After washing, the plates were blocked and each serially diluted substance was added to the wells. Introductionįor a binding assay, immunoplates were coated with 2.5 μg/mL His-tagged HER2-ECD protein (Sino Biological Inc.) in coating buffer and kept overnight at 4☌. These data suggest that DS-8201a has the potential to respond to not only T-DM1–refractory breast cancer and HER2-positive patients, but IHC 1+ and 2+/FISH–negative patients for whom current HER2-targeting therapies are ineffective. Moreover, DS-8201a was effective against T-DM1–insensitive tumors and HER2 low-expressing tumors. The stability in plasma was favorable and the safety profiles in rats and cynomolgus monkeys were acceptable into clinical trials. DS-8201a showed potent antitumor activity based on the combination of pharmacologic effects of the antibody component with topoisomerase I inhibition. DS-8201a is a HER2-targeting ADC structurally composed of a humanized anti-HER2 antibody, enzymatically cleavable peptide linker, and a novel topoisomerase I inhibitor. Currently, the development of a new drug linker system focusing on different types of drugs has been progressing. Most of the antibody–drug conjugates (ADC) in the market and in clinical trials are conjugated with the same type of drug, tubulin polymerization inhibitor. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1–insensitive HER2-positive cancers and low HER2–expressing cancers. DS-8201a, but not T-DM1, demonstrated antitumor efficacy against several breast cancer PDX models with low HER2 expression.Ĭonclusions: DS-8201a exhibited a potent antitumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. DS-8201a was effective in a T-DM1–insensitive PDX model with high 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 as being well tolerated in humans. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. DS-8201a also showed an inhibitory activity to Akt phosphorylation. Binding activity to HER2 and ADCC activity of DS-8201a were comparable with unconjugated anti-HER2 antibody. Results: DS-8201a exhibited a HER2 expression-dependent cell growth–inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.

The mechanism of action for the efficacy was also evaluated. Purpose: An anti-HER2 antibody–drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed.Įxperimental Design: In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models.

T dm1 mechanism of action