Preclinical radioimmunotargeting of folate receptor alpha using the monoclonal antibody conjugate DOTA-MORAb-003

Introduction: The in vitro and in vivo behavior of the radiolabeled monoclonal antibody MORAb-003 was investigated as a prelude to a clinical trial. Methods: The cellular retention of In-111- and. I-131-labeled MORAb-003 was investigated using IGROVI and SW620 cells. Biodistribution studies in tumor-bearing mice were performed with the more favorable agent. Results: Five 1,4,7,10-tetraazacyclododeane-N,N',N '',N'''-tetraacetic acid (DOTA) molecules were conjugated to MORAb-003 with no apparent loss of immunoreactivity. Radiolabeled MORAb-003 had a high affinity for the folate receptor alpha (FRA) expressed by both IGROVI and SW620 cells and was found to bind to around 8 x 10(5) and 7 x 10(5) sites/cell, respectively. Both cancer cell lines were found to internalize both I-131- and In-111-labeled MORAb-003, but In-111 was retained and I-131 was released as iodide. In athymic mice, In-111-DOTAMOR-Ab-003 was cleared from the blood with a single exponential biological clearance rate of 110 h. The uptake in SW620 tumors was 32 +/- 5%ID/g after.4 days. The clearance rate of activity from normal organs such as liver, kidney and spleen was similar to the blood clearance and was 5.36%ID/g, 4.03%ID/g and 4.36%ID/g at 1 day postinjection and 2.14%ID/g, 1.65%ID/g and 3.74%ID/g after 8 days, respectively. In a pilot clinical study, the biodistribution and tumor targeting of In-111-MORAb-003 was assessed in three patients undergoing treatment with cold MORAb-003. Conclusion: MORAb-003 is an attractive antibody for radioimmunoscintigraphy and possibly radioimmunotherapy of FRA-expressing cancers in addition to its potential direct therapeutic effects. (C) 2008 Elsevier Inc. All rights reserved.