Augmented antibody-based anticancer therapeutics boost neutrophil cytotoxicity

被引：49

作者：

Heemskerk, Niels ^{[1
]}

Gruijs, Mandy ^{[1
]}

Temming, A. Robin ^{[2
]}

Heineke, Marieke H. ^{[1
]}

Gout, Dennis, V ^{[1
]}

Hellingman, Tessa ^{[3
]}

Tuk, Cornelis W. ^{[1
]}

Winter, Paula J. ^{[1
]}

Lissenberg-Thunnissen, Suzanne ^{[2
]}

Bentlage, Arthur E. H. ^{[2
]}

de Donatis, Marco ^{[1
]}

Bogels, Marijn ^{[1
]}

Rosner, Thies ^{[4
,5
]}

Valerius, Thomas ^{[4
,5
]}

Bakema, Jantine E. ^{[6
]}

Vidarsson, Gestur ^{[2
]}

van Egmond, Marjolein ^{[1
,3
]}

机构：

[1] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Dept Mol Cell Biol & Immunol, Amsterdam Infect & Immun,Amsterdam UMC, De Boelelaan 1117, Amsterdam, Netherlands

[2] Univ Amsterdam, Dept Expt Immunohematol, Sanquin Res & Landsteiner Lab, Amsterdam UMC, Amsterdam, Netherlands

[3] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Dept Surg, Amsterdam UMC, De Boelelaan 1117, Amsterdam, Netherlands

[4] Univ Kiel, Sect Stem Cell Transplantat & Immunotherapy, Dept Med 2, Kiel, Germany

[5] Univ Hosp Schleswig Holstein, Kiel, Germany

[6] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Dept Otolaryngol Head Neck Surg, Amsterdam UMC, De Boelelaan 1117, Amsterdam, Netherlands

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2021年 / 131卷 / 06期

关键词：

FC-ALPHA-RI; COLONY-STIMULATING FACTOR; HIGH-AFFINITY RECEPTOR; HUMAN-IGG SUBCLASSES; HUMAN-IMMUNOGLOBULIN; TUMOR-CELLS; POLYMORPHONUCLEAR NEUTROPHILS; COMBINATION IMMUNOTHERAPY; MONOCLONAL-ANTIBODIES; EFFECTOR MECHANISMS;

D O I：

10.1172/JCI134680

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 (Fc?RI) but are unable to activate NK cells and have poorer half-life. Here, we combined the agonistic activity of IgG mAbs and Fc?RI 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.

引用

页数：17

共 78 条

[1] Neutrophils mediate antibody-induced antitumor effects in mice [J].