Abstract Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality with limited therapeutic options, highlighting the need for novel targeted therapies. Glypican-3 (GPC3) is highly expressed in HCC and minimally present in normal adult tissues, making it an attractive antigen for antibody-drug conjugate (ADC) development. STX002 is a next-generation ADC composed of a humanized anti-GPC3 antibody site-specifically conjugated to a potent topoisomerase I inhibitor payload via a cleavable linker. Topoisomerase I inhibitor-based ADCs have shown broad clinical benefit across solid tumors, and STX002 aims to leverage this class against a genetically and molecularly defined HCC target. STX002 demonstrated high-affinity, selective binding to GPC3 and robust internalization in GPC3-positive cells, resulting in potent target-dependent cytotoxicity with sub-nanomolar IC50 values and a measurable bystander effect. In vivo, STX002 induced deep and durable tumor regressions across a panel of GPC3-expressing HCC CDX and PDX models, including models refractory to standard-of-care tyrosine kinase inhibitors. Pharmacokinetic and tolerability studies revealed favorable systemic exposure, linker stability, and a wide therapeutic index with minimal off-target toxicity. Collectively, these data support STX002 as a differentiated GPC3-targeted topo-I ADC with strong preclinical efficacy and translational potential. STX002 represents a promising therapeutic candidate for addressing the substantial unmet need in HCC and warrants advancement toward IND-enabling studies and clinical development. Citation Format: Deepak Rohila, Sameena Wani, Atul Tandon, Jianhua Zhao, Anindya Bagchi, Ashutosh Tiwari, . STX002: A GPC3-targeted antibody-drug conjugate with potent and durable antitumor activity in preclinical models of hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5405.
Rohila et al. (2026) studied this question.