title: Immunogenicity of Isogenic IgG in Aggregates and Immune Complexes.
abstract: A paradox in monoclonal antibody (mAb) therapy is that despite the well-documented tolerogenic properties of deaggregated IgG, most therapeutic IgG mAb induce anti-mAb responses. To analyze CD4 T cell reactions against IgG in various physical states, we developed an adoptive transfer model using CD4+ T cells specific for a Vκ region-derived peptide in the hapten-specific IgG mAb 36-71. We found that heat-aggregated or immune complexes (IC) of mAb 36-71 elicited anti-idiotypic (anti-Id) antibodies, while the deaggregated form was tolerogenic. All 3 forms of mAb 36-71 induced proliferation of cognate CD4+ T cells, but the aggregated and immune complex forms drove more division cycles and induced T follicular helper cells (TFH) development more effectively than did the deaggregated form. These responses occurred despite no adjuvant and no or only trace levels of endotoxin in the preparations. Physical analyses revealed large differences in micron- and nanometer-sized particles between the aggregated and IC forms. These differences may be functionally relevant, as CD4+ T cell proliferation to aggregated, but not IC mAb 36-71, was nearly ablated upon peritoneal injection of B cell-depleting antibody. Our results imply that, in addition to denatured aggregates, immune complexes formed in vivo between therapeutic mAb and their intended targets can be immunogenic.
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver CO, United States of America.|Medical Scientist Training Program, University of Colorado School of Medicine, Denver, Colorado, United States of America.|Integrated Department of Immunology, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
authors.forename: J Benjamin
authors.initials: JB
authors.lastname: St Clair
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver CO, United States of America.|Integrated Department of Immunology, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
authors.forename: Thiago
authors.initials: T
authors.lastname: Detanico
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver CO, United States of America.|Integrated Department of Immunology, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
authors.forename: Katja
authors.initials: K
authors.lastname: Aviszus
authors.affiliation: Integrated Department of Immunology, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Kirchenbaum
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Merry
authors.initials: M
authors.lastname: Christie
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: John F
authors.initials: JF
authors.lastname: Carpenter
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver CO, United States of America.
authors.forename: Lawrence J
authors.identifier: http://orcid.org/0000-0003-1463-4162
authors.initials: LJ
authors.lastname: Wysocki
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000276:immunology*; D016130:Immunophenotyping; D051379:Mice
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G