Physiochemical and Biochemical Factors Influencing the Pharmacokinetics of Antibody Therapeutics
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Monoclonal antibodies are increasingly being developed to treat multiple disease areas, including those related to oncology, immunology, neurology, and ophthalmology. There are multiple factors, such as charge, size, neonatal Fc receptor (FcRn) binding affinity, target affinity and biology, immunoglobulin G (IgG) subclass, degree and type of glycosylation, injection route, and injection site, that could affect the pharmacokinetics (PK) of these large macromolecular therapeutics, which in turn could have ramifications on their efficacy and safety. This minireview examines how characteristics of the antibodies could be altered to change their PK profiles. For example, it was observed that a net charge modification of at least a 1-unit shift in isoelectric point altered antibody clearance. Antibodies with enhanced affinity for FcRn at pH 6.0 display longer serum half-lives and slower clearances than wild type. Antibody fragments have different clearance rates and tissue distribution profiles than full length antibodies. Fc glycosylation is perceived to have a minimal effect on PK while that of terminal high mannose remains unclear. More investigation is warranted to determine if injection route and/or site impacts PK. Nonetheless, a better understanding of the effects of all these variations may allow for the better design of antibody therapeutics.
KEY WORDSantibody FcRn glycosylation isoelectric point pharmacokinetics
Antigen binding fragment
Fc gamma receptor
Neonatal Fc receptor
The authors would like to thank Frank-Peter Theil, Enzo Palma, Wendy Putnam, and Devin Tesar for helpful discussion.
Conflict of Interest Statement
All authors are employees of Genentech, Inc., a member of the Roche Group, and are Roche stockholders.
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