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.
Centre for Immune Regulation, Department of Molecular Biosciences, University of Oslo, 0316 Oslo, Norway.
Jan Terje
JT
Andersen
Rikard
R
Pehrson
Vladimir
V
Tolmachev
Muluneh Bekele
MB
Daba
Lars
L
Abrahmsén
Caroline
C
Ekblad
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012549:Schistosoma japonicum; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D001426:Bacterial Proteins; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; C034284:IgG Fc-binding protein, Streptococcus; C508053:ERBB2 protein, human; C100688:Fc receptor, neonatal