Preclinical radioimmunotargeting of folate receptor alpha using the monoclonal antibody conjugate DOTA-MORAb-003.
BACKGROUND
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 111In- and 131I-labeled MORAb-003 was investigated using IGROV1 and SW620 cells. Biodistribution studies in tumor-bearing mice were performed with the more favorable agent.


RESULTS
Five 1,4,7,10-tetraazacyclododecane-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 IGROV1 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 131I- and 111In-labeled MORAb-003, but 111In was retained and 131I was released as iodide. In athymic mice, 111In-DOTA-MORAb-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 111In-MORAb-003 was assessed in three patients undergoing treatment with cold MORAb-003.


CONCLUSIONS
MORAb-003 is an attractive antibody for radioimmunoscintigraphy and possibly radioimmunotherapy of FRA-expressing cancers in addition to its potential direct therapeutic effects.
Smith-Jones
Peter M
PM
Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, Box 77, New York, NY 10021, USA. smithjop@mskcc.org
Pandit-Taskar
Neeta
N
Cao
Wei
W
O'Donoghue
Joseph
J
Philips
Martin D
MD
Carrasquillo
Jorge
J
Konner
Jason A
JA
Old
Lloyd J
LJ
Larson
Steven M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics*; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000188:drug therapy; D009375:Neoplasms, Glandular and Epithelial / Q000000981:diagnostic imaging / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy; D010865:Pilot Projects; D011859:Radiography; D016719:Radioimmunodetection / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D011956:Receptors, Cell Surface; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C527484:farletuzumab