癌症中CAPRIN-1膜定位的机制及人源化抗CAPRIN-1抗体TRK-950的开发

CAPRIN-1, initially reported as a cytoplasmic protein, has emerged as a novel cancer-specific therapeutic target. CAPRIN-1 is highly expressed on the cell membrane surface of a broad range of solid tumors, but not on normal cells (Okano, F et al., Cancer Res Commun 2023). However, the molecular mechanism underlying this cancer-specific membrane localization of CAPRIN-1 remains unclear. In this study, we aimed to elucidate the mechanism responsible for CAPRIN-1 membrane expression in cancer. We identified “Protein X” as a CAPRIN-1-binding partner under certain stress conditions. Our data indicate that “Protein X” is required for stress-induced membrane localization of CAPRIN-1 in cancer cells. Based on the promising expression profile of CAPRIN-1, we developed a humanized anti-CAPRIN-1 antibody, TRK-950, currently under clinical development. TRK-950 demonstrated safety and tolerability in a Phase-1 study (NCT02990481), and Phase-2 trials are ongoing in patients with gastric cancer (NCT06038578) and melanoma (NCT05423262). In parallel with clinical studies, we conducted non-clinical investigations to clarify TRK-950's anti-tumor mechanism. Our findings show that macrophage-mediated ADCP via Fcg receptors is critical for the TRK-950 efficacy as demonstrated using FcgR knockout and macrophage-depleted mouse models. Furthermore, TRK-950 combined with several approved anticancer drugs exhibited enhanced anti-tumor activity both in vitro and in vivo . In addition to the naked antibody, we are developing CAPRIN-1-targeted modalities such as ADCs and will present these encouraging results at this meeting. Collectively, these data support CAPRIN-1 as a promising target for antibody-based therapies.