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The effect of certolizumab drug concentration and anti-drug antibodies on TNF neutralisation
L.C. Berkhout1, E.H. Vogelzang2, M.M. Hart3, F.C. Loeff4, L. Dijk5, N.I. Derksen6, R. Wieringa7, W.A. Van Leeuwen8, C.L. Krieckaert9, A. De Vries10, M.T. Nurmohamed11, G.J. Wolbink12, T. Rispens13
- Department of Immunopathology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Amsterdam UMC, Academic Medical Centre, University of Amsterdam, The Netherlands.
- Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam, The Netherlands.
- Department of Immunopathology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Amsterdam UMC, Academic Medical Centre, University of Amsterdam, The Netherlands.
- Department of Immunopathology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Amsterdam UMC, Academic Medical Centre, University of Amsterdam, The Netherlands.
- Department of Immunopathology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Amsterdam UMC, Academic Medical Centre, University of Amsterdam, The Netherlands.
- Department of Immunopathology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Amsterdam UMC, Academic Medical Centre, University of Amsterdam, The Netherlands.
- Biologics Lab, Sanquin Diagnostic Services, Amsterdam, The Netherlands.
- Biologics Lab, Sanquin Diagnostic Services, Amsterdam, The Netherlands.
- Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam, The Netherlands.
- Biologics Lab, Sanquin Diagnostic Services, Amsterdam, The Netherlands.
- Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam; and Amsterdam Rheumatology and Immunology Center | Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands.
- Department of Immunopathology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Amsterdam UMC, Academic Medical Centre, University of Amsterdam; and Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam, The Netherlands.
- Department of Immunopathology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Amsterdam UMC, Academic Medical Centre, University of Amsterdam, The Netherlands. t.rispens@sanquin.nl
CER12177
2020 Vol.38, N°2
PI 0306, PF 0313
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PMID: 31498069 [PubMed]
Received: 19/02/2019
Accepted : 29/05/2019
In Press: 30/08/2019
Published: 26/03/2020
Abstract
OBJECTIVES:
Tumour necrosis factor (TNF) inhibitors like certolizumab, elicit an immunogenic response leading to the formation of anti-drug antibodies (ADAs). We sought to mechanistically investigate the relationship between certolizumab concentrations, ADAs, and the effective TNF neutralising capacity in sera of rheumatoid arthritis (RA) patients. TNF neutralising capacity of certolizumab was compared to the neutralising capacity of adalimumab.
METHODS:
Serum samples were collected from 40 consecutive certolizumab-treated RA patients at baseline and 4, 16, 28 and 52 weeks after treatment initiation [Dutch Trial Register NTR (Nederlands Trial Register) Trial NL2824 no. 2965]. Certolizumab concentration and ADA titre were measured with a certolizumab bridging enzyme-linked immunosorbent assay (ELISA) and a drug-tolerant radioimmunoassay (RIA), respectively. TNF neutralisation by certolizumab and adalimumab, in presence or absence of ADAs, was analysed with the TNF-sensitive WEHI bioassay.
RESULTS:
Despite a high incidence of ADAs during one year of follow-up (65%; 26/40 patients), certolizumab levels of >10 μg/ml were measured in most patients. The capacity for TNF neutralisation highly correlated with certolizumab serum concentration, whereas no association with ADAs was observed. Similar results were obtained for adalimumab. The relative in vitro neutralising potency was higher for certolizumab compared to adalimumab.
CONCLUSIONS:
Anti-certolizumab antibodies were detected in a large proportion of patients, but in most cases where ADAs were detected, certolizumab was also present in high concentrations, directly correlating with in vitro neutralising capacity. These results indicate that measurement of certolizumab drug levels, rather than ADAs, have direct clinical significance.
