), a novel B7-H3-targeting antibody-drug conjugate, demonstrates efficient payload delivery into tumor through target-dependent internalization

Abstract Ifinatamab deruxtecan (I-DXd; DS-7300) is a novel ADC which consists of an anti-B7-H3 antibody linked with a DNA topoisomerase I inhibiting anti-tumor agent, DXd. I-DXd has demonstrated potent anti-tumor activity in B7-H3-positive preclinical cancer models and showed early signs of promising clinical efficacy in patients with heavily pretreated, advanced solid tumors. ADCs are postulated to exert cytotoxicity specifically in tumors that express the target antigen via target-specific uptake of the compound. Accordingly, effective action of an ADC depends on multiple dynamic steps including antigen-specific binding, internalization, trafficking to lysosomes, linker cleavage and payload release, as well as payload potency. The goal of this research was to characterize I-DXd molecular dynamics in preclinical tumor cell models by investigating the relationship among target expression and dynamics, its translocation to lysosomes, lysosomal enzyme-mediated linker cleavage, and payload release after I-DXd treatment. As a result, I-DXd demonstrated target dependent internalization, efficient trafficking to lysosomes, and subsequent payload release in the studied tumor cell lines. Payload release levels generally correlated with target expression in vitro using a panel of cell lines with varying levels of B7-H3 expression. Also, in cell-line derived xenograft models, tumor tissue payload concentration corresponded to I-DXd binding at the cell membrane. These results suggest the importance of cell surface B7-H3 expression and ADC dynamics that lead to payload release in target expressing tumors to exert anti-tumor activity in non-clinical model. In addition to target-dependent uptake in tumor cells, it was observed in viable human lung tumor slices that B7-H3 was also expressed in several non-tumor cells including cancer-associated fibroblasts, endothelial cells, and macrophages in the tumor microenvironment and I-DXd was shown to be internalized in these B7-H3-expressing non-tumor cells. In summary, this pre-clinical study characterizes the relationship between B7-H3 expression in the tumor microenvironment and I-DXd molecular dynamics. Our results support developing I-DXd as a targeted therapy against advanced solid tumors known to overexpress B7-H3. Citation Format: Len Katsumata, Tsuneo Deguchi, Jun Hasegawa, Michiko Yamato, Yumi Nishiya, Akiko Watanabe, Tomoyo Honda, Megumi Minami, Naomi Kasanuki, Takanori Maejima, Sumie Muramatsu, Monika Herrmann, Nina Schulte, Gernot Polier, Xuya Wang, Takanori Yoshida, Nanae Izumi, Xiaozhong Qian, Toshinori Agatsuma, Kenji Nakamaru. Ifinatamab deruxtecan (I-DXd), a novel B7-H3-targeting antibody-drug conjugate, demonstrates efficient payload delivery into tumor through target-dependent internalization. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4891.