Preclinical safety profile of RC88-ADC：a novel mesothelin-targeted antibody conjugated with Monomethyl auristatin E. (2nd January 2023)

• Record Type: Journal Article
• Authors: Jiang, Jing; Li, Shenjun; Tang, Naping; Wang, Ling; Xin, Wei; Li, Shoufeng
• Is Part Of: Drug and chemical toxicology. Volume 46:Number 1(2023)
• Page Start: 24
• Page End: 34
• Publication Date: 2023-01-02
• Subjects: Mesothelin -- toxicology -- antibody drug conjugate -- RC88-ADC -- immunogenicity; Toxicology -- Periodicals; Drugs -- Toxicology -- Periodicals; Toxicology, Experimental -- Periodicals; 615.9005
• DOI: 10.1080/01480545.2021.2005085
• Languages: English
• ISSNs: 0148-0545

Abstract

Abstract: Mesothelin (MSLN) is an attractive therapeutic target for antibody drug conjugates (ADC) because of significant differences in expression pattern between diseased and normal tissues. RC88-ADC is a novel ADC, targeting MSLN, and inhibits tumor growth significantly in mice xenograft models. We performed an 11-week repeated dose toxicity study of RC88-ADC via intravenous injection in Cynomolgus Monkeys with an 8-Week recovery period according to International Conference on Harmonization (ICH) S9 and S6(R1). RC88-ADC was administered to groups of 5 male and 5 female monkeys at dose levels of 2.5, 5, and 10 mg/kg/2 weeks, meanwhile vehicle, naked antibody, small molecule groups were set up as the control. 4 animals died in 10 mg/kg group of RC88-ADC. The clinical symptoms mainly included ocular toxicity, weight loss and food intake decrease in the middle and high dose groups of RC88-ADC. RC88-ADC caused dose-related reversible myelosuppression, manifested as hematologic toxicity, which was consistent with the small molecule toxicity profile of its coupling. The highest non-severely toxic dose of RC88-ADC was 5 mg/kg in monkeys after repeated dosing. Nonetheless, the integrated analysis showed that RC88-ADC demonstrated an acceptable safety profile and provided an improved treatment window. These results pave the way for further investigation of RC88-ADC in humans.