A Novel Dual-Payload ADC Platform Integrating Exatecan and Triptolide to Enhance Antitumor Efficacy and Overcome Resistance

Abstract Antibody–drug conjugates (ADC) that utilize DNA topoisomerase I inhibitors, such as deruxtecan and SN-38, have significantly enhanced the efficacy of cancer treatment. However, the development of more effective ADCs to combat drug-resistant tumors remains a critical challenge. ADCs covalently link the topoisomerase I inhibitor exatecan and the RNA polymerase II inhibitor triptolide to the same antibody, thereby establishing a dual-killing mechanism against tumor cells. Through optimization of the linker design, this dual-payload ADC achieved precise drug delivery in vivo. Specifically, triptolide is initially released to downregulate the expression of the stress response protein heat shock protein 70 and the efflux pump P-glycoprotein in tumor cells, thereby significantly enhancing drug sensitivity and effectively overcoming resistance, followed by gradual exatecan release, further inhibiting tumor cell proliferation and survival. Experimental results demonstrated that this dual-payload ADC exhibits significant antitumor activity in both in vitro cell models and in vivo xenograft models, including cell line–derived xenograft and patient-derived xenograft models, successfully addressing the challenge of drug resistance encountered in traditional monotherapy. Additionally, non-Good Laboratory Practice–compliant toxicity studies have confirmed the favorable safety profile of this ADC. In summary, this study provides an innovative strategy for overcoming tumor resistance, demonstrating substantial potential for clinical translation, and offering promising therapeutic outcomes and prognosis for patients with cancer.