IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-64862-5.html
   My bibliography  Save this article

A monoclonal antibody that inhibits the shedding of CD16a and CD16b and promotes antibody-dependent cellular cytotoxicity against tumors

Author

Listed:
  • Bruna Taciane da Silva Bortoleti

    (Icahn School of Medicine at Mount Sinai)

  • Sophia Quasem

    (Icahn School of Medicine at Mount Sinai)

  • Stefanie Maurer

    (Icahn School of Medicine at Mount Sinai)

  • Xiaoxuan Zhong

    (Icahn School of Medicine at Mount Sinai
    Grossman School of Medicine, New York University)

  • Ruan Pimenta

    (Icahn School of Medicine at Mount Sinai)

  • Luiza Ribeiro de Lima Brandão

    (Icahn School of Medicine at Mount Sinai)

  • Matthew Hernandez

    (Icahn School of Medicine at Mount Sinai)

  • Melanie Fraidenburg

    (Icahn School of Medicine at Mount Sinai
    Yale School of Medicine)

  • Pedro Henrique Alves da Silva

    (Icahn School of Medicine at Mount Sinai)

  • Raymond Alvarez

    (Icahn School of Medicine at Mount Sinai
    Ichor Biologics, LLC)

  • Benjamin K. Chen

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Márcio Augusto Diniz

    (Icahn School of Medicine at Mount Sinai)

  • Brian Housman

    (Icahn School of Medicine at Mount Sinai)

  • Raja M. Flores

    (Icahn School of Medicine at Mount Sinai)

  • Rachel Brody

    (Icahn School of Medicine at Mount Sinai)

  • Thomas U. Marron

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Lucas Ferrari de Andrade

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

Abstract

CD16a triggers antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis by natural killer (NK) cells and macrophages in anti-tumor immunity. However, CD16a undergoes cleavage by ADAM17 that dampens its anti-tumor immunity. We here develop a monoclonal antibody (F9H4) that binds to CD16a and inhibits its cleavage. F9H4 retains CD16a on the surface of NK cells and macrophages, without triggering or blocking CD16a. F9H4 also binds to and inhibits shedding of CD16b by neutrophils, and inhibits CD16a/b shedding by leukocytes in tumor samples from lung cancer patients. F9H4 promotes ADCC against lung cancer cells that are opsonized by cetuximab, an epidermal growth factor receptor antibody that engages CD16a. F9H4 synergizes with cetuximab to inhibit human lung adenocarcinoma development in immunodeficient mice reconstituted with human NK cells. F9H4 combining with cetuximab also inhibits murine lung carcinoma growth in Fc gamma receptor-humanized mice, and such effect is mediated by NK cells and macrophages. The efficacy of F9H4+cetuximab in lung cancer models is the proof-of-concept for this new approach that promotes anti-tumor functions of Fc-enabled antibodies.

Suggested Citation

  • Bruna Taciane da Silva Bortoleti & Sophia Quasem & Stefanie Maurer & Xiaoxuan Zhong & Ruan Pimenta & Luiza Ribeiro de Lima Brandão & Matthew Hernandez & Melanie Fraidenburg & Pedro Henrique Alves da S, 2025. "A monoclonal antibody that inhibits the shedding of CD16a and CD16b and promotes antibody-dependent cellular cytotoxicity against tumors," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64862-5
    DOI: 10.1038/s41467-025-64862-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-64862-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-64862-5?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. Ting Zhou & William Damsky & Orr-El Weizman & Meaghan K. McGeary & K. Patricia Hartmann & Connor E. Rosen & Suzanne Fischer & Ruaidhri Jackson & Richard A. Flavell & Jun Wang & Miguel F. Sanmamed & Ma, 2020. "IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy," Nature, Nature, vol. 583(7817), pages 609-614, July.
    2. Stylianos Bournazos & Davide Corti & Herbert W. Virgin & Jeffrey V. Ravetch, 2020. "Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection," Nature, Nature, vol. 588(7838), pages 485-490, 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. Zhen Fan & Ying Liu & Xueying Lin & Jifu Zhang & Jiehong Chen & Shiming Yi & Cheng Hu & Xincheng Liu & Cui Guo & Cuiying Xu & Xiaoyu Chen & Xuyan Tian & Xuanming Liang & Yang Liu & Linyi Hu & Shanyu H, 2025. "Suppression of multiple mouse models of refractory malignancies by reprogramming IL-18 ligand-receptor interaction," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    2. Diego E. Sastre & Stylianos Bournazos & Maros Huliciak & Barbara Ann C. Grace & E. Josephine Boder & Jonathan Du & Nazneen Sultana & Tala Azzam & Trenton J. Brown & Maria W. Flowers & Pete Lollar & Ti, 2025. "The mechanistic basis for interprotomer deglycosylation of antibodies by corynebacterial IgG-specific endoglycosidases," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    3. Aaron Gupta & Kevin S. Kao & Rachel Yamin & Deena A. Oren & Yehuda Goldgur & Jonathan Du & Pete Lollar & Eric J. Sundberg & Jeffrey V. Ravetch, 2023. "Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobody," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Ugur Uslu & Lijun Sun & Sofia Castelli & Amanda V. Finck & Charles-Antoine Assenmacher & Regina M. Young & Zhijian J. Chen & Carl H. June, 2024. "The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Molly Went & Amit Sud & Charlie Mills & Abi Hyde & Richard Culliford & Philip Law & Jayaram Vijayakrishnan & Ines Gockel & Carlo Maj & Johannes Schumacher & Claire Palles & Martin Kaiser & Richard Hou, 2024. "Phenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Carolyn M. Boudreau & John S. Burke & Ashraf S. Yousif & Maya Sangesland & Sandra Jastrzebski & Chris Verschoor & George Kuchel & Daniel Lingwood & Harry Kleanthous & Iris Bruijn & Victoria Landolfi &, 2023. "Antibody-mediated NK cell activation as a correlate of immunity against influenza infection," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Felix Jünger & Dominic Ruh & Dominik Strobel & Rebecca Michiels & Dominik Huber & Annette Brandel & Josef Madl & Alina Gavrilov & Michael Mihlan & Caterina Cora Daller & Eva A. Rog-Zielinska & Winfrie, 2022. "100 Hz ROCS microscopy correlated with fluorescence reveals cellular dynamics on different spatiotemporal scales," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    8. Kirsten L. Todd & Junyun Lai & Kevin Sek & Yu-Kuan Huang & Dane M. Newman & Emily B. Derrick & Hui-Fern Koay & Dat Nguyen & Thang X. Hoang & Emma V. Petley & Cheok Weng Chan & Isabelle Munoz & Imran G, 2023. "A2AR eGFP reporter mouse enables elucidation of A2AR expression dynamics during anti-tumor immune responses," Nature Communications, Nature, vol. 14(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:16:y:2025:i:1:d:10.1038_s41467-025-64862-5. 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.