The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Clin Cancer Res. 2013 Mar 1;19(5):1126-38. doi: 10.1158/1078-0432.CCR-12-0989. Epub 2012 Dec 3.
Anti-EGF receptor (EGFR) antibodies and small-molecule tyrosine kinase inhibitors have shown activity in epithelial tumors; however, agents that work by blocking the EGFR growth signal are ineffective when the oncogenic stimulus arises downstream, such as in tumors with KRAS mutations. Antibodies of the IgG1 subclass can also kill tumor cells directly through antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of this is determined by the interaction of the Fc portion of the target cell-bound antibody and Fc receptors present on immune effector cells.
We report the development of GA201, a novel anti-EGFR monoclonal antibody with enhanced ADCC properties. GA201 was derived by humanization of the rat ICR62 antibody. The Fc region of GA201 was glycoengineered to contain bisected, afucosylated carbohydrates for enhanced binding to FcγRIIIA.
In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low- and high-affinity variants of FcγRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. This enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models. Efficacy of GA201 was further increased when administered in combination with chemotherapy (irinotecan).
These data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors. Clin Cancer Res; 19(5); 1126-38. ©2012 AACR.
抗表皮生长因子受体（EGFR）抗体和小分子酪氨酸激酶抑制剂在表皮肿瘤中显示出活性；然而，当致癌刺激物出现在下游时，如在具有 KRAS 突变的肿瘤中，阻断 EGFR 生长信号的药物则无效。IgG1 亚类的抗体也可以通过抗体依赖性细胞介导的细胞毒性（ADCC）直接杀死肿瘤细胞，并且这种功效取决于靶细胞结合抗体的 Fc 部分与存在于免疫效应细胞上的 Fc 受体的相互作用。
我们报告了一种新型抗 EGFR 单克隆抗体 GA201 的开发，该抗体具有增强的 ADCC 特性。GA201 通过大鼠 ICR62 抗体的人源化获得。GA201 的 Fc 区经过糖基工程处理，使其包含双分的、去岩藻糖基化的碳水化合物，以增强与 FcγRIIIA 的结合。
GA201 与 EGFR 的体外结合抑制了 EGF 配体结合、EGFR/HER2 异二聚化、下游信号转导和细胞增殖，其程度与西妥昔单抗相似。然而，GA201 与 FcγRIIIA 的低亲和力和高亲和力变体均表现出更好的结合。这导致与西妥昔单抗相比，对 KRAS 野生型和突变型肿瘤细胞系的 ADCC 诱导显著增强。这种增强的 ADCC 在一系列小鼠异种移植模型中转化为优越的体内疗效。当与化疗（伊立替康）联合使用时，GA201 的疗效进一步提高。
这些数据表明，GA201 可能比西妥昔单抗在 EGFR 阳性实体肿瘤患者中更有效，并且也可能代表 KRAS 突变肿瘤患者的一类首创治疗方法。临床癌症研究；19（5）；1126-38。©2012 AACR。
