Work

[225Ac]Ac-labeled matuzumab is an effective radioimmunotherapeutic against EGFR-positive triple negative breast cancer

Year: 2026

Type: article

Abstract: Background EGFR is overexpressed in TNBC, and “naked” anti-EGFR monoclonal antibodies have been evaluated in clinical trials with dismal effectiveness. Matuzumab is an anti-EGFR monoclonal antibody that can be used to develop theranostics. We posit that compared with “naked” antibodies, [ 225 Ac]Ac-Macropa-matuzumab will be effective against EGFR-positive TNBC xenografts. Methods We developed and characterized [ 225 Ac]Ac-Macropa-matuzumab. Cytotoxicity was studied in EGFR-positive MDA-MB-468 (high EGFR density), MDA-MB-231 (medium EGFR density) and MCF-7 (low EGFR density) 2D monolayer cells and 3D spheroids using live-cell imaging. Biodistribution was carried out in naïve female BALB/c and athymic nude BALB/c tumor-bearing mice. Radioimmunotherapy was studied after administration of 2 × 13 kBq [ 225 Ac]Ac-Macropa-matuzumab dose and compared with irrelevant IgG and saline-treated controls. Safety was evaluated in naïve female BALB/c mice. Results Biodistribution of [ 225 Ac]Ac-Macropa-matuzumab in mice bearing MDA-MB-468 and MDA-MB-231 xenografts showed the highest tumor uptake at 120 h post-injection (p.i.) and was 48.3 $$\:\pm\:$$ 28.6%IA/g and 39.0 $$\:\pm\:\:$$ 9.1%IA/g, respectively. In vitro, [ 225 Ac]Ac-Macropa-matuzumab suppressed the growth of EGFR-positive spheroids with an IC 50 of: MDA-MB-468 (5.3 $$\:\pm\:$$ 6.6 kBq/mL) ∼ MDA-MB-231 (4.9 $$\:\pm\:$$ 6.4 kBq/mL) < MCF-7 (132.7 $$\:\pm\:$$ 42.6 kBq/mL). [ 225 Ac]Ac-Macropa-matuzumab demonstrated favourable biodistribution and was cleared from most non-target organs by day-10 p.i. 57% of mice bearing MDA-MB-468 xenograft treated with [ 225 Ac]Ac-Macropa-matuzumab had complete remission (CR). Less pronounced effect was observed for MDA-MB-231 xenograft. Conclusion [ 225 Ac]Ac-Macropa-matuzumab was safe and effective against EGFR-positive TNBC.

Source: Breast Cancer Research

DOI: 10.1186/s13058-026-02220-z