Targeted α-Particle Radiation Therapy of HER1-Positive Disseminated Intraperitoneal Disease: An Investigation of the Human Anti-EGFR Monoclonal Antibody, Panitumumab

Abstract

Identifying molecular targets and an appropriate targeting vehicle, i.e., monoclonal antibodies (mAb) and their various forms, for radioimmunotherapy (RIT) remains an active area of research. Panitumumab, a fully human and less immunogenic mAb that binds to the epidermal growth factor receptor (Erb1; HER1), was evaluated for targeted α-particle radiation therapy using ²¹²Pb, an in vivo α generator. A single dose of ²¹²Pb-panitumumab administered to athymic mice bearing LS-174T intraperitoneal (i.p.) tumor xenografts was found to have greater therapeutic efficacy when directly compared with ²¹²Pb-trastuzumab, which binds to HER2. A dose escalation study determined a maximum effective working dose of ²¹²Pb-panitumumab to be 20μCi with a median survival of 35 days versus 25 days for the untreated controls. Pretreatment of tumor-bearing mice with paclitaxel and gemcitabine 24hours prior to injection of ²¹²Pb-pantiumumab at 10 or 20μCi resulted in the greatest enhanced therapeutic response at the higher dose with median survivals of 106 versus 192 days, respectively. The greatest therapeutic impact, however, was observed in the animals that were treated with topotecan 24hours prior to RIT and then again 24hours after RIT; the best response from this combination was also obtained with the lower 10-μCi dose of ²¹²Pb-panitumumab (median survival >280 days). In summary, ²¹²Pb-panitumumab is an excellent candidate for the treatment of HER1-positive disseminated i.p. disease. Furthermore, the potentiation of the therapeutic impact of ²¹²Pb-pantiumumab by chemotherapeutics confirms and validates the importance of developing a multimodal therapy regimen.