A monoclonal antibody that inhibits the shedding of CD16a and CD16b and promotes antibody-dependent cellular cytotoxicity against tumors
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.
Authors
- Luiza Ribeiro de Lima Brandão (ORCID: https://orcid.org/0000-0003-1508-3817)
- Lucas Ferrari de Andrade (ORCID: https://orcid.org/0000-0002-2137-2271)
- Ruan Pimenta (ORCID: https://orcid.org/0000-0002-3423-5647)
- Xiaoxuan Zhong (ORCID: https://orcid.org/0000-0003-4968-862X)
- Benjamin K. Chen (ORCID: https://orcid.org/0000-0002-5404-1997)
- Brian Housman
- Matthew C. Hernandez (ORCID: https://orcid.org/0000-0001-8084-9685)
- Márcio A. Diniz (ORCID: https://orcid.org/0000-0002-2427-7843)
- Pedro Henrique Alves da Silva
- Thomas U. Marron (ORCID: https://orcid.org/0000-0001-5903-8191)
- Raja M. Flores (ORCID: https://orcid.org/0000-0001-7718-7422)
- Raymond Alvarez
- Stefanie Maurer (ORCID: https://orcid.org/0000-0003-2423-3338)
- Bruna Taciane da Silva Bortoleti (ORCID: https://orcid.org/0000-0003-2631-6719)
- Rachel Brody (ORCID: https://orcid.org/0000-0001-9280-517X)
- Sophia Quasem
- Melanie Fraidenburg
Institutions
- Yale University (US)
- Cell Biologics (United States) (US)
- New York University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1038/s41467-025-64862-5
- Citations
- 3
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 4.08
Funders
- U.S. Department of Defense
- Elsa U. Pardee Foundation
- Leukemia and Lymphoma Society
- University of Bern
- National Institutes of Health
- National Cancer Institute