A mild phenoxysilyl linker for self-immolative release of antibody-drug conjugates

Self-immolative linkers have been widely used to construct prodrugs to improve their efficacy and safety. In this study, we report the use of phenoxysilyl linker as a self-immolative unit to prepare antibody-drug conjugates (ADCs). Phenoxysily based ADC Ate-PPS-CA4 was prepared and its release was systematically investigated by mass spectrometry. Biological evaluation showed that Ate-PPS-CA4 displayed the ability to target delivery and self-immolative release the active payload CA4 on PD-L1 positive cells MDA-MB-231. As the same with its payload CA4, it could arrest the cell cycle to the G2/M phase and induced changes in cell morphology at the dose of its IC50. The development of this linker with novel drug release mechanisms will expand the methodology to construct ADCs, especially for non-internalizing ADCs by extracellular cleavage.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.