Understanding the Chemical Characteristics of Payloads and the Expression of Tumor-Associated Antigens of ADCs in Clinical Development

Antibody–drug conjugates (ADCs) have become one of the most promising therapeutic strategies for the treatment of cancer. This family of agents is composed of an antibody, a cytotoxic drug, and a linker that conjugates the drug to the antibody. The optimization of each component can potentially improve clinical activity and reduce the toxicity profile. In this article, we collected data from public sources regarding all ADCs that are currently in clinical development and extracted information for payload chemical characteristics, antibody, and linker type. In addition, we also evaluated data from genomic data sets to explore the expression of the tumor-associated antigen (TAA) in nontransformed tissue compared with the tumor. We evaluated 121 ADCs in clinical development. The most frequent targets included ERBB2, followed by FOLR1 and EGFR. 73% of ADCs used cleavable linkers, and only 14% were noncleavable, with 13% considered as undisclosed. While analyzing the physicochemical characteristics using established rules, we observed that 86% of the payloads violated the Lipinski rules, 11% violated Ghose rules, and 42% violated Brenk rules. Only three payloads did not violate any rule: deruxtecan, exatecan, and SN38, all from the camptothecin family. Regarding the conjugation type, only trastuzumab deruxtecan, labetuzumab govitecan, sacituzumab govitecan, BYON3521, and SYD1875 used homogeneous conjugation. An interesting observation was that for some ADCs, TAA expression was higher in normal tissue than in the tumor. In summary, our analysis highlights that only a limited number of ADCs incorporate payloads with favorable physicochemical properties and that several ADCs currently under development target TAAs with higher expression in normal tissues than in the corresponding tumors.