抗IgE抗体奥马珠单抗通过变构效应发挥其治疗作用
2017/11/20
摘要
免疫球蛋白E与其受体FcϵRI 和CD23的相互作用在变态反应性疾病中发挥重要作用。奥马珠单抗是一种临床上公认有治疗作用的抗体，抑制IgE与FcϵRI的相互作用，阻止肥大细胞与嗜碱性粒细胞的激活，阻止B细胞中IgE与CD23分子的结合以及抗原递呈反应。我们探索了奥马珠单抗的Fab段与IgE的Fc段复杂的晶体结构，每个Fab段结合其Cϵ3结构域，游离的IgE Fc段有一种严重弯曲的结构，但在复合体中其仅仅是轻微弯曲的，伴随着Cϵ3结构域中大范围的构象变化，阻止IgE与FcϵRI发生作用。CD23在空间构象上被阻止与IgE结合是因为每个Cϵ3结构域都有重叠的结合位点。奥马珠单抗的Fab段结合位点的不断变化证实了FcϵRI变构抑制的机制与结构，揭示了奥马珠单抗是通过利用IgE的固有弹性和变构电位加速其与FcϵRI的解离过程。
Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab.
Davies AM, Allan EG, Keeble AH, Delgado J, Cossins BP, Mitropoulou AN, Pang MOY, Ceska T, Beavil AJ, Craggs G, Westwood M, Henry AJ, McDonnell JM, Sutton BJ.
Abstract
Immunoglobulin E and its interactions with receptors FcϵRI and CD23 play a central role in allergic disease. Omalizumab, a clinically approved therapeutic antibody, inhibits the interaction between IgE and FcϵRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cϵ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cϵ3 domains that inhibit the interaction with FcϵRI. CD23 binding is inhibited sterically due to overlapping binding sites on each Cϵ3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcϵRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcϵRI, exploiting the intrinsic flexibility and allosteric potential of IgE.
免疫球蛋白E与其受体FcϵRI 和CD23的相互作用在变态反应性疾病中发挥重要作用。奥马珠单抗是一种临床上公认有治疗作用的抗体，抑制IgE与FcϵRI的相互作用，阻止肥大细胞与嗜碱性粒细胞的激活，阻止B细胞中IgE与CD23分子的结合以及抗原递呈反应。我们探索了奥马珠单抗的Fab段与IgE的Fc段复杂的晶体结构，每个Fab段结合其Cϵ3结构域，游离的IgE Fc段有一种严重弯曲的结构，但在复合体中其仅仅是轻微弯曲的，伴随着Cϵ3结构域中大范围的构象变化，阻止IgE与FcϵRI发生作用。CD23在空间构象上被阻止与IgE结合是因为每个Cϵ3结构域都有重叠的结合位点。奥马珠单抗的Fab段结合位点的不断变化证实了FcϵRI变构抑制的机制与结构，揭示了奥马珠单抗是通过利用IgE的固有弹性和变构电位加速其与FcϵRI的解离过程。
（复旦大学附属中山医院呼吸内科 包晨 摘译 杨冬 审校）
（J Biol Chem. 2017 16;292(24):9975-9987.）
（J Biol Chem. 2017 16;292(24):9975-9987.）
Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab.
Davies AM, Allan EG, Keeble AH, Delgado J, Cossins BP, Mitropoulou AN, Pang MOY, Ceska T, Beavil AJ, Craggs G, Westwood M, Henry AJ, McDonnell JM, Sutton BJ.
Abstract
Immunoglobulin E and its interactions with receptors FcϵRI and CD23 play a central role in allergic disease. Omalizumab, a clinically approved therapeutic antibody, inhibits the interaction between IgE and FcϵRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cϵ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cϵ3 domains that inhibit the interaction with FcϵRI. CD23 binding is inhibited sterically due to overlapping binding sites on each Cϵ3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcϵRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcϵRI, exploiting the intrinsic flexibility and allosteric potential of IgE.
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