Payload of T-DM1 binds to cell surface cytoskeleton-associated protein 5 to mediate cytotoxicity of hepatocytes
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Yukinori Endo1, Kazuyo Takeda2, Nishant Mohan1, Yi Shen1, Jiangsong Jiang1, David Rotstein3 and Wen Jin Wu1
1Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA
2Microscopy and Imaging Core Facility, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA
3Division of Compliance, Office of Surveillance and Compliance, Center for Veterinary Medicine, U.S. Food and Drug Administration (FDA), Derwood, MD, USA
Wen Jin Wu, email: [email protected]
Keywords: cytoskeleton-associated protein 5 (CKAP5); antibody-drug conjugate (ADC); ado-trastuzumab emtansine (T-DM1); HER2; hepatotoxicity
Received: August 15, 2018 Accepted: November 26, 2018 Published: December 14, 2018
Off-target toxicity is a major cause of dose-limiting toxicity for antibody-drug conjugates (ADCs), mechanisms of which remain poorly understood. Here, we demonstrate that cytoskeleton-associated protein 5 (CKAP5) serves as a cell surface target for T-DM1 and that binding of T-DM1 to CKAP5 is mediated by payload (DM1). This study introduces a novel molecular mechanism of ADC payload-mediated interaction with cell surface molecules to induce cytotoxicity. Upon binding to CKAP5, T-DM1 causes cell membrane damage and leads to calcium influx into the cells, resulting in disorganized microtubule network and apoptosis. While binding of T-DM1 with HER2 is critical for killing HER2-positive tumor cells, our data suggest that cytotoxicity induced by T-DM1 interaction with CKAP5 may preferentially damage normal cells/tissues where HER2 expression is low or missing to cause off-target toxicity. This study provides molecular basis of ADC-induced off-target cytotoxicity and opens a new avenue for developing next generation of ADCs.
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