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CDH17 nanobodies facilitate rapid imaging of gastric cancer and efficient delivery of immunotoxin
Jingbo Ma,Xiaolong Xu,Chunjin Fu,Peng Xia,Ming Tian,Liuhai Zheng,Kun Chen,Xiaolian Liu,Yilei Li,Le Yu,Qinchang Zhu,Yangyang Yu,Rongrong Fan,Haibo Jiang,Zhifen Li,Chuanbin Yang,Chengchao Xu,Ying Long,J 한국생체재료학회 2022 생체재료학회지 Vol.26 No.4
Background: 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. Methods: 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. Results: 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. Conclusions: The study presents a novel imaging and drug delivery strategy by targeting CDH17. CDH17 nanobodybased immunotoxin is potentially a promising therapeutic modality for clinical translation against gastric cancer.
Beyond Canonical PROTAC: Biological targeted protein degradation (bioTPD)
Huifang Wang,Runhua Zhou,Fushan Xu,Kongjun Yang,Liuhai Zheng,Pan Zhao,Guangwei Shi,Lingyun Dai,Chengchao Xu,Le Yu,Zhijie Li,Jianhong Wang,Jigang Wang 한국생체재료학회 2023 생체재료학회지 Vol.27 No.00
Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential to modulate disease associated proteins that have previously been considered undruggable, by employing the host destructionmachinery. The exploration and discovery of cellular degradation pathways, including but not limited toproteasomes and lysosome pathways as well as their degraders, is an area of active research. Since the conceptof proteolysis-targeting chimeras (PROTACs) was introduced in 2001, the paradigm of TPD has been greatlyexpanded and moved from academia to industry for clinical translation, with small-molecule TPD being particularlyrepresented. As an indispensable part of TPD, biological TPD (bioTPD) technologies including peptide-, fusionprotein-, antibody-, nucleic acid-based bioTPD and others have also emerged and undergone significantadvancement in recent years, demonstrating unique and promising activities beyond those of conventional small molecule TPD. In this review, we provide an overview of recent advances in bioTPD technologies, summarize theircompositional features and potential applications, and briefly discuss their drawbacks. Moreover, we present somestrategies to improve the delivery efficacy of bioTPD, addressing their challenges in further clinical development.