An Anti-EGFR Antibody-Drug Radioconjugate Labeled with Actinium-225 Elicits Durable Anti-Tumor Responses in KRAS and BRAF Mutant Colorectal Cancer

Abstract Epidermal growth factor receptor (EGFR) is expressed in approximately 80-85% of colorectal cancer (CRC). While anti-EGFR antibodies benefit some CRC patients, tumors with kirsten rat sarcoma (KRAS) or B-rapidly accelerated fibrosarcoma (BRAF), a proto-oncogene serine/threonine protein kinase mutations are resistant. Here, 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 CRC models. The antibody-drug radioconjugate [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1 showed enhanced in vitro cytotoxicity compared to the unlabeled antibody-drug conjugate nimotuzumab-PEG6-DM1. [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1 extended the survival of mice bearing all tested xenografts compared to 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, while it was 24.5 and 39 days for the saline and nimotuzumab-PEG6-DM1 treated groups, respectively. PET imaging using the non-overlapping anti-EGFR radioimmunoconjugate [89Zr]Zr-DFO-matuzumab before and after treatment of orthotopic CRC xenografts showed that 1/5 mice from the treatment group had complete remission while 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 mutant and BRAFV600E mutant metastatic CRC.