title: 99mTc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study.
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 the99mTc-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.
authors.affiliation: Department of Radiology and Nuclear Medicine, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium. Bieke.Lambert@Ugent.be.
authors.forename: Bieke
authors.identifier: http://orcid.org/0000-0002-5674-0222
authors.initials: B
authors.lastname: Lambert
authors.affiliation: Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Carron
authors.affiliation: Department of Radiology and Nuclear Medicine, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: D'Asseler
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Klaus
authors.initials: K
authors.lastname: Bacher
authors.affiliation: Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Van den Bosch
authors.affiliation: Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.affiliation: Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Gust
authors.initials: G
authors.lastname: Verbruggen
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Laboratory of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dumolyn
authors.affiliation: Laboratory of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: De Vos
keywords: Biodistribution; Certolizumab pegol; Dosimetry; Rheumatoid arthritis; Spondyloarthritis