Monitoring Therapy Response of Experimental Arthritis with Radiolabeled Tracers Targeting Fibroblasts, Macrophages, or Integrin α_vβ₃

Abstract

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 α v β 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 111 In-RGD 2 (integrin α v β 3 ), 111 In-anti-F4/80-A3-1 (antimurine macrophage antibody), or 111 In-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 111 In-28H1 (anti-FAP), 111 In-anti-F4/80-A3-1, and 111 In-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 111 In-28H1, 111 In-anti-F4/80-A3-1, and 111 In-RGD 2 , respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for 111 In-28H1 (5.5 ± 1; excluding values . 25), 111 In-anti-F4/80-A3-1 (10.4 ± 4), and 111 In-RGD 2 (7.2 ± 1) than for control 111 In-DP47GS (0.7 ± 0.5; P 5 0.002), 111 In-rat IgG2b (0.5 ± 0.2; P 5 0.002), or coinjection of excess RGD 2 (3.5), indicating specific uptake of all tracers in arthritic joints. Conclusion: 111 In-28H1, 111 In-anti-F4/80-A3-1, and 111 In-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.

Multimodal [18F]FDG PET/CT Is a Direct Readout for Inflammatory Bone Repair: A Longitudinal Study in TNFα Transgenic Mice

“…This limitation can be overcome by in vivo imaging techniques using [ 18 F]FDG or [ 18 F]fluoride . However, they have not yet been used for monitoring therapeutic responses in individual animals …”

Antibody‐Based Tracers for PET/SPECT Imaging of Chronic Inflammatory Diseases

“…Given the studies described above, future exploration of radiolabeled antibodies for imaging chronic inflammatory diseases could take several directions. First, molecular probes targeting FAP at sites of inflammation showed relatively high accumulation compared to those targeting other surface markers on immune cells or adhesion molecules, thus suggesting their high potential for further development and application in various chronic inflammatory diseases …”

“…For example, Terry et al. conducted a comparison study with different tracers that target fibroblasts ( 111 In‐28H1), macrophages ( 111 In‐anti‐F4/80‐A3‐1), or integrin α v β 3 ( 111 In‐RGD 2 ), to compare their capabilities for monitoring therapeutic responses to etanercept in experimental arthritis . Whereas the uptake of each tracer in inflamed joints before treatment with etanercept was 23±15, 8±4, and 2±1 %ID g −1 for 111 In‐28H1, 111 In‐anti‐F4/80‐A3–1, and 111 In‐RGD 2 , respectively, it decreased significantly to 11±11, 4±4, and 1±0.2 %ID g −1 after treatment ( n =2–10, 4 joints/mouse, p <0.01).…”

“…For example, Te rry et al conducted ac omparison study with different tracers that target fibroblasts ( 111 In-28H1), macrophages ( 111 In-anti-F4/80-A3-1), or integrin a v b 3 ( 111 In-RGD 2 ), to compare their capabilities for monitoring therapeutic responses to etanercepti ne xperimental arthritis. [118] Whereas the uptake of each tracer in inflamed jointsbefore treatment with etanercept was 23 AE 15, 8 AE 4, and 2 AE 1%ID g À1 for 111 In-28H1, 111 In-anti-F4/80-A3-1,a nd 111 In-RGD 2 ,r espectively,i td ecreased significantly to 11 AE11,4AE 4, and1AE 0.2 %ID g À1 after treatment (n = 2-10, 4j oints/mouse, p < 0.01). In addition, arthritis-to-blood ratios of 111 In-28H1, 111 In-RGD 2 ,a nd 111 In-anti-F4/80-A3-1 antibodies were also higher than those of the control groups,t hus indicating specific uptake of the tracers in inflamed lesions.…”

Specificity Evaluation and Disease Monitoring in Arthritis Imaging with Complement Receptor of the Ig superfamily targeting Nanobodies

“…These enable earlier assessment of drug efficacy than radiographic outcomes27. In a recent study using 111 In-labelled antibodies targeting fibroblast activation protein, macrophages and integrin αvβ3, decreased joint uptake of tracers was observed in arthritic mice undergoing etanercept treatment28. In the current study using 99m Tc-NbV4m119 in CIA DBA/1 mice receiving dexamethasone as therapy, the recorded signals at day 42 were lower in the dexamethasone injected group as compared to the saline control group, but remained at least as high as those recorded at day 28 (i.e.…”