Augmented antibody-based anticancer therapeutics boost neutrophil cytotoxicity

Most clinically used anticancer mAbs are of the IgG isotype, which can eliminate tumor cells through NK cell-mediated antibody-dependent cellular cytotoxicity and macrophage-mediated antibody-dependent phagocytosis. IgG, however, ineffectively recruits neutrophils as effector cells. IgA mAbs induce...

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Bibliographic Details
Published in:	The Journal of clinical investigation Vol. 131; no. 6; pp. 1 - 16
Main Authors:	Heemskerk, Niels, Gruijs, Mandy, Temming, A Robin, Heineke, Marieke H, Gout, Dennis Y, Hellingman, Tessa, Tuk, Cornelis W, Winter, Paula J, Lissenberg-Thunnissen, Suzanne, Bentlage, Arthur Eh, de Donatis, Marco, Bögels, Marijn, Rösner, Thies, Valerius, Thomas, Bakema, Jantine E, Vidarsson, Gestur, van Egmond, Marjolein
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 15-03-2021
Subjects:	Antibodies Antigens Apoptosis Biomedical research Bispecific antibodies Cancer Cancer therapies Care and treatment Cell activation Colorectal cancer Colorectal carcinoma Cytotoxicity Effector cells Epidermal growth factor receptors Fc receptors Health aspects Hematology Immunoglobulin A Immunoglobulin G Immunotherapy Leukocyte migration Leukocytes (neutrophilic) Macrophages Methods Monoclonal antibodies Mutation Natural killer cells Neutrophils Phagocytosis Physiological aspects Tumor cells Netherlands Immunoglobulins Neutrophils Therapeutics
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Summary:	Most clinically used anticancer mAbs are of the IgG isotype, which can eliminate tumor cells through NK cell-mediated antibody-dependent cellular cytotoxicity and macrophage-mediated antibody-dependent phagocytosis. IgG, however, ineffectively recruits neutrophils as effector cells. IgA mAbs induce migration and activation of neutrophils through the IgA Fc receptor (FcαRI) but are unable to activate NK cells and have poorer half-life. Here, we combined the agonistic activity of IgG mAbs and FcαRI targeting in a therapeutic bispecific antibody format. The resulting TrisomAb molecules recruited NK cells, macrophages, and neutrophils as effector cells for eradication of tumor cells in vitro and in vivo. Moreover, TrisomAb had long in vivo half-life and strongly decreased B16F10gp75 tumor outgrowth in mice. Importantly, neutrophils of colorectal cancer patients effectively eliminated tumor cells in the presence of anti-EGFR TrisomAb but were less efficient in mediating killing in the presence of IgG anti-EGFR mAb (cetuximab). The clinical application of TrisomAb may provide potential alternatives for cancer patients who do not benefit from current IgG mAb therapy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authorship note: MG and ART contributed equally to this work.
ISSN:	0021-9738 1558-8238
DOI:	10.1172/jci134680