Immuno-PET and Immuno-SPECT of Rheumatoid Arthritis with Radiolabeled Anti–Fibroblast Activation Protein Antibody Correlates with Severity of Arthritis

Abstract

One of the most prominent cell populations playing a role in rheumatoid arthritis (RA) is activated fibroblast-like synoviocytes. Among many other proteins, fibroblast-like synoviocytes dominantly express fibroblast activation protein (FAP). Because of the high expression of FAP in arthritic joints, radioimmunoimaging of activated fibroblasts with anti-FAP antibodies might be an attractive noninvasive imaging tool in RA. Methods: SPECT and PET with 111 In-and 89 Zr-labeled anti-FAP antibody 28H1 was performed in mice with CIA. The radioactivity uptake in joints was quantified and correlated with arthritis score. Results: Both 111 In-28H1 and 89 Zr-28H1 showed high uptake in inflamed joints, being 3-fold higher than that of the irrelevant isotype-matched control antibody DP47GS, clearly indicating specific accumulation of 28H1. Uptake of 111 In-28H1 ranged from 2.2 percentage injected dose per gram (%ID/g) in noninflamed joints to 32.1 %ID/g in severely inflamed joints. DP47GS accumulation ranged from 1.6 %ID/g in noninflamed tissue to 12.0 %ID/g in severely inflamed joints. Uptake of 28H1 in inflamed joints correlated with arthritis score (Spearman ρ, 0.69; P , 0.0001) and increased with severity of arthritis. Conclusion: SPECT/CT imaging with the anti-FAP antibody 111 In-28H1 specifically visualized arthritic joints with high resolution, and tracer accumulation correlated with the severity of the inflammation in murine experimental arthritis. Background uptake of the radiolabeled antibody was low, resulting in excellent image quality. 89 Zr-28H1 was less favorable for RA imaging because of an elevated bone uptake of 89 Zr. Future studies will focus on the potential role of 28H1 as a tool to monitor therapy response early on.

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

“…Despite the fact that 18 F-FDG was suggested as a good tool to develop the therapeutic effect of novel therapies of inflammatory arthritis in the study by Kundu-Raychaudhuri et al (42), in a preclinical model Laverman et al showed that 18 F-FDG was inferior to other nuclear imaging tracers when correlating uptake of 18 F-FDG with arthritis score (8).…”

“…In previous studies, the authors did not see accumulation of any of the tracers in the joints of nonarthritic mice (8,12,13,18). The 3 tracers are different with regard to their targets, mechanism, and pharmacokinetics; they all measure something different, so a straight comparison was not performed here.…”

“…The affinity of all 3 tracers and the immunoreactive fraction of anti-F4/80-A3-1 (75%) have been determined previously (8,13,18). The immunoreactive fraction for 111 In-28H1 was 91.4% (Supplemental Fig.…”

“…One of the most prominent cell populations is activated fibroblastlike synoviocytes (6), which express fibroblast activation protein (FAP) (7) and could be imaged by micro-SPECT using radiolabeled antibodies against FAP, as shown by us recently (8). Other cell types include osteoclasts (9), which express integrin a v b 3 (10).…”

Immunocytokines: a novel class of products for the treatment of chronic inflammation and autoimmune conditions

“…The antibody 1-11E generated against ROS-CII was shown to localize selectively at inflamed joints in a mouse model of arthritis [52]. A recent study in the collagen-induced model of arthritis revealed that radiolabeled antibodies specific to fibroblast-activating protein (FAP) accumulated at the sites of disease, with uptake values that correlated with severity of inflammation [53]. Previously, FAP had been shown to be a suitable target for imaging of carcinoma [54].…”