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Protein Engineering, Vol 11, 1277-1283, Copyright © 1998 by Oxford University Press

ARTICLES

Single-chain Fv with manifold N-glycans as bifunctional scaffolds for immunomolecules

M Wang, LS Lee, A Nepomich, JD Yang, C Conover, M Whitlow and D Filpula
Enzon, Incorporated, Piscataway, NJ 08854-3969, USA.

Unlike natural antibodies, single-chain Fv (sFv) proteins normally lack asparagine-linked glycosylation. Many designed immunoconjugates and other therapeutics currently employ the advantageous conjugation chemistry or targeting properties provided by the glycoprotein oligosaccharide domain. sFv proteins with engineered N-glycan designs were evaluated in Pichia pastoris for glycosylation efficiency, expression level, oligosaccharide chain length and composition, and affinity. In contrast to nearly all natural glycoproteins, the engineered attachment of N-glycans conveniently near the polypeptide C- terminus was found to produce the optimal results. Furthermore, the percentage modification and chain length of the attached mannose chains were controllable by the use of tandem and overlapping Asn-X-Thr tripeptide sites. The glycosylated sFv mannose chains could be effectively conjugated to polyethylene glycol and the resulting conjugate displayed a 10-fold increased circulating life in mice. The potential to control polymer:sFv or drug:sFv molar ratios by site- specific conjugation may substantially improve the therapeutic efficacy of these minimal antigen-binding molecules.
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