title: DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan. ogitani.yusuke.ds@daiichisankyo.co.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ogitani
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Aida
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Hagihara
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamaguchi
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Ishii
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Harada
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Soma
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Okamoto
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Oitate
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Arakawa
authors.affiliation: Clinical Development Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Hirai
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Atsumi
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakada
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hayakawa
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Abe
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Agatsuma
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008453:Maytansine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D000068878:Trastuzumab / Q000494:pharmacology
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002166:Camptothecin; D000071877:Checkpoint Kinase 1; D006657:Histones; D018796:Immunoconjugates; D008453:Maytansine; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D059004:Topoisomerase I Inhibitors; D000068878:Trastuzumab; C000614160:trastuzumab deruxtecan; C508053:ERBB2 protein, human; C000605867:CHEK1 protein, human