Discovery of Novel N-Linked Camptothecin Linker-Payloads to Access Antibody-Drug Conjugates with High Target-Mediated In Vivo Efficacy.

Antibody-drug conjugates (ADCs) are transforming oncology by enabling targeted delivery of potent cytotoxic agents to tumors. However, challenges such as resistance and limited response to established ADCs highlight the need for improved linkers and novel payloads driven by rational multivariate design and extensive synthetic optimization. We describe a discovery chemistry campaign for novel camptothecin-based linker-payloads enabling high drug-to-antibody ratio (DAR) ADCs with good biophysical properties, good in vitro potency, and strong in vivo efficacy. Starting from exatecan, amine-containing cytotoxic analogs were synthesized and evaluated for potency and permeability. Optimization of protease-cleavable p-aminobenzyl carbamate (PABC) linkers with a focus on stability and polarity leads to the discovery of promising α-amino-isobutyramido-exatecan constructs. The corresponding high-DAR ADCs showed low aggregation, good in vitro potency, and robust target-mediated efficacy in vivo across two antibody-antigen pairs. These results demonstrate the potential of these linker-payloads and the broad applicability of this design strategy.