Design of Novel Exatecan-Amide Linker-Payloads for the Development of Stable, Low-Aggregating, and Highly Efficacious...

Through their uniquely effective combination of a target-selective antibody and a highly potent cytotoxic payload, antibody-drug conjugates (ADCs) are transforming cancer therapy. Nonetheless, the field has discovered that the multiparameter optimization of each component to further improve the balance of stability, efficacy, and tolerability is highly complex. However, synthetic and medicinal chemists are perfectly positioned to address such multifaceted design and accessibility challenges. The work described here outlines such an SAR campaign for the design and development of novel camptothecin-derived linker-payloads, with the most promising candidates leveraging a unique butanediol Exatecan-amide payload, an Ala-Ala protease-cleavable peptide linker, and a self-hydrolyzing maleimide with an α-branching PEGylated amide moiety, which provide low-aggregating (<5%) and stable (no DAR loss in vitro or in vivo) ADCs that demonstrate significant tumor regression in vivo. These linker-payloads are promising new leads for the treatment of cancer and represent a generalizable, modular, and advantageous linker platform.