title: Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease.
abstract: The MHC class I-like Fc receptor FcRn plays an essential role in extending the half-life (t(1/2)) of IgG antibodies and IgG-Fc-based therapeutics in the circulation. The goal of this study was to analyze the effect of human IgG1 (hIgG1) antibodies with enhanced in vitro binding to FcRn on their in vivo t(1/2) in mice expressing human FcRn (hFcRn). Mutants of the humanized monoclonal Herceptin antibody (Hu4D5-IgG1), directed against human epidermal growth factor receptor 2 (p185 (HER2)), show altered pH-dependent binding to hFcRn in vitro. Two engineered IgG1 mutants (N434A and T307A/E380A/N434A) showed a considerably extended t(1/2) in vivo compared with wild-type antibody in mice expressing an hFcRn transgene (Tg) but not in mice expressing the endogenous mouse FcRn. The efficiency of hFcRn-mediated protection was dependent on hFcRn Tg copy number. Moreover, when injected into FcRn-humanized mice at a concentration sufficient to partially saturate hFcRn, the engineered IgG1 mutants with an extended serum t(1/2) were most effective in reducing the t(1/2) of a tracer hIgG1 antibody. Finally, administration of mutant with high binding to hFcRn ameliorated arthritis induced by passive transfer with human pathogenic plasma. These results indicate that Fc regions modified for high binding affinity to hFcRn increases serum persistence of therapeutic antibodies, that the same approach can be exploited as an anti-autoimmune therapy to promote the clearance of endogenous pathogenic IgG and that FcRn-humanized mice are a promising surrogate for hIgG therapeutic development.
authors.affiliation: Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Stefka B
authors.initials: SB
authors.lastname: Petkova
authors.forename: Shreeram
authors.initials: S
authors.lastname: Akilesh
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sproule
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Christianson
authors.forename: Hana
authors.initials: H
authors.lastname: Al Khabbaz
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Brown
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Presta
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Meng
authors.forename: Derry C
authors.initials: DC
authors.lastname: Roopenian
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D001168:Arthritis / Q000276:immunology / Q000628:therapy*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D004306:Dose-Response Relationship, Immunologic; D005818:Genetic Engineering; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D011961:Receptors, Fc / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D007074:Immunoglobulin G; D011961:Receptors, Fc