Fehraltorf, Switzerland
Fehraltorf, Switzerland

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Droste P.,TU Braunschweig | Droste P.,Celerion Switzerland AG | Frenzel A.,TU Braunschweig | Frenzel A.,YUMAB GmbH | And 7 more authors.
BMC Biotechnology | Year: 2015

Background: Beside neurofibrillary tangles, amyloid plaques are the major histological hallmarks of Alzheimer's disease (AD) being composed of aggregated fibrils of β-amyloid (Aβ). During the underlying fibrillogenic pathway, starting from a surplus of soluble Aβ and leading to mature fibrils, multiple conformations of this peptide appear, including oligomers of various shapes and sizes. To further investigate the fibrillization of β-amyloid and to have tools at hand to monitor the distribution of aggregates in the brain or even act as disease modulators, it is essential to develop highly sensitive antibodies that can discriminate between diverse aggregates of Aβ. Results: Here we report the generation and characterization of a variety of amyloid-β specific human and human-like antibodies. Distinct fractions of monomers and oligomers of various sizes were separated by size exclusion chromatography (SEC) from Aβ42 peptides. These antigens were used for the generation of two Aβ42 specific immune scFv phage display libraries from macaque (Macaca fascicularis). Screening of these libraries as well as two naïve human phage display libraries resulted in multiple unique binders specific for amyloid-β. Three of the obtained antibodies target the N-terminal part of Aβ42 although with varying epitopes, while another scFv binds to the aα-helical central region of the peptide. The affinities of the antibodies to various Aβ42 aggregates as well as their ability to interfere with fibril formation and disaggregation of preformed fibrils were determined. Most significantly, one of the scFv is fibril-specific and can discriminate between two different fibril forms resulting from variations in the acidity of the milieu during fibrillogenesis. Conclusion: We demonstrated that the approach of animal immunization and subsequent phage display based antibody selection is applicable to generate highly specific anti β-amyloid scFvs that are capable of accurately discriminating between minute conformational differences. © 2015 Droste et al.


PubMed | Friedrich - Alexander - University, Erlangen - Nuremberg, Medizinischer Dienst der Krankenversicherungen Niedersachsen, Center for Addiction Research e and Celerion Switzerland AG
Type: | Journal: Alcohol (Fayetteville, N.Y.) | Year: 2016

Preclinical and clinical studies show associations between testosterone and brain-derived neurotrophic growth factor (BDNF) serum levels. BDNF and testosterone have been independently reported to influence alcohol consumption. Therefore, we aimed to investigate a possible interplay of testosterone and BDNF contributing to alcohol dependence. Regarding possible interplay of testosterone and BDNF and the activity of the hypothalamic pituitary axis (HPA), we included cortisol serum levels in our research. We investigated testosterone and BDNF serum levels in a sample of 99 male alcohol-dependent patients during alcohol withdrawal (day 1, 7, and 14) and compared them to a healthy male control group (n = 17). The testosterone serum levels were significantly (p < 0.001) higher in the patients group than in the control group and decreased significantly during alcohol withdrawal (p < 0.001). The decrease of testosterone serum levels during alcohol withdrawal (days 1-7) was significantly associated with the BDNF serum levels (day 1: p = 0.008). In a subgroup of patients showing high cortisol serum levels (putatively mirroring high HPA activity), we found a significant association of BDNF and testosterone as well as with alcohol craving measured by the Obsessive and Compulsive Drinking Scale (OCDS). Our data suggest a possible association of BDNF and testosterone serum levels, which may be relevant for the symptomatology of alcohol dependence. Further studies are needed to clarify our results.


Kleimann A.,Hannover Medical School | Kotsiari A.,Hannover Medical School | Sperling W.,Friedrich - Alexander - University, Erlangen - Nuremberg | Groschl M.,Celerion Switzerland AG | And 6 more authors.
Journal of Neural Transmission | Year: 2015

We examined potential changes in brain-derived neurotrophic factor (BDNF) serum levels and promoter methylation of the BDNF gene in 11 patients with treatment-resistant major depressive disorder during a series of electroconvulsive therapy (ECT). Blood samples were taken before, 1 and 24 h after ECT treatment sessions 1, 4, 7 and 10. Patients remitting under ECT had significantly lower mean promoter methylation rates, especially concerning the exon I promoter, compared to non-remitters (both p < 0.002). These findings may point to a depression subtype in which ECT is particularly beneficial. © 2014, Springer-Verlag Wien.


