Abstract
Over-expression of Human Epidermal Growth Factor Receptor 2 (HER2) is associated with a significant proportion of breast cancers. Targeting HER2 is possible with a monoclonal antibody called trastuzumab but metastatic HER2 positive tumours can develop resistance to this treatment. One approach to develop more potent therapeutic agents which retain the selectivity of trastuzumab is to attach a β(-) emitting radionuclide, such as copper-67, to the antibody for radioimmunotherapy. It is also possible to attach β(+) emitting copper-64 to antibodies for diagnostic imaging with positron emission tomography (PET). In this work, a cage amine sarcophagine (Sar) chelator is conjugated to trastuzumab to give Sar-trastuzumab which can be radiolabelled with either copper-64 or copper-67 at room temperature in minutes to give [(64)Cu]CuSar-trastuzumab and [(67)Cu]CuSar-trastuzumab respectively. The diagnostic imaging potential of [(64)Cu]CuSar-trastuzumab was evaluated in mice bearing HER2(+) SKOV-3 tumours showing that the tracer has very high tumour uptake and retention 48 hours after injection. The copper-67 variant, [(67)Cu]CuSar-trastuzumab, was highly therapeutically efficacious in the same tumour model with no signs of radiotoxicity. The combination of diagnostic PET imaging with [(64)Cu]CuSar-trastuzumab to guide radionuclide therapy with [(67)Cu]CuSar-trastzumab has significant potential for theranostic treatment of breast cancer and other HER2(+) disease that has become resistant to conventional immunotherapy.