Cy3‐tilmanocept labeling of macrophages in joints of mice with antibody‐induced arthritis and synovium of human patients with rheumatoid arthritis

Abstract

γ-Tilmanocept (99m Tc-tilmanocept) is a receptor-directed, radiolabeled tracer that is FDA-approved for guiding sentinel lymph node biopsy. Tilmanocept binds the C-type lectin mannose receptor (MR, CD206) on macrophages. In this study, nonradioactive, fluorescently-labeled Cy3-tilmanocept was used to detect CD206 + mononuclear cells in the cartilage of mice with antibody-induced arthritis and in the synovial fluid and tissue of human subjects with rheumatoid arthritis (RA) for comparison with osteoarthritis (OA), and healthy volunteer (HV) controls. Murine arthritis was induced by injection of monoclonal anti-cartilage antibody followed by injection of Escherichia coli lipopolysaccharide. Post-arthritis development (7-11 days), the mice were injected intravenously with Cy3-tilmanocept followed by in vivo and ex vivo epifluorescence imaging. Twophoton imaging, immunofluorescence, and immunohistochemistry were used to identify articular and synovial macrophages (CD206, F4/80, and Cy3-tilmanocept binding) in murine tissues. Cy3-tilmanocept epifluorescence was present in arthritic knees and elbows of murine tissues; no radiographic changes were noted in the skeletons. However, inflammatory arthritic changes were apparent by histopathology and immunohistochemistry (F4/80), immunofluorescence (CD206) and Cy3-tilmanocept binding. In human RA synovial fluid, Cy3-tilmanocept staining correlated with CD206 + / CD16 + cells; negligible labeling was observed in OA samples. Cy3-tilmanocept colocalized with CD206 and staining was significantly higher in RA synovial tissue compared to OA or HV. Our results demonstrate that imaging with Cy3-tilmanocept can detect in vivo inflammatory, CD206 + macrophages in an early arthritis animal model and in human RA patients. These data establish a novel tool for preclinical research of early arthritis and have implications for early RA detection and monitoring of therapeutic efficacy in humans.

Molecular imaging of tumor-associated macrophages in cancer immunotherapy

“…80 Mannose receptors targeting radiotracers are currently applied to the imaging of macrophages in the TME and proven to have important clinical significance for detecting tumor sentinel lymph nodes, 105 assessing atherosclerotic plaque stability 106 and detecting rheumatoid arthritis early. 107 Hence, MMR is a promising target for the noninvasive detection of macrophages to obtain diagnostic and prognostic information on inflammatory diseases and investigate targeted macrophage immunotherapy.…”

The GRP94 Inhibitor PU-WS13 Decreases M2-like Macrophages in Murine TNBC Tumors: A Pharmaco-Imaging Study with 99mTc-Tilmanocept SPECT

“…Its clinical routes of administration are subcutaneous/intradermal/intra- or peritumoral. However, several studies recently demonstrated that systemic administration of 99m Tc-Tilmanocept allowed the detection of M2-macrophages by single photon emission tomography (SPECT) imaging in several preclinical models of brain injury [ 12 ], arthritis [ 13 ], and atherosclerosis [ 14 ]. In addition, clinical trials are currently underway with systemic administration of 99m Tc-Tilmanocept, particularly in oncologic [ 15 , 16 ] and non-oncologic diseases [ 17 ].…”