Human IgG2 Antibodies against Epidermal Growth Factor Receptor Effectively Trigger Antibody-Dependent Cellular Cytotoxicity but, in Contrast to IgG1, Only by Cells of Myeloid Lineage
Human IgG2 Antibodies against Epidermal Growth Factor Receptor Effectively Trigger Antibody-Dependent Cellular Cytotoxicity but, in Contrast to IgG1, Only by Cells of Myeloid Lineage
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DOI：
10.4049/jimmunol.0900847
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发表时间：
2010-01-01
影响因子：
4.4
通讯作者：
Dechant, Michael
中科院分区：
文献类型：
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作者：
Schneider-Merck, Tanja;van Bueren, Jeroen J. Lammerts;Dechant, Michael
抗体依赖性细胞毒性（ADCC）通常被认为是人IgG1而非IgG2抗体免疫治疗的重要作用机制。表皮生长因子受体（EGF-R）抗体帕尼单抗是唯一被批准用于免疫治疗的人IgG2抗体，抑制EGF-R信号传导已被描述为其主要作用机制。在这项研究中，我们研究了帕尼单抗与zalutumumab的效应机制，zalutumumab是人类IgG1同型的EGF-R Ab。值得注意的是，panitumumab在骨髓效应细胞（即中性粒细胞和单核细胞）募集ADCC方面与zalutumumab一样有效，而NK细胞介导的ADCC仅由IgG1 Ab诱导。中性粒细胞介导的肿瘤细胞杀伤可由骨髓生长因子刺激，并通过Fc γ RIIa触发。panitumumab介导的ADCC受到功能性Fc γ RIIa-R131H多态性的显著影响，并且来自Fc γ RIIa-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。这种多态性不影响IgG1 Ab zalutumumab诱导的中性粒细胞ADCC。两种抗体的体内活性通过两种动物模型进行评估：一种是高剂量模型，其中信号抑制是主要的作用机制；另一种是低剂量模型，其中效应细胞募集起主要作用。Zalutumumab在高剂量模型中比panitumumab更有效，反映其诱导EGF-R下调和生长抑制的能力更强。在低剂量模型中，zalutumumab和panitumurnab类似地阻止肿瘤生长。因此，我们的结果确定髓细胞介导的ADCC是egf - r定向免疫治疗的一种有效和额外的作用机制。中华免疫学杂志，2010,18(4):592 - 592。
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 Fc gamma RIIa. Panitumumab-mediated ADCC was significantly affected by the functional Fc gamma RIIa-R131H polymorphism and was induced more effectively by neutrophils from Fc gamma RIIa-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 panitumurnab 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. The Journal of Immunology, 2010, 184: 512-520.