PT  - JOURNAL ARTICLE
AU  - Babeker, Hanan
AU  - Njotu, Fabrice Ngoh
AU  - Pougoue Ketchemen, Jessica
AU  - Monzer, Alissar
AU  - Tikum, Anjong Florence
AU  - Doroudi, Alireza
AU  - Nwangele, Emmanuel
AU  - Uppalapati, Maruti
AU  - Fonge, Humphrey
TI  - <sup>225</sup>Ac/<sup>89</sup>Zr-Labeled N4MU01 Radioimmunoconjugates as Theranostics Against Nectin-4–Positive Triple-Negative Breast Cancer
AID  - 10.2967/jnumed.124.268387
DP  - 2025 Apr 01
TA  - Journal of Nuclear Medicine
PG  - 592--598
VI  - 66
IP  - 4
4099  - http://jnm.snmjournals.org/content/66/4/592.short
4100  - http://jnm.snmjournals.org/content/66/4/592.full
SO  - J Nucl Med2025 Apr 01; 66
AB  - 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. Methods: N4MU01 was radiolabeled with 89Zr and 225Ac for imaging and radiotherapy, respectively, using TNBC xenograft and syngeneic models. Biodistribution and PET imaging of the [89Zr]Zr-deferoxamine (DFO)-N4MU01 radioimmunoconjugate was studied in mice bearing nectin-4–positive xenografts. Dosimetry and toxicity of [225Ac]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.nectin-4) syngeneic allograft. Results: The pharmacokinetic profile of the [89Zr]Zr-DFO-N4MU01 radioimmunoconjugate showed biphasic distribution with a moderate elimination half-life of 63 h. PET imaging and biodistribution of [89Zr]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. [225Ac]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 [225Ac]Ac-Macropa-N4MU01 was generally well tolerated, as indicated by hematologic, blood chemistry, and histopathologic analysis. Mice bearing MDA-MB-468 and 4T1.nectin-4 xenografts treated with 13 kBq of [225Ac]Ac-Macropa-N4MU01 had 100% (6/6) and 83.3% (5/6) complete tumor remissions, respectively. Conclusion: The specific tumor uptake and remarkable effectiveness against aggressive TNBC tumors are very promising and warrant the clinical development of N4MU01 radioimmunoconjugates.