IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46167-1.html
   My bibliography  Save this article

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

Author

Listed:
  • 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.
    KAN Research Institute, Inc.)

  • 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.
    KAN Research Institute, Inc.)

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.

Suggested Citation

  • Youya Nakazawa & Masayuki Miyano & Shuntaro Tsukamoto & Hiroyuki Kogai & Akihiko Yamamoto & Kentaro Iso & Satoshi Inoue & Yoshinobu Yamane & Yuki Yabe & Hirotatsu Umihara & Junichi Taguchi & Tsuyoshi , 2024. "Delivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46167-1
    DOI: 10.1038/s41467-024-46167-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46167-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-46167-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Li Wang & Abdel Saci & Peter M. Szabo & Scott D. Chasalow & Mireia Castillo-Martin & Josep Domingo-Domenech & Arlene Siefker-Radtke & Padmanee Sharma & John P. Sfakianos & Yixuan Gong & Ana Dominguez-, 2018. "EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Ankur Chakravarthy & Lubaba Khan & Nathan Peter Bensler & Pinaki Bose & Daniel D. De Carvalho, 2018. "TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. E. H. Puttock & E. J. Tyler & M. Manni & E. Maniati & C. Butterworth & M. Burger Ramos & E. Peerani & P. Hirani & V. Gauthier & Y. Liu & G. Maniscalco & V. Rajeeve & P. Cutillas & C. Trevisan & M. Poz, 2023. "Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Jingjing Qi & Hongxiang Sun & Yao Zhang & Zhengting Wang & Zhenzhen Xun & Ziyi Li & Xinyu Ding & Rujuan Bao & Liwen Hong & Wenqing Jia & Fei Fang & Hongzhi Liu & Lei Chen & Jie Zhong & Duowu Zou & Lia, 2022. "Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Maud Rijnders & J. Alberto Nakauma-González & Debbie G. J. Robbrecht & Alberto Gil-Jimenez & Hayri E. Balcioglu & Astrid A. M. Oostvogels & Maureen J. B. Aarts & Joost L. Boormans & Paul Hamberg & Mic, 2024. "Gene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Jiaye Liu & Yang Wang & Chunyang Mu & Meng Li & Kewei Li & Shan Li & Wenshuang Wu & Lingyao Du & Xiaoyun Zhang & Chuan Li & Wei Peng & Junyi Shen & Yang Liu & Dujiang Yang & Kaixiang Zhang & Qingyang , 2022. "Pancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Marina T. Broz & Emily Y. Ko & Kristin Ishaya & Jinfen Xiao & Marco Simone & Xen Ping Hoi & Roberta Piras & Basia Gala & Fernando H. G. Tessaro & Anja Karlstaedt & Sandra Orsulic & Amanda W. Lund & Ke, 2024. "Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Jeffrey S. Damrauer & Wolfgang Beckabir & Jeff Klomp & Mi Zhou & Elizabeth R. Plimack & Matthew D. Galsky & Petros Grivas & Noah M. Hahn & Peter H. O’Donnell & Gopa Iyer & David I. Quinn & Benjamin G., 2022. "Collaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46167-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.