Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers

Frontiers in Immunology

Weilin Wang¹  Zhe Ma²  Zhenxing Zhou²  Yanshan Huang²  Yongliang Fang²  Gaofeng Yao²  Jiali Dong²  Weiqin Jiang³  Weixiang Zhong⁴  Yongfeng Ding⁵  Yimin Lu⁵  Yinjun He⁶ 

[1] Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China;Department of Innovative Drug Discovery and Development, Zhejiang Doer Biologics Co., Ltd., Hangzhou, China;Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China;Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China;Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China;School of Medicine, Zhejiang University, Hangzhou, China;

关键词: Claudin 18.2;    VHH;    gastric cancer;    pancreatic cancer;    ADCC;    CDC;   

DOI  :  10.3389/fimmu.2022.885424

来源: DOAJ

【 摘 要 】

Claudin 18.2 (CLDN18.2), a tight junction (TJ) family protein controlling molecule exchange between cells, is frequently over-expressed in gastric cancer, pancreatic adenocarcinomas and in a fraction of non–small cell lung cancer cases. The tumor properties indicate that CLDN18.2 could be an attractive drug target for gastric and pancreatic cancers. In this study, we present effective strategies for developing anti-CLDN18.2 therapeutic candidates, based on variable domain of heavy chain of heavy chain antibodies (VHHs). CLDN18.2-specific VHHs were isolated by panning a phage display library from an alpaca immunized with a stable cell line highly expressing CLDN18.2. Humanized VHHs fused with human IgG1 Fc, as potential therapeutic candidates, exhibited desirable binding specificity and affinity to CLDN18.2. In vitro experiments showed that hu7v3-Fc was capable of eliciting both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) on CLDN18.2 positive tumor cells. In the mouse xenograft model, the anti-tumor efficacy of hu7v3-Fc was significantly more potent than Zolbetuximab, the benchmark anti-CLDN18.2 monoclonal antibody. Moreover, in vivo biodistribution using zirconium-89 (89Zr) labeled antibodies demonstrated that hu7v3-Fc (89Zr-hu7v3-Fc) exhibited a better tumor penetration and a faster tumor uptake than Zolbetuximab (89Zr-Zolbetuximab), which might be attributed to its smaller size and higher affinity. Taken together, anti-CDLN18.2 hu7v3-Fc is a promising therapeutic agent for human CLDN18.2 positive cancers. Furthermore, hu7v3 has emerged as a potential module for novel CLDN18.2 related therapeutics.

【 授权许可】

Unknown