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DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy
Zhe Ma1,2, Zhenxing Zhou2, Wenwen Duan2
1Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China.
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.
Insights
A novel tri-specific T cell engager, DR30318, targets Claudin 18.2 (CLDN18.2) for gastric and pancreatic cancers. This therapy shows significant tumor suppression and T cell-mediated cytotoxicity in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Claudin 18.2 (CLDN18.2) is a promising target for solid tumors, particularly gastric and pancreatic carcinomas.
- T cell engagers targeting CLDN18.2 offer a potent strategy to boost anti-cancer immune responses.
Purpose of the Study:
- To develop and evaluate a novel tri-specific T cell engager targeting CLDN18.2 for gastric and pancreatic cancer.
- To assess the efficacy and pharmacokinetic properties of the CLDN18.2-targeting T cell engager.
Main Methods:
- Development of a tri-specific antibody (DR30318) binding CLDN18.2, human serum albumin (HSA), and CD3.
- In vitro assessment of binding affinity, T cell-dependent cellular cytotoxicity (TDCC), and cytokine production (IL-6, IFN-γ).
- In vivo evaluation in gastric and pancreatic cancer xenograft models, including pharmacokinetic analysis and body weight monitoring.
Main Results:
- DR30318 exhibited binding to CLDN18.2, HSA, and CD3, and demonstrated in vitro TDCC activity.
- Pharmacokinetic studies showed a half-life of 22.2-28.6 hours in rodents and 41.8 hours in cynomolgus monkeys.
- Significant tumor suppression was observed in gastric and pancreatic cancer xenograft models without adverse effects on body weight, accompanied by induced cytokine production.
Conclusions:
- The tri-specific T cell engager DR30318 shows potent anti-tumor activity against CLDN18.2-expressing gastric and pancreatic cancers.
- DR30318 effectively redirects T cells to eliminate cancer cells, supporting its potential as a novel immunotherapy.
- Preclinical data suggest DR30318 is a promising candidate for further clinical development in solid tumor treatment.
