title: Effect of antigen binding affinity and effector function on the pharmacokinetics and pharmacodynamics of anti-IgE monoclonal antibodies.
abstract: Modulating the binding affinities to IgE or changing the FcγR binding properties of anti-IgE antibodies offers an opportunity to enhance the therapeutic potential of anti-IgE antibodies, but the influence of increased affinity to IgE or reduced Fc effector function on the pharmacological properties of anti-IgE therapies remains unclear. Our studies were designed to characterize the pharmacokinetics, pharmacodynamics and immune-complex distribution of two high-affinity anti-IgE monoclonal antibodies, high-affinity anti-IgE antibody (HAE) 1 and 2, in mice and monkeys. HAE1, also known as PRO98498, is structurally similar to omalizumab (Xolair®), a humanized anti-IgE IgG1 marketed for the treatment of asthma, but differs by 9 amino acid changes in the complementarity-determining region resulting in a 23-fold improvement in affinity. HAE2 is similar to HAE1, but its Fc region was altered to reduce binding to Fcγ receptors. As expected given the decreased binding to Fcγ receptors, systemic exposure to pre-formed HAE2:IgE complexes in mice was greater (six-fold) and distribution to the liver lower (four-fold) compared with HAE1:IgE complexes. In monkeys, systemic exposure to HAE1 was similar to that previously observed for omalizumab in this species, but required comparatively lower serum drug concentrations to suppress free IgE levels. HAE2 treatment resulted in greater exposure and greater increase of total IgE, relative to HAE1, because of decreased clearance of HAE2:IgE complexes. Overall, these data suggest that increased binding affinity to IgE may provide a more effective therapeutic for asthma patients, and that retaining FcγR binding of the anti-IgE antibody is important for elimination of anti-IgE:IgE complexes.
authors.affiliation: Departments of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, South San Francisco, CA, USA. mortensen.deborah@gene.com
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Mortensen
authors.forename: Saileta
authors.initials: S
authors.lastname: Prabhu
authors.forename: Eric G
authors.initials: EG
authors.lastname: Stefanich
authors.forename: Saloumeh
authors.initials: S
authors.lastname: Kadkhodayan-Fischer
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Gelzleichter
authors.forename: Dana
authors.initials: D
authors.lastname: Baker
authors.forename: Jenny
authors.initials: J
authors.lastname: Jiang
authors.forename: Kristin
authors.initials: K
authors.lastname: Wallace
authors.forename: Suhasini
authors.initials: S
authors.lastname: Iyer
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fielder
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Putnam
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001249:Asthma / Q000276:immunology / Q000628:therapy*; D000882:Haplorhini; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D008657:Metabolic Clearance Rate; D051379:Mice; D000069444:Omalizumab; D011485:Protein Binding / Q000235:genetics; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex; D011961:Receptors, Fc; D000069444:Omalizumab; D007073:Immunoglobulin E
keywords: Fc-gamma receptor; Immunoglobulin-E; anti-IgE; complex clearance; monoclonal antibody; pharmacodynamics; pharmacokinetics