Intravenous ^99mTc-tilmanocept in Planar and Fused SPECT/CT Imaging of Activated Macrophage Infiltration in Subjects with Active Rheumatoid Arthritis

Objectives: Activated macrophages play a critical role in rheumatoid arthritis (RA) by perpetuating inflammation via cytokine release and contributing to bone and cartilage destruction. Specific detection of activated macrophage infiltration can provide valuable immunodiagnostic insight towards joint inflammation and destruction, disease status, and therapeutic response in RA. ^99mTc-tilmanocept is a radiopharmaceutical that binds to the mannose receptor (CD206) with high affinity (K_D = 2.76 x 10^-11 M). In this report, initial safety and efficacy findings are discussed from Navidea’s Phase I dose escalation trial of intravenous (IV) ^99mTc-tilmanocept in RA subjects. Methods: Clinically diagnosed RA subjects received an IV injection of 50, 200, or 400µg tilmanocept radiolabeled with 1, 5, or 10 mCi of ^99mTc. 27 subjects were enrolled as follows - Group 1 (n=3): 50µg / 10mCi; Group 2 (n=3): 200µg / 10mCi; Group 3 (n=3): 400µg / 10mCi; Group 4 (n=3): 50µg / 5mCi; Group 5 (n=3): 200µg / 5mCi; Group 6 (n=3): 400µg / 5mCi; Group 7 (n=3): 50µg / 1mCi; Group 8 (n=3): 200µg / 1mCi; Group 9 (n=3): 400µg / 1mCi. Planar images of the whole body and bilateral hands were acquired at 60 and 180 minutes post-injection followed by additional SPECT/CT in regions of interest.

Results: IV injection of ^99mTc-tilmanocept was well-tolerated. No adverse drug reactions were observed in any dosing group. Planar imaging revealed strong specific anatomical delineation of ^99mTc-tilmanocept-positive joints. Additional SPECT/CT imaging revealed localization in the proximal interphalangeal joints, metacarpophalangeal joints, knee joints, ankle joints, shoulder joints, elbow joints, and periarticular synovial spaces, without localization in the cortical bone or osseous marrow spaces. A statistically significant difference in percent above background (%>BKG) was noted between visually positive and visually negative joints (p < 0.00001). No significant difference in %>BKG was noted between the 60 versus 180-minute post-injection imaging timepoints (p > 0.05) demonstrating the clinical assessment durability of the localization.

Conclusion: Joint-specific localization of ^99mTc-tilmanocept was visualized in subjects who had undergone multiple RA flares despite previous successful treatments. Activated macrophage infiltration appears to be a key component of the inflammatory etiology of these joints. Initial analyses suggest that ^99mTc-tilmanocept planar and SPECT/CT imaging can be performed as early as 60 minutes post-injection without compromising imaging efficacy. This provides an imaging modality for rheumatological diseases that can heighten patient compliance while providing valuable immunodiagnostic information. ^99mTc-tilmanocept imaging can also aid in tailoring appropriate therapeutic strategies for minimizing or eliminating macrophage-induced joint destruction as well as in monitoring disease response to anti-rheumatic drugs. Research Support: Supported by a grant from the National Inst Arthritis & Musculoskeletal & Skin Diseases/NIH, Grant R44AR067583 ClinicalTrials.gov Identifier: NCT02683421.

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