Abstract:
Glypican-3 (GPC3) represents an attractive target for hepatocellular carcinoma (HCC) therapy because it is highly expressed in HCC but not in adult normal tissue. Recently, high affinity anti-GPC3 antibodies have been developed; however, full antibodies may not penetrate evenly into tumor parenchyma, reducing their effectiveness. In this study, we compared a whole IgG antibody, anti-GPC3 YP7, with an anti-GPC3 human heavy chain antibody, HN3, with regard to their relative therapeutic effects. Both YP7 and HN3 bound to GPC3-positive A431/G1 cells and were internalized by the cells by in vitro evaluation with (125)I- and (111)In-radiolabeling antibodies. In vivo biodistribution and tumor accumulation was performed with (111)In-labeled antibodies, and intratumoral microdistribution was evaluated using fluorescently labeled antibodies (IR700). HN3 showed similar high tumor accumulation but superior homogeneity within the tumor compared with YP7. Using the same IR700 conjugated antibodies photoimmunotherapy (PIT) was performed in vitro and in a tumor-bearing mouse model in vivo. PIT with IR700-HN3 and IR700-YP7 demonstrated that comparable results could be achieved despite of low reaccumulation 24 h after the first NIR light exposure. These results indicated that a heavy-chain antibody, HN3, showed more favorable characteristics than YP7, a conventional IgG, as a therapeutic antibody platform for designing molecularly targeted agents against HCC.
摘要:
磷脂酰肌醇蛋白聚糖-3(GPC3)是肝细胞癌(HCC)治疗的有吸引力的靶标,因为它在HCC中高表达,但在成人正常组织中不高表达。最近,已经开发了高亲和力抗GPC3抗体;然而,完整的抗体可能无法均匀地渗透到肿瘤实质中,降低其效力。在这项研究中,我们比较了一个完整的IgG抗体,抗GPC3YP7,与抗GPC3人重链抗体,HN3,关于它们的相对治疗效果。YP7和HN3均与GPC3阳性A431/G1细胞结合,并通过用(125)I和(111)放射性标记抗体进行体外评估而被细胞内化。体内生物分布和肿瘤积累用(111)标记的抗体进行,使用荧光标记的抗体(IR700)评估肿瘤内微分布。与YP7相比,HN3显示出相似的高肿瘤积累,但在肿瘤内具有更好的同质性。使用相同的IR700缀合的抗体,在体外和在体内荷瘤小鼠模型中进行光免疫疗法(PIT)。使用IR700-HN3和IR700-YP7的PIT表明,尽管在第一次NIR光暴露后24小时有低的再积累,但仍可以获得可比的结果。这些结果表明,重链抗体,HN3,显示比YP7,常规IgG更有利的特性,作为设计针对HCC的分子靶向药物的治疗性抗体平台。