Bimekizumab, a Novel Humanized IgG1 Antibody That Neutralizes Both IL-17A and IL-17F

Abstract

Interleukin (IL)-17A is a key driver of inflammation and the principal target of anti-IL-17 therapeutic monoclonal antibodies. IL-17A, and its structurally similar family member IL-17F, have been shown to be functionally dysregulated in certain human immune-mediated inflammatory diseases such as psoriasis, psoriatic arthritis, and axial spondyloarthritis. Given the overlapping biology of these two cytokines, we postulated that dual neutralization of IL-17A and IL-17F may provide a greater depth of clinical response in IL-17-mediated diseases than IL-17A inhibition alone. We identified 496.g1, a humanized antibody with strong affinity for IL-17A but poor affinity for IL-17F. Affinity maturation of 496.g1 to 496.g3 greatly enhanced the affinity of the Fab fragment for IL-17F while retaining strong binding to IL-17A. As an IgG1, the affinity for IL-17A and IL-17F was 3.2 pM and 23 pM, respectively. Comparison of 496.g3 IgG1 with the commercially available anti-IL-17A monoclonal antibodies ixekizumab and secukinumab, by surface plasmon resonance and in a human in vitro IL-17A functional assay, showed that 496.g3 and ixekizumab display equivalent affinity for IL-17A, and that both antibodies are markedly more potent than secukinumab. In contrast to ixekizumab and secukinumab, 496.g3 exhibited the unique feature of also being able to neutralize the biological activity of IL-17F. Therefore, antibody 496.g3 was selected for clinical development for its ability to neutralize the biologic function of both IL-17A and IL-17F and was renamed bimekizumab (formerly UCB4940). Early clinical data in patients with psoriasis, in those with psoriatic arthritis, and from the Phase 2 studies in psoriasis, psoriatic arthritis, and ankylosing spondylitis, are encouraging and support the targeted approach of dual neutralization of IL-17A and IL-17F. Taken together, these findings provide the rationale for the continued clinical evaluation of bimekizumab in patients with immune-mediated inflammatory diseases.

Modulatory Impact of Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients on T Helper Cell Differentiation

“…The Th17 cells produce IL-17A and IL-17F, two structurally related members of the IL-17 family with overlapping pro-inflammatory activities that function as homo- and heterodimers (IL-17AF). Dysregulated expression of IL-17A and IL-17F is associated with AS and dual inhibition of these cytokines gives promising results [ 30 ]. Mesenchymal stem cells of various origins are known to support Treg cells and normalize the function of other Th subsets [ 14 , 25 , 31 , 32 ].…”

Antibodies to watch in 2021

“…Bimekizumab’s affinities for IL-17A and IL-17 F are 3.2 pM and 23 pM, respectively, and it can bind both the homodimers and heterodimers of these two cytokines. 72 Marketing applications for bimekizumab as a treatment for psoriasis are undergoing regulatory review in the US and EU.…”

An Overview of Bimekizumab for the Treatment of Psoriatic Arthritis: The Evidence so Far

“…Most non-hematopoietic cells possess IL-17 receptors, including fibroblasts, epithelial cells and synoviocytes, 8 but despite this ubiquitous presence, IL-17 seems to have only moderate inflammatory capability per se, rather recruiting and amplifying other pathways, such as IL-6, IL-8, TNF and inflammatory-cell attracting chemokines. 6 , 7 , 9 , 10 …”

“…Within the entire IL-17 family, IL-17F is the most structurally homologous (~50%) to IL-17A 8 ( Figure 1 ). They can both be secreted as homodimers (ie IL-17A/A or IL-17F/F) or as heterodimers of IL-17A/IL-17F, 9 sharing signaling pathways through the same heterodimeric complex of IL-17 receptors A and C (IL-RA/RC) and biologic function.…”

“…Bimekizumab is a humanized monoclonal IgG1 antibody that selectively neutralizes both IL-17A and IL-17F. In in vitro models, bimekizumab appears to be as potent as ixekizumab at inhibiting IL-17A (also more potent than secukinumab) 8 but, unlike those drugs, also possesses the unique ability to inhibit IL-17F as well, functioning as a dual inhibitor. Unlike brodalumab, an IL-17 receptor A blocker – which targets not only IL-17A and F signaling but also IL-17 C, D and E – bimekizumab spares IL-17E (also known as IL-25), for example, which is believed to have anti-inflammatory properties.…”