1. Enhancing Neutrophil Cytotoxicity of a Panel of Clinical EGFR Antibodies by Fc Engineering to IgA3.0.
- Author
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Chan C, Jansen JHM, Hendriks IST, van der Peet IC, Verdonschot MEL, Passchier EM, Tsioumpekou M, Nederend M, Klomp SA, Valerius T, Peipp M, Leusen JHW, and Olofsen PA
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Xenograft Model Antitumor Assays, Immunoglobulin Fc Fragments immunology, Immunoglobulin Fc Fragments pharmacology, Immunoglobulin A immunology, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents, Immunological pharmacology, Protein Engineering, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Female, ErbB Receptors antagonists & inhibitors, ErbB Receptors immunology, Neutrophils immunology, Neutrophils drug effects, Neutrophils metabolism, Antibody-Dependent Cell Cytotoxicity immunology, Antibody-Dependent Cell Cytotoxicity drug effects
- Abstract
EGFR plays an essential role in cellular signaling pathways that regulate cell growth, proliferation, and survival and is often dysregulated in cancer. Several monoclonal IgG antibodies have been clinically tested over the years, which exert their function via blocking the ligand binding domain (thereby inhibiting downstream signaling) and inducing Fc-related effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). However, these IgG antibodies do not optimally recruit neutrophils, which are the most abundant white blood cell population in humans. Therefore, we reformatted six therapeutic EGFR antibodies (cetuximab, panitumumab, nimotuzumab, necitumumab, zalutumumab, and matuzumab) into the IgA3.0 format, which is an IgA2 isotype adapted for clinical application. Reformatting these antibodies preserved Fab-mediated functions such as EGFR binding, growth inhibition, and ligand blockade. In addition, whole leukocyte ADCC was significantly increased when using this panel of IgA3.0 antibodies compared with their respective IgG counterparts, with no major differences between IgA3.0 antibodies. In vivo, IgA3.0 matuzumab outperformed the other antibodies, resulting in the strongest suppression of tumor outgrowth in a long intraperitoneal model. We showed that neutrophils are important for the suppression of tumor outgrowth. IgA3.0 matuzumab exhibited reduced receptor internalization compared with the other antibodies, possibly accounting for its superior in vivo Fc-mediated tumor cell killing efficacy. In conclusion, reformatting EGFR antibodies into an IgA3.0 format increased Fc-mediated killing while retaining Fab-mediated functions and could therefore be a good alternative for the currently available antibody therapies., (©2024 American Association for Cancer Research.)
- Published
- 2024
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