title: Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys.
abstract: Engineering monoclonal antibodies (mAbs) with improved binding to the neonatal Fc receptor (FcRn) is a strategy that can extend their in vivo half-life and slow their systemic clearance. Published reports have predominantly characterized the pharmacokinetics of mAbs after intravenous administration. Recently, studies in mice suggest FcRn may also play a role in affecting the subcutaneous bioavailability of mAbs. Herein, we examined whether five mAbs engineered with the T250Q/M428L Fc mutations that improved their FcRn interactions, and subsequently their in vivo pharmacokinetics after intravenous administration, had improved subcutaneous bioavailability compared with their wild-type counterparts in cynomolgus monkeys. Similar to the intravenous administration findings, the pharmacokinetic profiles of our variant mAbs after subcutaneous injection showed improved half-life or clearance. In contrast, a clear effect was not observed on the subcutaneous bioavailability. We expect that while FcRn may play a role in determining mAb subcutaneous bioavailability, multiple biopharmaceutical and physiological factors are likely to influence the success of engineering strategies aimed at targeting this pathway for improving bioavailability.
authors.affiliation: Eli Lilly Research Laboratories; Eli Lilly Corporate Center; Indianapolis, IN USA; Departments of Drug Disposition Development/Commercialization; Eli Lilly Research Laboratories; Eli Lilly Corporate Center; Indianapolis, IN USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Datta-Mannan
authors.affiliation: Eli Lilly Research Laboratories; Eli Lilly Corporate Center; Indianapolis, IN USA; Biotechnology Discovery Research; Eli Lilly Research Laboratories; Eli Lilly Corporate Center; Indianapolis, IN USA.
authors.forename: Derrick R
authors.initials: DR
authors.lastname: Witcher
authors.affiliation: Eli Lilly Research Laboratories; Eli Lilly Corporate Center; Indianapolis, IN USA; Biotechnology Discovery Research; Eli Lilly Research Laboratories; Eli Lilly Corporate Center; Indianapolis, IN USA.
authors.forename: Jirong
authors.initials: J
authors.lastname: Lu
authors.affiliation: Eli Lilly Research Laboratories; Eli Lilly Corporate Center; Indianapolis, IN USA; Departments of Drug Disposition Development/Commercialization; Eli Lilly Research Laboratories; Eli Lilly Corporate Center; Indianapolis, IN USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Wroblewski
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D002460:Cell Line; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D055104:Infusions, Subcutaneous; D008252:Macaca fascicularis; D051379:Mice; D020125:Mutation, Missense; D011961:Receptors, Fc / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D011994:Recombinant Proteins; C100688:Fc receptor, neonatal