Abstract 1785: Development of dual-payload anti-GPC3 antibody-drug conjugate by dual-payload antibody conjugation (AD2C) platform for hepatocellular carcinoma treatment

Abstract Glypican-3 (GPC3) has been reported as a promising target for the treatment of hepatocellular carcinoma (HCC). Although current therapies are available, tumor heterogeneity and the development of drug resistance continue to pose significant challenges to effective treatment. Therefore, combination therapy has emerged as a promising strategy to address these challenges. Acepodia successfully established a Dual-Payload Antibody Conjugation (AD2C) platform utilizing our proprietary bioorthogonal chemistry, which allows conjugating two (or multiple) different payloads to the antibody without requiring antibody engineering. In this study, we developed an anti-GPC3 antibody with dual payloads (anti-GPC3 AD2C) through our AD2C platform to enhance treatment efficacy of HCC. The anti-GPC3 AD2C exhibits comparable GPC3 binding affinity and internalization to the parental anti-GPC3 antibody. No significant degradation or aggregation was observed after long-term storage, demonstrating the stability of anti-GPC3 AD2C. In the pharmacokinetics study, anti-GPC3 AD2C showed a similar terminal half-life (T1/2) to the parental antibody, and its volume of distribution (Vss) was equivalent to the blood volume, indicating primary distribution in the blood. These findings suggest that the dual-payload conjugation has a limited impact on the in vivo stability and safety of the anti-GPC3 AD2C. The in vitro efficacy studies show that anti-GPC3 AD2C exhibits enhanced cytotoxicity compared to the mono-payload ADCs and parental antibody in GPC3-expressing cancer cell lines but not in the GPC3 negative cell lines and primary normal cells. The HCC xenograft study further demonstrated that the anti-GPC3 AD2C completely suppressed tumor growth at doses of up to 10 mg/kg, with no significant body weight change observed. In conclusion, the dual-payload ADC produced by AD2C platform offers a potential strategy to overcome tumor heterogeneity and drug resistance while maintaining an ideal safety profile, supporting its potential clinical application in HCC treatment. Citation Format: Hao-Kang Li, Cheng-Wei Lai, Chien-Yu Lin, Yi-Jang Chen, Pei-Ju Leng, Chao-Min Cheng, Sai-Wen Tang, Shih-Chia Hsiao. Development of dual-payload anti-GPC3 antibody-drug conjugate by dual-payload antibody conjugation (AD2C) platform for hepatocellular carcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1785.