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99mTc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients : a biodistribution and dosimetry study

Bieke Lambert (UGent) , Philippe Carron (UGent) , Yves D'Asseler (UGent) , Klaus Bacher (UGent) , Filip Van den Bosch (UGent) , Dirk Elewaut (UGent) , August Verbruggen (UGent) , Rudi Beyaert (UGent) , Caroline Dumolyn (UGent) and Filip De Vos (UGent)
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Abstract
Background: Biologicals directed against tumour necrosis factor (TNF) have proven their efficacy in the treatment of spondyloarthritis and rheumatoid arthritis. We present a radiolabelling method for certolizumab pegol (CZP), a commercially available humanized Fab'-fragment directed against TNF. A biodistribution and dosimetry study was conducted. Tc-S-HYNIC CZP was synthesized. The in vitro TNF neutralizing activity was tested by exposing L929s-cells to various concentrations 99mTc-S-HYNIC CZP and measuring TNF-induced cytotoxicity. For biodistribution and dosimetry, WB images and blood and urine sampling were performed up to 24 h pi. Cumulative activities were estimated using mono-exponential fitting, and organ doses were estimated using OLINDA/EXM. The effective dose was calculated using the International Commission on Radiological Protection 103 recommendations. The uptake of the tracer in the peripheral joints was assessed visually and semiquantitatively. Results: In vitro tests showed blocking of TNF cytotoxicity by the Tc-99m-S-HYNIC CZP formulation comparable to the effect obtained with the unlabelled CZP with or without the HYNIC linker. We analysed eight patients with rheumatoid arthritis or spondyloarthritis. The highest mean absorbed organ doses were recorded for kidneys, spleen, and liver: 56 (SD 7), 34 (SD 6), and 33 (SD 7) mu Gy/MBq. The effective dose was 6.1 (SD 0.9) mSv for a mean injected activity of 690 (SD 35) MBq. The urinary excretion was 15.1% (SD 8.1) of the IA at 22.5 h. Blood analysis yielded a distribution half-life of 1.2 h (SD 1.5) and an elimination half-life of 26.9 h (SD 2.7). Visual analysis of the scans revealed marked tracer accumulation in the clinically affected peripheral joints. In addition, there was a statistically significant higher uptake of the tracer in the swollen joints (median uptake ratio compared to background of 3.3 in rheumatoid arthritis and 2.4 in peripheral spondyloarthritis) compared to clinically negative joints (respectively 1.3 and 1.6). Conclusions: We present a radiolabelling technique for CZP, a Fab'-fragment directed against TNF and currently used as a therapeutic agent in rheumatology. An effective dose of 6.1 mSv (SD 0.9) was estimated. We confirmed the uptake of this new radiopharmaceutical in clinically affected peripheral joints.
Keywords
Certolizumab pegol, Rheumatoid arthritis, Spondyloarthritis, Biodistribution, Dosimetry, TUMOR-NECROSIS-FACTOR, SOCIETY CLASSIFICATION CRITERIA, RANDOMIZED CONTROLLED-TRIALS, AXIAL SPONDYLOARTHRITIS, ANKYLOSING-SPONDYLITIS, ANTIBODY FRAGMENTS, METAANALYSIS, EFFICACY, THERAPIES

