Monitoring Therapy Response of Experimental Arthritis with Radiolabeled Tracers Targeting Fibroblasts, Macrophages, or Integrin αvβ3

Rheumatoid arthritis is an autoimmune disease resulting in chronic synovial inflammation. Molecular imaging could be used to monitor therapy response, thus enabling tailored therapy regimens and enhancing therapeutic outcome. Here, we hypothesized that response to etanercept could be monitored by radionuclide imaging in arthritic mice. We tested 3 different targets, namely fibroblast activation protein (FAP), macrophages, and integrin alpha(v)beta(3). Methods: Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT scans were acquired at 1, 24, and 48 h after injection of In-111-RGD(2) (integrin alpha(v)beta(3)), In-111-anti-F4/80-A3-1 (antimurine macrophage antibody), or In-111-28H1 (anti-FAP antibody), respectively, with nonspecific controls included. Mice were dissected after the last scan, and scans were analyzed quantitatively and were correlated with macroscopic scoring. Results: Experimental arthritis was imaged with In-111-28H1 (anti-FAP), In-111-anti-F4/80-A3-1, and In-111-RGD(2). Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers from 23 15, 8 4, and 2 1 percentage injected dose per gram (%ID/g) to 11 +/- 11 (P < 0.001), 4 +/- 4 (P < 0.001), and 1 +/- 0.2 %ID/g (P < 0.01) for In-111-28H1, In-111-anti-F4/80-A3-1, and In-111-RGD(2), respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for In-111-28H1 (5.5 +/- 1; excluding values > 25), In-111-anti-F4/80-A3-1 (10.4 +/- 4), and In-111-RGD(2) (7.2 +/- 1) than for control In-111-DP47GS (0.7 +/- 0.5; P = 0.002), In-111-rat IgG(2)b (0.5 +/- 0.2; P = 0.002), or coinjection of excess RGD(2) (3.5), indicating specific uptake of all tracers in arthritic joints. Conclusion: (1111)n-28H1, In-111-anti -F4/80-A3-1, and In-111-RGD(2) can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies, however, still need to be performed.