CD44 variant 5 (CD44v5) is a good target in intrahepatic cholangiocarcinoma (CCA), according to a new study published in the journal Cancer Research. This finding supports the investigation of antibody–drug conjugate-based therapies targeting it for the treatment of the disease.
Novel treatments are urgently needed for intrahepatic CCA, 1 of the deadliest types of cancer, the researchers noted.
Read more about the subtypes of CCA
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Previous research has shown that CD44 variant isoforms are selectively expressed in intrahepatic CCA cells, they added. In the present study, a team of researchers from China reported that CD44v5 was specifically expressed in intrahepatic CCA tumor cells.
The team then developed an antibody–drug conjugate targeting CD44v5 that they called H1D8-DC. This antibody-drug conjugate consisted of a humanized anti-CD44v5 monoclonal antibody a microtubule inhibitor monomethyl auristatin E.
The researchers showed that H1D8-DC bound to CD44v5 efficiently and was internalized by cells expressing CD44v5 on their surface.
They also reported that because of the high expression of cathepsin B in intrahepatic CCA cells, the drug was preferentially released in cancer cells. This way, it exhibited potent cytotoxicity even at very low concentrations.
The researchers also conducted in vivo experiments and demonstrated that H1D8-DC was effective against intrahepatic CCA cells expressing CD44v5 inducing tumor regression in patient-derived xenograft models without leading to any significant adverse toxicity.
“Overall, in this study we provide insights regarding CD44v5 as a potential therapeutic target of [intrahepatic CCA] and a rationale for further clinical investigation of CD44v5-targeted H1D8-DC-based approaches for [intrahepatic CCA] treatment,” the researchers concluded.
CCA is a group of rare malignant tumors that originate from cells of the biliary tree. Based on their anatomical origin, there are 3 different subtypes of CCA: perihilar CCA, intrahepatic CCA, and distal CCA. Intrahepatic CCA is the second most frequent type of primary liver cancer.
CD44 is a transmembrane glycoprotein receptor and the most common surface marker in both normal and cancer stem cells. Different CD44 variants that are the product of alternative splicing are predominantly expressed in epithelial-type carcinomas including intrahepatic CCA.
Reference
Bei Y, He J, Dong X, et al. Targeting CD44 variant 5 with an antibody-drug conjugate is an effective therapeutic strategy for intrahepatic cholangiocarcinoma. Cancer Res. Published online May 19, 2023. doi:10.1158/0008-5472.CAN-23-0510
