title: Quantitative cumulative biodistribution of antibodies in mice: effect of modulating binding affinity to the neonatal Fc receptor.
abstract: The neonatal Fc receptor (FcRn) plays an important and well-known role in antibody recycling in endothelial and hematopoietic cells and thus it influences the systemic pharmacokinetics (PK) of immunoglobulin G (IgG). However, considerably less is known about FcRn's role in the metabolism of IgG within individual tissues after intravenous administration. To elucidate the organ distribution and gain insight into the metabolism of humanized IgG1 antibodies with different binding affinities FcRn, comparative biodistribution studies in normal CD-1 mice were conducted. Here, we generated variants of herpes simplex virus glycoprotein D-specific antibody (humanized anti-gD) with increased and decreased FcRn binding affinity by genetic engineering without affecting antigen specificity. These antibodies were expressed in Chinese hamster ovary cell lines, purified and paired radiolabeled with iodine-125 and indium-111. Equal amounts of I-125-labeled and In-111-labeled antibodies were mixed and intravenously administered into mice at 5 mg/kg. This approach allowed us to measure both the real-time IgG uptake (I-125) and cumulative uptake of IgG and catabolites (In-111) in individual tissues up to 1 week post-injection. The PK and distribution of the wild-type IgG and the variant with enhanced binding for FcRn were largely similar to each other, but vastly different for the rapidly cleared low-FcRn-binding variant. Uptake in individual tissues varied across time, FcRn binding affinity, and radiolabeling method. The liver and spleen emerged as the most concentrated sites of IgG catabolism in the absence of FcRn protection. These data provide an increased understanding of FcRn's role in antibody PK and catabolism at the tissue level.
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Yip
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Enzo
authors.initials: E
authors.lastname: Palma
authors.affiliation: Drug Delivery Department; Pharma Technical Development, Genentech; South San Francisco, CA USA.
authors.forename: Devin B
authors.initials: DB
authors.lastname: Tesar
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Mundo
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.affiliation: Non-Clinical Operations; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Torres
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Noe A
authors.initials: NA
authors.lastname: Reyes
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Ben Q
authors.initials: BQ
authors.lastname: Shen
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fielder
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Saileta
authors.initials: S
authors.lastname: Prabhu
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Khawli
authors.affiliation: Preclinical and Translational Pharmacokinetics; Genentech Research & Early Development; South San Francisco, CA USA.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Boswell
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D007205:Indium Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D051379:Mice; D059748:Proteolysis; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D011961:Receptors, Fc
keywords: FcRn; biodistribution; indium; metabolism; pharmacokinetics; radiolabeled