An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions
An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions
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DOI：
10.1080/19420862.2015.1022692
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发表时间：
2015-05-04
期刊：
影响因子：
5.3
通讯作者：
Brezski, Randall J.
中科院分区：
文献类型：
--
作者：
Kinder, Michelle;Greenplate, Allison R.;Brezski, Randall J.
细胞毒性治疗性单克隆抗体（mAb）通常通过Fc区与免疫系统的细胞和体液组分相互作用引发免疫效应子功能来介导靶细胞杀伤。关键功能包括抗体依赖性细胞介导的细胞毒性（ADCC）、抗体依赖性细胞吞噬作用（ADCP）和补体依赖性细胞毒性（CDC）。然而，人们越来越认识到，沿着细胞杀伤功能，抗体依赖性细胞因子释放（ADCR）的诱导也可以影响疾病微环境和治疗结果。历史上，大多数Fc工程化方法旨在调节ADCC、ADCP或CDC。在本研究中，我们描述了一种Fc工程方法，虽然不会导致ADCC或ADCP受损，但会深刻影响ADCR。因此，当外周血单核细胞用作对抗mAb调理的肿瘤细胞的效应细胞时，所述mAb变体引起与IgG1相似的细胞因子谱和量。相比之下，尽管变体用巨噬细胞效应细胞引起与IgG1相似水平的肿瘤细胞杀伤，但变体不引起巨噬细胞介导的针对mAb调理的肿瘤细胞的ADCR。这项研究表明，Fc工程方法可以用来解偶联巨噬细胞介导的吞噬和随后的细胞杀伤功能从细胞因子释放。
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.