Trastuzumab Labeled to High Specific Activity with 111In by Site-Specific Conjugation to a Metal-Chelating Polymer Exhibits Amplified Auger Electron-Mediated Cytotoxicity on HER2-Positive Breast Cancer Cells

Our objective was to evaluate the cytotoxicity toward HER2-positive human breast cancer (BC) cells of trastuzumab modified site−specifically with a metal-chelating polymer (MCP) that presents multiple DTPA chelators for complexing 111In. 111In emits subcellular range Auger electrons that induce multiple lethal DNA double-strand breaks (DSBs) in cells. MCPs were synthesized with a polyglutamide backbone with 24 or 29 pendant DTPA groups, with or without nuclear translocation sequence (NLS) peptide modification and a terminal hydrazide group for reaction with aldehydes generated by sodium periodate (NaIO4)-oxidation of glycans on the Fc-domain of trastuzumab. Trastuzumab was site-specifically modified with two DTPA and labeled with 111In for comparison (trastuzumab-NH-Bn-DTPA-111In). The maximum specific activity (SA) for labeling trastuzumab-Hy-MCP with 111In was 90-fold greater than for trastuzumab-NH-Bn-DTPA-111In [8.9 MBq/μg (1.5 × 106 MBq/μmol) vs 0.1 MBq/μg (1.2 × 104 MBq/μmol)]. Trastuzumab-Hy-MCP-11...