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


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

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@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} }