Development and characterization of CR101-ADC, a fully-human anti-claudin18.2 monoclonal antibody-drug conjugate
Miao Zhang1, Haibin Yuan2, Xian Li3
1School of Synthetic Biology and Biomanufacturing, State Key Laboratory of Synthetic Biology, Tianjin Key Laboratory of Biological and Pharmaceutical Engineering, Tianjin University, Tianjin, 300350, China; China Resources Biopharmaceutical Company Limited, Shenzhen, 518000, China.
Abstract:
Claudin18.2 (CLDN18.2) is a stomach-specific tight junction protein aberrantly exposed in multiple cancers, particularly gastric and pancreatic malignancies, making it an attractive therapeutic target. Here, we developed CR101-ADC, a novel antibody-drug conjugate (ADC) constructed from a fully human anti-CLDN18.2 monoclonal antibody conjugated to the microtubule inhibitor MMAE via a cleavable linker. The CR101 antibody exhibits high affinity and specificity for claudin18.2, demonstrating superior tumor cell-killing efficiency compared to IMAB362. Additionally, CR101 shows cross-species reactivity in humans, mice, and monkeys, simplifying preclinical pharmacology and efficacy studies. In vitro pharmacodynamic studies confirmed that CR101-ADC effectively induces targeted cytotoxicity, while multiple tumor models demonstrated its potent anti-tumor activity and favorable safety profile with minimal toxicity. Transcriptomic analysis revealed that CR101-ADC primarily affects cytoskeletal, inflammatory, and stress pathways and represents a promising candidate for the treatment of gastrointestinal malignancies. Collectively, these findings demonstrate that CR101-ADC combines high specificity, potent intracellular drug delivery, and favorable safety, representing a promising next-generation therapeutic candidate for CLDN18.2-positive gastrointestinal cancers.
Insights
A new antibody-drug conjugate, CR101-ADC, targets Claudin18.2 (CLDN18.2) in gastrointestinal cancers. It shows potent anti-tumor activity and a favorable safety profile, offering a promising therapeutic option.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Claudin18.2 (CLDN18.2) is a stomach-specific protein found in gastric and pancreatic cancers.
- CLDN18.2 presents an attractive target for cancer therapeutics due to its aberrant expression in malignancies.
Purpose of the Study:
- To develop and evaluate CR101-ADC, a novel antibody-drug conjugate targeting CLDN18.2.
- To assess the efficacy, specificity, and safety of CR101-ADC in preclinical models of gastrointestinal cancers.
Main Methods:
- CR101-ADC was constructed using a fully human anti-CLDN18.2 antibody linked to MMAE.
- In vitro and in vivo studies evaluated CR101's affinity, specificity, cytotoxicity, anti-tumor activity, and safety.
- Transcriptomic analysis was performed to understand the drug's mechanism of action.
Main Results:
- CR101 antibody demonstrated high affinity and specificity for CLDN18.2, outperforming IMAB362 in tumor cell killing.
- CR101-ADC exhibited potent anti-tumor activity and a favorable safety profile with minimal toxicity in preclinical models.
- Cross-species reactivity was observed in humans, mice, and monkeys, facilitating preclinical studies.
Conclusions:
- CR101-ADC is a promising next-generation therapeutic candidate for CLDN18.2-positive gastrointestinal cancers.
- The conjugate combines high specificity, effective drug delivery, and a favorable safety profile.
- CR101-ADC's mechanism involves affecting cytoskeletal, inflammatory, and stress pathways.
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