68Ga/177Lu-Labeled Seribantumab as the Theranostic Drugs in Treating HER3-Positive Hepatocellular Carcinoma

Abstract

Purpose Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its high recurrence rate, poor response to systemic therapies, and unfavorable prognosis. Human epidermal growth factor receptor 3 (HER3) has emerged as a clinically relevant molecular target in HCC. Seribantumab is a fully human IgG2 monoclonal antibody against HER3 and can inhibit downstream pro-survival signaling and exert potential antitumor effects. This study aimed to develop Seribantumab-based HER3-targeted radionuclide drug conjugates (68Ga/177Lu-Seribantumab) for HER3-targeted imaging and radionuclide therapy of HCC. Methods Seribantumab was conjugated with isothiocyanate-benzyl-DOTA and radiolabeled with 68Ga or 177Lu. 177Lu-Seribantumab was evaluated for radiochemical purity, stability, cellular uptake, cytotoxicity, cell-cycle distribution, DNA damage, and apoptosis. PET/CT imaging, biodistribution, therapeutic efficacy, and histology were assessed in HepG2 xenograft mice treated with 68Ga/177Lu-Seribantumab. Results Both 68Ga-Seribantumab and 177Lu-Seribantumab exhibited high radiochemical purity (>95%) and stability. 177Lu-Seribantumab showed HER3-specific cellular uptake and cytotoxic effects in HepG2 cells. 177Lu-Seribantumab induced G1-phase cell-cycle arrest and enhanced DNA damage and apoptosis (29.1 ± 2.1%) in HepG2 cells, consistent with HER3-targeted effects accompanied by radionuclide-associated cytotoxicity. Similar cell-cycle and apoptotic effects were observed in Huh7 cells. Furthermore, PET/CT showed partly HER3-mediated tumor uptake of 68Ga-Seribantumab, although the tumor-to-liver contrast was modest. SPECT/CT imaging further demonstrated sustained tumor accumulation of 177Lu-Seribantumab in HepG2 xenografts, reaching 1.1 ± 0.1%ID/mL at 24 h, thereby supporting its tumor-targeting capability and therapeutic potential. Histopathological and immunohistochemical analyses revealed extensive tumor necrosis, increased Caspase-3 expression, reduced Ki67 positivity, and decreased HER3-positive tumor cell populations after treatment with radionuclide drug conjugates (RDCs), further supporting the antitumor activity of 177Lu-Seribantumab. Conclusion 68Ga/177Lu-conjugated Seribantumab enables HER3-targeted molecular imaging and radionuclide therapy in HER3-positive HCC models. These findings support the potential of Seribantumab-based RDCs as a theranostic strategy for HER3-positive HCC.