Among renal cell carcinoma subtypes, only papillary renal cell carcinoma demonstrated relevant TROP-2 positivity as a rationale for antibody-drug conjugates targeting TROP-2

Objective To evaluate the expression of trophoblast cell surface antigen-2 (TROP-2), a broadly expressed antibody-drug conjugate (ADC) target, in non-clear cell renal cell carcinoma (non-ccRCC) and to conduct a proof-of-concept analysis assessing the effect of TROP-2-directed ADC Sacituzumab govitecan (SG) in RCC cell lines. Methods A cohort comprising a ccRCC (n=44), pRCC (n=22), chRCC (n=22), and benign tumors subcohort (n=8) including oncocytoma and angiomyolipoma, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score. The cytotoxic efficacy of the TROP-2-targeted ADC Sacituzumab govitecan (SG) in vitro was analysed using Western Blot, FACS, and MTT assay. Results We observed increased TROP-2 mRNA expression levels in pRCC compared to ccRCC, chRCC and benign tumors (p<0.001). Immunohistochemical analysis revealed moderate to strong membranous TROP-2 expression in most of pRCC patients [n=20/22 with H-score ≥ 100, median H-score 265 (IQR 202.5-290)], while TROP-2 was absent or weak in patients with ccRCC and chRCC (p<0.0001). Additionally, we detected soluble TROP-2 in the serum of RCC patients, establishing a strong positive correlation with membranous TROP-2 expression (ρ=0.78, p=0.0001, R ² =0.52), indicating its potential as a non-invasive biomarker for RCC. In vitro findings indicated that the efficacy of SG depended on the extent of TROP-2 expression. Notably, SG inhibited the growth of TROP-2 expressing Caki-1 cells, whereas TROP-2 negative 769-P cells were resistant to SG (p<0.01). Conclusion In conclusion, the substantial expression of TROP-2 in pRCC, combined with our preclinical in vitro results, provides preclinical evidence supporting the potential effectiveness of TROP-2-directed ADCs such as SG in patients with TROP-2 positive metastatic pRCC.