title: The pharmacokinetics of an albumin-binding Fab (AB.Fab) can be modulated as a function of affinity for albumin.
abstract: 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 microM. 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 microM 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.
authors.affiliation: Department of Assay, Genentech, Inc. South San Francisco, CA 94080, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Nguyen
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Reyes
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Paul
authors.initials: P
authors.lastname: McDonald
authors.forename: Wai Lee T
authors.initials: WL
authors.lastname: Wong
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Damico
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D000915:Antibody Affinity; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D006207:Half-Life; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism*; D008970:Molecular Weight; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D000068878:Trastuzumab
chemical_list: D000418:Albumins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; D000068878:Trastuzumab