Hanaoka Hirofumi, Nagaya Tadanobu, Sato Kazuhide, Nakamura Yuko, Watanabe Rira, Harada Toshiko, Gao Wei, Feng Mingqian, Phung Yen, Kim Insook, Paik Chang H, Choyke Peter L, Ho Mitchell, Kobayashi Hisataka
†Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
‡Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
Mol Pharm. 2015 Jun 1;12(6):2151-7. doi: 10.1021/acs.molpharmaceut.5b00132. Epub 2015 May 19.
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.
磷脂酰肌醇蛋白聚糖-3（GPC3）是肝细胞癌（HCC）治疗中一个有吸引力的靶点，因为它在HCC中高表达，但在成人正常组织中不表达。最近，已经开发出了高亲和力的抗GPC3抗体；然而，完整抗体可能无法均匀地渗透到肿瘤实质中，从而降低其有效性。在本研究中，我们比较了全IgG抗体抗GPC3 YP7和抗GPC3人重链抗体HN3的相对治疗效果。通过用（125）I和（111）In放射性标记抗体进行体外评估，YP7和HN3均能与GPC3阳性的A431/G1细胞结合并被细胞内化。用（111）In标记的抗体进行体内生物分布和肿瘤蓄积研究，并用荧光标记抗体（IR700）评估肿瘤内的微分布。与YP7相比，HN3显示出相似的高肿瘤蓄积，但在肿瘤内的同质性更好。使用相同的IR700偶联抗体在体外和体内荷瘤小鼠模型中进行光免疫治疗（PIT）。用IR700-HN3和IR700-YP7进行PIT表明，尽管在第一次近红外光照射后24小时再蓄积率较低，但仍可获得可比的结果。这些结果表明，作为一种设计针对HCC的分子靶向药物的治疗性抗体平台，重链抗体HN3比传统IgG YP7具有更有利的特性。
