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

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.