Department of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany.
J Immunol. 2010 Jan 1;184(1):512-20. doi: 10.4049/jimmunol.0900847. Epub 2009 Nov 30.
Ab-dependent cellular cytotoxicity (ADCC) is usually considered an important mechanism of action for immunotherapy with human IgG1 but not IgG2 Abs. The epidermal growth factor receptor (EGF-R) Ab panitumumab represents the only human IgG2 Ab approved for immunotherapy and inhibition of EGF-R signaling has been described as its principal mechanism of action. In this study, we investigated effector mechanisms of panitumumab compared with zalutumumab, an EGF-R Ab of the human IgG1 isotype. Notably, panitumumab was as effective as zalutumumab in recruiting ADCC by myeloid effector cells (i.e., neutrophils and monocytes) in contrast to NK cell-mediated ADCC, which was only induced by the IgG1 Ab. Neutrophil-mediated tumor cell killing could be stimulated by myeloid growth factors and was triggered via FcgammaRIIa. Panitumumab-mediated ADCC was significantly affected by the functional FcgammaRIIa-R131H polymorphism and was induced more effectively by neutrophils from FcgammaRIIa-131H homozygous donors than from -131R individuals. This polymorphism did not affect neutrophil ADCC induced by the IgG1 Ab zalutumumab. The in vivo activity of both Abs was assessed in two animal models: a high-dose model, in which signaling inhibition is a dominant mechanism of action, and a low-dose model, in which effector cell recruitment plays a prominent role. Zalutumumab was more effective than panitumumab in the high-dose model, reflecting its stronger ability to induce EGF-R downmodulation and growth inhibition. In the low-dose model, zalutumumab and panitumumab similarly prevented tumor growth. Thus, our results identify myeloid cell-mediated ADCC as a potent and additional mechanism of action for EGF-R-directed immunotherapy.
抗体依赖的细胞细胞毒性 (ADCC) 通常被认为是免疫疗法中使用人 IgG1 抗体而不是 IgG2 抗体的重要作用机制。表皮生长因子受体 (EGF-R) 抗体帕尼单抗代表唯一批准用于免疫治疗的人 IgG2 抗体，并且已经描述了抑制 EGF-R 信号传导是其主要作用机制。在这项研究中，我们研究了帕尼单抗与 zalutumumab（一种人 IgG1 同种型的 EGF-R 抗体）相比的效应机制。值得注意的是，与 NK 细胞介导的 ADCC 相反，帕尼单抗通过髓样效应细胞（即中性粒细胞和单核细胞）招募 ADCC 的效果与 zalutumumab 相当，而 NK 细胞介导的 ADCC 仅由 IgG1 抗体诱导。髓样生长因子可刺激中性粒细胞介导的肿瘤细胞杀伤，并且通过 FcγRIIa 触发。帕尼单抗介导的 ADCC 明显受功能性 FcγRIIa-R131H 多态性影响，并且来自 FcγRIIa-131H 纯合供体的中性粒细胞比来自 -131R 个体的中性粒细胞更有效地诱导 ADCC。该多态性不影响由 IgG1 抗体 zalutumumab 诱导的中性粒细胞 ADCC。在两种动物模型中评估了两种抗体的体内活性：高剂量模型，其中信号抑制是主要作用机制，以及低剂量模型，其中效应细胞募集起着突出作用。Zalutumumab 在高剂量模型中比 panitumumab 更有效，反映了其更强的诱导 EGF-R 下调和生长抑制的能力。在低剂量模型中，zalutumumab 和 panitumumab 同样阻止了肿瘤生长。因此，我们的结果确定髓样细胞介导的 ADCC 是 EGF-R 导向免疫治疗的一种有效且额外的作用机制。
