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Open Access 01-05-2024 | Pancreatic Cancer | Research

DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy

Authors: Zhe Ma, Zhenxing Zhou, Wenwen Duan, Gaofeng Yao, Shimei Sheng, Sidou Zong, Xin Zhang, Changkui Li, Yuanyuan Liu, Fengting Ou, Maha Raja Dahar, Yanshan Huang, Lushan Yu

Published in: Cancer Immunology, Immunotherapy | Issue 5/2024

Abstract

Background

Claudin 18.2 (CLDN18.2) is a highly anticipated target for solid tumor therapy, especially in advanced gastric carcinoma and pancreatic carcinoma. The T cell engager targeting CLDN18.2 represents a compelling strategy for enhancing anti-cancer efficacy.

Methods

Based on the in-house screened anti-CLDN18.2 VHH, we have developed a novel tri-specific T cell engager targeting CLDN18.2 for gastric and pancreatic cancer immunotherapy. This tri-specific antibody was designed with binding to CLDN18.2, human serum albumin (HSA) and CD3 on T cells.

Results

The DR30318 demonstrated binding affinity to CLDN18.2, HSA and CD3, and exhibited T cell-dependent cellular cytotoxicity (TDCC) activity in vitro. Pharmacokinetic analysis revealed a half-life of 22.2–28.6 h in rodents and 41.8 h in cynomolgus monkeys, respectively. The administration of DR30318 resulted in a slight increase in the levels of IL-6 and C-reactive protein (CRP) in cynomolgus monkeys. Furthermore, after incubation with human PBMCs and CLDN18.2 expressing cells, DR30318 induced TDCC activity and the production of interleukin-6 (IL-6) and interferon-gamma (IFN-γ). Notably, DR30318 demonstrated significant tumor suppression effects on gastric cancer xenograft models NUGC4/hCLDN18.2 and pancreatic cancer xenograft model BxPC3/hCLDN18.2 without affecting the body weight of mice.

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Title: DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy
Authors: Zhe Ma
Zhenxing Zhou
Wenwen Duan
Gaofeng Yao
Shimei Sheng
Sidou Zong
Xin Zhang
Changkui Li
Yuanyuan Liu
Fengting Ou
Maha Raja Dahar
Yanshan Huang
Lushan Yu
Publication date: 01-05-2024
Publisher: Springer Berlin Heidelberg
Keywords: Pancreatic Cancer
Pancreatic Cancer
Gastric Cancer
Gastric Cancer
Cytokines
Published in: Cancer Immunology, Immunotherapy / Issue 5/2024
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-024-03673-x

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Abstract

Background

Methods

Results

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