The Target Atlas for Antibody-Drug Conjugates across Solid Cancers

Abstract

Abstract Antibody-Drug Conjugates (ADCs) is a rapidly developing type of oncology therapeutic, spanning the targeted therapy for hematologic malignancies and solid cancers. A major requirement in ADC research is the identification of ideal surface antigens that can distinguish target cells from most mammalian cell types. Herein, we develop an algorithm and comply a comprehensive cell membrane protein annotation dataset integrated from the large transcriptome, proteome, and genome data from 19 types of solid cancer and normal tissues, to discover potentially therapeutic surface antigens for ADC targeting. The resulting target landscape includes 165 target-indication combinations and 75 cell surface protein candidates, 35 of which with features suitable for ADC targeting are never reported in ADC research and development. In addition, we identify a total of 159 ADCs from 760 clinical trials, 72 ADCs among them targeting 36 unique antigens are currently under interventional evaluation for various types of solid cancers. We analyze their normal tissue expression using the comprehensive annotation dataset and reveal a broad range of profiles for the current ADC targets. In addition, we emphasize that the biological effects of target antigens could improve their clinical actionability and put forward to comprehensively assess the drugability of target antigens from multiple aspects. This is the first attempt at pan-cancer ADC target exploration over the past two decades, and our findings indicate that the target atlas across solid cancers can provide great opportunities to expand the broader prospects of ADC therapies.