Monitoring therapy response of experimental arthritis with radiolabeled tracers targeting fibroblasts, macrophages or integrin αvβ3

Samantha Y A Terry; Marije Koenders; Gerben Franssen; Tapan Nayak; Anne Freimoser-Grundschober; Christian Klein; Wim Oyen; Otto Boerman; Peter Laverman

doi:10.2967/jnumed.115.162628

Monitoring therapy response of experimental arthritis with radiolabeled tracers targeting fibroblasts, macrophages or integrin αvβ3

Samantha Y A Terry, Marije Koenders, Gerben Franssen, Tapan Nayak, Anne Freimoser-Grundschober, Christian Klein, Wim Oyen, Otto Boerman, Peter Laverman

Imaging Chemistry & Biology

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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 three different targets namely fibroblast activation protein (FAP), macrophages, and integrin αvβ3.

METHODS: Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT (Single photon emission computed tomography/ X-ray computed tomography) scans were acquired at 1, 24 and 48 h after injecting (111)In-RGD2 (integrin αvβ3), (111)In-anti-F4/80-A3-1 (anti-murine 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-RGD2. Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers; it decreased from 23±15 %ID/g, 8±4 %ID/g, 2±1 %ID/g to 11±11 %ID/g (p<0.001), 4±4 %ID/g (p<0.001), 1±0.2 %ID/g (p<0.01) for (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2, respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for (111)In-28H1 (5.5±1; excluding values over 25), (111)In-anti-F4/80-A3-1 (10.4±4), and (111)In-RGD2 (7.2±1) than for control (111)In-DP47GS (0.7±0.5; P = 0.002), (111)In-rat IgG2b (0.5±0.2; P = 0.002), or coinjection of excess RGD2, (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-RGD2 can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies however still need to be carried out.

Original language	English
Pages (from-to)	467-472
Journal	Journal of Nuclear Medicine
Volume	57
Issue number	3
Early online date	3 Dec 2015
DOIs	https://doi.org/10.2967/jnumed.115.162628
Publication status	Published - 1 Mar 2016

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Monitoring Therapy Response of_TERRY_Firstonline3December2015_GREEN AAMAccepted author manuscript, 600 KB

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title = "Monitoring therapy response of experimental arthritis with radiolabeled tracers targeting fibroblasts, macrophages or integrin αvβ3",

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 three different targets namely fibroblast activation protein (FAP), macrophages, and integrin αvβ3.METHODS: Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT (Single photon emission computed tomography/ X-ray computed tomography) scans were acquired at 1, 24 and 48 h after injecting (111)In-RGD2 (integrin αvβ3), (111)In-anti-F4/80-A3-1 (anti-murine 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-RGD2. Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers; it decreased from 23±15 %ID/g, 8±4 %ID/g, 2±1 %ID/g to 11±11 %ID/g (p<0.001), 4±4 %ID/g (p<0.001), 1±0.2 %ID/g (p<0.01) for (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2, respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for (111)In-28H1 (5.5±1; excluding values over 25), (111)In-anti-F4/80-A3-1 (10.4±4), and (111)In-RGD2 (7.2±1) than for control (111)In-DP47GS (0.7±0.5; P = 0.002), (111)In-rat IgG2b (0.5±0.2; P = 0.002), or coinjection of excess RGD2, (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-RGD2 can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies however still need to be carried out.",

author = "Terry, {Samantha Y A} and Marije Koenders and Gerben Franssen and Tapan Nayak and Anne Freimoser-Grundschober and Christian Klein and Wim Oyen and Otto Boerman and Peter Laverman",

note = "Copyright {\textcopyright} 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.",

year = "2016",

month = mar,

day = "1",

doi = "10.2967/jnumed.115.162628",

language = "English",

volume = "57",

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journal = "Journal of Nuclear Medicine",

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T1 - Monitoring therapy response of experimental arthritis with radiolabeled tracers targeting fibroblasts, macrophages or integrin αvβ3

AU - Terry, Samantha Y A

AU - Koenders, Marije

AU - Franssen, Gerben

AU - Nayak, Tapan

AU - Freimoser-Grundschober, Anne

AU - Klein, Christian

AU - Oyen, Wim

AU - Boerman, Otto

AU - Laverman, Peter

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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 three different targets namely fibroblast activation protein (FAP), macrophages, and integrin αvβ3.METHODS: Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT (Single photon emission computed tomography/ X-ray computed tomography) scans were acquired at 1, 24 and 48 h after injecting (111)In-RGD2 (integrin αvβ3), (111)In-anti-F4/80-A3-1 (anti-murine 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-RGD2. Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers; it decreased from 23±15 %ID/g, 8±4 %ID/g, 2±1 %ID/g to 11±11 %ID/g (p<0.001), 4±4 %ID/g (p<0.001), 1±0.2 %ID/g (p<0.01) for (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2, respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for (111)In-28H1 (5.5±1; excluding values over 25), (111)In-anti-F4/80-A3-1 (10.4±4), and (111)In-RGD2 (7.2±1) than for control (111)In-DP47GS (0.7±0.5; P = 0.002), (111)In-rat IgG2b (0.5±0.2; P = 0.002), or coinjection of excess RGD2, (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-RGD2 can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies however still need to be carried out.

AB - 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 three different targets namely fibroblast activation protein (FAP), macrophages, and integrin αvβ3.METHODS: Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT (Single photon emission computed tomography/ X-ray computed tomography) scans were acquired at 1, 24 and 48 h after injecting (111)In-RGD2 (integrin αvβ3), (111)In-anti-F4/80-A3-1 (anti-murine 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-RGD2. Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers; it decreased from 23±15 %ID/g, 8±4 %ID/g, 2±1 %ID/g to 11±11 %ID/g (p<0.001), 4±4 %ID/g (p<0.001), 1±0.2 %ID/g (p<0.01) for (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2, respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for (111)In-28H1 (5.5±1; excluding values over 25), (111)In-anti-F4/80-A3-1 (10.4±4), and (111)In-RGD2 (7.2±1) than for control (111)In-DP47GS (0.7±0.5; P = 0.002), (111)In-rat IgG2b (0.5±0.2; P = 0.002), or coinjection of excess RGD2, (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-RGD2 can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies however still need to be carried out.

U2 - 10.2967/jnumed.115.162628

DO - 10.2967/jnumed.115.162628

M3 - Article

C2 - 26635344

SN - 1535-5667

VL - 57

SP - 467

EP - 472

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

IS - 3

ER -

Monitoring therapy response of experimental arthritis with radiolabeled tracers targeting fibroblasts, macrophages or integrin αvβ3

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