Immuno-PET Imaging of TNF-α in Colitis Using ⁸⁹Zr-DFO-infliximab

Abstract

Tumor necrosis factor-alpha (TNF-α) neutralization has become increasingly important in the treatment of inflammatory bowel diseases (IBD). A series of monoclonal antibodies were approved in the clinic for anti-TNF-α therapy. However, a comprehensive assessment of TNF-α levels throughout the colon, which facilitates the diagnosis of IBD and predicts anti-TNF-α efficacy, remains challenging. Here, we radiolabeled infliximab with long-lived radionuclides 89 Zr for immuno-positron emission tomography (PET) imaging of TNF-α in vivo. The increased TNF-α level was detected in the inflammatory colon of the dextran sodium sulfate-induced colitis mice. The immuno-PET imaging of 89 Zr-desferrioxamine-infliximab reveals a high uptake (7.1 ± 0.3%ID/g) in the inflammatory colon, which is significantly higher than in the healthy control and blocked groups. The colon-tomuscle ratio reached more than 10 and was maintained at a high level for 10 h after injection. The ex vivo biodistribution study also verified the superior uptake in the inflammatory colon. This study provides an in vivo immune-PET approach to molecular imaging of the pro-inflammatory cytokine TNF-α. It is promising in diagnosing and predicting efficacy in both IBD and other autoimmune diseases.

Radioimmune Imaging of α4β7 Integrin and TNFα for Diagnostic and Therapeutic Applications in Inflammatory Bowel Disease

“…We selected two human therapeutic biomarkers (α 4 β 7 integrin and TNFα) and developed two radiopharmaceuticals to study their expression in DSS-treated mice. As anti-α 4 β 7 integrin or anti-TNFα mAb, we chose mouse-specific antibodies to avoid poor affinity of anti-human antibodies, as previously described [ 19 ], despite other authors having successfully used radiolabelled infliximab in mice [ 20 ]. Control isotype mAb was selected as control and radiolabelled with 99m Tc.…”

Druggability of Targets for Diagnostic Radiopharmaceuticals

“…Common target proteins that have been used for nuclear imaging are classified by subcellular localization, based on their primary localization (Figure ). For extracellular proteins, there are amyloid β (Aβ), alpha-synuclein (α-Syn), interleukins (ILs), tumor necrosis factor α (TNF-α), , interferon-gamma (INF-γ), matrix metalloproteinases (MMPs), , and collagen . For cell surface proteins, there are GLUT1, TSPO, , Tau, dopamine D2 receptor (DRD2), dopamine transporter (DAT), HER2, integrins, , PSMA, fibroblast activation protein-α (FAP-α), somatostatin receptors (SSTRs), metabotropic glutamate receptors (mGluR), 5-hydroxytryptamine receptor (5-HTR), cluster of differentiation 8 (CD8), C-X-C motif chemokine receptor 4 (CXCR4), and PD1/PD-L1 .…”

Repurposing iron chelators for accurate positron emission tomography imaging tracking of radiometal‐labeled cell transplants

“…In addition, these chelators have demonstrated a good safety profile with no serious side effects despite being taken over long term 38,39 . In addition to its clinical use as an iron chelator, DFO's strong affinity for Zr 4+ has led to its use for radiolabeling proteins and antibodies with 89 Zr for PET imaging 40,41 . For example, DFO‐conjugated trastuzumab has been widely investigated as an 89 Zr‐immunoPET tracer for HER2‐positive breast cancer detection 42 .…”