Department of Chemistry, Western Washington University, Bellingham, WA; and.
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University, Atlanta, GA.
Blood. 2021 May 27;137(21):2981-2986. doi: 10.1182/blood.2020008940.
Antibody inhibitor development in hemophilia A represents the most significant complication resulting from factor VIII (fVIII) replacement therapy. Recent studies have demonstrated that epitopes present in the C1 domain contribute to a pathogenic inhibitor response. In this study, we report the structure of a group A anti-C1 domain inhibitor, termed 2A9, in complex with a B domain-deleted, bioengineered fVIII construct (ET3i). The 2A9 epitope forms direct contacts to the C1 domain at 3 different surface loops consisting of Lys2065-Trp2070, Arg2150-Tyr2156, and Lys2110-Trp2112. Additional contacts are observed between 2A9 and the A3 domain, including the Phe1743-Tyr1748 loop and the N-linked glycosylation at Asn1810. Most of the C1 domain loops in the 2A9 epitope also represent a putative interface between fVIII and von Willebrand factor. Lastly, the C2 domain in the ET3i:2A9 complex adopts a large, novel conformational change, translocating outward from the structure of fVIII by 20 Å. This study reports the first structure of an anti-C1 domain antibody inhibitor and the first fVIII:inhibitor complex with a therapeutically active fVIII construct. Further structural understanding of fVIII immunogenicity may result in the development of more effective and safe fVIII replacement therapies.
抗血友病因子 A 抗体抑制剂的产生是因子 VIII（fVIII）替代疗法最严重的并发症。最近的研究表明，C1 结构域中的表位有助于产生致病性抑制剂反应。在这项研究中，我们报告了一种 A 组抗 C1 结构域抑制剂 2A9 与缺失 B 结构域的、经过生物工程改造的 fVIII 构建体（ET3i）复合物的结构。2A9 表位与 3 个不同的表面环直接接触 C1 结构域，这 3 个表面环由 Lys2065-Trp2070、Arg2150-Tyr2156 和 Lys2110-Trp2112 组成。在 2A9 和 A3 结构域之间还观察到额外的接触，包括 Phe1743-Tyr1748 环和 Asn1810 处的 N-连接糖基化。2A9 表位中的大多数 C1 结构域环也代表 fVIII 和血管性血友病因子之间的潜在界面。最后，ET3i:2A9 复合物中的 C2 结构域采用了一种大的、新颖的构象变化，从 fVIII 的结构向外移动了 20 Å。这项研究报告了第一个抗 C1 结构域抗体抑制剂的结构和第一个具有治疗活性的 fVIII 构建体的 fVIII:抑制剂复合物。进一步了解 fVIII 的免疫原性可能会导致开发更有效和安全的 fVIII 替代疗法。
