Optimizing the binding affinity of a carrier protein: A case study on the interaction between soluble ifnar2 and interferon β

Tal Peleg-Shulman, Laila C. Roisman, Gordin Zupkovitz, Gideon Schreiber

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Prolonging the circulatory half-life of low mass protein drugs can be achieved either by administration of a pro-drug or through co-injection with a carrier protein that will slowly release the active protein. The rate of release is concentration and affinity dependent. The optimal relationship between these two in prolonging the half-life of a pro-drug is the focus of this work. Interferon (IFN) β is one of the most widely used protein drugs in the clinic. Here, we show that the circulatory half-life of IFNβ can be significantly extended by co-administration with the extracellular domain of the IFN receptor ifnar2 (ifnar2-EC). To investigate the concentration/affinity relation, a range of tighter binding ifnar2-EC mutants was designed that bind IFNβ, but not IFNα2, up to 50-fold tighter compared with the wild-type ifnar2-EC. This increased affinity is related to a slower dissociation rate, whereas the association of IFNβ with ifnar2-EC is already near optimum. Using the wild-type and mutant receptors, we investigated their potential in occluding IFNβ from circulation in a tissue culture assay, as well as in rats. To determine the potential of ifnar2-EC as a carrier protein, we co-administered a mixture of IFNβ and ifnar2-EC to rats both intravenously and subcutaneously, and followed the blood plasma concentrations of IFNβ over time. The tighter binding ifnar2-EC mutant had a clear advantage in prolonging the half-life of IFNβ in circulation, even when lower protein concentrations were administered. A numerical simulation of the in vivo data demonstrates that the optimal binding affinity of a carrier protein is around the concentration needed to obtain optimal activity of the ligand.

Original languageEnglish
Pages (from-to)18046-18053
Number of pages8
JournalJournal of Biological Chemistry
Issue number17
StatePublished - 23 Apr 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Optimizing the binding affinity of a carrier protein: A case study on the interaction between soluble ifnar2 and interferon β'. Together they form a unique fingerprint.

Cite this