Enhancing Neutrophil Cytotoxicity of a Panel of Clinical EGFR Antibodies by Fc Engineering to IgA3.0.

Autor:	Chan C; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Jansen JHM; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Hendriks IST; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., van der Peet IC; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Verdonschot MEL; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Passchier EM; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Tsioumpekou M; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Nederend M; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Klomp SA; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Valerius T; Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, Christian-Al-brechts University Kiel and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany., Peipp M; Division of Antibody-Based Immunotherapy, Department of Medicine II, Christian Albrechts University Kiel and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany., Leusen JHW; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Olofsen PA; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Sep 04; Vol. 23 (9), pp. 1317-1331.
DOI:	10.1158/1535-7163.MCT-24-0217
Abstrakt:	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.)
Databáze:	MEDLINE
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