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State of survival code 20209/20/2023 ![]() ![]() ![]() Even patients who undergo curative resection have poor outcomes due to the high rate of tumor recurrence ( 2). Most patients with ICC often present at late stages with either locally advanced and unresectable or metastatic disease at diagnosis. ![]() Because of the steadily increasing prevalence, ICC is the second most frequent type of primary liver cancer, accounting for 15% of cases ( 1). Intrahepatic cholangiocarcinoma (ICC) is a group of malignancies of the biliary epithelium (cholangiocytes) that arise in the intrahepatic biliary tree. These data demonstrate that CD44v5 is a bona fide target in ICC and provide a rationale for the clinical investigation of a CD44v5-targeted ADC-based approach. In vivo studies showed that H1D8–DC was effective against CD44v5-positive ICC cells and induced tumor regression in patient-derived xenograft models, whereas no significant adverse toxicities were observed. Because of the high expression of cathepsin B in ICC cells, the drug was preferentially released in cancer cells but not in normal cells, thus inducing potent cytotoxicity at picomolar concentrations. H1D8–DC exhibited efficient antigen binding and internalization in cells expressing CD44v5 on the cell surface. A CD44v5-targeted ADC, H1D8–DC (H1D8–drug conjugate), was developed that comprises a humanized anti-CD44v5 mAb conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE) via a cleavable valine–citrulline-based linker. CD44v5 protein was expressed on the surface of most ICC tumors (103 of 155). In this study, we observed the specific expression of CD44 variant 5 (CD44v5) in ICC tumors. Studies have shown that CD44 variant isoforms, rather than the CD44 standard isoform, are selectively expressed in ICC cells, providing an opportunity for the development of an antibody–drug conjugate (ADC)–based targeted therapeutic strategy. ICC is among the deadliest malignancies, highlighting that novel treatments are urgently needed. Intrahepatic cholangiocarcinoma (ICC) is the second most frequent type of primary liver cancer. ![]()
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