Toward clinical development of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC).

626 Background: SYD985 is a HER2-targeting ADC based on trastuzumab and vc-seco-DUBA, Synthon Biopharmaceuticals proprietary cleavable linker-duocarmycin payload. This paper describes the direct comparison of SYD985 to T-DM1 (ado-trastuzumab emtansine) in vitro and in vivo. Methods: Cell survival was tested in 96-wells plates using the CellTiter-Glo luminescent assay kit (Promega); cell line-based and breast cancer patient-derived tumor-based xenograft experiments were done in SPF athymic nu/nu mice (n=8 per group). A polyclonal rabbit anti-human HER2 (DAKO) antibody was used in the IHC analysis. In vitro data analysis comprised the sigmoidal dose-response equation with variable slope in GraphPad Prism. Results: In vitro, SYD985 and T-DM1 were compared head-to-head in a panel of 8 cell lines expressing different levels of HER2. In cell lines with high HER2 expression (HER2 3+), both SYD985 and T-DM1 show similar potencies and activities. In cell lines with low HER2 expression (HER2 2+ and 1+), SYD985 was ...