Simultaneous exposure to FcγR and FcαR on monocytes and macrophages enhances antitumor activity in vivo
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Bingyu Li1,*, Lijun Xu1,*, Fei Tao1, Kun Xie1, Zhiqiang Wu1, You Li1, Jie Li1, Kaiming Chen1, Chenyu Pi1, Andrew Mendelsohn2, James W. Larrick2, Hua Gu1 and Jianmin Fang1,3,4,5,6
1School of Life Sciences and Technology, Tongji University, Shanghai, China
2Panorama Research Institute, Sunnyvale, CA, USA
3Shanghai Tongji Hospital, Tongji University, Shanghai, China
4Tongji University Suzhou Institute, Suzhou, China
5Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
6Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
*These authors have contributed equally to this work
Jianmin Fang, email: [email protected]
Hua Gu, email: [email protected]
Keywords: antitumor activity, relapse, antibody-dependent cell-mediated cytotoxicity, in vivo mouse model, CD20
Received: August 15, 2016 Accepted: March 11, 2017 Published: April 10, 2017
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-expressing effector cells as well as the inhibitory effects of certain FcγRs 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 (FcγR and FcαR) 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 FcαRI (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 FcαRI. Our findings supported targeting of FcαRI on monocytes and macrophages for improved tumor immunotherapy.
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