Svar Life Science France, Villejuif, France.
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Front Immunol. 2020 Oct 15;11:515556. doi: 10.3389/fimmu.2020.515556. eCollection 2020.
Highly sensitive reporter-gene assays have been developed that allow both the direct vascular endothelial growth factor (VEGF) neutralizing activity of bevacizumab and the ability of bevacizumab to activate antibody dependent cellular cytotoxicity (ADCC) to be quantified rapidly and in a highly specific manner. The use of these assays has shown that in 46 patients with ovarian cancer following four cycle of bevacizumab treatment, and in longitudinal samples from the two patients that respond to bevacizumab therapy from a small cohort of patients with glioblastoma, that there is a reasonably good correlation between bevacizumab drug levels determined by ELISA and bevacizumab activity, determined using either the VEGF-responsive reporter gene, or the ADCC assays. One of the two primary non-responders with glioblastoma exhibited high levels of ADCC activity suggesting reduced bevacizumab Fc engagement in contrast to the other primary non-responder, and the two secondary non-responders with a decreasing bevacizumab PK profile, determined by ELISA that exhibited low to undetectable ADCC activity. Drug levels were consistently higher than bevacizumab activity determined using the reporter gene assay in serial samples from one of the secondary non-responders and lower in some samples from the other secondary non-responder and ADCC activity was markedly lower in all samples from these patients suggesting that bevacizumab activity may be partially neutralized by anti-drug neutralizing antibodies (NAbs). These results suggest that ADCC activity may be correlated with the ability of some patients to respond to treatment with bevacizumab while the use of the VEGF-responsive reporter-gene assay may allow the appearance of anti-bevacizumab NAbs to be used as a surrogate maker of treatment failure prior to the clinical signs of disease progression.
已经开发出了高度敏感的报告基因检测法，可以快速且高度特异性地定量检测贝伐单抗的直接血管内皮生长因子 (VEGF) 中和活性和贝伐单抗激活抗体依赖细胞毒性 (ADCC) 的能力。这些检测法的应用表明，在接受贝伐单抗治疗 4 个周期的 46 名卵巢癌患者中，以及在接受贝伐单抗治疗的 2 名小队列脑胶质母细胞瘤患者的纵向样本中，ELISA 测定的贝伐单抗药物水平与贝伐单抗活性之间存在相当好的相关性，该活性通过 VEGF 反应报告基因或 ADCC 检测来确定。两名脑胶质母细胞瘤原发性无应答者之一表现出高 ADCC 活性，这表明与另一名原发性无应答者相比，贝伐单抗 Fc 结合减少，而两名具有降低的贝伐单抗 PK 特征的继发性无应答者（通过 ELISA 确定）表现出低至无法检测到的 ADCC 活性。在一名继发性无应答者的连续样本中，药物水平始终高于使用报告基因检测法确定的贝伐单抗活性，而在另一名继发性无应答者的一些样本中则较低，所有这些患者的 ADCC 活性均明显降低，这表明贝伐单抗活性可能部分被抗药物中和抗体（NAb）中和。这些结果表明，ADCC 活性可能与一些患者对贝伐单抗治疗产生反应的能力相关，而使用 VEGF 反应报告基因检测法可能允许将出现抗贝伐单抗 NAb 用作疾病进展临床迹象之前治疗失败的替代标志物。
