Preclinical evaluation shows effective tumor targeting and growth inhibition in HER2-positive models, suggesting clinical potential.
Human epidermal growth factor receptor 2 (HER2) is overexpressed in various malignancies, making it an attractive target for radiotheranostics. Nanobodies offer an ideal platform for radiopharmaceutical development. Here, we reported a novel HER2-specific nanobody (NB46) engineered with a C-terminal glycine-serine-cysteine (GSC) tripeptide for site-specific NOTA conjugation and radiolabeling with ⁶⁸Ga and ¹⁷⁷Lu. [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-NOTA-NB46 exhibited high HER2 affinity and specificity in vitro. In HER2-positive tumor-bearing mice, the radiotheranostic agents showed rapid blood clearance, favorable biodistribution, high tumor accumulation, and low nontarget uptake. [¹⁷⁷Lu]Lu-NOTA-NB46 demonstrated prolonged tumor retention. Single-dose therapy with [¹⁷⁷Lu]Lu-NOTA-NB46 significantly inhibited tumor growth and extended survival in a dose-dependent manner with good tolerability. The kidneys were the primary dose-limiting organ. [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-NOTA-NB46 represents a promising radiotheranostic pair for HER2-positive tumors, supporting its further translation into clinical investigation.
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Zhao et al. (2026) studied this question.
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