Nature Communications (Mar 2024)

Delivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models

  • Youya Nakazawa,
  • Masayuki Miyano,
  • Shuntaro Tsukamoto,
  • Hiroyuki Kogai,
  • Akihiko Yamamoto,
  • Kentaro Iso,
  • Satoshi Inoue,
  • Yoshinobu Yamane,
  • Yuki Yabe,
  • Hirotatsu Umihara,
  • Junichi Taguchi,
  • Tsuyoshi Akagi,
  • Atsumi Yamaguchi,
  • Minaho Koga,
  • Kohta Toshimitsu,
  • Toshifumi Hirayama,
  • Yohei Mukai,
  • Akihito Machinaga

DOI
https://doi.org/10.1038/s41467-024-46167-1
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 17

Abstract

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Abstract Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all cancers. To improve PDAC therapy, we establish screening systems based on organoid and co-culture technologies and find a payload of antibody–drug conjugate (ADC), a bromodomain and extra-terminal (BET) protein degrader named EBET. We select CEACAM6/CD66c as an ADC target and developed an antibody, #84.7, with minimal reactivity to CEACAM6-expressing normal cells. EBET-conjugated #84.7 (84-EBET) has lethal effects on various PDAC organoids and bystander efficacy on CEACAM6-negative PDAC cells and cancer-associated fibroblasts. In mouse studies, a single injection of 84-EBET induces marked tumor regression in various PDAC-patient-derived xenografts, with a decrease in the inflammatory phenotype of stromal cells and without significant body weight loss. Combination with standard chemotherapy or PD-1 antibody induces more profound and sustained regression without toxicity enhancement. Our preclinical evidence demonstrates potential efficacy by delivering BET protein degrader to PDAC and its microenvironment via CEACAM6-targeted ADC.