In vivo examination of (188)Re(I)-tricarbonyl-labeled trastuzumab to target HER2-overexpressing breast cancer.
BACKGROUND
Trastuzumab (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 beta- or alpha emitters can be used as radioimmunotherapeutic agent for the similar purpose but with additional radiation effect.


METHODS
In this study, trastuzumab was labeled with (188)Re for radioimmunotherapy of HER2/neu-positive breast cancer. (188)Re(I)-tricarbonyl ion, [(188)Re(OH(2))(3)(CO)(3)](+), was employed as a precursor for directly labeling the monoclonal antibody with (188)Re. The immunoreactivity of (188)Re(I)-trastuzumab was estimated by competition receptor-binding assay using HER2/neu-overexpressive BT-474 human breast cancer cells. The localization properties of (188)Re(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.


RESULTS
When incubated with human serum albumin and histidine at 25 degrees C, (188)Re(I)-trastuzumab was found to be stable within 24 h. The IC(50) of (188)Re(I)-trastuzumab was found to be 22.63+/-4.57 nM. (188)Re(I)-trastuzumab was shown to accumulate specifically in BT-474 tumor tissue in in vivo biodistribution studies. By microSPECT/CT, the image of (188)Re localized BT-474 tumor was clearly visualized within 24 h. In contrast, (188)Re(I)-trastuzumab uptake in HER2-low-expressing MCF-7 tumor was minimal, and the (188)Re image at the localization of the tumor was dim.


CONCLUSIONS
These results reveal that (188)Re(I)-trastuzumab could be an appropriate radioimmunotherapeutic agent for the treatment of HER2/neu-overexpressing cancers.
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
Kuo-Ting
KT
Chen
Te-Wei
TW
Lee
Jem-Mau
JM
Lo
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000737:chemistry / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D012211:Rhenium / Q000737:chemistry / Q000627:therapeutic use*; D013194:Staining and Labeling; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D012211:Rhenium; D000068878:Trastuzumab