Abstract 1762: A novel antibody drug conjugate linker enabling production of ADCs with high drug to antibody ratios and fast payload release for improved efficacy

Abstract Antibody drug conjugates (ADCs) represent an attractive approach to bring very cytotoxic drugs into tumors while avoiding systemic toxicities. Currently, most commercially available ADCs come with toxicities associated with the nonspecific release of the payload in the circulation. We have developed a novel drug multi-linker technology that enables the generation of stable and potent ADCs. It is selectively recognized and cleaved by the carboxydipeptidase activity of Cathepsin B that has been shown to be overexpressed in cancer cells. The technology allows for a fast and specific cleavage, which results in efficient drug release in the tumor. Different payloads can be attached to antibodies, and the drug to antibody ratio (DAR) can be modulated up to DAR16, resulting in customed cytotoxic activity. Here we characterize the properties of the multi-linker using different payloads, different DARs, and trastuzumab as the targeting antibody. Trastuzumab based multi-linker ADCs were generated and tested in vitro and in vivo. The linker-payload kinetic release and the cytotoxicity of these ADCs were assessed in vitro. Pharmacokinetic (PK) and pharmacodynamic properties of selected multi-linker ADCs were then investigated in relevant in vivo models and compared to trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-Dxd). Trastuzumab based multi-linker ADCs were shown to efficiently target Her2 expressing cells. In vitro, increasing the DAR had a positive effect on cytotoxicity. In a breast cancer model expressing low levels of Her2, a trastuzumab based multi-linker ADC with mertansine (DM1) at DAR8 showed superior activity, including complete tumor regressions, as compared to T-DM1 and T-Dxd and was well tolerated. In addition, the trastuzumab based multi-linker ADCs showed total antibody PK profiles comparable to T-DM1 and good stability in plasma. In conclusion, these results demonstrate that this novel linker technology can be used to produce stable and high DAR ADCs with improved efficacy. Citation Format: Noemie Luong, Nathalie Bellocq, Leo Marx, Mathilde Pantin, Benjamin Tchumi, Marie-Claude Roubaudi-Fraschini, Camille Riff, Manfred Mutter, Antoine Attinger. A novel antibody drug conjugate linker enabling production of ADCs with high drug to antibody ratios and fast payload release for improved efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1762.