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

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 Silva, Raymond Alvarez, Benjamin K. Chen, Márcio Augusto Diniz, Brian Housman, Raja M. Flores, Rachel Brody, Thomas U. Marron and Lucas Ferrari de Andrade ()
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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
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
Pedro Henrique Alves da Silva: Icahn School of Medicine at Mount Sinai
Raymond Alvarez: Icahn School of Medicine at Mount Sinai
Benjamin K. Chen: 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
Lucas Ferrari de Andrade: Icahn School of Medicine at Mount Sinai

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64862-5

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