MODIFICATION OF CD4 IMMUNOADHESIN WITH MONOMETHOXYPOLY(ETHYLENE GLYCOL) ALDEHYDE VIA REDUCTIVE ALKYLATION

Citation
Sm. Chamow et al., MODIFICATION OF CD4 IMMUNOADHESIN WITH MONOMETHOXYPOLY(ETHYLENE GLYCOL) ALDEHYDE VIA REDUCTIVE ALKYLATION, Bioconjugate chemistry, 5(2), 1994, pp. 133-140
Citations number
53
Categorie Soggetti
Biology,Chemistry
Journal title
ISSN journal
10431802
Volume
5
Issue
2
Year of publication
1994
Pages
133 - 140
Database
ISI
SICI code
1043-1802(1994)5:2<133:MOCIWM>2.0.ZU;2-U
Abstract
CD4 immunoadhesin (CD4-IgG) is a chimeric glycoprotein molecule compri sed of the gp120-binding portion of human CD4 fused to the hinge and F c 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 mo dified CD4-IgG chemically by attaching monomethoxypoly(ethylene glycol ) (MePEG) moieties to lysine residues via reductive alkylation. We syn thesized MePEG aldehyde and investigated reaction conditions for addin g a range of MePEG moieties per protein molecule. At neutral pH in the presence of sodium cyanoborohydride, the reaction was sufficiently sl ow to allow for significant control over the extent of MePEGylation. A ddition of 7.7 or 14.4 MePEG moieties to CD4-IgG resulted in an approx imately 4- or 5-fold increase, respectively, in the persistence of the protein in rats, as compared with unmodified CD4-IgG. These results s uggest that the therapeutic utility of a human receptor IgG chimera ca n be improved by MePEGylation technology, provided that the modified i mmunoadhesin retains its biological activity in vivo. Such modificatio n can lead to a significant additional increase in the in vivo residen ce time of the protein.