title: Protective effect of a germline, IL-17-neutralizing antibody in murine models of autoimmune inflammatory disease.
abstract: Monoclonal antibodies (mAbs) inhibiting cytokines have recently emerged as new drug modalities for the treatment of chronic inflammatory diseases. Interleukin-17 (IL-17) is a T-cell-derived central mediator of autoimmunity. Immunization with Qβ-IL-17, a virus-like particle based vaccine, has been shown to produce autoantibodies in mice and was effective in ameliorating disease symptoms in animal models of autoimmunity. To characterize autoantibodies induced by vaccination at the molecular level, we generated mouse mAbs specific for IL-17 and compared them to germline Ig sequences. The variable regions of a selected hypermutated high-affinity anti-IL-17 antibody differed in only three amino acid residues compared to the likely germline progenitor. An antibody, which was backmutated to germline, maintained a surprisingly high affinity (0.5 nM). The ability of the parental hypermutated antibody and the derived germline antibody to block inflammation was subsequently tested in murine models of multiple sclerosis (experimental autoimmune encephalomyelitis), arthritis (collagen-induced arthritis), and psoriasis (imiquimod-induced skin inflammation). Both antibodies were able to delay disease onset and significantly reduced disease severity. Thus, the mouse genome unexpectedly encodes for antibodies with the ability to functionally neutralize IL-17 in vivo.
authors.affiliation: Cytos Biotechnology AG, Schlieren, Switzerland.
authors.forename: Kiran
authors.initials: K
authors.lastname: Dallenbach
authors.forename: Patrik
authors.initials: P
authors.lastname: Maurer
authors.forename: Till
authors.initials: T
authors.lastname: Röhn
authors.forename: Franziska
authors.initials: F
authors.lastname: Zabel
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
authors.forename: Martin F
authors.initials: MF
authors.lastname: Bachmann
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D001483:Base Sequence; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy; D005260:Female; D006825:Hybridomas / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007167:Immunotherapy / Q000379:methods*; D007249:Inflammation / Q000276:immunology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology / Q000628:therapy; D016415:Sequence Alignment; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D018074:Vaccines, Conjugate
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D020381:Interleukin-17; D057127:Single-Chain Antibodies; D018074:Vaccines, Conjugate
keywords: Affinity; Antibody; Collagen-induced arthritis; Experimental autoimmune encephalitis; IL-17 Psoriasis