Extending half-life by indirect targeting of the neonatal Fc receptor (FcRn) using a minimal albumin binding domain.

Abstract

The therapeutic and diagnostic efficiency of engineered small proteins, peptides, and chemical drug candidates is hampered by short in vivo serum half-life. Thus, strategies to tailor their biodistribution and serum persistence are highly needed. An attractive approach is to take advantage of the exceptionally long circulation half-life of serum albumin or IgG, which is attributed to a pH-dependent interaction with the neonatal Fc receptor (FcRn) rescuing these proteins from intracellular degradation. Here, we present molecular evidence that a minimal albumin binding domain (ABD) derived from streptococcal protein G can be used for efficient half-life extension by indirect targeting of FcRn. We show that ABD, and ABD recombinantly fused to an Affibody molecule, in complex with albumin does not interfere with the strictly pH-dependent FcRn-albumin binding kinetics. The same result was obtained in the presence of IgG. An in vivo study performed in rat confirmed that the clinically relevant human epidermal growth factor 2 (HER2)-targeting Affibody molecule fused to ABD has a similar half-life and biodistribution profile as serum albumin. The proof-of-concept described may be broadly applicable to extend the in vivo half-life of short lived biological or chemical drugs ultimately resulting in enhanced therapeutic or diagnostic efficiency, a more favorable dosing regimen, and improved patient compliance.

DOI: 10.1074/jbc.M110.164848

5 Figures and Tables

0502011201220132014201520162017
Citations per Year

221 Citations

Semantic Scholar estimates that this publication has 221 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Andersen2011ExtendingHB, title={Extending half-life by indirect targeting of the neonatal Fc receptor (FcRn) using a minimal albumin binding domain.}, author={Jan Terje Andersen and Rikard Pehrson and Vladimir Tolmachev and Muluneh Bekele Daba and Lars Bertil Abrahms{\'e}n and Caroline Ekblad}, journal={The Journal of biological chemistry}, year={2011}, volume={286 7}, pages={5234-41} }