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.

Keywords: IL-17A; IL-17F; anti-IL-17A; bimekizumab; dual neutralization; dual targeting; monoclonal antibody.

Figure 1

Binding of 496.g1 to human recombinant IL-17A–F. Recombinant cytokines (A–F) were coated onto high-binding ELISA plates. Titrations of 496.g1 or isotype control antibody were added, starting at concentrations of 10 μg/mL. Optical density (OD) absorbance was measured at 450 nm. Values represent average absorbance and standard deviation of six technical replicates.

Figure 2

Predicted percentage of IL-17A and IL-17F bound to 496.g1 in psoriatic skin based on a target-mediated drug disposition model. Simulations are based on a 160 mg dose IV every 4 weeks (arrow) and partitioning of 30% of the antibody into the skin and indicate insufficient binding of 496.g1 to completely inhibit IL-17F in psoriatic skin.

Figure 3

Affinity of 496.g3 to IL-17A and IL-17F. Anti-human F(ab′)₂ was immobilized onto a CM5 sensor chip surface followed by the capture of either 496.g1 or 496.g3 Fabs. The association phase showed an increase in response over time following the injection of varying concentrations of IL-17A (5–0.313 nM) and IL-17F (5–0.625 nM) and this was followed by the dissociation phase when buffer replaced the IL-17A and IL-17F.

Figure 4

Inhibition of IL-6 production from normal human dermal fibroblasts (NHDFs) stimulated with TNF in combination with IL-17A or IL-17F by IL-17-specific antibodies. (A) IL-17A (0.15 nM) or (B) IL-17F (25 nM) in combination with TNFα (0.025 nM) was pre-incubated with titrations of 496.g1, 496.g3 or an irrelevant antigen-specific human IgG1 isotype control for 1 h before addition to cells. NHDFs were subsequently stimulated for 18–20 h before IL-6 protein levels in the supernatant were determined by homogeneous time-resolved fluorescence. As shown in both figures, stimulation of NHDFs by TNF or IL-17A or IL-17F individually failed to elicit sufficient production of IL-6. Each condition was tested in duplicate and the data shown is representative of three separate experiments. Two-way ANOVA, Bonferroni post-test analysis was performed to compare inhibition of 496.g1 vs. 496.g3 (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

Figure 5

Comparative efficacy of 496.g3 with the approved anti-IL-17A antibodies secukinumab and ixekizumab in inhibiting IL-6 production by normal human dermal fibroblasts (NHDFs). As seen in panel (A) 496.g3 was the only antibody that inhibited IL-6 production in response to stimulation by all three cytokines. In panel (B), 496.g3 maintained complete inhibition of IL-6 production, while the efficacy of ixekizumab declined with each stepwise increase in the ratio of IL-17F to IL-17A. Potency curves were calculated relative to NHDFs activated with TNF alone. In both sets of experiments, IL-17A (1 ng/mL), IL-17A/F (30 ng/mL), or IL-17F (30 ng/mL) in combination with TNF (1 ng/mL) were pre-incubated with titrations of 496.g3, ixekizumab (A,B) and secukinumab (A) for 1 h before addition to NHDFs. The cells were subsequently stimulated for 18–20 h before IL-6 protein levels in the supernatant were determined by homogeneous time-resolved fluorescence. Each condition was tested in duplicate and the data shown is representative of three separate experiments. Two-way ANOVA, Bonferroni post-test analysis was performed to compare inhibition of 496.g3 vs. secukinumab (black stars) or ixekizumab (blue stars) (* p < 0.05, ** p < 0.01, * p < 0.001, **** p < 0.0001).

Figure 6

Mechanism of action of bimekizumab. By selectively binding to IL-17A, IL-17F, and the IL-17A/F heterodimer, bimekizumab inhibits the activation of the IL-17RA/RC receptor complex by these cytokines, and the subsequent inflammatory cascade.