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Simultaneous exposure to Fc?R and Fc?R on monocytes and macrophages enhances antitumor activity in vivo.

ABSTRACT: Therapeutic antibodies are effective for tumor immunotherapy and exhibit prominent clinical effects. All approved antibody therapeutics utilize IgG as the molecular format. Antibody-dependent cell-mediated cytotoxicity (ADCC) is a key mechanism for tumor cell killing by antibodies. For IgG antibodies, ADCC depends on Fc?R-expressing cells, such as natural killer (NK) cells. However, in patients with a high tumor burden, antibody therapeutics may lose efficacy owing to exhaustion of Fc?R-expressing effector cells as well as the inhibitory effects of certain Fc?Rs on effector cells. To achieve more potent effector functions, we engineered an anti-CD20 antibody to contain both IgG Fc and IgA Fc domains. These engineered antibodies interacted with both IgG and IgA Fc receptors (Fc?R and Fc?R) and recruited a broader range of effector cells, including monocytes, macrophages, neutrophils, and NK cells, thereby enhancing antibody-dependent cellular phagocytosis. Using transgenic mice expressing the Fc?RI (CD89) in macrophages, we demonstrated that recombinant antibodies bearing the chimeric IgG and IgA Fc exhibited potent in vivo antitumor activity. Additionally, in a short-term peritoneal model using CD20-transfected LLC target cells, the in vivo cytotoxic activity of hybrid recombinant antibodies was mediated by macrophages with significant reduction in the absence of Fc?RI. Our findings supported targeting of Fc?RI on monocytes and macrophages for improved tumor immunotherapy.

SUBMITTER: Li B

PROVIDER: S-EPMC5503618 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Simultaneous exposure to FcγR and FcαR on monocytes and macrophages enhances antitumor activity in vivo.

Li Bingyu B Xu Lijun L Tao Fei F Xie Kun K Wu Zhiqiang Z Li You Y Li Jie J Chen Kaiming K Pi Chenyu C Mendelsohn Andrew A Larrick James W JW Gu Hua H Fang Jianmin J

Oncotarget 20170601 24

Therapeutic antibodies are effective for tumor immunotherapy and exhibit prominent clinical effects. All approved antibody therapeutics utilize IgG as the molecular format. Antibody-dependent cell-mediated cytotoxicity (ADCC) is a key mechanism for tumor cell killing by antibodies. For IgG antibodies, ADCC depends on FcγR-expressing cells, such as natural killer (NK) cells. However, in patients with a high tumor burden, antibody therapeutics may lose efficacy owing to exhaustion of FcγR-expressi ...[more]

PMID: 28454118

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Project description:Macrophages are phagocytic cells with great importance in guiding multiple stages of inflammation and tissue repair. By producing a large number of biologically active molecules, they can affect the behavior of other cells and events, such as the foreign body response and angiogenesis. Since protein adsorption to biomaterials is crucial for the inflammatory process, we addressed the ability of the pro-inflammatory molecule fibrinogen (Fg) to modulate macrophage behavior toward tissue repair/regeneration. For this purpose, we used chitosan (Ch) as a substrate for Fg adsorption. Freshly isolated human monocytes were seeded on Ch substrates alone or previously adsorbed with Fg, and allowed to differentiate into macrophages for 10 days. Cell adhesion and morphology, formation of foreign body giant cells (FBGC), and secretion of a total of 80 cytokines and growth factors were evaluated. Both substrates showed similar numbers of adherent macrophages along differentiation as compared with RGD-coated surfaces, which were used as positive controls. Fg did not potentiate FBGC formation. In addition, actin cytoskeleton staining revealed the presence of punctuate F-actin with more elongated and interconnecting cells on Ch substrates. Antibody array screening and quantification of inflammation- and wound-healing-related factors indicated an overall reduction in Ch-based substrates versus RGD-coated surfaces. At late times, most inflammatory agents were down-regulated in the presence of Fg, in contrast to growth factor production, which was stimulated by Fg. Importantly, on Ch+Fg substrates, fully differentiated macrophages produced significant amounts of macrophage inflammatory protein-1delta (MIP-1?), platelet-derived growth factor-BB, bone morphogenetic protein (BMP)-5, and BMP-7 compared with Ch alone. In addition, other important factors involved in bone homeostasis and wound healing, such as growth hormone, transforming growth factor-?3, and insulin-like growth factor-binding proteins, as well as several angiogenic mediators, including endocrine gland-derived vascular endothelial factor, fibroblast growth factor-7, and placental growth factor, were significantly promoted by Fg. This work provides a new perspective on the inflammatory response in the context of bone repair/regeneration mediated by a pro-inflammatory protein (Fg) adsorbed onto a biomaterial (Ch) that does not otherwise exhibit osteogenic properties.

Dataset Information

Simultaneous exposure to Fc?R and Fc?R on monocytes and macrophages enhances antitumor activity in vivo.

Publications

Simultaneous exposure to FcγR and FcαR on monocytes and macrophages enhances antitumor activity in vivo.

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