Glypican 3型
肝细胞癌
药品
体内
癌症
肝癌
免疫毒素
癌症研究
医学
抗体
效力
吉西他滨
单克隆抗体
嵌合抗原受体
抗体-药物偶联物
体外
免疫疗法
内科学
药理学
化学
生物
免疫学
生物技术
生物化学
作者
Ying Fu,Daniel J. Urban,Roger R. Nani,Yifan Zhang,Nan Li,Haiying Fu,Hamzah Shah,Alexander P. Gorka,Rajarshi Guha,Lu Chen,Matthew D. Hall,Martin J. Schnermann,Mitchell Ho
出处
期刊:Hepatology
[Wiley]
日期:2019-02-19
卷期号:70 (2): 563-576
被引量:67
摘要
Hepatocellular carcinoma (HCC) is the second most common cause of cancer‐related death in the world. Therapeutic outcomes of HCC remain unsatisfactory, and novel treatments are urgently needed. GPC3 (glypican‐3) is an emerging target for HCC, given the findings that 1) GPC3 is highly expressed in more than 70% of HCC; (2) elevated GPC3 expression is linked with poor HCC prognosis; and (3) GPC3‐specific therapeutics, including immunotoxin, bispecific antibody and chimeric antigen receptor T cells. have shown promising results. Here, we postulate that GPC3 is a potential target of antibody‐drug conjugates (ADCs) for treating liver cancer. To determine the payload for ADCs against liver cancer, we screened three large drug libraries (> 9,000 compounds) against HCC cell lines and found that the most potent drugs are DNA‐damaging agents. Duocarmycin SA and pyrrolobenzodiazepine dimer were chosen as the payloads to construct two GPC3‐specific ADCs: hYP7‐DC and hYP7‐PC. Both ADCs showed potency at picomolar concentrations against a panel of GPC3‐positive cancer cell lines, but not GPC3 negative cell lines. To improve potency, we investigated the synergetic effect of hYP7‐DC with approved drugs. Gemcitabine showed a synergetic effect with hYP7‐DC in vitro and in vivo . Furthermore, single treatment of hYP7‐PC induced tumor regression in multiple mouse models. Conclusion : We provide an example of an ADC targeting GPC3, suggesting a strategy for liver cancer therapy.
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