title: A strategy for risk mitigation of antibodies with fast clearance.
abstract: A majority of human therapeutic antibody candidates show pharmacokinetic properties suitable for clinical use, but an unexpectedly fast antibody clearance is sometimes observed that may limit the clinical utility. Pharmacokinetic data in cynomolgus monkeys collected for a panel of 52 antibodies showed broad distribution of target-independent clearance values (2.4-61.3 mL/day/kg), with 15 (29%) having clearance > 10 mL/day/kg. Alteration in the interaction with the recycling FcRn receptor did not account for the faster than expected clearance observed for the antibodies; off-target binding was presumed to account for the fast clearance. We developed an assay based on ELISA detection of non-specific binding to baculovirus particles that can identify antibodies having increased risk for fast clearance. This assay can be used during lead generation or optimization to identify antibodies with increased risk of having fast clearance in both humans and cynomolgus monkeys, and thus increase the likelihood of obtaining a suitable drug candidate.
authors.affiliation: Antibody Engineering Department, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Isidro
authors.initials: I
authors.lastname: Hötzel
authors.forename: Frank-Peter
authors.initials: FP
authors.lastname: Theil
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Bernstein
authors.forename: Saileta
authors.initials: S
authors.lastname: Prabhu
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.forename: Leah
authors.initials: L
authors.lastname: Quintana
authors.forename: Jeff
authors.initials: J
authors.lastname: Lutman
authors.forename: Renuka
authors.initials: R
authors.lastname: Sibia
authors.forename: Pamela
authors.initials: P
authors.lastname: Chan
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.forename: Paul
authors.initials: P
authors.lastname: Fielder
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Carter
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kelley
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D016367:Baculoviridae / Q000276:immunology; D055808:Drug Discovery; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D020379:Risk Adjustment; D014771:Virion / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal
keywords: FcRn; antibody; baculovirus; non-specific binding; pharmacokinetics