Abstract ND09: BAY 3547926: Novel targeted radionuclide therapy for hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer ranking sixth among all cancers and the third leading cause of cancer death worldwide in 2020. Despite the advent of systemic therapies with tyrosine kinase and later immune checkpoint inhibitors, the prognosis of patients with HCC is still dismal and therefore new more effective therapies are needed. Glypican-3 (GPC3) is an oncofetal protein overexpressed in ∼75% of HCC lesions and with limited membrane expression in healthy adult tissues which makes it an attractive target for targeted radionuclide therapy. Targeted alpha therapy (TAT) induces difficult-to-repair clustered DNA double strand breaks by delivering an alpha-particle payload specifically to the lesion using tumor antigen targeting moieties. Patients suitable for TAT can be selected from the larger population by adopting an approach employing paired molecular imaging. We present herein the development of a GPC3 actinium-225 (225Ac), 225Ac-GPC3 therapeutic agent, and a zirconium-89 (89Zr), 89Zr-GPC3 imaging agent, suitable for targeting GPC3-expressing tumors. 225Ac-GPC3 is a novel GPC3 targeting high affinity antibody, conjugated with a macropa chelator for efficient and stable radiolabeling with 225Ac. In vitro, 225Ac-GPC3 induced DNA double-strand breaks and selectively reduced cell viability in a panel of HCC cancer cell lines in GPC3-expression dependent manner. In vivo, 225Ac-GPC3 highly accumulated in tumors while a low uptake and fast clearance were observed in normal organs using human HCC xenograft models. 225Ac-GPC3 significantly inhibited tumor growth in a dose and GPC3-expression dependent manner. Increased level of γH2AX, indicating DNA double strand breaks, was demonstrated for 225Ac-GPC3 in a subcutaneous xenograft HCC tumor model. In an orthotopic HCC model, 225Ac-GPC3 led to a marked reduction of serum alpha-fetoprotein levels and induced complete tumor regression. Furthermore, it was demonstrated that the α-emissions co-localized with GPC3-positive malignant tissue in liver sections. The imaging surrogate agent 89Zr-GPC3, GPC3 targeted antibody conjugated to an efficient chelator (DFO*) for 89Zr, demonstrated comparable ex vivo biodistribution and clearance to 225Ac-GPC3 in an HCC mouse model. These data and additional non-clinical data enabled the initiation of the phase I clinical study of the 89Zr-GPC3 imaging agent (NCT06345001) in patients with HCC or other selected solid tumors. PET imaging was used to measure the whole-body biodistribution at multiple total mass doses. Adequate biodistribution was observed, and no unexpected uptake was detected. PET imaging data was also used to estimate 225Ac dosimetry to key normal organs. The preclinical and clinical imaging results supported the initiation of the first-in-human trial to evaluate 225Ac-GPC3. BANTAM-01 (NCT06764316) is a multicenter, open label, non-randomized study to evaluate the safety and tolerability, PK, and anti-tumor activity of 225Ac-GPC3 alone and in combination. The study is now active and enrolling GPC3 positive HCC patients. Citation Format: Jenny Karlsson, Franziska Siegel, Ingrid Moen, Arne Scholz, Anne Mobergslien, Frans Suurs, Ana Oteiza, Vasiliki Pelekanou, Charles Glaus, Stefan Zimmermann. BAY 3547926: Novel targeted radionuclide therapy for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND09.