Development and Preclinical Evaluation of a Novel 68Ga/177Lu-Labeled Nanobody for Radiotheranostics of HER2-Positive...

Area of Science:

• Biomedical Imaging and Therapeutics
• Molecular Oncology
• Radiopharmaceutical Chemistry

Background:

• Human epidermal growth factor receptor 2 (HER2) is a key target in various cancers.
• Nanobodies are promising scaffolds for developing targeted radiopharmaceuticals.
• Radiotheranostics combine diagnostic imaging and targeted therapy.

Purpose of the Study:

• To develop and evaluate a novel HER2-specific nanobody (NB46) for HER2-targeted radiotheranostics.
• To assess the potential of NB46 labeled with Gallium-68 (⁶⁸Ga) for imaging and Lutetium-177 (¹⁷⁷Lu) for therapy.

Main Methods:

• Engineered NB46 with a GSC tag for site-specific NOTA conjugation.
• Radiolabeled NB46 with ⁶⁸Ga and ¹⁷⁷Lu.
• Evaluated in vitro HER2 binding affinity and specificity.
• Assessed biodistribution, tumor uptake, and pharmacokinetics in HER2-positive tumor-bearing mice.
• Determined therapeutic efficacy and tolerability of ¹⁷⁷Lu-NOTA-NB46 in vivo.

Main Results:

• ⁶⁸Ga/¹⁷⁷Lu-NOTA-NB46 showed high affinity and specificity for HER2.
• In vivo studies revealed rapid blood clearance, favorable biodistribution, high tumor accumulation, and low off-target uptake.
• ¹⁷⁷Lu-NOTA-NB46 exhibited prolonged tumor retention and significant dose-dependent tumor growth inhibition.
• Therapy with ¹⁷⁷Lu-NOTA-NB46 extended survival with good tolerability, identifying kidneys as the primary dose-limiting organ.

Conclusions:

• ⁶⁸Ga/¹⁷⁷Lu-NOTA-NB46 is a promising radiotheranostic pair for HER2-positive malignancies.
• The developed nanobody demonstrates potential for clinical translation in HER2-targeted cancer therapy and imaging.