Generation and characterization of a humanized anti-IL-17A rabbit monoclonal antibody

• Published in: Protein expression and purification 2021-11, Vol.187, p.105950, Article 105950
• Main Authors: Chen, Wei, Kong, Yong, Li, Wang, Zhou, Yi, Wu, Meijuan, Chen, Tao, Wu, Yiliang, Qiao, Huaiyao, Qiu, Zhihua, Qiu, Jiwan
• Format: Article
• Language: English
• Subjects: Affinity; Animals; Antibodies, Monoclonal, Humanized - immunology; Antibodies, Monoclonal, Humanized - pharmacokinetics; Autoimmune disease; Autoimmune Diseases - drug therapy; Chemokine CXCL1 - immunology; Chemotactic Factors - immunology; Dose-Response Relationship, Drug; Humanized IL-17A monoclonal antibody; Humans; IL-17A; Interleukin-17 - immunology; Interleukin-6 - immunology; Interleukin-8 - immunology; Keratinocytes - immunology; Macaca mulatta; Mice; Neutralization; Rabbits; Signal Transduction
• ISSN: 1046-5928; 1096-0279
• DOI: 10.1016/j.pep.2021.105950

Interleukin-17A (IL-17A) produced by Th17 cells, contributes to the pathogenesis of various autoimmune diseases by stimulating the release of cytokines and chemokines and its regulation. Anti-IL-17A antibody which blocks the function of IL-17A has been proved to be an effective treatment of autoimmune disease. The aim of our study was to generate a potential humanized anti-IL-17A therapeutic monoclonal antibody (mAb) through a comprehensive panel of in vitro and in vivo biological activity studies, as well as physicochemical characterization. HZD37-5, a humanized monoclonal antibody specifically recognizing N78 loci of IL-17A, binds to human and rhesus monkeys, blocks IL-17 induced signal transduction and the release of IL-6, IL-8, CXCL-1 and G-GSF. In an in vivo efficacy mouse model, HZD37-5 significantly inhibited human IL-17A induced-keratinocyte chemoattractant (KC) secretion in a dose-dependent manner. The pharmacokinetics (PK) study result of HZD37-5 in rhesus monkeys indicated that HZD37-5 had favorable PK characteristics with limited distribution (78.0–78.8 ml/kg), slow elimination (5.00–6.45 ml/day/kg), long half-life (9.1–10.7 days) and high bioavailability (103%) following a single IV or SC dose at 1.5 mg/kg. These findings provided a comprehensive preclinical characterization of HZD37-5 and supported that it may be developed as a potential therapeutic for the treatment of autoimmune diseases, including psoriasis, psoriatic arthritis, axial spondyloarthritis, etc. •Immunization and selection of candidate antibodies in New Zealand white rabbit.•Humanization of 37# rabbit antibody.•Affinity and neutralization activities of humanized antibodies HZD37-1 and HZD37-5.•HZD37-5 inhibited keratinocyte chemoattractant (KC) release induced by human IL-17A in mice.•Epitope mapping for HZD37-5 and pharmacokinetics (PK) of HZD37-5 in rhesus monkeys.