PEDS Advance Access originally published online on April 18, 2006
Protein Engineering Design and Selection 2006 19(7):291-297; doi:10.1093/protein/gzl011
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The pharmacokinetics of an albumin-binding Fab (AB.Fab) can be modulated as a function of affinity for albumin
1 Departments of Assay and Automation Technology, Genentech, Inc. South San Francisco, CA 94080, USA 2 Departments of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc. South San Francisco, CA 94080, USA 3 Departments of Antibody Engineering, Genentech, Inc. South San Francisco, CA 94080, USA 4 Departments of Process Sciences, Genentech, Inc. South San Francisco, CA 94080, USA
5To whom correspondence should be addressed. E-mail: msd{at}gene.com
An AB.Fab (albumin-binding Fab) consists of a Fab and a phage-derived albumin-binding peptide. This molecule is capable of binding both antigen and albumin simultaneously. Using a Fab derived from Herceptin® we generated a panel of AB.Fab variants with wide-ranging affinities for albumin. An assay that measured AB.Fab binding to albumin in solution was developed to most accurately reflect the binding affinity for albumin in vivo. Affinity varied depending upon the species of albumin tested. For rat and rabbit albumin, affinities ranged from 0.04 to 2.5 µM. Reduced affinity for albumin correlated with a reduced half-life and higher clearance rates in both species; the beta half-life ranged 6-fold while clearance ranged over 50-fold in rats and 20-fold in rabbits. To estimate the pharmacokinetic properties of an AB.Fab in humans, AB.Fab variants with similar affinities for rat and rabbit albumin were selected. Using their pharmacokinetic parameters and the principles of allometric scaling for albumin, we estimate an approximate beta half-life for an AB.Fab with 0.5 µM affinity for albumin of up to 4 days in humans with a clearance of 76 ml/h. These variants demonstrate the ability to modulate the clearance of a Fab fragment in vivo and help to establish guidelines for pharmacokinetic engineering of molecules through albumin binding.
Keywords: AB.Fab/albumin affinity/albumin-binding Fab/half-life/Herceptin/pharmacokinetics
Received January 19, 2006; revised March 10, 2006; accepted March 14, 2006.
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