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(99m)Tc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study

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 b...

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Autores principales: Lambert, Bieke, Carron, Philippe, D’Asseler, Yves, Bacher, Klaus, Van den Bosch, Filip, Elewaut, Dirk, Verbruggen, Gust, Beyaert, Rudi, Dumolyn, Caroline, De Vos, Filip
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5151115/
https://www.ncbi.nlm.nih.gov/pubmed/27957720
http://dx.doi.org/10.1186/s13550-016-0245-0
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author Lambert, Bieke
Carron, Philippe
D’Asseler, Yves
Bacher, Klaus
Van den Bosch, Filip
Elewaut, Dirk
Verbruggen, Gust
Beyaert, Rudi
Dumolyn, Caroline
De Vos, Filip
author_facet Lambert, Bieke
Carron, Philippe
D’Asseler, Yves
Bacher, Klaus
Van den Bosch, Filip
Elewaut, Dirk
Verbruggen, Gust
Beyaert, Rudi
Dumolyn, Caroline
De Vos, Filip
author_sort Lambert, Bieke
collection PubMed
description 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 (99m)Tc-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) μGy/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.
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spelling pubmed-51511152016-12-27 (99m)Tc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study Lambert, Bieke Carron, Philippe D’Asseler, Yves Bacher, Klaus Van den Bosch, Filip Elewaut, Dirk Verbruggen, Gust Beyaert, Rudi Dumolyn, Caroline De Vos, Filip EJNMMI Res Original Research 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 (99m)Tc-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) μGy/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. Springer Berlin Heidelberg 2016-12-12 /pmc/articles/PMC5151115/ /pubmed/27957720 http://dx.doi.org/10.1186/s13550-016-0245-0 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research
Lambert, Bieke
Carron, Philippe
D’Asseler, Yves
Bacher, Klaus
Van den Bosch, Filip
Elewaut, Dirk
Verbruggen, Gust
Beyaert, Rudi
Dumolyn, Caroline
De Vos, Filip
(99m)Tc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study
title (99m)Tc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study
title_full (99m)Tc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study
title_fullStr (99m)Tc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study
title_full_unstemmed (99m)Tc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study
title_short (99m)Tc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study
title_sort (99m)tc-labelled s-hynic certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5151115/
https://www.ncbi.nlm.nih.gov/pubmed/27957720
http://dx.doi.org/10.1186/s13550-016-0245-0
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