抗IgE单克隆抗体奥马珠单抗通过与Fcγ受体结合引起不良反应
2019/12/09
摘要
奥马珠单抗是一种抗IgE的单克隆抗体，已被批准用于治疗重症哮喘和慢性自发性荨麻疹。奥马珠单抗的使用与所报道的副作用有关，从注射部位的局部皮肤炎症到全身过敏反应不等。迄今为止，奥马珠单抗诱导不良反应的机制仍是不清楚的。在这里，我们证明了奥马珠单抗与IgE之间形成的免疫复合物可以通过FcγR人源化小鼠中IgG受体（FcγRs）的结合诱导皮肤炎症和过敏反应。我们进一步开发了奥马珠单抗的Fc工程突变体，并证明了该单克隆抗体与奥马珠单抗在阻断IgE介导的过敏反应方面同样有效，但不会诱导FcγR依赖性的不良反应。总体而言，我们的数据表明，奥马珠单抗可通过与FcγRs结合来诱导皮肤炎症和过敏反应，并证明单克隆抗体的Fc工程化形式可用于减少此类不良反应。
The anti-IgE mAb Omalizumab induces adverse reactions by engaging Fcγ receptors.
Balbino B, Herviou P, Godon O, Stackowicz J, Richard-Le Goff O, Iannascoli B, Sterlin D, Brûlé S, Millot GA, Harris FM, Voronina VA, Nadeau KC, Macdonald LE, Murphy AJ, Bruhns P, Reber LL.
Abstract
Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of Omalizumab is associated with reported side effects, ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which Omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between Omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (FcγRs) in FcγR-humanized mice. We further developed an Fc-engineered mutant version of Omalizumab, and demonstrated that this mAb is equally potent as Omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-dependent adverse reactions. Overall, our data indicate that Omalizumab can induce skin inflammation and anaphylaxis by engaging FcγRs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.
奥马珠单抗是一种抗IgE的单克隆抗体，已被批准用于治疗重症哮喘和慢性自发性荨麻疹。奥马珠单抗的使用与所报道的副作用有关，从注射部位的局部皮肤炎症到全身过敏反应不等。迄今为止，奥马珠单抗诱导不良反应的机制仍是不清楚的。在这里，我们证明了奥马珠单抗与IgE之间形成的免疫复合物可以通过FcγR人源化小鼠中IgG受体（FcγRs）的结合诱导皮肤炎症和过敏反应。我们进一步开发了奥马珠单抗的Fc工程突变体，并证明了该单克隆抗体与奥马珠单抗在阻断IgE介导的过敏反应方面同样有效，但不会诱导FcγR依赖性的不良反应。总体而言，我们的数据表明，奥马珠单抗可通过与FcγRs结合来诱导皮肤炎症和过敏反应，并证明单克隆抗体的Fc工程化形式可用于减少此类不良反应。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(J Clin Invest. 2019 Nov 26. pii: 129697. doi: 10.1172/JCI129697. [Epub ahead of print])
(J Clin Invest. 2019 Nov 26. pii: 129697. doi: 10.1172/JCI129697. [Epub ahead of print])
The anti-IgE mAb Omalizumab induces adverse reactions by engaging Fcγ receptors.
Balbino B, Herviou P, Godon O, Stackowicz J, Richard-Le Goff O, Iannascoli B, Sterlin D, Brûlé S, Millot GA, Harris FM, Voronina VA, Nadeau KC, Macdonald LE, Murphy AJ, Bruhns P, Reber LL.
Abstract
Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of Omalizumab is associated with reported side effects, ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which Omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between Omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (FcγRs) in FcγR-humanized mice. We further developed an Fc-engineered mutant version of Omalizumab, and demonstrated that this mAb is equally potent as Omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-dependent adverse reactions. Overall, our data indicate that Omalizumab can induce skin inflammation and anaphylaxis by engaging FcγRs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.
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