Development of ^sup 124^I Immuno-PET Targeting Tumor Vascular TEM1/Endosialin

• Published in: The Journal of nuclear medicine (1978) Vol. 55; no. 3; p. 500
• Main Authors: Chacko, Ann-Marie, Li, Chunsheng, Nayak, Madhura, Mikitsh, John L, Hu, Jia, Hou, Catherine, Grasso, Luigi, Nicolaides, Nicholas C, Muzykantov, Vladimir R, Divgi, Chaitanya R, Coukos, George
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.03.2014
• Subjects: Cells; Monoclonal antibodies; Rodents; Tissues; Tumors
• ISSN: 0161-5505; 1535-5667

Tumor endothelial marker 1 (TEM1/endosialin) is a tumor vascular marker highly overexpressed in multiple human cancers with minimal expression in normal adult tissue. In this study, we report the preparation and evaluation of 124I-MORAb-004, a humanized monoclonal antibody targeting an extracellular epitope of human TEM1 (hTEM1), for its ability to specifically and sensitively detect vascular cells expressing hTEM1 in vivo. MORAb-004 was directly iodinated with 125I and 124I, and in vitro binding and internalization parameters were characterized. The in vivo behavior of radioiodinated MORAb-004 was characterized in mice bearing subcutaneous ID8 tumors enriched with mouse endothelial cells expressing hTEM1 and by biodistribution and small-animal immuno-PET studies. MORAb-004 was radiolabeled with high efficiency and isolated in high purity. In vitro studies demonstrated specific and sensitive binding of MORAb-004 to MS1 mouse endothelial cells expressing hTEM1, with no binding to control MS1 cells. 125I-MORAb-004 and 124I-MORAb-004 both had an immunoreactivity of approximately 90%. In vivo biodistribution experiments revealed rapid, highly specific and sensitive uptake of MORAb-004 in MS1-TEM1 tumors at 4 h (153.2 ± 22.2 percentage injected dose per gram [%ID/g]), 24 h (127.1 ± 42.9 %ID/g), 48 h (130.3 ± 32.4 %ID/g), 72 h (160.9 ± 32.1 %ID/g), and 6 d (10.7 ± 1.8 %ID/g). Excellent image contrast was observed with 124I-immuno-PET. MORAb-004 uptake was statistically higher in TEM1-positive tumors than in control tumors. Binding specificity was confirmed by blocking studies using excess nonlabeled MORAb-004. In our preclinical model, with hTEM1 exclusively expressed on engineered murine endothelial cells that integrate into the tumor vasculature, 124I-MORAb-004 displays high tumor-to-background tissue contrast for detection of hTEM1 in easily accessible tumor vascular compartments. These studies strongly suggest the clinical utility of 124I-MORAb-004 immuno-PET in assessing TEM1 tumor-status.