Bimekizumab, a Novel Humanized IgG1 Antibody That Neutralizes Both IL-17A and IL-17F
Bimekizumab, a Novel Humanized IgG1 Antibody That Neutralizes Both IL-17A and IL-17F
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DOI：
10.3389/fimmu.2020.01894
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发表时间：
2020-08-21
影响因子：
7.3
通讯作者：
Griffiths, Meryn
中科院分区：
文献类型：
--
作者：
Adams, Ralph;Maroof, Asher;Griffiths, Meryn
白细胞介素（IL）-17A是炎症的关键驱动因素，也是抗IL-17治疗性单克隆抗体的主要靶标。IL-17 A及其结构相似的家族成员IL-17 F已显示在某些人免疫介导的炎性疾病如银屑病、银屑病关节炎和中轴性脊柱关节炎中功能失调。鉴于这两种细胞因子的重叠生物学，我们假设IL-17 A和IL-17 F的双重中和可以在IL-17介导的疾病中提供比单独的IL-17 A抑制更深的临床应答。我们鉴定了496.g1，一种对IL-17 A具有强亲和力但对IL-17 F具有差亲和力的人源化抗体。496.g1至496.g3的亲和力成熟极大地增强了Fab片段对IL-17 F的亲和力，同时保留了与IL-17 A的强结合。作为IgG 1，对IL-17 A和IL-17 F的亲和力分别为3.2 pM和23 pM。通过表面等离子体共振和在人体外IL-17 A功能测定中比较496.g3 IgG 1与市售抗IL-17 A单克隆抗体ixekizumab和阿基诺单抗，表明496.g3和ixekizumab对IL-17 A显示出等同的亲和力，并且两种抗体均明显比阿基诺单抗更有效。与ixekizumab和埃克单抗相反，496.g3表现出也能够中和IL-17 F的生物活性的独特特征。因此，选择抗体496.g3用于临床开发，因为其能够中和IL-17 A和IL-17 F的生物学功能，并将其重命名为bimekizumab（以前称为UCB 4940）。银屑病患者、银屑病关节炎患者以及银屑病、银屑病关节炎和强直性脊柱炎II期研究的早期临床数据令人鼓舞，并支持IL-17 A和IL-17 F双重中和的靶向方法。综上所述，这些发现为bimekizumab在免疫介导的炎症性疾病患者中的持续临床评价提供了依据。
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 humanin vitroIL-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.