Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Int J Cancer. 2012 Aug 15;131(4):956-69. doi: 10.1002/ijc.26427. Epub 2011 Nov 19.
An antibody simultaneously targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), two major tumor growth-driving machineries, may provide a novel effective strategy for optimizing tumor targeting and maximizing potential clinical benefits. Human domain antibodies selected against VEGF and EGFR were formatted into a fully human dual-targeting IgG (DT-IgG) to directly target both antigens in a single molecule. We evaluated the efficacy of DT-IgG in comparison with bevacizumab and cetuximab alone and in combination in the lung cancer cell line A549 (low EGFR expression and KRAS mutant) and the head and neck squamous cell carcinoma (HNSCC) cell line Tu212 (high EGFR expression and KRAS wild type) in vitro and in vivo. DT-IgG suppressed Tu212 and A549 cell growth, inhibited EGFR activation and induced apoptosis as effectively as cetuximab, and neutralized VEGF as effectively as bevacizumab. DT-IgG induced EGFR-dependent VEGF internalization, constituting a novel antiangiogenesis mechanism. In xenograft models with lung and head and neck cancer cell lines, DT-IgG displayed efficacy equivalent to bevacizumab in diminishing tumor growth despite its short serum half-life (36 hr in rats) and both agents may constitute preferable alternatives to cetuximab in KRAS-mutant tumors. Immunofluorescence staining revealed that localization of DT-IgG was similar to that of cetuximab, largely associated with EGFR+tumor cells. Our proof of principle study suggests a DT-IgG against EGFR and VEGF as an alternative therapeutic strategy with potentially enhanced clinical benefit.
一种同时针对表皮生长因子受体（EGFR）和血管内皮生长因子（VEGF）这两种主要肿瘤生长驱动机制的抗体，可能为优化肿瘤靶向和最大化潜在临床获益提供一种新的有效策略。针对 VEGF 和 EGFR 选择的人源结构域抗体被构建成完全人源双靶向 IgG（DT-IgG），以在单个分子中直接针对这两种抗原。我们评估了 DT-IgG 与贝伐珠单抗和西妥昔单抗单独以及联合在体外和体内肺癌细胞系 A549（低 EGFR 表达和 KRAS 突变）和头颈部鳞状细胞癌（HNSCC）细胞系 Tu212（高 EGFR 表达和 KRAS 野生型）中的疗效。DT-IgG 抑制 Tu212 和 A549 细胞生长，有效抑制 EGFR 激活并诱导细胞凋亡，与西妥昔单抗相当，并与贝伐珠单抗一样有效中和 VEGF。DT-IgG 诱导 EGFR 依赖性 VEGF 内化，构成一种新的抗血管生成机制。在带有肺癌和头颈部癌细胞系的异种移植模型中，尽管 DT-IgG 的血清半衰期（大鼠为 36 小时）较短，但 DT-IgG 在抑制肿瘤生长方面与贝伐珠单抗等效，并可能成为 KRAS 突变肿瘤中西妥昔单抗的更好替代药物。免疫荧光染色显示，DT-IgG 的定位与西妥昔单抗相似，主要与 EGFR+肿瘤细胞相关。我们的原理研究表明，针对 EGFR 和 VEGF 的 DT-IgG 作为一种替代治疗策略具有潜在增强的临床获益。
