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- Deisenhammer, F, et al.
(författare)
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Prediction of natalizumab anti-drug antibodies persistency
- 2019
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 25:3, s. 392-398
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Tidskriftsartikel (refereegranskat)abstract
- Anti-drug antibodies (ADA) against natalizumab develop early during treatment. ADA persistency is defined by two consecutive positive results as performed by the current qualitative ELISA assay (positive/negative). Very little is known about the magnitude of the natalizumab ADA response and persistency. Design/methods: We developed a highly sensitive natalizumab ADA titration assay on the Meso Scale Discovery (MSD) platform and a pharmacokinetic (PK) assay. We included 43 patients with a positive ELISA-ADA result within 6 months of treatment initiation (baseline) of whom a follow-up serum sample was available 12–30 months after treatment start. MSD-ADA titres and drug levels were measured. Results: Median MSD-ADA titre at baseline was 4881 and 303 at follow-up. A titre of >400 at baseline had a 94% sensitivity and 89% specificity to predict ADA persistency. Reversion to ADA negativity occurred in 10 patients with mean drug levels of 10.8 μg/mL. The median trough drug level in ADA-positive samples was 0 µg/mL. PK levels and ADA titres correlated strongly negatively ( r = −0.67). Conclusion: High baseline natalizumab ADA titres accurately predict persistency. Despite continuous treatment, the majority of patients with persistent ADA had no detectable drug levels indicating loss of efficacy in line with phase 3 study results.
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- Haessler, S, et al.
(författare)
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A Genetic Association Test Accounting for Skewed X-Inactivation With Application to Biotherapy Immunogenicity in Patients With Autoimmune Diseases
- 2022
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Ingår i: Frontiers in medicine. - : Frontiers Media SA. - 2296-858X. ; 9, s. 856917-
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Tidskriftsartikel (refereegranskat)abstract
- Despite being assayed on commercialized DNA chips, the X chromosome is commonly excluded from genome-wide association studies (GWAS). One of the reasons is the complexity to analyze the data taking into account the X-chromosome inactivation (XCI) process in women and in particular the XCI process with a potentially skewed pattern. This is the case when investigating the role of X-linked genetic variants in the occurrence of anti-drug antibodies (ADAs) in patients with autoimmune diseases treated by biotherapies. In this context, we propose a novel test statistic for selecting loci of interest harbored by the X chromosome that are associated with time-to-event data taking into account skewed X-inactivation (XCI-S). The proposed statistic relies on a semi-parametric additive hazard model and is straightforward to implement. Results from the simulation study show that the test provides higher power gains than the score tests from the Cox model (under XCI process or its escape) and the Xu et al.'s XCI-S likelihood ratio test. We applied the test to the data from the real-world observational multicohort study set-up by the IMI-funded ABIRISK consortium for identifying X chromosome susceptibility loci for drug immunogenicity in patients with autoimmune diseases treated by biotherapies. The test allowed us to select two single nucleotide polymorphisms (SNPs) with high linkage disequilibrium (rs5991366 and rs5991394) located in the cytoband Xp22.2 that would have been overlooked by the Cox score tests and the Xu et al.'s XCI-S likelihood ratio test. Both SNPs showed a similar protective effect for drug immunogenicity without any occurrence of ADA positivity for the homozygous females and hemizygous males for the alternative allele. To our knowledge, this is the first study to investigate the association between X chromosome loci and the occurrence of anti-drug antibodies. We think that more X-Chromosome GWAS should be performed and that the test is well-suited for identifying X-Chromosome SNPs, while taking into account all patterns of the skewed X-Chromosome inactivation process.
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- Sun, Ying, et al.
(författare)
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Asymmetrical effects of mesophyll conductance on fundamental photosynthetic parameters and their relationships estimated from leaf gas exchange measurements
- 2014
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Ingår i: Plant, Cell and Environment. - : John Wiley & Sons. - 0140-7791 .- 1365-3040. ; 37:4, s. 978-994
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Tidskriftsartikel (refereegranskat)abstract
- Worldwide measurements of nearly 130 C3 species covering all major plant functional types are analysed in conjunction with model simulations to determine the effects of mesophyll conductance (gm) on photosynthetic parameters and their relationships estimated fromA/Ci curves. We find that an assumption of infinite gm results in up to 75% underestimation for maximum carboxylation rate Vcmax, 60% for maximum electron transport rate Jmax, and 40% for triose phosphate utilization rate Tu. Vcmax is most sensitive, Jmax is less sensitive, and Tuhas the least sensitivity to the variation of gm. Because of this asymmetrical effect of gm, the ratios of Jmax to Vcmax, Tu to Vcmax and Tu toJmax are all overestimated. An infinite gm assumption also limits the freedom of variation of estimated parameters and artificially constrains parameter relationships to stronger shapes. These findings suggest the importance of quantifying gm for understanding in situphotosynthetic machinery functioning. We show that a nonzero resistance to CO2 movement in chloroplasts has small effects on estimated parameters. A non-linear function with gm as input is developed to convert the parameters estimated under an assumption of infinite gm to proper values. This function will facilitate gm representation in global carbon cycle models.
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- Ternant, D, et al.
