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

## TL;DR

This study introduces SHR-A1921, a new antibody-drug conjugate that targets Trop-2 in prostate cancer and shows strong preclinical antitumor activity.

## Contribution

The paper presents SHR-A1921, a novel Trop-2-targeted ADC with potent preclinical efficacy and safety in prostate cancer models.

## Key findings

- SHR-A1921 specifically targets Trop-2 and induces DNA damage and apoptosis in Trop-2-expressing tumor cells.
- In vivo, SHR-A1921 showed significant antitumor activity in Trop-2-positive xenograft tumors and organoids.
- Safety assessments in rats showed an acceptable safety profile for SHR-A1921.

## Abstract

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.

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.

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.

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.