Preclinical targeted alpha therapy of B7-H3-positive tumors using [ ²²⁵ Ac]Ac-Macropa-PEG ₂ -enoblituzumab via EDC/NHS-mediated conjugation

MATERIALS AND Functional studies involved saturated binding & internalization analyses using CD276-positive DU145-B7-H3 cells and CD276-negative CHO-K1 controls. Biodistribution, dosimetry, and therapeutic effectiveness were assessed using DU145-B7-H3 xenograft-bearing mice model with excess Enoblituzumab blocking and non-target CHO-K1 controls. RESULTS: = 0.18 ± 0.05 nM) and time-dependent internalization were observed in DU145-B7-H3 cells, with minimal uptake in CHO-K1 controls. In vivo studies showed gradual tumor accumulation (15.7 ± 1.1%ID/g at 72 h) with sustained retention and favorable tumor-to-background ratios. CHO-K1 xenografts showed minimal uptake, and blocking significantly reduced tumor accumulation, confirming receptor-mediated targeting. Therapy studies demonstrated significant tumor growth inhibition and prolonged survival with good tolerability. CONCLUSIONS: -Enoblituzumab shows strong stability, specificity, and therapeutic efficacy, supporting further development as a promising translational candidate for targeted alpha therapy of B7-H3-expressing malignancies.