期刊
ONCOLOGY REPORTS
卷 45, 期 2, 页码 776-785出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/or.2020.7893
关键词
HER-3; liver cancer; antibody-drug conjugates; targeted therapy; monomethyl auristatin F
类别
资金
- Fondazione AIRC (Italian Association for Cancer Research) [18467, 20043]
- AIRC fellowship
- Italian Ministry of Instruction, University, and Research under the national project PON ricerca e innovazione 2014-2020
Liver cancer is an aggressive disease with poor prognosis for which therapeutic options are limited. Recently developed ADCs targeting HER3 receptor show promising therapeutic potential and may serve as an alternative treatment for liver cancer with high HER3 expression.
Liver cancer (LC) is an aggressive disease with a markedly poor prognosis. Therapeutic options are limited, and, until recently the only FDA-approved agent for first-line treatment of patients with LC was the multi-kinase inhibitor sorafenib, which exhibits limited activity and an increased overall survival (OS) of only 3 months over placebo. Therefore, the development of alternative therapeutic molecules for the treatment of LC is an urgent medical need. Antibody-drug conjugates (ADCs) are an emerging class of novel anticancer agents, which have been developed recently for the treatment of malignant conditions, including LC, and are being studied in preclinical and clinical settings. Our group has recently generated an ADC [EV20/monomethyl auristatin F (MMAF)] by coupling the HER3 targeting antibody (EV20) to MMAF via a non-cleavable maleimidocaproyl linker. This ADC was revealed to possess potent therapeutic activity in melanoma and breast carcinoma. In the present study, using western blot and flow cytometric analysis, it was reported that HER-3 receptor was highly expressed in LC and activated by its ligand NRG-1 beta in a panel of LC cell lines, thus indicating that this receptor may serve as a suitable target for ADC therapy. A novel ADC [EV20-sss-valine-citrulline (vc)/MMAF] was generated, in which the cytotoxic payload MMAF was site-specifically coupled to an engineered variant of EV20 via a vc cleavable linker. Cytotoxicity assays were performed to investigate in vitro antitumor activity of EV20-sss-vc/MMAF and it was compared to EV20/MMAF, which revealed only modest activity in LC.EV20-sss-vc/MMAF exhibited a significant cell killing activity in several LC cell lines. Additionally, in vivo xenograft experiments revealed that EV20-sss-vc/MMAF inhibited growth of LC tumors. The present data indicated that EV20-sss-vc/MMAF is a worthy candidate for the treatment of HER-3 positive LC.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据