On receiving the Best Oral Award
I am very honored to receive the prestigious Best Oral Award at the 37th Annual Meeting of the Japanese Pharmacokinetic Society. I would like to express my sincere gratitude to the judges and all the people involved in the Japanese Pharmacokinetics Society.
Recently, research and development of antibody-drug conjugates (ADCs) have been actively conducted. ADCs are antibody-drug conjugates consisting of a monoclonal antibody, a highly toxic drug (payload) and a linker, which enable drug delivery specifically to target cells. ADCs are antibody drugs that enable target cell-specific drug delivery. The administered ADCs bind to antigens on the cell surface and are internalized into cells via endocytosis. The detailed mechanism of the intracellular fate of ADCs has not been fully elucidated, as it varies depending on the antibody, payload, and linker moiety.
In this study, we investigated the mechanism of intracellular regulation of trastuzumab emtansine (T-DM1), an ADC used for the treatment of HER2-positive breast cancer, and found that the lysosomal orphan transporter SLC46A3, a gene previously reported to be involved in T-DM1 drug expression, is involved in the regulation of the steroid conjugation of trastuzumab emtansine. We also found that Lys-SMCC-DM1, a lysosomal degradation product of T-DM1, is directly transported into the cytoplasm. This finding indicates that T-DM1 is transported directly through the membrane. This finding indicates that the efflux process of Lys-SMCC-DM1 from lysosomes to the cytosol by SLC46A3 is important for the expression of T-DM1’s medicinal effects. The results of this study are expected to elucidate the mechanism of drug efflux from the lysosome and to be useful for the development of new ADCs and new drug discovery modalities utilizing lysosomal transporters.
Finally, we would like to take this opportunity to thank Professor Katsuo Inoue, Assistant Professor Hisanao Kishimoto, Assistant Professor Satoshi Higuchi, and students at the Department of Pharmacokinetics and Pharmacodynamics, Tokyo University of Pharmacy and Life Sciences, Associate Professor Yoshiyuki Shirasaka at the Laboratory of Pharmacokinetics, Kanazawa University, and Professor Ryuhei Takada at the Department of Pharmacy, The University of Tokyo Hospital for their guidance in conducting this research.