Department of Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China; Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China.
Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China.
Mol Immunol. 2023 Oct;162:125-132. doi: 10.1016/j.molimm.2023.08.007. Epub 2023 Sep 6.
Hepatocellular carcinoma (HCC) remains one of the most common and highly fatal malignancies in humans worldwide with increasing prevalence and limited therapeutic options. For many decades, many researchers have attempted to find effective curative methods for HCC and great strides have been made. GPC3 is overexpressed in HCC, but not in normal liver, making it a rational immunotherapeutic target for HCC. GC33, a humanized mAb directed against GPC3, is a safe and well-tolerated therapy choice for patients with HCC, which tested in a phase I trial in advanced HCC patients. Phase II trials of GC33 to evaluate its efficacy and safety in advanced or metastatic HCC, showed no significant differences in overall survival and progression-free survival compared with the placebo. Retrospective analysis indicates that high drug exposure and high CD16 expression may contribute to the clinical efficacy of GC33. Chugai Pharmaceutical has restarted its Phase I trial of GC33, continuing to explore its clinical value targeting GPC3 in solid tumors. To enhance the antitumor potency of GC33, we designed a GPC3/CD16A bispecific antibody (QDEB). In this study, we obtained QDEB at high purity and assessed its effectiveness in the therapy of HCC compared with GC33. In vitro cytotoxicity assays and in vivo experiments demonstrated that QDEB could enhance anti-tumor efficacy compared with GC33. CD16A activation and increased cytokines release were associated with higher anti-tumor activity. In conclusion, this bispecific antibody may possibly help develop new therapeutic strategies for HCC and develop new treatment options in the future.
肝细胞癌（HCC）仍然是全球最常见和致命的恶性肿瘤之一，其发病率不断上升，治疗选择有限。几十年来，许多研究人员一直在努力寻找治疗 HCC 的有效方法，并取得了重大进展。GPC3 在 HCC 中过度表达，但在正常肝脏中不表达，使其成为 HCC 的合理免疫治疗靶点。GC33 是一种针对 GPC3 的人源化单克隆抗体，是 HCC 患者安全且耐受良好的治疗选择，已在晚期 HCC 患者的 I 期试验中进行了测试。GC33 用于评估其在晚期或转移性 HCC 中的疗效和安全性的 II 期试验结果显示，与安慰剂相比，总生存期和无进展生存期无显著差异。回顾性分析表明，高药物暴露和高 CD16 表达可能有助于 GC33 的临床疗效。中外制药已重新启动 GC33 的 I 期试验，继续探索其针对实体瘤中 GPC3 的临床价值。为了增强 GC33 的抗肿瘤效力，我们设计了一种 GPC3/CD16A 双特异性抗体（QDEB）。在这项研究中，我们获得了高纯度的 QDEB，并评估了其与 GC33 相比在 HCC 治疗中的效果。体外细胞毒性试验和体内实验表明，QDEB 可增强抗肿瘤疗效。CD16A 的激活和细胞因子的释放增加与更高的抗肿瘤活性相关。总之，这种双特异性抗体可能有助于开发 HCC 的新治疗策略，并为未来开发新的治疗选择。
