title: Mining the human autoantibody repertoire: isolation of potent IL17A-neutralizing monoclonal antibodies from a patient with thymoma.
abstract: Anti-cytokine autoantibodies have been widely reported to be present in human plasma, both in healthy subjects and in patients with underlying autoimmune conditions, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or thymic epithelial neoplasms. While often asymptomatic, they can cause or facilitate a wide range of diseases including opportunistic infections. The potential therapeutic value of specific neutralizing anti-cytokine autoantibodies has not been thoroughly investigated. Here we used mammalian cell display to isolate IL17A-specific antibodies from a thymoma patient with proven high-titer autoantibodies against the same. We identified 3 distinct clonotypes that efficiently neutralized IL17A in a cell-based in vitro assay. Their potencies were comparable to those of known neutralizing antibodies, including 2, AIN457 (secukinumab) and ixekizumab that are currently in clinical development for the treatment of various inflammatory disorders. These data clearly demonstrate that the human autoantibody repertoire can be mined for antibodies with high therapeutic potential for clinical development.
authors.affiliation: a Valneva Austria GmbH ; Campus Vienna Biocenter 3; Vienna , Austria.
authors.forename: Roger R
authors.initials: RR
authors.lastname: Beerli
authors.forename: Monika
authors.initials: M
authors.lastname: Bauer
authors.forename: Andrea
authors.initials: A
authors.lastname: Fritzer
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Rosen
authors.forename: Regula B
authors.initials: RB
authors.lastname: Buser
authors.forename: Markus
authors.initials: M
authors.lastname: Hanner
authors.forename: Melanie
authors.initials: M
authors.lastname: Maudrich
authors.forename: Mario
authors.initials: M
authors.lastname: Nebenfuehr
authors.forename: Jorge Alejandro Sepulveda
authors.initials: JA
authors.lastname: Toepfer
authors.forename: Susanne
authors.initials: S
authors.lastname: Mangold
authors.forename: Anton
authors.initials: A
authors.lastname: Bauer
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Browne
authors.forename: Andreas
authors.initials: A
authors.lastname: Meinke
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D061067:Antibodies, Monoclonal, Humanized / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D000915:Antibody Affinity / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D002460:Cell Line; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D013945:Thymoma / Q000097:blood / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D020381:Interleukin-17; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; C549079:ixekizumab; C555450:secukinumab
keywords: AIN457; APECED, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; CDR, complementary-determining region; CMC, Chronic mucocutaneous candidiasis; FACS, fluorescence-activated cell sorting; HFF-1, Human Foreskin Fibroblasts; IL17; IL17A, Interleukin 17A; PBMCs, peripheral blood mononuclear cells; RT-PCR, Reverse transcription polymerase chain reaction; Sindbis virus; huFc-γ1, human Fc-gamma 1; human autoantibodies; ixekizumab; mAb, monoclonal antibody; mammalian cell display; monoclonal antibodies; scFv-Fc; scFvs, single chain variable fragments; secukinumab