Discovery of Topoisomerase 1 Inhibitor Exatecan Derivative-Based HER2-Targeting ADC (DS-8201a)

Abstract

Antibody-drug conjugates（ADCs）represent a promising drug class which expresses a wider therapeutic window than conventional chemotherapeutic agents by effecting efficient and specific drug delivery to antigen-expressing tumor cells. DS-8201a is a HER2-targeting ADC structurally composed of a humanized anti-HER2 antibody, enzymatically cleavable peptide-linker, and a novel topoisomerase 1 inhibitor. This ADC achieves a high drug-to-antibody-ratio（DAR 7 to 8）with homogeneous conjugation with the DNA topoisomerase 1 inhibitor. DS-8201a exhibited a HER2 expression-dependent cell growth inhibitory activity and induced a dose-dependent tumor regression in a HER2-positive gastric cancer NCI-N87 cell line derived xenograft（CDX）model and sufficient effectiveness in a T-DM1-nsensitive patient derived xenograft（PDX）model with low HER2 expression. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a’s being well tolerated in humans. These studies suggest that DS-8201a, a novel HER2-targeting ADC, may be more efficacious and have a broader patient population than T-DM1 in tumors which current anti-HER2 therapies are ineffective such as T-DM1 insensitive tumors and low HER2-expressing tumors.