PEDS Advance Access published online on April 2, 2008
Protein Engineering Design and Selection, doi:10.1093/protein/gzm067
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Article |
Anti-serum albumin domain antibodies for extending the half-lives of short lived drugs
Domantis Limited, 315 Cambridge Science Park, Cambridge, CB4 0WG, UK
1 To whom correspondence should be addressed. lucy.holt{at}domantis.com
We have used phage display to isolate a range of human domain antibodies (dAbs) that bind to mouse, rat and/or human serum albumin (SA) and can be expressed at very high levels in bacterial, yeast or mammalian cell culture. In contrast to non-SA-binding dAbs, which have terminal half-lives of less than 45 min, the half-lives of these 12 kDa ‘AlbudAbs’ can match the half-life of SA itself. To demonstrate the use of AlbudAbs for extending the half-lives of therapeutic drugs, we created a fusion of the interleukin-1 receptor antagonist (IL-1ra) with an AlbudAb. Soluble IL-1ra is potent inhibitor of IL-1 signalling that is approved for the treatment of rheumatoid arthritis but has a relatively short in vivo half-life. Here we show that although the AlbudAb/IL-1ra fusion has a similar in vitro potency, its in vivo efficacy can be dramatically improved due to its extended serum half-life. AlbudAbs could potentially be used to generate a range of long half-life versions of many different drugs in order to improve their dosing regimen and/or clinical effect.
Keywords: AlbudAb/albumin/domain antibody/half-life/dAb
Received October 22, 2007; revised October 22, 2007; accepted October 24, 2007.