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In vivo polysialylation to enhance the pharmacokinetic profile of therapeutic proteins and immunomodulation

Ref-Nr: TA-2016-10 Universität für Bodenkultur Wien


Kurzfassung

An important factor for the clinical and commercial success of protein based drugs lies in optimal bioavailability, which is a major challenge for pharmaceutical industry. It has been shown that Polysialic acid (PolySia), large negatively charged sugar chains, has the ability to modulate protein pharmacokinetics, bio-distribution and bioavailability. In addition, PolySia contributes to anti-inflammatory processes.


Hintergrund

PolySia is a unique glycopolymer of α2,8-linked sialic acid residues, originally identified on neural cell adhesion molecule (NCAM) of vertebrates. PolySia mediates diverse biological functions and has great potential in therapeutic use. Chemical or in vitro PolySia engineering has made a remarkable impact on pharmacokinetic properties of recombinant therapeutic glycoproteins. Here we demonstrate the in vivo protein PolySia by intensive glycoengineering of a plant-based expression platform.


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Lösung

Nicotiana benthamiana plants are well suited for the generation of therapeutic glycoproteins with defined glycan structures. By genetic deconstruction and overexpression of mammalian glycosylation proteins we have developed plant glycosylation mutants which can efficiently synthesize mammalian like di-sialylated N-glycan structures. To further elongate di-sialylated structures towards PolySia we transiently expressed two human polysialyltransferases in our engineered plants along with Ig5FN1, the naturally polysialylated domain of NCAM. HPLC analysis of the plant produced Ig5FN1 exhibited N-glycans carrying a chain length exceeding 40 sialic acid residues.


Vorteile

  • PolySia is a natural product thus biodegradable and non immunogenic
  • Extended half lives provide lower frequency of dosage-applications
  • Extended half lives improved pharmacological activity
  • PolySia protects proteins from degradation

Anwendungsbereiche

One of the major concerns in recombinant biologics is  rapid  clearance from blood stream. The attachment of polymers like polyethylene glycol (PEG) and more recently PolySia is a promising approach to overcome this limitation.


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Wissenstransferzentrum Ost (WTZ Ost)

Mag.a Michaela Amstötter-Visotschnig
+43 1 47654 33033
michael.amstötter-visotschnig@boku.ac.at
www.wtz-ost.at
Adresse
Peter-Jordan-Straße 70/III
1190 Wien



Entwicklungsstand

Teststadium


Stichworte

polysialic acid, polysialylation, glycopolymer, plant expression system

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