(författare)
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TROUGH CONCENTRATION AND ESTIMATED CLEARANCE CAN DETECT IMMUNOGENICITY TO ADALIMUMAB IN RA PATIENTS: A PROSPECTIVE LONGITUDINAL MULTICENTRE STUDY
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 1449-1450
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Anti-Drug Antibodies (ADA) to adalimumab increase drug clearance in rheumatoid arthritis (RA).Objectives:To study the ability of drug concentration or estimating clearance to identify ADA to adalimumab.Methods:Adalimumab concentration was measured with a validated ELISA. ADA was measured using a capture ELISA (Theradiag®) and the Meso scale discovery (MSD) platform. Using a bayesian PK model, adalimumab clearance was estimated at 1, 3, 6 and 12 months. Predictions for ADA presence were calculated, and the correlation between ADA and adalimumab clearance was analysed.Results:We analyzed 108 samples from 53 RA patients. Serum concentrations and clearance estimates showed good prediction performance for ADA presence (Table 1). There was a correlation between adalimumab clearance and ADA (Figure 1).Table 1.Immunogenicity prediction of adalimumab, using trough concentration or estimated clearanceTime of visitADA methodAdalimumab trough concentrationAdalimumab estimated clearanceAUC ROCp-valueAUC ROCp-valueMonth 1THER.55.6411.52.8358MSD.65.0821.61.1872Month 3THER.89.0006.91.0003MSD.73.0096.72.0131Month 6THER.95.0035.95.0035MSD.85.0004.84.0006Month 12THER.87.0045.86.0057MSD.88.0002.88.0002Figure 1.correlation between adalimumab estimated clearance and ADA as provided by the Meso scale discovery (MSD) plateformConclusion:Adalimumab concentration and clearance should be considered as reliable predictors for ADA presence in RA patients.Acknowledgments:Measurement of adalimumab serum concentrations was performed within the ‘Centre pilote de suivi biologique des anticorps thérapeutiques’ (CePiBAc)– Pilot centre for therapeutic antibodies monitoring platform of Tours University Hospital, which was cofinanced by the European Regional Development Fund (ERDF). We thank Oscar Knight, Delphine Delord and Fabien Giannoni (ABIRISK lab technician), Caroline Brochon and Anne Claire Duveau (CePIBAc), Aliette Decock-Giraudaud (Centre de ressource-Biobank), Sophie Tourdot (ABRISIK Project manager), Aline Doublet (Assistance Publique Hopitaux de Paris, Agnès Hincelin-Méry (Sanofi, Chilly-Mazarin, France). This work has received support from the Innovative Medicines Initiative Joint Undertaking (IMI JU) under grant agreement no. 115303, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions.Disclosure of Interests:David Ternant Consultant of: Sanofi and Amgen., Jamal Elhasnaoui: None declared, Natacha Szely: None declared, Salima Hacein-Bey: None declared, Aude Gleizes: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Jessica Manson: None declared, Martin SOUBRIER: None declared, Olilvier Brocq: None declared, Jérôme Avouac: None declared, Anna Fogdell-Hahn Grant/research support from: Biogen Idec and Pfizer., Consultant of: Pfizer, Biogen, Merck-Serono, and Sanofi-Genzyme., Pierre Dönnes: None declared, Gilles Paintaud Grant/research support from: Amgen, Genzyme (Sanofi), Lilly, Merck, Novartis, and Roche Pharma., Consultant of: Chugai, Novartis and Shire (Takeda), with remunerations received by his institution., Céline Desvignes: None declared, Florian Deisenhammer: None declared, Sebastian Spindeldreher Employee of: Novartis, Marc Pallardy: None declared, Xavier Mariette Consultant of: BMS, Gilead, Medimmune, Novartis, Pfizer, Servier, UCB, Denis Mulleman Grant/research support from: Non-governmental organisation Lions Club Tours Val de France, French Society for Rheumatology., Consultant of: Pfizer, Novartis.
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| 13. |
- Yi, Chuixiang, et al.
(författare)
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Climate control of terrestrial carbon exchange across biomes and continents
- 2010
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the relationships between climate and carbon exchange by terrestrial ecosystems is critical to predict future levels of atmospheric carbon dioxide because of the potential accelerating effects of positive climate-carbon cycle feedbacks. However, directly observed relationships between climate and terrestrial CO2 exchange with the atmosphere across biomes and continents are lacking. Here we present data describing the relationships between net ecosystem exchange of carbon (NEE) and climate factors as measured using the eddy covariance method at 125 unique sites in various ecosystems over six continents with a total of 559 site-years. We find that NEE observed at eddy covariance sites is (1) a strong function of mean annual temperature at mid-and high-latitudes, (2) a strong function of dryness at mid-and low-latitudes, and (3) a function of both temperature and dryness around the mid-latitudinal belt (45 degrees N). The sensitivity of NEE to mean annual temperature breaks down at similar to 16 degrees C (a threshold value of mean annual temperature), above which no further increase of CO2 uptake with temperature was observed and dryness influence overrules temperature influence.
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| 14. |
- Jensen, Poul Erik H., et al.
(författare)
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Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis : Results from the ABIRISK prospective cohort study
- 2019
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Ingår i: Journal of Neuroimmunology. - : Elsevier. - 0165-5728 .- 1872-8421. ; 326, s. 19-27
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Tidskriftsartikel (refereegranskat)abstract
- Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.
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