In vivo examination of 188Re(I)-tricarbonyl-labeled trastuzumab to target HER2-overexpressing breast cancer

IntroductionTrastuzumab (Herceptin), a humanized IgG1 monoclonal antibody directed against the extracellular domain of the HER2 protein, acts as an immunotherapeutic agent for HER2-overexpressing human breast cancers. Radiolabeled trastuzumab with β- or α emitters can be used as radioimmunotherapeutic agent for the similar purpose but with additional radiation effect.MethodsIn this study, trastuzumab was labeled with ¹⁸⁸Re for radioimmunotherapy of HER2/neu-positive breast cancer. ¹⁸⁸Re(I)-tricarbonyl ion, [¹⁸⁸Re(OH₂)₃(CO)₃]⁺, was employed as a precursor for directly labeling the monoclonal antibody with ¹⁸⁸Re. The immunoreactivity of ¹⁸⁸Re(I)-trastuzumab was estimated by competition receptor-binding assay using HER2/neu-overexpressive BT-474 human breast cancer cells. The localization properties of ¹⁸⁸Re(I)-trastuzumab within both tumor and normal tissues of athymic mice bearing BT-474 human breast cancer xenografts (HER2/neu-overexpressive) and similar mice bearing MCF-7 human breast cancer xenografts (HER2/neu-low expressive) were investigated.ResultsWhen incubated with human serum albumin and histidine at 25°C, ¹⁸⁸Re(I)-trastuzumab was found to be stable within 24 h. The IC₅₀ of ¹⁸⁸Re(I)-trastuzumab was found to be 22.63±4.57 nM. ¹⁸⁸Re(I)-trastuzumab was shown to accumulate specifically in BT-474 tumor tissue in in vivo biodistribution studies. By microSPECT/CT, the image of ¹⁸⁸Re localized BT-474 tumor was clearly visualized within 24 h. In contrast, ¹⁸⁸Re(I)-trastuzumab uptake in HER2-low-expressing MCF-7 tumor was minimal, and the ¹⁸⁸Re image at the localization of the tumor was dim.ConclusionThese results reveal that ¹⁸⁸Re(I)-trastuzumab could be an appropriate radioimmunotherapeutic agent for the treatment of HER2/neu-overexpressing cancers.