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

  • Nat Commun. 2024 Mar 11;15(1):2192. doi: 10.1038/s41467-024-46167-1.
Youya Nakazawa  #  1 ,  Masayuki Miyano  #  2 ,  Shuntaro Tsukamoto  2 ,  Hiroyuki Kogai  2 ,  Akihiko Yamamoto  2 ,  Kentaro Iso  2 ,  Satoshi Inoue  2 ,  Yoshinobu Yamane  2 ,  Yuki Yabe  2 ,  Hirotatsu Umihara  2 ,  Junichi Taguchi  2 ,  Tsuyoshi Akagi  2  3 ,  Atsumi Yamaguchi  2 ,  Minaho Koga  2 ,  Kohta Toshimitsu  2 ,  Toshifumi Hirayama  3 ,  Yohei Mukai  3 ,  Akihito Machinaga  2  3
Affiliations
  • 1. Tsukuba Research Laboratory, Eisai Co., Ltd., Ibaraki, Japan. [email protected].
  • 2. Tsukuba Research Laboratory, Eisai Co., Ltd., Ibaraki, Japan.
  • 3. KAN Research Institute, Inc., Kobe, Japan.
  • # Contributed equally.
PMID: 38467634 DOI: 10.1038/s41467-024-46167-1
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.

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