Abstract
BackgroundTreatment of hepatocellular carcinoma (HCC) using antibody-based targeted therapies, such as antibody conjugates and chimeric antigen receptor T (CAR-T) cell therapy, shows potent antitumor efficacy. Glypican-3 (GPC3) is an emerging HCC therapeutic target; therefore, antibodies against GPC3 would be useful tools for developing immunotherapies for HCC.MethodsWe isolated a novel human monoclonal antibody, 32A9, by phage display technology. We determined specificity, affinity, epitope and anti-tumor activity of 32A9, and developed 32A9-based immunotherapy technologies for evaluating the potency of HCC treatment in vitro or in vivo.Results32A9 recognized human GPC3 with potent affinity and specificity. The epitope of 32A9 was located in the region of the GPC3 protein core close to the modification sites of the HS chain and outside of the Wnt-binding site of GPC3. The 32A9 antibody significantly inhibited HCC xenograft tumor growth in vivo. We then pursued two 32A9-based immunotherapeutic strategies by constructing an immunotoxin and CAR-T cells. The 32A9 immunotoxin exhibited specific cytotoxicity to GPC3-positive cancer cells, while 32A9 CAR-T cells efficiently eliminated GPC3-positive HCC cells in vitro and caused HCC xenograft tumor regressions in vivo.ConclusionsOur study provides a rationale for 32A9 as a promising GPC3-specific antibody candidate for HCC immunotherapy.
Highlights
Treatment of hepatocellular carcinoma (HCC) using antibody-based targeted therapies, such as antibody conjugates and chimeric antigen receptor T (CAR-T) cell therapy, shows potent antitumor efficacy
GPC3 was highly expressed in HCC patients and HCC cell lines To evaluate the expression of GPC3 in HCC patients, we performed immunohistochemistry staining of HCC tumors and normal liver tissue (Table 1)
We found that GPC3 was expressed in HCC tumors but not in normal liver tissue
Summary
Treatment of hepatocellular carcinoma (HCC) using antibody-based targeted therapies, such as antibody conjugates and chimeric antigen receptor T (CAR-T) cell therapy, shows potent antitumor efficacy. GPC3 is expressed in fetal liver, where it is involved in organ morphogenesis by regulating cell proliferation through modulation of Wnt and Hedgehog signaling, and is turned off upon physiological maturity [8,9,10]. The expression of GPC3 is restored in most HCC patients through unknown mechanisms. GPC3 is expressed in 70–80% of HCC patients but not in normal adult tissues [11]. Many studies have reported that GPC3 promotes the development of HCC as a coreceptor in Wnt and HGF signaling [15,16,17,18]. GPC3 is identified as a potent diagnostic marker and promising therapeutic target for HCC
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