Jason L J Dearling1, Ala Daka, Nuphar Veiga, Dan Peer, Alan B Packard. 1. *Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Boston Children's Hospital, Boston, MA; †Harvard Medical School, Boston, MA; ‡Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Department of Materials Science and Engineering, Faculty of Engineering; and §the Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel.
Abstract
BACKGROUND: Positron emission tomography combined with a specific probe presents the ability to noninvasively assess inflammatory bowel disease. We previously reported increased intestinal uptake of a Cu-labeled anti-β7 integrin antibody (clone FIB504.64) in colitic mice. Here, we evaluated an anti-α4β7 integrin antibody (clone DATK32), and the F(ab')2 and Fab fragments of the anti-β7 antibody, which should have faster blood clearance than the intact antibody, as imaging probes for the detection of colitis in a mouse model. METHODS: The immunoproteins were labeled with Cu, injected into mice with dextran sodium sulphate-induced colitis. Positron emission tomography data were collected between 1 and 48 hours postinjection. RESULTS: Focal uptake of the anti-β7 fragments was observed in the gut as early as 1 hour postinjection, and they cleared more rapidly from normal tissues than the whole antibody. For example, the blood concentrations at 24 hours postinjection were 23.3 ± 3.0% ID/g for Cu-labeled DATK32, 12.9 ± 2.1% ID/g for FIB504.64, 4.1 ± 0.4% ID/g for FIB504.64-F(ab')2, and 0.62 ± 0.2% ID/g for FIB504.64-Fab (P < 0.0001, analysis of variance). The ratio of uptake of DATK32 between the colitis and control groups in the large intestine (1.38) was lower than for the FIB504.64 fragments (3.15 for F(ab')2, 1.84 for Fab) or intact FIB504.64 (1.78). CONCLUSIONS: The lower intestinal uptake ratio of the Cu-labeled anti-α4β7 antibody (DATK32) compared with the anti-β7 immunoproteins suggests that targeting all β7-expressing lymphocytes, not just those expressing α4β7, is a more promising route to the development of an inflammatory bowel disease imaging agent. The FIB504.64-F(ab')2 fragment demonstrated the greatest differential between colitis and control groups, and is therefore the most promising lead molecule for the development of an inflammatory bowel disease-specific imaging agent.
BACKGROUND: Positron emission tomography combined with a specific probe presents the ability to noninvasively assess inflammatory bowel disease. We previously reported increased intestinal uptake of a Cu-labeled anti-β7 integrin antibody (clone FIB504.64) in colitic mice. Here, we evaluated an anti-α4β7 integrin antibody (clone DATK32), and the F(ab')2 and Fab fragments of the anti-β7 antibody, which should have faster blood clearance than the intact antibody, as imaging probes for the detection of colitis in a mouse model. METHODS: The immunoproteins were labeled with Cu, injected into mice with dextran sodium sulphate-induced colitis. Positron emission tomography data were collected between 1 and 48 hours postinjection. RESULTS: Focal uptake of the anti-β7 fragments was observed in the gut as early as 1 hour postinjection, and they cleared more rapidly from normal tissues than the whole antibody. For example, the blood concentrations at 24 hours postinjection were 23.3 ± 3.0% ID/g for Cu-labeled DATK32, 12.9 ± 2.1% ID/g for FIB504.64, 4.1 ± 0.4% ID/g for FIB504.64-F(ab')2, and 0.62 ± 0.2% ID/g for FIB504.64-Fab (P < 0.0001, analysis of variance). The ratio of uptake of DATK32 between the colitis and control groups in the large intestine (1.38) was lower than for the FIB504.64 fragments (3.15 for F(ab')2, 1.84 for Fab) or intact FIB504.64 (1.78). CONCLUSIONS: The lower intestinal uptake ratio of the Cu-labeled anti-α4β7 antibody (DATK32) compared with the anti-β7 immunoproteins suggests that targeting all β7-expressing lymphocytes, not just those expressing α4β7, is a more promising route to the development of an inflammatory bowel disease imaging agent. The FIB504.64-F(ab')2 fragment demonstrated the greatest differential between colitis and control groups, and is therefore the most promising lead molecule for the development of an inflammatory bowel disease-specific imaging agent.
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