Preparation and characterization of ⁹⁰Y- and ¹⁷⁷Lu-labeled cetuximab for therapeutic applications in vitro and in vivo

Cetuximab (C225) as a chimeric monoclonal antibody specifically targets the epidermal growth factor receptor (EGFR) that is often overexpressed in human malignancies. This phenotype is associated with tumor aggressiveness, treatment
resistance and biological heterogeneity with potential to bypass the blockade of the EGFR signaling pathways.
The aim of this work was to modify the C225 for radiolabeling with therapeutic radionuclides like ⁹⁰Y and ¹⁷⁷Lu as a prerequisite for combination of endoradionuclide therapy with antibody-, chemo- or external radiation therapy for routine application.
C225 was conjugated with the bifunctional chelator CHX-A″-DTPA up to a molar DTPA to C225 ratio of 5. The EGFR-affinity of the immunoconjugate resulted in 94% versus 100% of the unmodified C225 measured with enzyme-linked immunosorbent assay on EGFR-positive tumor cell line A431. DTPA-C225 was labeled with ⁹⁰YCl₃ or ¹⁷⁷LuCl₃ within 30 min with a radiolabeling yield of N95%. The radio-immunoconjugates exhibited high accumulation in squamous cell carcinoma xenotransplanted tumors shown by single photon emission computed tomography and autoradiography. The radiolabeled C225 can be produced in routine with high avidity and specific activity as prerequisite for long term preclinical therapeutic studies.