title: Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A.
abstract: Interleukin (IL)-17A exists as a homodimer (A/A) or as a heterodimer (A/F) with IL-17F. IL-17A is expressed by a subset of T-cells, called Th17 cells, at inflammatory sites. Most cell types can respond to the local production of IL-17A because of the near ubiquitous expression of IL-17A receptors, IL-17RA and IL-17RC. IL-17A stimulates the release of cytokines and chemokines designed to recruit and activate both neutrophils and memory T-cells to the site of injury or inflammation and maintain a proinflammatory state. IL-17A-producing pathogenic T-cells contribute to the pathogenesis of autoimmune diseases, including psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. This study describes the generation and characterization of ixekizumab, a humanized IgG4 variant IL-17A-neutralizing antibody. Ixekizumab binds human and cynomolgus monkey IL-17A with high affinity and binds rabbit IL-17A weakly but does not bind to rodent IL-17A or other IL-17 family members. Ixekizumab effectively inhibits the interaction between IL-17A and its receptor in binding assays and potently blocks IL-17A-induced GRO or KC secretion in cell-based assays. In an in vivo mouse pharmcodynamic model, ixekizumab blocks human IL-17A-induced mouse KC secretion. These data provide a comprehensive preclinical characterization of ixekizumab, for which the efficacy and safety have been demonstrated in human clinical trials in psoriasis and psoriatic arthritis.
authors.affiliation: Biotechnology Discovery Research, Indianapolis, IN, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Biotechnology Discovery Research, Indianapolis, IN, USA.
authors.forename: Jirong
authors.initials: J
authors.lastname: Lu
authors.affiliation: Applied Molecular Evolution, Lilly Biotechnology Center, San Diego, CA, USA.
authors.forename: Barrett W
authors.initials: BW
authors.lastname: Allan
authors.affiliation: Applied Molecular Evolution, Lilly Biotechnology Center, San Diego, CA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Biotechnology Discovery Research, Indianapolis, IN, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tetreault
authors.affiliation: Biotechnology Discovery Research, Indianapolis, IN, USA.
authors.forename: Chi-Kin
authors.initials: CK
authors.lastname: Chow
authors.affiliation: Applied Molecular Evolution, Lilly Biotechnology Center, San Diego, CA, USA.
authors.forename: Barbra
authors.initials: B
authors.lastname: Barmettler
authors.affiliation: Applied Molecular Evolution, Lilly Biotechnology Center, San Diego, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Nelson
authors.affiliation: Biotechnology Discovery Research, Indianapolis, IN, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Bina
authors.affiliation: Bioproduct Research and Development, Indianapolis, IN, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Huang
authors.affiliation: Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Wroblewski
authors.affiliation: Biotechnology Discovery Research, Indianapolis, IN, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Kikly
keywords: IL-17A monoclonal antibody; anti-IL-17A; ixekizumab