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.
Yusuke Ogitani  1 ,  Tetsuo Aida  2 ,  Katsunobu Hagihara  2 ,  Junko Yamaguchi  2 ,  Chiaki Ishii  2 ,  Naoya Harada  2 ,  Masako Soma  2 ,  Hiromi Okamoto  2 ,  Masataka Oitate  2 ,  Shingo Arakawa  2 ,  Takehiro Hirai  3 ,  Ryo Atsumi  2 ,  Takashi Nakada  2 ,  Ichiro Hayakawa  2 ,  Yuki Abe  2 ,  Toshinori Agatsuma  2
Affiliations
  • 1. Daiichi Sankyo Co., Ltd., Tokyo, Japan. [email protected].
  • 2. Daiichi Sankyo Co., Ltd., Tokyo, Japan.
  • 3. Clinical Development Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
PMID: 27026201 DOI: 10.1158/1078-0432.CCR-15-2822
Abstract

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.

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