These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: A new method to produce monoPEGylated dimeric cytokines shown with human interferon-α2b.
    Author: Chang CH, Rossi EA, Cardillo TM, Nordstrom DL, McBride WJ, Goldenberg DM.
    Journal: Bioconjug Chem; 2009 Oct 21; 20(10):1899-907. PubMed ID: 19736932.
    Abstract:
    We have adapted the dock-and-lock (DNL) method into a novel PEGylation technology using human interferon-α2b (IFN-α2b) as an example. Central to DNL is a pair of distinct protein domains involved in the natural association between cAMP-dependent protein kinase (PKA) and A-kinase anchoring proteins (AKAPs). These domains serve as linkers for site-specific conjugation of poly(ethylene glycol) (PEG) to a dimeric form of IFN-α2b. The combination of a fusion protein comprising IFN-α2b and the dimerization-and-docking domain (DDD) of PKA with a PEG-derivatized anchoring domain (AD) of an interactive AKAP results in facile formation of a trimeric complex containing two copies of IFN-α2b and a single site-specifically linked PEG chain. Three such monoPEGylated dimers of IFN-α2b have been generated, the first with a 20 kDa linear PEG, referred to as α2b-362, the second with a 30 kDa linear PEG (α2b-413), and the third with a 40 kDa branched PEG (α2b-457). All three retained antiviral and antitumor activity in vitro and showed improved pharmacokinetic properties in mice, which translated into potent and prolonged therapeutic efficacy in the Daudi human lymphoma xenograft model. We anticipate wide applicability of the DNL method for developing long-acting therapeutics that are dimeric and monoPEGylated with the increased bioavailability allowing for less frequent dosing.
    [Abstract] [Full Text] [Related] [New Search]