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- W4384342289 abstract "<div>Abstract<p>Intrahepatic cholangiocarcinoma (ICC) is the second most frequent type of primary liver cancer. ICC is among the deadliest malignancies, highlighting that novel treatments are urgently needed. 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. In this study, we observed the specific expression of CD44 variant 5 (CD44v5) in ICC tumors. CD44v5 protein was expressed on the surface of most ICC tumors (103 of 155). 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. H1D8–DC exhibited efficient antigen binding and internalization in cells expressing CD44v5 on the cell surface. 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. <i>In vivo</i> 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. These data demonstrate that CD44v5 is a <i>bona fide</i> target in ICC and provide a rationale for the clinical investigation of a CD44v5-targeted ADC-based approach.</p>Significance:<p>Elevated expression of CD44 variant 5 in intrahepatic cholangiocarcinoma confers a targetable vulnerability using the newly developed antibody–drug conjugate H1D8–DC, which induces potent growth suppressive effects without significant toxicity.</p></div>" @default.
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- W4384342289 date "2023-07-14" @default.
- W4384342289 modified "2023-09-25" @default.
- W4384342289 title "Data from Targeting CD44 Variant 5 with an Antibody–Drug Conjugate Is an Effective Therapeutic Strategy for Intrahepatic Cholangiocarcinoma" @default.
- W4384342289 doi "https://doi.org/10.1158/0008-5472.c.6742362.v1" @default.
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