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.

Phase II Study of ABT‐122, a Tumor Necrosis Factor– and Interleukin‐17A–Targeted Dual Variable Domain Immunoglobulin, in Patients With Psoriatic Arthritis With an Inadequate Response to Methotrexate

“…The affinity and potency of ABT‐122 with regard to its interactions with TNF and IL‐17A were comparable to those of antibodies directed solely against TNF and antibodies directed solely against IL‐17A 27, 29, 30. The PASI90 skin responses in particular suggest that ABT‐122 is functioning largely through its effects on anti‐TNF activity, since the greater efficacy expected with the addition of IL‐17A inhibition 13, 14 was not seen.…”

Efficacy and Safety of Ixekizumab in Patients with Active Psoriatic Arthritis: 52-week Results from a Phase III Study (SPIRIT-P1)

“…Ixekizumab (IXE) is a high-affinity monoclonal antibody that selectively targets IL-17A 9 and is an approved treatment for moderate to severe psoriasis. In a 24-week placebo-controlled phase III study (SPIRIT-P1), biologic disease-modifying antirheumatic drugs (bDMARD)-naive patients with active PsA showed improvements in manifestations of PsA after IXE treatment 10 .…”

Efficacy of ixekizumab compared to etanercept and placebo in patients with moderate‐to‐severe plaque psoriasis and non‐pustular palmoplantar involvement: results from three phase 3 trials (UNCOVER‐1, UNCOVER‐2 and UNCOVER‐3)

“…6 The relationship between palmoplantar types and subtypes is an area of significant interest and research especially relating to genetic similarities and differences and therapeutic options. [12][13][14][15][16] Ixekizumab (Taltz â ; Eli Lilly and Company, IN, USA) is a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A 17 and has been shown to be highly effective in the treatment of moderate-to-severe plaque psoriasis in three phase 3 studies (UNCOVER-1, 18 UNCOVER-2 19 and UNCOVER-3 19 ). 12 Topical and conventional systemic therapies and phototherapy are often ineffective, difficult to administer and/or limited by adverse effects for individual patients.…”