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Development of novel PEGylation approaches based on non-covalent interactions

Defense Thèse de doctorat : Univ. Genève, 2011 - Sc. 4294 - 2011/02/04
Abstract Biopharmaceuticals hold important value for the treatment of severe diseases. However, stability concerns remain one of the main obstacles for their successful market authorization. Generally, physical instabilities (in particular aggregation), in vivo immunogenicity, and short circulation half-lifes due to enzymatic degradation and fast renal elimination pose major challenges. After PEGylation, the covalent conjugation of poly(ethylene glycol) to biopharmaceuticals, decreased enzymatic degradation, prolonged plasma half-lifes, reduced in vivo immunogenicity, and improved formulation stability have been reported. However, several challenges remain for covalent PEGylation: i) the chemical processing and subsequent purification needed to attach the PEG may represent further stress on the protein, resulting in increased aggregation and possible loss of activity, ii) heterogeneous products are obtained requiring separation and characterization, and iii) an observed reduced in vivo bioactivity resulting from decreased interactions of the drug with its receptor due to steric shielding by the PEG. As described in this thesis, we addressed the need for alternative PEGylation approaches by development of novel techniques based on non-covalent interactions.
Keywords Protein aggregationStabilitySalmon calcitoninProtein formulationNon-covalent PEGylation
URN: urn:nbn:ch:unige-158136
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MULLER, Claudia. Development of novel PEGylation approaches based on non-covalent interactions. Université de Genève. Thèse, 2011. doi: 10.13097/archive-ouverte/unige:15813 https://archive-ouverte.unige.ch/unige:15813

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Deposited on : 2011-05-16

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