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

Abstract

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 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.

CONCLUSION:

MORAb-003 is an attractive antibody for radioimmunoscintigraphy and possibly radioimmunotherapy of FRA-expressing cancers in addition to its potential direct therapeutic effects.

• Authors: Peter M Smith-Jones, Neeta Pandit-Taskar, Wei Cao, Joseph O'Donoghue, Martin D Philips, Jorge Carrasquillo, Jason A Konner, Lloyd J Old, Steven M Larson
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 35 Issue 3 Pg. 343-51 (Apr 2008) ISSN: 0969-8051 [Print] United States
• PMID: 18355690 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Carrier Proteins
• Folate Receptors, GPI-Anchored
• Heterocyclic Compounds, 1-Ring
• Immunoconjugates
• Indium Radioisotopes
• Iodine Radioisotopes
• Radiopharmaceuticals
• Receptors, Cell Surface
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• farletuzumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Biological Transport, Active
• Carrier Proteins (analysis, chemistry, metabolism)
• Cell Line, Tumor
• Drug Evaluation, Preclinical
• Female
• Folate Receptors, GPI-Anchored
• Heterocyclic Compounds, 1-Ring (pharmacokinetics)
• Humans
• Immunoconjugates (pharmacokinetics)
• Indium Radioisotopes (pharmacokinetics)
• Iodine Radioisotopes (pharmacokinetics)
• Male
• Metabolic Clearance Rate
• Mice
• Mice, Nude
• Neoplasm Recurrence, Local (diagnostic imaging, drug therapy)
• Neoplasms, Glandular and Epithelial (diagnostic imaging, drug therapy)
• Ovarian Neoplasms (diagnostic imaging, drug therapy)
• Pilot Projects
• Radiography
• Radioimmunodetection (methods)
• Radiopharmaceuticals (pharmacokinetics)
• Receptors, Cell Surface (analysis, chemistry, metabolism)
• Tissue Distribution