Van Baar B.L.M.,QPS Netherlands B.V. | Verhaeghe T.,Janssen R and D | Heudi O.,Novartis | Rohde M.,Lundbeck | And 6 more authors.
Bioanalysis | Year: 2013

Background: In the framework of wider exploration of the application of dried blood spots (DBS) in bioanalysis, by the DBS consortium of the European Bioanalytical Forum, one team of five laboratories investigated the merits of the various ways of IS addition prior to LC-MS/MS analysis. A set of 22 pharmaceutical compounds with log P in the range of 0-10 was selected for this purpose. Assessments were made of precision, recovery, and of the effects of prolonged storage. Results: Assay precision was not significantly different for 3 month-aged samples as compared with 'fresh" samples stored for 7-22 days. Extraction recovery from 3 month-aged spots decreased for some of the analytes; the most widely employed addition of IS in the extraction solvent does not compensate for recovery in such cases. Conclusion: From the overall results, it is clear that there is no 'one size fits all" approach to IS addition in DBS bioanalysis. © 2013 Future Science Ltd.


Edkins T.J.,Edkins Pharma Services LLC | Koller-Eichhorn R.,Koller and Koller LLC | Alhadeff J.A.,Center Valley | Mayer U.,Celerion Switzerland AG | And 2 more authors.
Clinical and Vaccine Immunology | Year: 2012

Collagenase Clostridium histolyticum (CCH) contains a fixed ratio of class I (AUX-I) and class II (AUX-II) collagenases and is used as treatment for Dupuytren's contracture. These two Zn-dependent enzymes, produced by the Gram-positive bacterium Clostridium histolyticum, are related functionally to matrix metalloproteinases (MMPs) which, among other functions, degrade the extracellular matrix. Since AUX-I and AUX-II exhibit sequence similarities to human MMPs, we assessed MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3) for cross-reactivity with anti-AUX-I and anti-AUX-II antibodies in patient serum. Serum samples from 71 subjects enrolled in a long-term clinical study (58 males and 13 females; 63 ± 10 years old [mean ± standard error]) were evaluated for cross-reactivity with the five MMPs using the two validated enzyme-linked immunosorbent assays (ELISAs). Inhibition cutoff points for anti-AUX-I and anti-AUX-II antibodies were based on assay inhibition obtained with a nonspecific protein, bovine gamma globulin, which was tested for each clinical sample. No MMP cross-reactivity was found for any of the 71 clinical antibody-positive sera evaluated. Sequence identity assessments indicated minimal, nonmeaningful alignments of the MMPs and AUX-I/AUX-II. Furthermore, clinical adverse event assessments indicated no safety signals related to MMP inhibition. The bioanalytical results, sequence identity, and clinical assessments consistently did not demonstrate cross-reactivity between CCH antidrug antibodies and endogenous human matrix metalloproteinases. The results presented here suggest that treatment of Dupuytren's contracture patients with CCH does not lead to any clinical adverse events associated with MMP inhibition. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Pihl S.,Lundbeck | Andersen L.,Novo Nordisk AS | Bruzelius K.,Ferring Pharmaceuticals A S | Schiebl C.,Celerion Switzerland AG | Golob M.,Merck Serono
Bioanalysis | Year: 2015

Aim: Long-Term stability testing of drug candidates in biological matrix is a key parameter in bioanalytical method validation. The European Bioanalysis Forum formed a Topic Team to evaluate the use of isochronic design for long-Term stability testing of large molecules. Method: Isochronic design is based on storage of samples at a reference temperature (below-130°C) where the samples are considered stable. The stability samples are stored at the intended storage temperature and then transferred to the reference temperature, while a set of reference samples is stored the entire storage period at the reference temperature. Stability and reference samples will then be analyzed in one run at the end of the storage period. The mean concentrations of the stability samples are compared either to their nominal concentrations or to the mean concentrations of the reference samples. Conclusion: The design minimizes day-To-day variation, reduces workload and adds to the flexibility in the laboratory. © 2015 Future Science Ltd.


