Anti-serum albumin domain antibodies for extending the half-lives of short lived drugs.
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.
Holt
Lucy J
LJ
Domantis Limited, 315 Cambridge Science Park, Cambridge, CB4 0WG, UK. lucy.holt@domantis.com
Basran
Amrik
A
Jones
Kate
K
Chorlton
Jennifer
J
Jespers
Laurent S
LS
Brewis
Neil D
ND
Tomlinson
Ian M
IM
D000418:Albumins / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003094:Collagen / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004345:Drug Industry / Q000379:methods*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000737:chemistry; D051379:Mice; D008969:Molecular Sequence Data; D019151:Peptide Library; D015202:Protein Engineering / Q000379:methods*; D051381:Rats; D017386:Sequence Homology, Amino Acid
D000418:Albumins; D053590:Interleukin 1 Receptor Antagonist Protein; D019151:Peptide Library; D003094:Collagen