SPECT Imaging of Joint Inflammation with Nanobodies Targeting the Macrophage Mannose Receptor in a Mouse Model for Rheumatoid Arthritis

Put, Stéphanie; Schoonooghe, Steve; Devoogdt, Nick; Schurgers, Evelien; Avau, Anneleen; Mitera, Tania; D’Huyvetter, Matthias; Baetseĺier, Patrick De; Raes, Geert; Lahoutte, Tony; Matthys, Patrick

doi:10.2967/jnumed.112.111781

Cited by 83 publications

(83 citation statements)

References 40 publications

(52 reference statements)

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“…Put et al provide a review on general tracers and radiolabeled biologicals used to image inflammatory processes (30). Previous studies have focused mostly on targeting macrophages-either with radiolabeled folate (31)(32)(33), with (R)-11 C-PK11195 or translocator protein TSPO (34-36) (which has also been used clinically), or with radiolabeled nanobodies (37)-or by targeting CD163 receptors (38) or mannose receptors (39). Unfortunately, images acquired using radiolabeled folate led to poor-quality images (31), most probably due to general low uptake of the tracers in the joints (32), a feature also seen with the anti-CRIg Nanobody 99m Tc-NbV4m119 (37).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…Several innovative approaches have been already explored for molecular imaging of RA, including probes targeting cell proliferation, matrix metalloproteinases, folate receptors, macrophage mannose receptor with antibodies, or nanobodies, with the key of success depending of the sensitivity of the markers (39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

^99mTc-NTP 15-5 Imaging for Cartilage Involvement in Experimental Rheumatoid Arthritis: Comparison with Routinely Used Molecular Imaging Methods and Sensitivity to Chronic Nonsteroidal Antiinflammatory Drug Treatment

et al. 2015

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This study determined, using the intraarticular complete Freund adjuvant arthritis mice model, whether the radiotracer 99m Tc-N-(triethylammonium)-3-propyl- [15]ane-N5 ( 99m Tc-NTP 15-5) targeting proteoglycans has a pathophysiologic validity for in vivo imaging of rheumatoid arthritis (RA) and its response to chronic nonsteroidal antiinflammatory drugs. Methods: We investigated the time course of cartilage remodeling by 99m Tc-NTP 15-5 scintigraphy, bone damages by 99m Tc-hydroxymethylene diphosphonate imaging, inflammation by 18 F-FDG PET, and joint proteoglycan content and pain behavior in animals, without and with meloxicam treatment. Paw circumference, thermal pain behavior, and histology as well as proteoglycan content of the whole joint were determined. Results: 99m Tc-NTP 15-5 showed specific tracer accumulation within RA joints, with a significant increase in scintigraphic ratio observed in RA versus shams from day 3 to day 28. 18 F-FDG evidenced uptake in RA joints from day 15 to day 29. Animals treated with meloxicam (5 mg/kg) exhibited a dose-dependent decrease in both 99m Tc-NTP 15-5 and 18 F-FDG uptake ratios versus saline-treated animals. 99m Tc-hydroxymethylene diphosphonate bone scans were only positive at day 14 in RA versus shams, with a significant effect of meloxicam. An increase in proteoglycans of RA joint and thermal pain behavior were observed and were dose-dependently reduced by meloxicam. Conclusion: These experimental results bring data in favor of the 99m Tc-NTP 15-5 radiotracer for assessing, in vivo, cartilage remodeling in RA that could be used to monitor therapy.

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“…Equipped with a radionuclide, they can be applied as imaging tracers in a single-photon emission computed tomography (SPECT) or positron emission tomography (PET)-based set-up allowing in vivo visualization of tumours, artherosclerotic plaques and rheumatoid arthritis-associated inflammation sites [36][37][38]. Nanobodies are also capable of stabilizing proteins in a particular conformation and of minimizing structural flexibility.…”

Section: Nanobody Applicationsmentioning

confidence: 99%

A Nanobody‐Based Approach to Amyloid Diseases, the Gelsolin Case Study

Verhelle¹,

Gettemans²

2016

Exploring New Findings on Amyloidosis

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Gelsolin amyloidosis (AGel) is an autosomal-dominant inherited disease caused by point mutations in the gelsolin gene. At the protein level, these mutations result in the loss of a Ca 2+ -binding site, crucial for the correct folding and function. In the trans-Golgi network, this mutant plasma gelsolin is cleaved by furin, giving rise to a 68 kDa Cterminal fragment. When secreted in the extracellular matrix, this fragment undergoes proteolysis by MT1-MMP-like proteases, resulting in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies, the variable part of the heavy chain of heavychain antibodies, have been used as molecular chaperones for mutant plasma gelsolin and the 68 kDa C-terminal fragment in an attempt to inhibit their pathogenic proteolysis. Furthermore, these nanobodies have also been tested and applied as a 99m Tc-based imaging agent in the gelsolin amyloidosis mouse model.

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SPECT Imaging of Joint Inflammation with Nanobodies Targeting the Macrophage Mannose Receptor in a Mouse Model for Rheumatoid Arthritis

Cited by 83 publications

References 40 publications

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

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

^99mTc-NTP 15-5 Imaging for Cartilage Involvement in Experimental Rheumatoid Arthritis: Comparison with Routinely Used Molecular Imaging Methods and Sensitivity to Chronic Nonsteroidal Antiinflammatory Drug Treatment

A Nanobody‐Based Approach to Amyloid Diseases, the Gelsolin Case Study

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SPECT Imaging of Joint Inflammation with Nanobodies Targeting the Macrophage Mannose Receptor in a Mouse Model for Rheumatoid Arthritis

Cited by 83 publications

References 40 publications

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

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

99mTc-NTP 15-5 Imaging for Cartilage Involvement in Experimental Rheumatoid Arthritis: Comparison with Routinely Used Molecular Imaging Methods and Sensitivity to Chronic Nonsteroidal Antiinflammatory Drug Treatment

A Nanobody‐Based Approach to Amyloid Diseases, the Gelsolin Case Study

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Product

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

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

^99mTc-NTP 15-5 Imaging for Cartilage Involvement in Experimental Rheumatoid Arthritis: Comparison with Routinely Used Molecular Imaging Methods and Sensitivity to Chronic Nonsteroidal Antiinflammatory Drug Treatment