Ac/Zr-Labeled N4MU01 Radioimmunoconjugates as Theranostics Against Nectin-4-Positive Triple-Negative Breast Cancer.

Nectin-4 is an overexpressed biomarker in 60%-70% of triple-negative breast cancer (TNBC) cases and an ideal target for radiotherapy and PET imaging. In this study, theranostic radioimmunoconjugates were developed using a fully human anti-nectin-4 antibody (N4MU01). The imaging properties and therapeutic effectiveness of the radioimmunoconjugates were evaluated using TNBC models. N4MU01 was radiolabeled with Zr and Ac for imaging and radiotherapy, respectively, using TNBC xenograft and syngeneic models. Biodistribution and PET imaging of the [Zr]Zr-deferoxamine (DFO)-N4MU01 radioimmunoconjugate was studied in mice bearing nectin-4-positive xenografts. Dosimetry and toxicity of [Ac]Ac-Macropa-N4MU01 were studied in naïve BALB/c mice, and the therapeutic efficacy was evaluated with two doses of 13 or two doses of 18.6 kBq, administered 10 d apart in athymic BALB/c nude mice bearing either a human TNBC MDA-MB-468 xenograft or a human nectin-4-transfected 4T1 (4T1.) syngeneic allograft. The pharmacokinetic profile of the [Zr]Zr-DFO-N4MU01 radioimmunoconjugate showed biphasic distribution with a moderate elimination half-life of 63 h. PET imaging and biodistribution of [Zr]Zr-DFO-N4MU01 in mice bearing the MDA-MB-468 xenograft showed high tumor uptake of 13.2 ± 1.12 percent injected activity per gram at 120 h. [Ac]Ac-Macropa-N4MU01 was effectively internalized in MDA-MB-468 and was cytotoxic to the cells with a 50% inhibition concentration of 1.2 kBq/mL. Toxicity studies revealed that 15 kBq of [Ac]Ac-Macropa-N4MU01 was generally well tolerated, as indicated by hematologic, blood chemistry, and histopathologic analysis. Mice bearing MDA-MB-468 and 4T1. xenografts treated with 13 kBq of [Ac]Ac-Macropa-N4MU01 had 100% (6/6) and 83.3% (5/6) complete tumor remissions, respectively. The specific tumor uptake and remarkable effectiveness against aggressive TNBC tumors are very promising and warrant the clinical development of N4MU01 radioimmunoconjugates.