9SG2

Ixekizumab Fab in complex with human IL-17A

9SG2 の概要

• エントリーDOI: 10.2210/pdb9sg2/pdb
• 関連するPDBエントリー: 9SFX 9SG0
• 分子名称: Interleukin-17A, Ixekizumab Fab heavy-chain, Ixekizumab Fab light-chain (3 entities in total)
• 機能のキーワード: cytokine, therapeutic antibody, ixekizumab
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 64800.74

構造登録者

Rondeau, J.-M.,Lehmann, S. (登録日: 2025-08-21, 公開日: 2025-10-29)

主引用文献

Ungan, D.,Be, C.,Baczyk, P.,Mittermeier, S.,Lehmann, S.,Wiesmann, C.,Huber, T.,Kolbinger, F.,Rondeau, J.M.
IL-17A complexes with therapeutic antibodies exhibit distinct size distributions, potentially contributing to clinically observed immunogenicity.
Mabs, 17:2575840-2575840, 2025

PubMed Abstract: Monoclonal antibodies are well established as promising treatment options for a broad range of patients with severe diseases. In some cases, the formation of anti-drug antibodies (ADA) may limit their clinical use and potentially affect safety and efficacy for patients. Despite extensive research, some factors contributing to the immunogenicity of therapeutic antibodies remain poorly understood. In particular, the immunogenicity potential associated with multivalent antibody formats targeting oligomeric protein antigens has thus far received insufficient attention. Large, target-related immune complexes (TRICs) may be formed that can trigger Fc-mediated downstream effects and have the potential to contribute to the development of an ADA response. Here, we present experimental evidence highlighting the roles of epitope, paratope, and binding geometry in defining the composition and size distribution of TRICs formed by IL-17A, a homodimeric cytokine, with four clinical anti-IL-17 antibodies, secukinumab (Cosentyx), ixekizumab (Taltz), bimekizumab (Bimzelx) and CJM112. Widely different ADA incidence rates have been reported for these antibodies. We found that all four antibodies formed closed-chain TRICs, each comprising two or more IgG molecules connected by an equivalent number of IL-17A homodimers. Secukinumab, the antibody with the lowest ADA incidence rate, uniquely exhibited primarily 2 + 2 closed-chain complexes. In contrast, CJM112 and bimekizumab showed higher amounts of 3 + 3 and 4 + 4 complexes. Additionally, CJM112, and to a greater extent, bimekizumab and ixekizumab, formed very high molecular weight TRICs. Our findings underscore the importance of conducting in-depth biophysical analyses of TRICs formed by therapeutic antibody candidates targeting multivalent protein antigens, to develop safer and more efficacious treatments.

PubMed: 41111004
DOI: 10.1080/19420862.2025.2575840

実験手法

X-RAY DIFFRACTION (2.92 Å)