DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1

Clin Cancer Res. 2016 Oct 15;22(20):5097-5108. doi: 10.1158/1078-0432.CCR-15-2822. Epub 2016 Mar 29.


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.

Experimental 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. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.

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. Binding activity to HER2 and ADCC activity of DS-8201a were comparable with unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. 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 was effective in a T-DM1-insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated antitumor efficacy against several breast cancer PDX models with low HER2 expression.

Conclusions: DS-8201a exhibited a potent antitumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. 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. Clin Cancer Res; 22(20); 5097-108. ©2016 AACR.

MeSH terms

  • Ado-Trastuzumab Emtansine
  • Animals
  • Antibodies, Monoclonal, Humanized* / adverse effects
  • Antibodies, Monoclonal, Humanized* / pharmacokinetics
  • Antibodies, Monoclonal, Humanized* / pharmacology
  • Antibody-Dependent Cell Cytotoxicity / drug effects
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Checkpoint Kinase 1 / metabolism
  • Female
  • Histones / metabolism
  • Humans
  • Immunoconjugates* / adverse effects
  • Immunoconjugates* / pharmacokinetics
  • Immunoconjugates* / pharmacology
  • Macaca fascicularis
  • Maytansine / analogs & derivatives
  • Maytansine / pharmacology
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms / drug therapy*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / immunology
  • Topoisomerase I Inhibitors / pharmacology*
  • Trastuzumab / pharmacology


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Histones
  • Immunoconjugates
  • Topoisomerase I Inhibitors
  • Maytansine
  • trastuzumab deruxtecan
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Proto-Oncogene Proteins c-akt
  • Trastuzumab
  • Ado-Trastuzumab Emtansine
  • Camptothecin