A strategy for risk mitigation of antibodies with fast clearance |
| |
| Authors: | Isidro H?tzel Frank-Peter Theil Lisa J Bernstein Saileta Prabhu Rong Deng Leah Quintana Jeff Lutman Renuka Sibia Pamela Chan Daniela Bumbaca Paul Fielder Paul J Carter Robert F Kelley |
| |
| Institution: | 1.Antibody Engineering Department; Genentech, Inc.; South San Francisco, CA USA;2.Early PK/PD Department; Genentech, Inc.; South San Francisco, CA USA;3.Biostatistics Department; Genentech, Inc.; South San Francisco, CA USA;4.Biochemical and Cellular Pharmacology Department; Genentech, Inc.; South San Francisco, CA USA |
| |
| 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. |
| |
| Keywords: | antibody pharmacokinetics non-specific binding baculovirus FcRn |
|
|
