An Anti-EGFR Antibody-Drug Radioconjugate Labeled with Actinium-225 Elicits Durable Antitumor Responses in KRAS- and...

EGFR is expressed in approximately 80% to 85% of colorectal cancers. Although anti-EGFR antibodies benefit some patients with colorectal cancer, tumors with Kirsten rat sarcoma viral oncogene (KRAS) or B-rapidly accelerated fibrosarcoma (BRAF), a proto-oncogene serine/threonine protein kinase, mutations are resistant. In this study, we developed a theranostic approach that uses an anti-EGFR antibody-drug conjugate labeled with either [225Ac]Ac or [89Zr]Zr and evaluated the strategy against KRAS- and BRAF-mutant EGFR-positive colorectal cancer models. The antibody-drug radioconjugate [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1 showed enhanced in vitro cytotoxicity compared with the unlabeled antibody-drug conjugate nimotuzumab-PEG6-DM1. [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1 extended the survival of mice bearing all tested xenografts compared with untreated and nimotuzumab-PEG6-DM1-treated controls. For the BRAFV600E-mutant xenograft, the median survival was not reached following treatment with [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1, whereas it was 24.5 and 39 days for the saline-treated and nimotuzumab-PEG6-DM1-treated groups, respectively. Micro-PET/CT imaging using the nonoverlapping anti-EGFR radioimmunoconjugate [89Zr]Zr-DFO-matuzumab before and after treatment of orthotopic colorectal cancer xenografts showed that 1/5 mice in the treatment group had complete remission, whereas metastatic spread was prevented in the other mice (4/5). These results show that treatment with [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1 is a potential therapeutic approach for KRAS- and BRAFV600E-mutant metastatic colorectal cancer. Significance: Radiolabeling with [225Ac]Ac improves the efficacy of an anti-EGFR antibody-drug conjugate in KRAS- and BRAFV600E-mutant colorectal cancer, providing hope for patients with these mutations who do not qualify for EGFR-targeted therapies.