Zhang Ke, Liu Jeffrey, Truong Thao, Zukin Elyssa, Chen Wendy, Saxon Andrew
Sixal Inc., Los Angeles, CA 90095; and
Section of Clinical Immunology/Allergy, Division of Pulmonary, Critical Care, and Clinical Immunology/Allergy, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
J Immunol. 2017 May 15;198(10):3823-3834. doi: 10.4049/jimmunol.1602022. Epub 2017 Apr 10.
Allergic disorders have now become a major worldwide public health issue, but the effective treatment options remain limited. We report a novel approach to block allergic reactivity by targeting the surface-bound IgE of the allergic effector cells via low-affinity anti-human IgE Abs with dissociation constants in the 10 to 10 M range. We demonstrated that these low-affinity anti-IgE mAbs bind to the cell surface-bound IgE without triggering anaphylactic degranulation even at high concentration, albeit they would weakly upregulate CD203c expression on basophils. This is in contrast to the high-affinity anti-IgE mAbs that trigger anaphylactic degranulation at low concentration. Instead, the low-affinity anti-IgE mAbs profoundly block human peanut- and cat-allergic IgE-mediated basophil CD63 induction indicative of anaphylactic degranulation; suppress peanut-, cat-, and dansyl-specific IgE-mediated passive cutaneous anaphylaxis; and attenuate dansyl IgE-mediated systemic anaphylaxis in human FcεRIα transgenic mouse model. Mechanistic studies reveal that the ability of allergic reaction blockade by the low-affinity anti-IgE mAbs was correlated with their capacity to downregulate the surface IgE and FcεRI level on human basophils and the human FcεRIα transgenic mouse bone marrow-derived mast cells via driving internalization of the IgE/FcεRI complex. Our studies demonstrate that targeting surface-bound IgE with low-affinity anti-IgE Abs is capable of suppressing allergic reactivity while displaying an excellent safety profile, indicating that use of low-affinity anti-IgE mAbs holds promise as a novel therapeutic approach for IgE-mediated allergic diseases.
过敏性疾病现已成为全球主要的公共卫生问题，但有效的治疗选择仍然有限。我们报告了一种新方法，通过低亲和力抗人IgE抗体靶向变应效应细胞表面结合的IgE来阻断过敏反应，其解离常数在10至10 M范围内。我们证明，即使在高浓度下，这些低亲和力抗IgE单克隆抗体也能结合细胞表面结合的IgE而不引发过敏脱颗粒，尽管它们会轻微上调嗜碱性粒细胞上CD203c的表达。这与低浓度时引发过敏脱颗粒的高亲和力抗IgE单克隆抗体形成对比。相反，低亲和力抗IgE单克隆抗体能显著阻断人花生和猫过敏IgE介导的嗜碱性粒细胞CD63诱导，这表明过敏脱颗粒；抑制花生、猫和丹磺酰特异性IgE介导的被动皮肤过敏反应；并在人FcεRIα转基因小鼠模型中减轻丹磺酰IgE介导的全身性过敏反应。机制研究表明，低亲和力抗IgE单克隆抗体阻断过敏反应的能力与其通过驱动IgE/FcεRI复合物内化下调人嗜碱性粒细胞和人FcεRIα转基因小鼠骨髓来源肥大细胞表面IgE和FcεRI水平的能力相关。我们的研究表明，用低亲和力抗IgE抗体靶向表面结合的IgE能够抑制过敏反应，同时显示出优异的安全性，这表明使用低亲和力抗IgE单克隆抗体有望成为IgE介导的过敏性疾病的一种新治疗方法。
