title: Different adaptations of IgG effector function in human and nonhuman primates and implications for therapeutic antibody treatment.
abstract: Safety of human therapeutic Abs is generally assessed in nonhuman primates. Whereas IgG1 shows identical FcγR interaction and effector function profile in both species, fundamental differences in the IgG2 and IgG4 Ab subclasses were found between the two species. Granulocytes, the main effector cells against IgG2- and IgG4-opsonized bacteria and parasites, do not express FcγRIIIb, but show higher levels of FcγRII in cynomolgus monkey. In humans, IgG2 and IgG4 adapted a silent Fc region with weak binding to FcγR and effector functions, whereas, in contrast, cynomolgus monkey IgG2 and IgG4 display strong effector function as well as differences in IgG4 Fab arm exchange. To balance this shift toward activation, the cynomolgus inhibitory FcγRIIb shows strongly increased affinity for IgG2. In view of these findings, in vitro and in vivo results for human IgG2 and IgG4 obtained in the cynomolgus monkey have to be cautiously interpreted, whereas effector function-related effects of human IgG1 Abs are expected to be predictable for humans.
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. max.warncke@novartis.com
authors.forename: Max
authors.initials: M
authors.lastname: Warncke
authors.forename: Thomas
authors.initials: T
authors.lastname: Calzascia
authors.forename: Michele
authors.initials: M
authors.lastname: Coulot
authors.forename: Nicole
authors.initials: N
authors.lastname: Balke
authors.forename: Ratiba
authors.initials: R
authors.lastname: Touil
authors.forename: Frank
authors.initials: F
authors.lastname: Kolbinger
authors.forename: Christoph
authors.initials: C
authors.lastname: Heusser
mesh_terms: D000818:Animals; D001483:Base Sequence; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D006098:Granulocytes / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D008252:Macaca fascicularis; D008969:Molecular Sequence Data; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D013045:Species Specificity
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D007074:Immunoglobulin G; D017452:Receptors, IgG