Document 0622
 DOCN  M9480622
 TI    Modification of CD4 immunoadhesin with monomethoxypoly(ethylene glycol)
       aldehyde via reductive alkylation.
 DT    9410
 AU    Chamow SM; Kogan TP; Venuti M; Gadek T; Harris RJ; Peers DH; Mordenti J;
       Shak S; Ashkenazi A; Department of Process Science, Genentech, Inc.,
       South San; Francisco, California 94080.
 SO    Bioconjug Chem. 1994 Mar-Apr;5(2):133-40. Unique Identifier : AIDSLINE
       MED/94304966
 AB    CD4 immunoadhesin (CD4-IgG) is a chimeric glycoprotein molecule
       comprised of the gp120-binding portion of human CD4 fused to the hinge
       and Fc portions of human IgG. As a candidate for human therapeutic use,
       CD4-IgG represents an important advance over soluble CD4, insofar as the
       systemic clearance in humans of CD4-IgG is significantly slower. In an
       effort to prolong its in vivo residence time even further, we have
       modified CD4-IgG chemically by attaching monomethoxypoly(ethylene
       glycol) (MePEG) moieties to lysine residues via reductive alkylation. We
       synthesized MePEG aldehyde and investigated reaction conditions for
       adding a range of MePEG moieties per protein molecule. At neutral pH in
       the presence of sodium cyanoborohydride, the reaction was sufficiently
       slow to allow for significant control over the extent of MePEGylation.
       Addition of 7.7 or 14.4 MePEG moieties to CD4-IgG resulted in an
       approximately 4- or 5-fold increase, respectively, in the persistence of
       the protein in rats, as compared with unmodified CD4-IgG. These results
       suggest that the therapeutic utility of a human receptor IgG chimera can
       be improved by MePEGylation technology, provided that the modified
       immunoadhesin retains its biological activity in vivo. Such modification
       can lead to a significant additional increase in the in vivo residence
       time of the protein.
 DE    Alkylation  Animal  CD4 Immunoadhesins/*CHEMISTRY  Electrophoresis,
       Polyacrylamide Gel  Human  HIV Envelope Protein gp120/METABOLISM
       IgG/CHEMISTRY  Male  Nuclear Magnetic Resonance  Oxidation-Reduction
       Peptide Mapping  Polyethylene Glycols/*CHEMISTRY/CHEMICAL SYNTHESIS
       Rats  Rats, Sprague-Dawley  Recombinant Proteins/CHEMISTRY  Sequence
       Analysis  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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