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Verfasst von:Faber, Bart [VerfasserIn]   i
 Houard, Sophie [VerfasserIn]   i
 Havelange, Nicolas [VerfasserIn]   i
Titel:Production, quality control, stability and pharmacotoxicity of a malaria vaccine comprising three highly similar PfAMA1 protein molecules to overcome antigenic variation
Verf.angabe:Bart W. Faber, Stephan Hellwig, Sophie Houard, Nicolas Havelange, Jürgen Drossard, Hubert Mertens, Alexander Croon, Robin Kastilan, Richard Byrne, Nicole van der Werff, Marjolein van der Eijk, Alan W. Thomas, Clemens H.M. Kocken, Edmond J. Remarque
Fussnoten:Gesehen am 28.08.2017
Titel Quelle:Enthalten in: Public Library of Science: PLoS one
Jahr Quelle:2016
Band/Heft Quelle:11(2016,10) Artikel-Nummer e0164053, 32 Seiten
ISSN Quelle:1932-6203
Abstract:Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading asexual blood stage vaccine candidate for malaria. In preparation for clinical trials, three Diversity Covering (DiCo) PfAMA1 ectodomain proteins, designed to overcome the intrinsic polymorphism that is present in PfAMA1, were produced under Good Manufacturing Practice (GMP) in Pichia pastoris. Using identical methodology, the 3 strains were cultivated in 70-L scale fed-batch fermentations and PfAMA1-DiCos were purified by two chromatography steps, an ultrafiltration/diafiltration procedure and size exclusion chromatography, resulting in highly pure (>95%) PfAMA1-DiCo1, PfAMA1 DiCo2 and PfAMA1 DiCo3, with final yields of 1.8, 1.9 and 1.3 gram, respectively. N-terminal determinations showed that approximately 50% of each of the proteins lost 12 residues from their N-terminus, in accordance with SDS-PAGE (2 main bands) and MS-data. Under reducing conditions a site of limited proteolytic cleavage within a disulphide bonded region became evident. The three proteins quantitatively bound to the mAb 4G2 that recognizes a conformational epitope, suggesting proper folding of the proteins. The lyophilized Drug Product (1:1:1 mixture of PfAMA1-DiCo1, DiCo2, DiCo3) fulfilled all pre-set release criteria (appearance, dissolution rate, identity, purity, protein content, moisture content, sub-visible particles, immuno-potency (after reconstitution with adjuvant), abnormal toxicity, sterility and endotoxin), was stable in accelerated and real-time stability studies at -20°C for over 24 months. When formulated with adjuvants selected for clinical phase I evaluation, the Drug Product did not show adverse effect in a repeated-dose toxicity study in rabbits. The Drug Product has entered a phase Ia/Ib clinical trial.
DOI:doi:10.1371/journal.pone.0164053
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Kostenfrei: Verlag: http://dx.doi.org/10.1371/journal.pone.0164053
 Kostenfrei: Verlag: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164053
 DOI: https://doi.org/10.1371/journal.pone.0164053
Datenträger:Online-Ressource
Sprache:eng
K10plus-PPN:1562795732
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