Development of galectin-3 targeted radioimmunoligands for cancer theranostics.

Abstract

Galectin-3 is associated with aggression, proliferation, and metastasis in various refractory cancers. Although galectin-3 targeted positron emission tomography (PET) tracers have shown considerable promise for cancer diagnosis, the therapeutic potential of galectin-3-directed radiopharmaceutical therapy for refractory or untreatable malignancies remains largely unexplored. This study aimed to develop novel galectin-3-targeted radioimmunoligands and verify their radiotheranostic potential in multiple tumor models. Two novel galectin-3 targeted monoclonal antibodies (QMAb-1 and QMAb-2) were labeled with both ⁸⁹Zr and ¹⁷⁷Lu. PET/CT imaging of [⁸⁹Zr]Zr-DFO-QMAb-1 and [⁸⁹Zr]Zr-DFO-QMAb-2 were evaluated in mouse tumor models with varying galectin-3 expression levels. Besides, the therapeutic efficacy of [¹⁷⁷Lu]Lu-DTPA-QMAb-1 and [¹⁷⁷Lu]Lu-DTPA-QMAb-2 was also investigated. The superior tumor uptake and retention time of [⁸⁹Zr]Zr-DFO-QMAb-1 was observed. Notably, [⁸⁹Zr]Zr-DFO-QMAb-1 demonstrated minimal off-target accumulation and rapid clearance from the bloodstream and major organs. Furthermore, [¹⁷⁷Lu]Lu-DTPA-QMAb-1 showed potent anti-tumor efficacy without inducing hematotoxicity and major organ damage, highlighting its therapeutic potential and safety profile. This study expands the repertoire of the galectin-3 radiopharmaceutical toolbox by harnessing high affinity mAbs as ligands, offering a new modality for the diagnosis and treatment of galectin-3-positive cancers. In addition, the favorable performance of [⁸⁹Zr]Zr-DFO-QMAb-1 and [¹⁷⁷Lu]Lu-DTPA-QMAb-1 theranostic pair in triple-negative breast cancer models further supports their clinical application potential across a range of refractory malignancies.