Butikofer L.,Celerion Switzerland AG | Lemaillet G.,Celerion Switzerland AG | Faust H.,Celerion Switzerland AG
Bioanalysis | Year: 2012

Background: Drug tolerance of anti-drug antibody (ADA) assays is becoming increasingly important due to the high number of newly emerging long-acting drugs. Methods to estimate and improve drug tolerance in ADA assays are needed. Results: The relevance and precision of drug tolerance estimates in a bridging ELISA depended on characteristics and concentration of the surrogate control antibody together with assay cut point level. Stepwise and coincubation procedures were optimized for drug tolerance and sensitivity by adapting concentrations of reagents used for capture and detection of ADAs. In combination with acid treatment of samples, increase in drug tolerance of over 20-fold was achieved without losing sensitivity in two different assays. Acid treatment reduced drug interference observed in preclinical samples and prevented underestimation of ADA response. Conclusion: In a risk-based approach it may be possible to reliably predict in vivo drug tolerance using carefully chosen surrogate controls. General guidelines for development of drug-tolerant bridging ELISAs are presented. © 2012 Future Science Ltd.


Glahn A.,Hannover Medical School | Knorrenschild R.R.,Clinic for Psychiatry | Rhein M.,Hannover Medical School | Nassab M.H.,Hannover Medical School | And 6 more authors.
European Addiction Research | Year: 2014

Disturbances of volume-regulating peptides like vasopressin (AVP) and atrial natriuretic peptide (ANP) have been described in early abstinent alcohol-dependent patients. In a longitudinal approach, we investigated whether changes in AVP and ANP serum levels correlated to cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoters on days 1, 7 and 14 of alcohol withdrawal. We analyzed the blood samples of 99 patients suffering from alcohol dependence alongside age- and BMI-matched controls. Concerning AVP promoter methylation, we observed an interaction between time of measurement and CpG loci with CpG 2 showing a significant increase in methylation from day 1 to 14. Serum levels of AVP were significantly decreased in the patient group. Compared to healthy controls, promoter-related DNA methylation of the ANP promoter was significantly reduced on days 7 and 14. Moreover, we detected a significant interaction between CpG position and group. In both cases the difference was mainly observed at CpG 1. The present study shows significant changes in the methylation status of individual CpG sites of AVP and ANP. Observing respective alterations of AVP serum protein levels in alcohol-dependent patients during detoxification treatment, we consider methylation as a possible mode of regulation for these proteins during alcohol detoxification. © 2013 S. Karger AG, Basel.


PubMed | Novo Nordisk AS, Ferring Pharmaceuticals A S, Merck Serono, Lundbeck and Celerion Switzerland AG
Type: Journal Article | Journal: Bioanalysis | Year: 2015

Long-term stability testing of drug candidates in biological matrix is a key parameter in bioanalytical method validation. The European Bioanalysis Forum formed a Topic Team to evaluate the use of isochronic design for long-term stability testing of large molecules.Isochronic design is based on storage of samples at a reference temperature (below -130C) where the samples are considered stable. The stability samples are stored at the intended storage temperature and then transferred to the reference temperature, while a set of reference samples is stored the entire storage period at the reference temperature. Stability and reference samples will then be analyzed in one run at the end of the storage period. The mean concentrations of the stability samples are compared either to their nominal concentrations or to the mean concentrations of the reference samples.The design minimizes day-to-day variation, reduces workload and adds to the flexibility in the laboratory.


PubMed | Celerion Switzerland AG
Type: Evaluation Studies | Journal: Bioanalysis | Year: 2012

Drug tolerance of anti-drug antibody (ADA) assays is becoming increasingly important due to the high number of newly emerging long-acting drugs. Methods to estimate and improve drug tolerance in ADA assays are needed.The relevance and precision of drug tolerance estimates in a bridging ELISA depended on characteristics and concentration of the surrogate control antibody together with assay cut point level. Stepwise and coincubation procedures were optimized for drug tolerance and sensitivity by adapting concentrations of reagents used for capture and detection of ADAs. In combination with acid treatment of samples, increase in drug tolerance of over 20-fold was achieved without losing sensitivity in two different assays. Acid treatment reduced drug interference observed in preclinical samples and prevented underestimation of ADA response.In a risk-based approach it may be possible to reliably predict in vivo drug tolerance using carefully chosen surrogate controls. General guidelines for development of drug-tolerant bridging ELISAs are presented.

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