Glypican-3 Specific Antibody Drug Conjugate for Hepatocellular Carcinoma

Authors

• Y Fu
• D Urban
• R Nani
• M Hall
• M Schnermann
• M Ho

Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. Therapeutic outcomes in HCC remain unsatisfactory, novel treatments are urgently needed. GPC3 is a potential target for HCC. The hypothesis of using anti-GPC3 antibody drug conjugate to treat HCC patients has not been tested in clinical trials. Here we report the development of hYP7-DC, a humanized anti-GPC3 antibody conjugated to a highly potent duocarmycin DNA damaging agent through cysteine via protease-cleavable linker. In the preclinical test, hYP7-DC showed potency at picomolar range against a panel of GPC3-positive liver cancer cell lines and was more than 100-fold selective against GPC3-negative cell lines. Mechanistic studies indicate the cytotoxic effect involves GPC3 induced ADC internalization and apoptosis. hYP7-DC showed antitumor effect in vivo in two mouse models. To improve the ADC efficacy, we screened two libraries of drugs (NCATS Pharmaceutical Collection and Mechanism Interrogation PlatE) in clinical trials or approved by FDA against Hep3B liver cancer cell line which overexpresses GPC3. Pyrrolobenzodiazepine dimer (PBD) is identified as the most potent small molecule, which was used to construct a new anti-GPC3 ADC, hYP7-PC. hYP7-PC showed approx. 10 times more potency and selectivity than hYP7-DC against a panel of liver cancer cell lines in vitro. Moreover, hYP7-PC (single dose, 5mg/kg) caused tumor remission in Hep3B HCC xenograft model. Together, these data suggest that hYP7-PC has GPC3-directed antitumor activity and support clinical testing of this novel therapeutic in patients with GPC3-posivitve liver cancer.

Scientific Focus Area: Molecular Biology and Biochemistry

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