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Chicago
Lambert, Bieke, Philippe Carron, Yves D’Asseler, Klaus Bacher, Filip Van den Bosch, Dirk Elewaut, August Verbruggen, Rudi Beyaert, Caroline Dumolyn, and Filip De Vos. 2016. “99mTc-labelled S-HYNIC Certolizumab Pegol in Rheumatoid Arthritis and Spondyloarthritis Patients : a Biodistribution and Dosimetry Study.” Ejnmmi Research 6.
APA
Lambert, Bieke, Carron, P., D’Asseler, Y., Bacher, K., Van den Bosch, F., Elewaut, D., Verbruggen, A., et al. (2016). 99mTc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients : a biodistribution and dosimetry study. EJNMMI RESEARCH, 6.
Vancouver
1.
Lambert B, Carron P, D’Asseler Y, Bacher K, Van den Bosch F, Elewaut D, et al. 99mTc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients : a biodistribution and dosimetry study. EJNMMI RESEARCH. 2016;6.
MLA
Lambert, Bieke, Philippe Carron, Yves D’Asseler, et al. “99mTc-labelled S-HYNIC Certolizumab Pegol in Rheumatoid Arthritis and Spondyloarthritis Patients : a Biodistribution and Dosimetry Study.” EJNMMI RESEARCH 6 (2016): n. pag. Print.
@article{8502594,
  abstract     = {Background: Biologicals directed against tumour necrosis factor (TNF) have proven their efficacy in the treatment of spondyloarthritis and rheumatoid arthritis. We present a radiolabelling method for certolizumab pegol (CZP), a commercially available humanized Fab'-fragment directed against TNF. A biodistribution and dosimetry study was conducted. 
Tc-S-HYNIC CZP was synthesized. The in vitro TNF neutralizing activity was tested by exposing L929s-cells to various concentrations 99mTc-S-HYNIC CZP and measuring TNF-induced cytotoxicity. For biodistribution and dosimetry, WB images and blood and urine sampling were performed up to 24 h pi. Cumulative activities were estimated using mono-exponential fitting, and organ doses were estimated using OLINDA/EXM. The effective dose was calculated using the International Commission on Radiological Protection 103 recommendations. The uptake of the tracer in the peripheral joints was assessed visually and semiquantitatively. 
Results: In vitro tests showed blocking of TNF cytotoxicity by the Tc-99m-S-HYNIC CZP formulation comparable to the effect obtained with the unlabelled CZP with or without the HYNIC linker. We analysed eight patients with rheumatoid arthritis or spondyloarthritis. The highest mean absorbed organ doses were recorded for kidneys, spleen, and liver: 56 (SD 7), 34 (SD 6), and 33 (SD 7) mu Gy/MBq. The effective dose was 6.1 (SD 0.9) mSv for a mean injected activity of 690 (SD 35) MBq. The urinary excretion was 15.1\% (SD 8.1) of the IA at 22.5 h. Blood analysis yielded a distribution half-life of 1.2 h (SD 1.5) and an elimination half-life of 26.9 h (SD 2.7). Visual analysis of the scans revealed marked tracer accumulation in the clinically affected peripheral joints. In addition, there was a statistically significant higher uptake of the tracer in the swollen joints (median uptake ratio compared to background of 3.3 in rheumatoid arthritis and 2.4 in peripheral spondyloarthritis) compared to clinically negative joints (respectively 1.3 and 1.6). 
Conclusions: We present a radiolabelling technique for CZP, a Fab'-fragment directed against TNF and currently used as a therapeutic agent in rheumatology. An effective dose of 6.1 mSv (SD 0.9) was estimated. We confirmed the uptake of this new radiopharmaceutical in clinically affected peripheral joints.},
  articleno    = {88},
  author       = {Lambert, Bieke and Carron, Philippe and D'Asseler, Yves and Bacher, Klaus and Van den Bosch, Filip and Elewaut, Dirk and Verbruggen, August and Beyaert, Rudi and Dumolyn, Caroline and De Vos, Filip},
  issn         = {2191-219X},
  journal      = {EJNMMI RESEARCH},
  keyword      = {Certolizumab pegol,Rheumatoid arthritis,Spondyloarthritis,Biodistribution,Dosimetry,TUMOR-NECROSIS-FACTOR,SOCIETY CLASSIFICATION CRITERIA,RANDOMIZED CONTROLLED-TRIALS,AXIAL SPONDYLOARTHRITIS,ANKYLOSING-SPONDYLITIS,ANTIBODY FRAGMENTS,METAANALYSIS,EFFICACY,THERAPIES},
  language     = {eng},
  pages        = {9},
  title        = {99mTc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients : a biodistribution and dosimetry study},
  url          = {http://dx.doi.org/10.1186/s13550-016-0245-0},
  volume       = {6},
  year         = {2016},
}

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