Journal Article

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

Brody, Rachel, Fraidenburg, Melanie, Alvarez, Raymond, Chen, Benjamin K., Ferrari de Andrade, Lucas, Housman, Brian, Marron, Thomas U., da Silva Bortoleti, Bruna Taciane, Ribeiro de Lima Brandão, Luiza, Maurer, Stefanie, Alves da Silva, Pedro Henrique, Flores, Raja M., Zhong, Xiaoxuan, Pimenta, Ruan, Hernandez, Matthew, Quasem, Sophia, Diniz, Márcio Augusto

2025

Overview

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. CD16a triggers antibody-dependent cellular cytotoxicity but CD16a shedding dampens its anti-tumor activity. Here the authors develop a monoclonal antibody (F9H4) that prevents CD16a shedding, which synergizes with a tumor cell opsonizing antibody (cetuximab) to elicit natural killer cell-driven immunity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/31 / 631/250/2152/2153/1291 / 631/250/2504/2506 / 64/110 / 64/60 / 692/4028/67/580 / 82/80 / ADAM17 Protein - metabolism / Adenocarcinoma / Animals / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - pharmacology / Antibody-Dependent Cell Cytotoxicity - drug effects / Antibody-Dependent Cell Cytotoxicity - immunology / Anticancer properties / Antineoplastic Agents, Immunological - pharmacology / Antitumor agents / Cancer / Cell Line, Tumor / Cetuximab - pharmacology / Cleavage / Cytotoxicity / Epidermal growth factor / Fc receptors / Female / Flow cytometry / GPI-Linked Proteins - immunology / GPI-Linked Proteins - metabolism / Growth factors / Humanities and Social Sciences / Humans / Immunity / Immunodeficiency / Immunotherapy / Killer Cells, Natural - drug effects / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Kinases / Leukocytes (neutrophilic) / Lung cancer / Lung carcinoma / Lung Neoplasms - drug therapy / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Macrophages / Macrophages - drug effects / Macrophages - immunology / Macrophages - metabolism / Mice / Monoclonal antibodies / multidisciplinary / Mutation / Natural killer cells / Neutrophils / Neutrophils - drug effects / Neutrophils - immunology / Neutrophils - metabolism / Opsonization / Phagocytosis / Proteins / Receptors / Receptors, IgG - immunology / Receptors, IgG - metabolism / Science / Science (multidisciplinary) / Shedding / Toxicity / Tumors / Xenograft Model Antitumor Assays