Glycoengineering of Therapeutic Antibodies Enhances Monocyte/Macrophage-Mediated Phagocytosis and Cytotoxicity
Glycoengineering of Therapeutic Antibodies Enhances Monocyte/Macrophage-Mediated Phagocytosis and Cytotoxicity
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DOI：
10.4049/jimmunol.1301249
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发表时间：
2014-03-01
影响因子：
4.4
通讯作者：
Bacac, Marina
中科院分区：
文献类型：
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作者：
Herter, Sylvia;Birk, Martina C.;Bacac, Marina
治疗性抗体具有多种临床相关的作用机制，包括干扰肿瘤细胞信号传导、激活补体依赖的细胞毒作用、抗体依赖的细胞毒作用(ADCC)、抗体依赖的细胞吞噬作用(ADCP)和诱导适应性免疫。鉴于吞噬系细胞在治疗性抗体作用机制中的重要作用，我们在不同的实验条件下分析了糖工程抗体(GE)与野生型(WT)抗体(具有增强的FcγRIIIa[CD16A]结合亲和力)触发的单核细胞和巨噬细胞的FcγR受体依赖的效应功能。我们首先在经典和非经典中间单核细胞-M1和M2c巨噬细胞群上定义了精确的Fc-Gamma R谱。我们进一步证明，在缺乏非特异性内源性IgG的情况下，WT和GE Abs表现出类似的结合并诱导类似的效应功能(ADCC和ADCP)。然而，在这些免疫球蛋白的存在下(即，在更接近生理条件的情况下)，GE Abs表现出显著更好的结合并促进更强的单核细胞和巨噬细胞活性。这些数据表明，除了增强CD16A依赖的NK细胞的细胞毒性外，糖工程还通过在更接近生理环境的条件下增强与CD16A的结合来增强单核细胞和巨噬细胞的吞噬和细胞毒活性。
Therapeutic Abs possess several clinically relevant mechanisms of action including perturbation of tumor cell signaling, activation of complement-dependent cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cellular phagocytosis (ADCP), and induction of adaptive immunity. In view of the important role of phagocytic lineage cells in the mechanism of action of therapeutic Abs, we analyzed Fc gamma R receptor-dependent effector functions of monocytes and macrophages triggered by glycoengineered (GE) Abs (having enhanced Fc gamma RIIIa [CD16a] binding affinity) versus their wild-type (WT) counterparts under different experimental conditions. We first defined the precise Fc gamma R repertoire on classical and nonclassical intermediate monocytes-M1 and M2c macrophage populations. We further show that WT and GE Abs display comparable binding and induce similar effector functions (ADCC and ADCP) in the absence of nonspecific, endogenous IgGs. However, in the presence of these IgGs (i.e., in a situation that more closely mimics physiologic conditions), GE Abs display significantly superior binding and promote stronger monocyte and macrophage activity. These data show that in addition to enhancing CD16a-dependent NK cell cytotoxicity, glycoengineering also enhances monocyte and macrophage phagocytic and cytotoxic activities through enhanced binding to CD16a under conditions that more closely resemble the physiologic setting.