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, [225Ac]Ac-Macropa-matuzumab will be effective against EGFR-positive TNBC xenografts. Methods We developed and characterized [225Ac]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 [225Ac]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 [225Ac]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 <InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(\:\pm\:\)</EquationSource> </InlineEquation> 28.6%IA/g and 39.0 <InlineEquation ID="IEq2"> <EquationSource Format="TEX">\(\:\pm\:\:\)</EquationSource> </InlineEquation> 9.1%IA/g, respectively. In vitro, [225Ac]Ac-Macropa-matuzumab suppressed the growth of EGFR-positive spheroids with an IC50 of: MDA-MB-468 (5.3 <InlineEquation ID="IEq3"> <EquationSource Format="TEX">\(\:\pm\:\)</EquationSource> </InlineEquation> 6.6 kBq/mL) ∼ MDA-MB-231 (4.9 <InlineEquation ID="IEq4"> <EquationSource Format="TEX">\(\:\pm\:\)</EquationSource> </InlineEquation> 6.4 kBq/mL) < MCF-7 (132.7 <InlineEquation ID="IEq5"> <EquationSource Format="TEX">\(\:\pm\:\)</EquationSource> </InlineEquation> 42.6 kBq/mL). [225Ac]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 [225Ac]Ac-Macropa-matuzumab had complete remission (CR). Less pronounced effect was observed for MDA-MB-231 xenograft. Conclusion [225Ac]Ac-Macropa-matuzumab was safe and effective against EGFR-positive TNBC.

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

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2026年1月16日

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Anjong Florence Tikum,
Dede Api Fon,
Fabrice Ngoh Njotu,
Nikita Henning,
Emmanuel Nwangele,
Hanan Babeker,
Jessica Pougoue Ketchemen,
Alireza Doroudi,
Maruti Uppalapati,
Humphrey Fonge

摘要

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, [²²⁵Ac]Ac-Macropa-matuzumab will be effective against EGFR-positive TNBC xenografts.

Methods

We developed and characterized [²²⁵Ac]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 [²²⁵Ac]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 [²²⁵Ac]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, [²²⁵Ac]Ac-Macropa-matuzumab suppressed the growth of EGFR-positive spheroids with an IC₅₀ 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). [²²⁵Ac]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 [²²⁵Ac]Ac-Macropa-matuzumab had complete remission (CR). Less pronounced effect was observed for MDA-MB-231 xenograft.

Conclusion

[²²⁵Ac]Ac-Macropa-matuzumab was safe and effective against EGFR-positive TNBC.

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

摘要

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