Novel GPC3-targeting antibody-drug conjugate using novel payload or dual payloads to treat hepatocellular carcinoma and non-small-cell lung cancer

Glypican-3 (GPC3) is a highly promising therapeutic target due to its selective, abundant overexpression in hepatocellular carcinoma (HCC) and certain subsets of non-small cell lung cancer (NSCLC), while being largely absent in normal adult tissues. A Phase 1 trial with a GPC3-targeted CAR-T therapy showed an objective response rate of 57 percent in heavily pre-treated patients with advanced HCC, highlighting the potential of GPC3 as a viable tumor-specific antigen for targeted therapy. ADC modality offers distinct advantages over CAR-T therapies, including off-the-shelf availability, lack of risk of cytokine release syndrome, and significant accessibility and cost advantages. However, HCC is known to be resistant to traditional chemotherapy thus traditional ADC payloads likely won't work. We have developed a series of next-generation anti-GPC3 antibody-drug conjugates that combine our proprietary GPC3-targeting antibody and distinct payload classes including topoisomerase inhibitor and a novel protein degrader. Compared to benchmark GPC3-targeting antibodies, our antibody binds a unique epitope on GPC3, resulting in enhanced internalization and significantly improved ADC-mediated cytotoxicity in GPC3-positive cells. Our novel protein degrader payload showed broad anti-proliferative activity in vitro, including potent cytotoxicity in DXd-resistant cell lines and HCC cell lines. In vivo, our GPC3 single-payload or dual-payload ADC molecules showed robust anti-tumor efficacy in multiple HCC and NSCLC CDX and PDX models. We believe that our anti-GPC3 ADC can be an effective off-the-shelf biologic therapy for HCC and NSCLC patients.