title: Targeted Fcγ Receptor (FcγR)-mediated Clearance by a Biparatopic Bispecific Antibody.
abstract: Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. Although monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6-mediated signaling. The BiSAb formed large immune complexes with IL-6 that can bind Fcγ receptors on phagocytic cells and are rapidly internalized. In addition, rapid clearance of the BiSAb·IL-6 complex was observed in mice while the parental antibodies prolonged the serum half-life of IL-6. Intravital imaging of the liver in mice confirmed that the rapid clearance of these large immune complexes was associated with Fcγ receptor-dependent binding to Kupffer cells in the liver. The approach described here provides a general strategy for therapeutic antibodies with the ability to not only neutralize but also actively drive clearance of their soluble antigens.
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering.
authors.forename: Srinath
authors.initials: S
authors.lastname: Kasturirangan
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering.
authors.forename: G Jonah
authors.initials: GJ
authors.lastname: Rainey
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering.
authors.forename: Linda
authors.initials: L
authors.lastname: Xu
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering.
authors.forename: Alyse
authors.initials: A
authors.lastname: Portnoff
authors.affiliation: Oncology, and.
authors.forename: Tracy
authors.initials: T
authors.lastname: Chen
authors.affiliation: Oncology, and.
authors.forename: Christine
authors.initials: C
authors.lastname: Fazenbaker
authors.affiliation: Oncology, and.
authors.forename: Helen
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Analytical Biotechnology, Medimmune LLC, Gaithersburg, Maryland 20878 and.
authors.forename: Jared
authors.initials: J
authors.lastname: Bee
authors.affiliation: the Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Zhutian
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: the Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Craig
authors.initials: C
authors.lastname: Jenne
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering.
authors.forename: Herren
authors.initials: H
authors.lastname: Wu
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering, gaoc@medimmune.com.
authors.forename: Changshou
authors.initials: C
authors.lastname: Gao
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism*; D000936:Antigen-Antibody Complex / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D015850:Interleukin-6; D017452:Receptors, IgG; D000093242:Interleukin-6 Inhibitors
keywords: Fc receptor; IL-6; antibody; antibody engineering; electron microscopy (EM); macrophage; microscopic imaging; pharmacokinetics; protein complex