DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy
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Published on: February 8, 2018
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.
