Van Bezooijen J.S.,Hospital Pharmacy |
Schreurs M.W.J.,Erasmus University Rotterdam |
Te Velthuis H.,Sanquin Reagents |
Te Velthuis H.,Sanquin Research and Landsteiner Laboratory |
And 3 more authors.
Therapeutic Drug Monitoring | Year: 2017
Aim: Etanercept has shown to mediate a favorable effect on immune-mediated inflammatory diseases (IMID), including plaque psoriasis. Therapeutic drug monitoring (TDM) of etanercept could improve clinical outcome and cost-effectiveness. A high intrapatient variability (IPV) of etanercept trough concentrations at standard dosing would reduce the feasibility of therapeutic drug monitoring. Studies have focused on the interpatient differences associated with the exposure to biologics. The aim of this study was to determine IPV of etanercept and correlate etanercept trough concentrations and IPV with treatment response. Methods: Repetitive serum samples of 29 psoriasis patients on standard etanercept maintenance treatment were collected. In these samples, etanercept trough concentrations were determined and IPV was assessed in relation to response to treatment. Results: The median IPV of etanercept trough concentrations was 33.7% (Q1 = 21.3% and Q3 = 51.7%) ranging from 8% to 155%. All 6 nonresponders showed an IPV at or above the median value of 33.7%. The 6 nonresponders showed a higher IPV as compared to the 23 responders (53.9% versus 24.2%; P = 0.031). The mean etanercept trough concentration for each patient ranged from 0.7 to 6.8 mcg/mL, with a median trough concentration of 2.7 mcg/mL. Patients with an IPV above the median had lower mean etanercept trough concentrations compared to patients with an IPV below the median (1.96 mcg/mL, 95% CI, 1.7-2.4 versus 3.2 mcg/mL, 95% CI, 2.7-4.0; P = 0.001). Conclusions: The median IPV of etanercept trough concentrations in this study population was 33.7%. A higher IPV was correlated with lower etanercept trough concentrations and with nonresponsiveness. Prospective trials are required to demonstrate the value of adjusting the etanercept dose based on drug trough concentrations. The relatively high IPV observed in this study may complicate therapeutic drug monitoring. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Dekkers G.,University of Amsterdam |
Treffers L.,University of Amsterdam |
Plomp R.,Leiden University |
Bentlage A.E.H.,University of Amsterdam |
And 14 more authors.
Frontiers in Immunology | Year: 2017
Glycosylation of the immunoglobulin G (IgG)-Fc tail is required for binding to Fc-gamma receptors (FcγRs) and complement-component C1q. A variety of IgG1-glycoforms is detected in human sera. Several groups have found global or antigen-specific skewing of IgG glycosylation, for example in autoimmune diseases, viral infections, and alloimmune reactions. The IgG glycoprofiles seem to correlate with disease outcome. Additionally, IgG-glycan composition contributes significantly to Ig-based therapies, as for example IVIg in autoimmune diseases and therapeutic antibodies for cancer treatment. The effect of the different glycan modifications, especially of fucosylation, has been studied before. However, the contribution of the 20 individual IgG glycoforms, in which the combined effect of all 4 modifications, to the IgG function has never been investigated. Here, we combined six glyco-engineering methods to generate all 20 major human IgG1-glycoforms and screened their functional capacity for FcγR and complement activity. Bisection had no effect on FcγR or C1q-binding, and sialylation had no- or little effect on FcγR binding. We confirmed that hypo-fucosylation of IgG1 increased binding to FcγRIIIa and FcγRIIIb by ~17-fold, but in addition we showed that this effect could be further increased to ~40-fold for FcγRIIIa upon simultaneous hypo-fucosylation and hyper-galactosylation, resulting in enhanced NK cell-mediated antibody-dependent cellular cytotoxicity. Moreover, elevated galactosylation and sialylation significantly increased (independent of fucosylation) C1q-binding, downstream complement deposition, and cytotoxicity. In conclusion, fucosylation and galactosylation are primary mediators of functional changes in IgG for FcγR- and complement-mediated effector functions, respectively, with galactose having an auxiliary role for FcγRIII-mediated functions. This knowledge could be used not only for glycan profiling of clinically important (antigen-specific) IgG but also to optimize therapeutic antibody applications. © 2017 Dekkers, Treffers, Plomp, Bentlage, de Boer, Koeleman, Lissenberg-Thunnissen, Visser, Brouwer, Mok, Matlung, van den Berg, van Esch, Kuijpers, Wouters, Rispens, Wuhrer and Vidarsson.
Te Velthuis H.,Sanquin Reagents |
Te Velthuis H.,Sanquin Research |
Knop I.,Sanquin Reagents |
Stam P.,Sanquin Reagents |
And 9 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2011
Background: High serum concentrations of monoclonal free light chain (FLC) kappa or lambda are markers of plasma cell dyscrasia. Methods: We developed new, latex-enhanced, specific nephelometric assays based on monoclonal antibodies for the determination of FLC kappa and lambda in serum, EDTA plasma and Li-heparin plasma for use on the Siemens BN™ systems. Results: Reference ranges were determined from 369 samples: FLC kappa 6.7-22.4 mg/L, FLC lambda 8.3-27.0 mg/L and kappa/lambda ratio 0.31-1.56. Protection from falsely low results due to antigen excess is obtained with a built-in pre-reaction in the assay protocols. Lot-to-lot consistency between three different lots of reagent, calibrators and supplementary reagent lots showed normalized differences <7.5%. The reproducibility of serum samples varied between 4% and 7%. The method comparison with Freelite™ assays showed normalized differences of 19.7%, 32.7% and 21.7%, respectively, for FLC kappa, lambda and ratio, correlations of 0.94, 0.77 and 0.73, and concordance rates of 99.2%, 94.2% and 95%. Conclusions: N Latex FLC demonstrates high precision, good lot-to-lot consistency and freedom from a high-dose hook effect. The method comparison between Freelite™ and the N Latex FLC assays showed good clinical concordance. Further studies need to reveal the clinical value of the new FLC assays. © 2011 by Walter de Gruyter Berlin Boston.