title: An engineered human IgG1 antibody with longer serum half-life.
abstract: The serum half-life of IgG Abs is regulated by the neonatal Fc receptor (FcRn). By binding to FcRn in endosomes, IgG Abs are salvaged from lysosomal degradation and recycled to the circulation. Several studies have demonstrated a correlation between the binding affinity of IgG Abs to FcRn and their serum half-lives in mice, including engineered Ab fragments with longer serum half-lives. Our recent study extended this correlation to human IgG2 Ab variants in primates. In the current study, several human IgG1 mutants with increased binding affinity to human FcRn at pH 6.0 were generated that retained pH-dependent release. A pharmacokinetics study in rhesus monkeys of one of the IgG1 variants indicated that its serum half-life was approximately 2.5-fold longer than the wild-type Ab. Ag binding was unaffected by the Fc mutations, while several effector functions appeared to be minimally altered. These properties suggest that engineered Abs with longer serum half-lives may prove to be effective therapeutics in humans.
authors.affiliation: Protein Design Labs, Fremont, CA 94555, USA. phinton@pdl.com
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hinton
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Xiong
authors.forename: Mary G
authors.initials: MG
authors.lastname: Johlfs
authors.forename: Meina Tao
authors.initials: MT
authors.lastname: Tang
authors.forename: Stephen
authors.initials: S
authors.lastname: Keller
authors.forename: Naoya
authors.initials: N
authors.lastname: Tsurushita
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D001666:Binding Sites, Antibody; D003602:Cytotoxicity, Immunologic; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood* / Q000737:chemistry; D008253:Macaca mulatta; D008958:Models, Molecular; D015202:Protein Engineering; D011961:Receptors, Fc / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal