ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Preclinical Activity of SHR-A1921, A Novel Antibody-Drug Conjugate Targeting Trophoblast Cell-surface antigen2(Trop-2)in prostate cancer
Provisionally accepted
- 1Nanjing University Medical School, Nanjing, China
- 2Nanjing Drum Tower Hospital, Nanjing, China
- 3Nanjing University of Chinese Medicine, Nanjing, China
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Background Despite advances in the 5-year survival rates for prostate cancer patients, progression to metastatic castration-resistant prostate cancer (mCRPC) remains a significant challenge following standard treatments. Antibody-drug conjugates (ADCs) are an emerging class of biopharmaceuticals that combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs. Trophoblast cell surface antigen 2 (Trop-2) is overexpressed in prostate cancer, particularly in metastatic forms. Methods Response to this, we developed a novel Trop-2-targeted antibody-drug conjugate (ADC), SHR-A1921, which incorporates a potent DNA topoisomerase I inhibitor,SHR9265. Its in vitro cytotoxicity was assessed across prostate cancer cell lines with differential Trop-2 expression. Subcutaneous xenograft models were established for in vivo tumor-suppressive activity evaluation, and patient-derived organoid models validated its potential clinical efficacy. Results In preclinical models, SHR-A1921 specifically bound to Trop-2, followed by internalization into tumor cells and subsequent intracellular trafficking to lysosomes, where the release of SHR9265 occurred. This resulted in DNA damage and apoptosis in Trop-2-expressing tumor cells in vitro. In vivo, SHR-A1921 exhibited significant antitumor activity, inducing DNA damage in Trop-2-positive xenograft tumors. Additionally, SHR-A1921 demonstrated antitumor effects in Trop-2-expressing prostate cancer organoids. Safety assessments in rats indicated that SHR-A1921 had an acceptable safety profile. Conclusions SHR-A1921 is a promising Trop-2-targeted ADC that leverages innovative technology to deliver potent antitumor activity against Trop-2-expressing prostate cancer cells, with an acceptable safety profile observed in preclinical studies. These results highlight the promising clinical potential of SHR-A1921 as a therapeutic option for prostate cancer patients with Trop-2-positive tumors.
Keywords: Antibody-drug conjugates, patient-derived organoids, prostate cancer, SHR-A1921, targeted therapy, Trop-2
Received: 26 Sep 2025; Accepted: 29 Jan 2026.
Copyright: © 2026 Wang, Xu, Peng, Han, Huang, Guo and Qiu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xuefeng Qiu
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