Preclinical evaluation and mechanistic analysis of antitumor effects of the novel anti-CD147 antibody DS-1471a in liver cancer models

DS-1471a is a humanized antibody that targets CD147, a transmembrane glycoprotein frequently overexpressed in cancer cells, and has undergone a phase 1 clinical study for advanced solid tumors. To further investigate DS-1471a's therapeutic potential and the underlying molecular mechanisms involved, we examined its efficacy in patient-derived xenograft (PDX) models of liver cancer. DS-1471a exhibited potent antitumor effects in multiple PDX models, with positive correlations observed between DS-1471a efficacy and expression of CD147 and related proteins such as SMAD4, ARF6, and FBXO22. Among these proteins, overexpression of FBXO22, a ubiquitin ligase, enhanced DS-1471a efficacy in liver cancer xenograft models. Mechanistic analysis showed that FBXO22 overexpression was associated with reduced expression of p21/CDKN1A, a cyclin-dependent kinase inhibitor previously characterized as a degradation target of FBXO22, suggesting a potential regulatory relationship between these proteins. Moreover, in tumor models lacking p21, DS-1471a efficacy was also enhanced, whereas DS-1471a-resistant tumors expressed higher levels of p21 protein. Although direct causal relationships remain to be fully established, these results suggest possible mechanisms underlying DS-1471a efficacy involving not only CD147 expression but also FBXO22 and p21. Taken together, these preclinical findings indicate a potential clinical benefit of DS-1471a and provide useful mechanistic insights for liver cancer treatment.