TY - JOUR
T1 - Augmented antibody-based anticancer therapeutics boost neutrophil cytotoxicity
AU - Heemskerk, Niels
AU - Gruijs, Mandy
AU - Robin Temming, A.
AU - Heineke, Marieke H.
AU - Gout, Dennis Y.
AU - Hellingman, Tessa
AU - Tuk, Cornelis W.
AU - Winter, Paula J.
AU - Lissenberg-Thunnissen, Suzanne
AU - Bentlage, Arthur E. H.
AU - de Donatis, Marco
AU - Bögels, Marijn
AU - Rösner, Thies
AU - Valerius, Thomas
AU - Bakema, Jantine E.
AU - Vidarsson, Gestur
AU - van Egmond, Marjolein
N1 - Funding Information: This work is supported by Worldwide Cancer Research (grant 15-1240) and Cancer Center Amsterdam (to MVE). RBL-hCD89 cells and LysM-EGFP mice were a gift from Renato C. Monteiro (Faculté de Médecine, Université Paris Diderot) and Thomas Graf (Centre for Genomic Regulation), respectively. Lifeact mScarlet was a gift from Jaap D. van Buul (Sanquin Research and Landsteiner Laboratory, Amsterdam UMC), Joachim Goedhart and TWJ Gadella Jr. (Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands). We would like to thank Katarzyna Olesek for technical assistance. Publisher Copyright: © 2021 American Society for Clinical Investigation. All rights reserved.
PY - 2021/3/15
Y1 - 2021/3/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85102699772&partnerID=8YFLogxK
U2 - https://doi.org/10.1172/JCI134680
DO - https://doi.org/10.1172/JCI134680
M3 - Article
C2 - 33561014
SN - 0021-9738
VL - 131
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 6
M1 - e134680
ER -