Integrated radio-theranostics using a [ ⁸⁹ Zr]Zr-/[ ¹⁷⁷ Lu]Lu-labeled B7-H3 antibody-drug conjugate for prostate cancer

Rationale: Prostate cancer remains a leading cause of cancer-related mortality in men.Although PSMA-directed theranostics have achieved clinical success, heterogeneous expression and therapy-induced downregulation limit their broad applicability.B7-H3 (CD276), which is highly and stably expressed in prostate cancer, represents a promising alternative theranostic target.Methods: A B7-H3 targeted antibody-drug conjugate (ADC) was radiolabeled with [ 89 Zr]Zr-for immunoPET imaging and [ 177 Lu]Lu for radionuclide therapy.In vitro binding specificity, in vivo tumor targeting, biodistribution, therapeutic efficacy, dosimetry, and safety were systematically assessed in prostate cancer xenograft models, with comparisons to radiolabeled antibody, ADC monotherapy, sequential therapy, and vehicle controls.Results: Histological analysis in prostate cancer patients suggested B7-H3 was consistently and highly expressed in primary and metastatic lesions and remained stable under therapeutic intervention.[ 89 Zr]Zr-B7-H3 ADC immunoPET imaging demonstrated high and specific tumor uptake (33.2 1.0 %ID/g at 144 h) and favorable tumor-to-background ratios.Therapeutic studies revealed that [ 177 Lu]Lu-B7-H3 ADC achieved marked tumor growth inhibition and survival benefit, with comparable efficacy even if reduced the dose of ADC in the treatment system.Integrated [ 177 Lu]Lu-ADC therapy outperformed radiolabeled antibody, ADC monotherapy, and sequential treatment strategies.No additional organ toxicity was observed compared with ADC alone, and transient hematological changes following [ 177 Lu]Lu administration were reversible.Conclusions: The [ 89 Zr]Zr-/[ 177 Lu]Lu-B7-H3 ADC theranostic platform enables accurate imaging, precise tumor targeting, and enhanced antitumor efficacy at reduced ADC doses without increasing systemic toxicity, supporting its translational potential for prostate cancer.