Triptolide-based cleavable antibody-drug conjugates for pancreatic cancer

Abstract

Antibody-drug conjugates (ADCs) have emerged as a highly promising modality for the treatment of various tumors, including pancreatic cancer. Due to the modular nature of ADCs, their efficacy is heavily influenced by the choice of antibody, payload, and linker. Given the therapeutic potential of triptolide for pancreatic cancer, this study aims to harness triptolide as the cytotoxic payload to construct ADCs targeting pancreatic cancer. Silyl ethers were utilized for the first time as cleavable linkers to connect triptolide with an antibody. This is because silyl ethers can be easily synthesized and the rate of drug release can be regulated by modifying the silyl ether groups. The release profile of the resulting linkers was investigated. And considering the balance between cleavage and stability, one silyl ether-based linker was selected to prepare an ADC, named A10. Meanwhile, a traditional dipeptide linker-based ADC, A9, was synthesized for comparison. The ADC A10 demonstrated superior inhibitory effects compared to ADC A9, both in vitro and in vivo. A10 displayed targeted cytotoxicity against cells with high PD-L1 expression and demonstrated a bystander killing effect on cells with low PD-L1 expression. In vivo imaging studies indicated that fluorescently labeled A10 accumulated in tumor regions. Additionally, significant antitumor activities of A10 were observed against Panc 08.13-derived tumor xenografts.