Ma Jingbo, Xu Xiaolong, Fu Chunjin, Xia Peng, Tian Ming, Zheng Liuhai, Chen Kun, Liu Xiaolian, Li Yilei, Yu Le, Zhu Qinchang, Yu Yangyang, Fan Rongrong, Jiang Haibo, Li Zhifen, Yang Chuanbin, Xu Chengchao, Long Ying, Wang Jigang, Li Zhijie
Department of Hyperbaric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China.
College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, P. R. China.
Biomater Res. 2022 Nov 26;26(1):64. doi: 10.1186/s40824-022-00312-3.
It is highly desirable to develop new therapeutic strategies for gastric cancer given the low survival rate despite improvement in the past decades. Cadherin 17 (CDH17) is a membrane protein highly expressed in cancers of digestive system. Nanobody represents a novel antibody format for cancer targeted imaging and drug delivery. Nanobody targeting CHD17 as an imaging probe and a delivery vehicle of toxin remains to be explored for its theragnostic potential in gastric cancer.
Naïve nanobody phage library was screened against CDH17 Domain 1-3 and identified nanobodies were extensively characterized with various assays. Nanobodies labeled with imaging probe were tested in vitro and in vivo for gastric cancer detection. A CDH17 Nanobody fused with toxin PE38 was evaluated for gastric cancer inhibition in vitro and in vivo.
Two nanobodies (A1 and E8) against human CDH17 with high affinity and high specificity were successfully obtained. These nanobodies could specifically bind to CDH17 protein and CDH17-positive gastric cancer cells. E8 nanobody as a lead was extensively determined for tumor imaging and drug delivery. It could efficiently co-localize with CDH17-positive gastric cancer cells in zebrafish embryos and rapidly visualize the tumor mass in mice within 3 h when conjugated with imaging dyes. E8 nanobody fused with toxin PE38 showed excellent anti-tumor effect and remarkably improved the mice survival in cell-derived (CDX) and patient-derived xenograft (PDX) models. The immunotoxin also enhanced the anti-tumor effect of clinical drug 5-Fluorouracil.
The study presents a novel imaging and drug delivery strategy by targeting CDH17. CDH17 nanobody-based immunotoxin is potentially a promising therapeutic modality for clinical translation against gastric cancer.
尽管在过去几十年中生存率有所提高，但胃癌的生存率仍然很低，因此开发新的治疗策略非常必要。钙黏蛋白17（CDH17）是一种在消化系统癌症中高度表达的膜蛋白。纳米抗体是一种用于癌症靶向成像和药物递送的新型抗体形式。靶向CHD17的纳米抗体作为成像探针和毒素递送载体在胃癌中的诊疗潜力仍有待探索。
针对CDH17结构域1-3筛选天然纳米抗体噬菌体文库，并通过各种检测方法对鉴定出的纳米抗体进行广泛表征。用成像探针标记的纳米抗体在体外和体内进行胃癌检测试验。评估与毒素PE38融合的CDH17纳米抗体在体外和体内对胃癌的抑制作用。
成功获得了两种针对人CDH17的具有高亲和力和高特异性的纳米抗体（A1和E8）。这些纳米抗体可以特异性结合CDH17蛋白和CDH17阳性胃癌细胞。以E8纳米抗体为先导，广泛用于肿瘤成像和药物递送研究。当与成像染料偶联时，它可以在斑马鱼胚胎中与CDH17阳性胃癌细胞有效共定位，并在3小时内快速显示小鼠体内的肿瘤块。与毒素PE38融合的E8纳米抗体显示出优异的抗肿瘤效果，并显著提高了细胞来源（CDX）和患者来源异种移植（PDX）模型中小鼠的生存率。该免疫毒素还增强了临床药物5-氟尿嘧啶的抗肿瘤效果。
本研究提出了一种靶向CDH17的新型成像和药物递送策略。基于CDH17纳米抗体的免疫毒素可能是一种有前景的临床转化治疗胃癌的方法。
