Ko Dongjoon, Kim Eunmi, Shin Eun-Ae, Nam Seo Hee, Yoon Junghwa, Lee Jin-Sook, Lee Yunhee, Park Sora, Ha Kyungsoo, Choi So-Young, Lee Jung Weon, Kim Semi
Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejon 34141, Korea.
Department of Functional Genomics, Korea University of Science and Technology, Daejon 34113, Korea.
Mol Ther Oncolytics. 2022 Jan 31;24:452-466. doi: 10.1016/j.omto.2022.01.006. eCollection 2022 Mar 17.
The transmembrane 4 L six family member 5 (TM4SF5) is aberrantly expressed in hepatocellular and colorectal cancers, and has been implicated in tumor progression, suggesting that it could serve as a novel therapeutic target. Previously, we screened a murine antibody phage-display library to generate a novel monoclonal antibody, Ab27, that is specific to the extracellular loop 2 of TM4SF5. In this study, we evaluated the effects of chimeric Ab27 using cancer cells expressing endogenous TM4SF5 or stably overexpressing TM4SF5 and . Monotherapy with Ab27 significantly decreased tumor growth in liver and colon cancer xenograft models, including a sorafenib-resistant model, and decreased the phosphorylation of focal adhesion kinase (FAK), p27, and signal transducer and activator of transcription 3 (STAT3). No general Ab27 toxicity was observed . Combination treatment with Ab27 and sorafenib or doxorubicin exerted higher antitumor activity than monotherapy. In addition, we humanized the Ab27 sequence by the complementarity-determining region (CDR) grafting method. The humanized antibody Ab27-hz9 had reduced immunogenicity but exhibited target recognition and antitumor activity comparable with those of Ab27. Both Ab27 and Ab27-hz9 efficiently targeted tumor cells expressing TM4SF5 . These observations strongly support the further development of Ab27-hz9 as a novel therapeutic agent against liver and colorectal cancers.
跨膜4L六家族成员5（TM4SF5）在肝细胞癌和结直肠癌中异常表达，并与肿瘤进展有关，这表明它可能成为一个新的治疗靶点。此前，我们筛选了一个鼠源抗体噬菌体展示文库，以产生一种针对TM4SF5细胞外环2的新型单克隆抗体Ab27。在本研究中，我们使用表达内源性TM4SF5或稳定过表达TM4SF5的癌细胞评估了嵌合Ab27的作用。Ab27单药治疗显著降低了肝癌和结肠癌异种移植模型（包括索拉非尼耐药模型）中的肿瘤生长，并降低了粘着斑激酶（FAK）、p27以及信号转导和转录激活因子3（STAT3）的磷酸化水平。未观察到Ab27的一般毒性。Ab27与索拉非尼或阿霉素联合治疗比单药治疗具有更高的抗肿瘤活性。此外，我们通过互补决定区（CDR）嫁接法对Ab27序列进行了人源化改造。人源化抗体Ab27-hz9的免疫原性降低，但表现出与Ab27相当的靶向识别和抗肿瘤活性。Ab27和Ab27-hz9均能有效靶向表达TM4SF5的肿瘤细胞。这些观察结果有力地支持了进一步开发Ab27-hz9作为一种针对肝癌和结直肠癌的新型治疗药物。
