Optimizing the binding affinity of a carrier protein: a case study on the interaction between soluble ifnar2 and interferon beta - PubMed (original) (raw)
. 2004 Apr 23;279(17):18046-53.
doi: 10.1074/jbc.M400033200. Epub 2004 Feb 11.
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- PMID: 14960565
- DOI: 10.1074/jbc.M400033200
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Optimizing the binding affinity of a carrier protein: a case study on the interaction between soluble ifnar2 and interferon beta
Tal Peleg-Shulman et al. J Biol Chem. 2004.
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Abstract
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) beta is one of the most widely used protein drugs in the clinic. Here, we show that the circulatory half-life of IFNbeta 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 IFNbeta, but not IFNalpha2, 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 IFNbeta with ifnar2-EC is already near optimum. Using the wild-type and mutant receptors, we investigated their potential in occluding IFNbeta 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 IFNbeta and ifnar2-EC to rats both intravenously and subcutaneously, and followed the blood plasma concentrations of IFNbeta over time. The tighter binding ifnar2-EC mutant had a clear advantage in prolonging the half-life of IFNbeta 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.
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