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Abstract 2898: A biparatopic HER2xHER2 antibody drug conjugate with potent anti-tumor activity

A biparatopic HER2xHER2 antibody drug conjugate with potent anti-tumor activity. The antibody drug conjugate (ADC) Trastuzumab-emtansine (T-DM1) targets the well-characterized breast cancer oncogene HER2 and is active in tumors that express very high levels of HER2 protein. However, tumors expressing intermediate levels of HER2 remain resistant to T-DM1 therapy, apparently due to insufficient lysosomal trafficking of T-DM1. We generated a series of biparatopic HER2xHER2 antibodies in which each arm recognizes a distinct epitope of HER2. One of our HER2xHER2 antibodies bound to cells with greater avidity than Trastuzumab and formed visible cell surface clusters that were efficiently internalized. While some of the internalized HER2xHER2 antibody trafficked to lysosomes and promoted HER2 degradation, a significant fraction recycled back to the plasma membrane through recycling endosomes. To exploit the increased internalization and recycling of the HER2xHER2 antibody, ADCs were generated by site-specific conjugation of Tubulysin A payload through a protease-cleavable linker. Recent data suggest that cleavage of this linker does not require lysosomal trafficking, but can occur in recycling endosomes as well. HER2xHER2-Tubulysin killed cell lines expressing high (IHC3+) and intermediate (IHC2+) HER2 levels with subnanomolar IC50, while exhibiting very weak killing of cells expressing low (IHC1+) HER2 levels (IC50 greater than 10nM). HER2xHER2-Tubulysin induced complete and durable tumor regression and outperformed T-DM1 in a collection of IHC3+ and 2+ tumor xenograft models (including PDX). Our work shows that a detailed understanding of antibody trafficking can enable the design of more effective ADCs and suggests that HER2xHER2-Tubulysin is a potential clinical candidate for HER2 IHC2+ breast cancer. Citation Format: Andres Perez Bay, Devon Faulkner, Shiwani Tiwari, Carla Castanaro, Xiang Zheng, Arthur Kunz, Thomas Nittoli, Amy Han, William Olson, Gavin Thurston, Christopher Daly, Julian Andreev. A biparatopic HER2xHER2 antibody drug conjugate with potent anti-tumor activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2898.