Secukinumab, a human monoclonal antibody that selectively neutralizes IL-17A, has consistently shown low anti-drug antibody responses in patients with psoriasis, psoriatic arthritis, and ankylosing spondylitis. Secukinumab has also shown lower in vitro immunogenicity potential compared with other monoclonal antibodies used to treat psoriasis and psoriatic arthritis, and a significantly lower in vitro T cell precursor frequency compared with ixekizumab, which targets the same antigen. Here, secukinumab and ixekizumab were further examined regarding their specific T cell epitopes. Secukinumab- or ixekizumab-specific CD4 T cell lines were generated from 31 healthy, treatment-naïve donors via 28-day co-culture with mature monocyte-derived dendritic cells exposed to either antibody. Consistent with previous data, the frequency of preexisting T cells to secukinumab was significantly lower as compared with ixekizumab. Only two T cell lines from two different donors could be derived for secukinumab, but no specific T cell epitope was identified. In contrast, 32 T cell lines from eight donors were obtained for ixekizumab. For 11 of these T cell lines, the specific T cell epitopes could be identified and confirmed by major histocompatibility complex-associated peptide proteomics as being naturally presented peptides. All identified T cell epitopes cluster in four main regions that are overlapping with the complementarity-determining regions HCDR3, LCDR1, LCDR2 and LCDR3. Interestingly, ixekizumab CDRs contain amino acids that are not found in any of the germline family members. These amino acids may be associated with the higher number of T cell epitopes identified for ixekizumab light chain and may contribute to the increased in vitro immunogenicity potential observed for ixekizumab vs. secukinumab.

中文翻译：

---

健康供体中苏金单抗和伊克珠单抗的 T 细胞表位定位。

苏金单抗是一种选择性中和 IL-17A 的人单克隆抗体，在银屑病、银屑病关节炎和强直性脊柱炎患者中一直显示出低抗药抗体反应。与用于治疗银屑病和银屑病关节炎的其他单克隆抗体相比，苏金单抗还显示出较低的体外免疫原性潜力，与靶向相同抗原的 ixekizumab 相比，其体外 T 细胞前体频率显着降低。在这里，苏金单抗和 ixekizumab 进一步检查了它们的特定 T 细胞表位。Secukinumab 或 ixekizumab 特异性 CD4 T 细胞系是从 31 名健康、未接受过治疗的供体通过与暴露于任一抗体的成熟单核细胞衍生树突细胞共培养 28 天产生的。与之前的数据一致，与 ixekizumab 相比，预先存在的 T 细胞对苏金单抗的频率显着降低。对于苏金单抗，只能从两个不同供体中衍生出两个 T 细胞系，但没有鉴定出特定的 T 细胞表位。相比之下，ixekizumab 获得了来自 8 个供体的 32 个 T 细胞系。对于这些 T 细胞系中的 11 个，可以通过主要组织相容性复合体相关肽蛋白质组学鉴定和确认特定的 T 细胞表位是天然呈递的肽。所有鉴定出的 T 细胞表位都聚集在与互补决定区 HCDR3、LCDR1、LCDR2 和 LCDR3 重叠的四个主要区域中。有趣的是，ixekizumab CDR 包含在任何种系家族成员中均未发现的氨基酸。