An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions

作者：Kinder Michelle^*; Greenplate Allison R; Strohl William R; Jordan Robert E; Brezski Randall J

来源：mAbs, 2015, 7(3): 494-504.

DOI：10.1080/19420862.2015.1022692

• Fc gamma R, Fc gamma receptor
• ADCP, antibody-dependent cellular phagocytosis
• DC, dendritic cell
• mAbs, monoclonal antibodies
• PBMC, peripheral blood mononuclear cell
• CDC, complement-dependent cytotoxicity
• IL, interleukin
• NK, natural killer
• APCs, antigen-presenting cells
• IFN, interferon
• TNF, tumor necrosis factor
• ADCC, antibody-dependent cell-mediated cytotoxicity
• ADCR, antibody-dependent cytokine release

Cytotoxic therapeutic monoclonal antibodies (mAbs) often mediate target cell-killing by eliciting immune effector functions via Fc region interactions with cellular and humoral components of the immune system. Key functions include antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). However, there has been increased appreciation that along with cell-killing functions, the induction of antibody-dependent cytokine release (ADCR) can also influence disease microenvironments and therapeutic outcomes. Historically, most Fc engineering approaches have been aimed toward modulating ADCC, ADCP, or CDC. In the present study, we describe an Fc engineering approach that, while not resulting in impaired ADCC or ADCP, profoundly affects ADCR. As such, when peripheral blood mononuclear cells are used as effector cells against mAb-opsonized tumor cells, the described mAb variants elicit a similar profile and quantity of cytokines as IgG1. In contrast, although the variants elicit similar levels of tumor cell-killing as IgG1 with macrophage effector cells, the variants do not elicit macrophage-mediated ADCR against mAb-opsonized tumor cells. This study demonstrates that Fc engineering approaches can be employed to uncouple macrophage-mediated phagocytic and subsequent cell-killing functions from cytokine release.

• 出版日期2015-5-4