Tripp Catherine S, Cuff Carolyn, Campbell Andrew L, Hendrickson Barbara A, Voss Jeff, Melim Terry, Wu Chengbin, Cherniack Andrew D, Kim Kenneth
AbbVie, Global Pharmaceutical R&D, Worcester, MA, USA.
AbbVie, Global Pharmaceutical R&D, North Chicago, IL, USA.
Adv Ther. 2017 Jun;34(6):1364-1381. doi: 10.1007/s12325-017-0525-8. Epub 2017 Apr 28.
A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study.
Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma.
In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo.
RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis).
AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript.
基于在小鼠哮喘模型中评估的白细胞介素（IL）-13受体阻断差异，研发出一种独特的抗IL-13单克隆抗体RPC4046；在一项首次人体研究中对RPC4046的安全性、耐受性、药代动力学和药效学进行了评估。
在卵清蛋白诱导的小鼠哮喘模型中评估具有不同受体阻断特异性的抗IL-13抗体。对健康成年人和轻度至中度控制哮喘患者进行了一项随机、双盲、安慰剂对照、剂量递增的首次人体研究（NCT00986037），使用RPC4046。
在卵清蛋白模型中，与单独阻断IL-13Rα1相比，阻断IL-13与两种IL-13受体（IL-13Rα1和IL-13Rα2）的结合可抑制更多哮喘表型特征，并更全面地使与哮喘相关的独特IL-13基因转录正常化。在人体中，RPC4046的暴露量呈剂量依赖性增加；健康受试者和哮喘患者的药代动力学相似，阻断两种IL-13受体对IL-13基因转录有独特影响。少数参与者（28%）产生了抗药抗体，这些抗体是短暂的，似乎不影响药代动力学。健康受试者和哮喘患者的不良事件谱相似，无剂量相关或给药途径差异、全身输注相关反应或哮喘症状恶化。不良事件为轻度至中度，无报告可能与RPC4046相关或导致停药。与安慰剂相比，RPC4046治疗时非严重上呼吸道感染更常见。
RPC4046是一种新型抗IL-13抗体，可阻断IL-13与两种受体的结合，并更全面地阻断哮喘表型。这些结果支持对RPC4046用于IL-13相关过敏性/炎症性疾病（如哮喘和嗜酸性食管炎）进行进一步研究。
艾伯维公司赞助了这些研究，并参与了研究的设计和实施、数据管理、数据分析、数据解读以及稿件的撰写和审批。
