A monoclonal antibody targeting B7-H3 in human embryonic stem cells exhibits anti-tumor activity in hepatocellular carcinoma xenografts

Abstract

B7-H3 is highly expressed with limited heterogeneity in various cancer types including hepatocellular carcinoma (HCC) but shows low expression in normal tissues. We generated monoclonal antibodies (MAbs) against surface molecules on human embryonic stem cells (hESCs) and found that NPB40, one of the MAbs, binds to HCC cells, but only weakly to primary hepatocytes. Immunoprecipitation with mass spectrometry identified that NPB40 recognizes B7-H3. In tumorsphere cultures, the expression of B7-H3 interacting with NPB40 was significantly increased, as were known cancer stem cell (CSC) markers. After cell sorting by NPB40, NPB40-high HCC cells showed higher clonogenic survival than NPB40-low HCC cells, suggesting B7-H3 as a potential CSC marker on HCC cells. NPB40 and Chi-NPB40, a chimeric form of NPB40, induced internalization of B7-H3 and inhibited cell proliferation of HCC cells by toxic payload delivery via anti-human secondary antibody drug conjugates (ADCs) and Chi-NPB40 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro . NPB40 and Chi-NPB40 injection also suppressed tumor growth in a xenograft nude mouse model of HCC. The results suggest that NPB40 may be developed as a therapeutic antibody for HCC patients.