title: Preclinical Efficacy and Safety Assessment of an Antibody-Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma.
abstract: OBJECTIVE
  The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody-drug conjugate (ADC) being developed for the treatment of breast cancer.
  
  
  METHODS
  RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys.
  
  
  RESULTS
  By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy.
  
  
  CONCLUSIONS
  RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552-62. ©2015 AACR.
authors.affiliation: Takeda California, Inc., San Diego, California.
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Takeda California, Inc., San Diego, California.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Miyakawa
authors.affiliation: Takeda California, Inc., San Diego, California.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kato
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mori
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Arai
authors.affiliation: Takeda California, Inc., San Diego, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Armanini
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Gelmon
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Rinat
authors.initials: R
authors.lastname: Yerushalmi
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Gao
authors.affiliation: Takeda California, Inc., San Diego, California.
authors.forename: Gregory
authors.initials: G
authors.lastname: Landes
authors.affiliation: Takeda California, Inc., San Diego, California.
authors.forename: Mary
authors.initials: M
authors.lastname: Haak-Frendscho
authors.affiliation: Takeda California, Inc., San Diego, California.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Elias
authors.affiliation: Takeda California, Inc., San Diego, California. asimmons@clovisoncology.com.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Simmons
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D024201:Bystander Effect; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D008453:Maytansine / Q000008:administration & dosage / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018675:Toxicity Tests; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D018796:Immunoconjugates; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D008453:Maytansine; D051096:Proto-Oncogene Proteins c-ret