Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, Medical Research Center-Asthma United Kingdom Centre in Allergic Mechanisms of Asthma, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
Am J Respir Crit Care Med. 2021 Jul 1;204(1):23-33. doi: 10.1164/rccm.202011-4107OC.
Sensitization to Fel d 1 ( allergen 1) contributes to persistent allergic rhinitis and asthma. Existing treatment options for cat allergy, including allergen immunotherapy, are only moderately effective, and allergen immunotherapy has limited use because of safety concerns. To explore the relationship among the pharmacokinetic, clinical, and immunological effects of anti-Fel d 1 monoclonal antibodies (REGN1908-1909) in patients after treatment. Patients received REGN1908-1909 ( = 36) or a placebo ( = 37) in a phase 1b study. Fel d 1-induced basophil and IgE-facilitated allergen binding responses were evaluated at baseline and Days 8, 29, and 85. Cytokine and chemokine concentrations in nasal fluids were measured, and REGN1908-1909 inhibition of allergen-IgE binding in patient serum was evaluated. Peak serum drug concentrations were concordant with maximal observed clinical response. The anti-Fel d 1 IgE/cat dander IgE ratio in pretreatment serum correlated with Total Nasal Symptom Score improvement. The allergen-neutralizing capacity of REGN1908-1909 was observed in serum and nasal fluid and was detected in an inhibition assay. Type 2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL17/TARC, CCL5/RANTES [regulated upon activation, normal T-cell expressed and secreted]) in nasal fluid were inhibited in REGN1908-1909-treated patients compared with placebo ( < 0.05 for all); IL-13 and IL-5 concentrations correlated with Total Nasal Symptom Score improvement. assays demonstrated that REGN1908 and REGN1909 combined were more potent than each alone for inhibiting FcεRI- and FcεRII (CD23)-mediated allergic responses and subsequent T-cell activation. A single, passive-dose administration of Fel d 1-neutralizing IgG antibodies improved nasal symptoms in cat-allergic patients and was underscored by suppression of FcεRI-, FcεRII-, and T-helper cell type 2-mediated allergic responses. Clinical trial registered with www.clinicaltrials.gov (NCT02127801).
对 Fel d 1（过敏原 1）的致敏作用导致持续性过敏性鼻炎和哮喘。现有的猫过敏治疗选择，包括过敏原免疫疗法，只有中度疗效，并且由于安全性问题，过敏原免疫疗法的使用受到限制。本研究旨在探索抗 Fel d 1 单克隆抗体（REGN1908-1909）治疗后患者的药代动力学、临床和免疫学效应之间的关系。
在一项 1b 期研究中，患者接受 REGN1908-1909（n=36）或安慰剂（n=37）治疗。在基线和第 8、29 和 85 天评估 Fel d 1 诱导的嗜碱性粒细胞和 IgE 促进的过敏原结合反应。测量鼻液中的细胞因子和趋化因子浓度，并评估 REGN1908-1909 抑制患者血清中过敏原-IgE 结合的能力。
血清药物峰浓度与最大观察到的临床反应一致。治疗前血清中抗 Fel d 1 IgE/猫皮屑 IgE 比值与总鼻部症状评分改善相关。REGN1908-1909 在血清和鼻液中具有中和过敏原的能力，并在抑制试验中检测到。与安慰剂相比，REGN1908-1909 治疗的患者鼻液中的 2 型细胞因子（IL-4、IL-5 和 IL-13）和趋化因子（CCL17/TARC、CCL5/RANTES[激活后正常 T 细胞表达和分泌]）被抑制（所有均<0.05）；IL-13 和 IL-5 浓度与总鼻部症状评分改善相关。
体外试验表明，REGN1908 和 REGN1909 联合使用比单独使用更能抑制 FcεRI 和 FcεRII（CD23）介导的过敏反应和随后的 T 细胞激活。单次被动剂量给予 Fel d 1 中和 IgG 抗体可改善猫过敏患者的鼻部症状，并通过抑制 FcεRI、FcεRII 和辅助性 T 细胞 2 介导的过敏反应得到强调。该临床试验已在 www.clinicaltrials.gov 注册（NCT02127801）。
