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 and Akihito Machinaga
Additional contact information
Youya Nakazawa: Eisai Co., Ltd.
Masayuki Miyano: Eisai Co., Ltd.
Shuntaro Tsukamoto: Eisai Co., Ltd.
Hiroyuki Kogai: Eisai Co., Ltd.
Akihiko Yamamoto: Eisai Co., Ltd.
Kentaro Iso: Eisai Co., Ltd.
Satoshi Inoue: Eisai Co., Ltd.
Yoshinobu Yamane: Eisai Co., Ltd.
Yuki Yabe: Eisai Co., Ltd.
Hirotatsu Umihara: Eisai Co., Ltd.
Junichi Taguchi: Eisai Co., Ltd.
Tsuyoshi Akagi: Eisai Co., Ltd.
Atsumi Yamaguchi: Eisai Co., Ltd.
Minaho Koga: Eisai Co., Ltd.
Kohta Toshimitsu: Eisai Co., Ltd.
Toshifumi Hirayama: KAN Research Institute, Inc.
Yohei Mukai: KAN Research Institute, Inc.
Akihito Machinaga: Eisai Co., Ltd.

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46167-1

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