Preclinical activity of SHR-A1921, a novel antibody-drug conjugate targeting trophoblast cell-surface antigen2 (Trop-2) in prostate cancer

  • Front Pharmacol. 2026 Mar 3:17:1713983. doi: 10.3389/fphar.2026.1713983.
Binyu Wang  #  1  2 ,  Qiuya Xu  #  2  3 ,  Shan Peng  #  4 ,  Zheng Han  1  2 ,  Haifeng Huang  1  2 ,  Hongqian Guo  1  2  3 ,  Xuefeng Qiu  1  2  3
Affiliations
  • 1. Department of Urology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
  • 2. Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
  • 3. Department of Urology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 4. Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
  • # Contributed equally.
PMID: 41929251 DOI: 10.3389/fphar.2026.1713983
Abstract

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.

Conclusion: 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
SHR-A1921; Trop-2; antibody-drug conjugates; patient-derived organoids; prostate cancer; targeted therapy.
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