Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States.
Sanofi, Bridgewater, NJ, United States.
Front Immunol. 2024 Nov 11;15:1466372. doi: 10.3389/fimmu.2024.1466372. eCollection 2024.
Development of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety.
To describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD).
This analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two long-term open-label extension (N=2,287) trials of subcutaneous dupilumab in adults and pediatric patients with moderate-to-severe AD. ADA, NAb, and dupilumab concentration in serum were assessed using validated immunoassays. ADA impacts on efficacy (EASI) and safety were assessed.
Treatment-emergent ADAs were observed in up to 8.6% (aged ≥18 years), 16.0% (12-17 years), 5.3% (6-11 years), and 2.0% (6 months to 5 years) dupilumab-treated patients. Among dupilumab-treated patients, ≤3.7% had persistent responses, <1% had high titers (≥10,000), and ≤5.1% were NAb-positive. NAbs were more common in patients with moderate- and high-titer ADA responses. High-titer ADAs, while infrequent, were the variable most associated with lower dupilumab concentrations in serum and loss of efficacy, independent of NAb status. Efficacy was generally similar in ADA-positive and -negative patients. For most patients with high- or moderate-titer ADAs, titers decreased and efficacy improved over time with continued dupilumab treatment. ADA-positive and -negative patients had similar incidences of treatment-emergent and serious treatment-emergent adverse events. One patient with high-titer ADAs developed serum sickness.
In patients with AD, ADAs and NAbs had minimal impact on dupilumab concentration, efficacy, and safety, except for high-titer ADAs in a small number of patients.
ClinicalTrials.gov, identifiers (NCT02277743, NCT02277769, NCT02260986, NCT02395133, NCT01949311, NCT03054428, NCT03345914, NCT02612454, and NCT03346434).
单克隆抗体的抗药物抗体（ADAs）和中和抗体（NAbs）的产生可能会对药代动力学、疗效和/或安全性产生不利影响。
描述度普利尤单抗在特应性皮炎（AD）患者中的 ADAs 和 NAbs 的发生率、滴度和持久性，以及它们对药代动力学、疗效和安全性的影响。
本分析包括 7 项度普利尤单抗治疗成人和儿科中重度 AD 的 3 期随机、安慰剂对照（N=2992）和 2 项长期开放标签扩展（N=2287）试验。采用经验证的免疫分析法评估血清中的 ADA、NAb 和度普利尤单抗浓度。评估 ADA 对疗效（EASI）和安全性的影响。
多达 8.6%（年龄≥18 岁）、16.0%（12-17 岁）、5.3%（6-11 岁）和 2.0%（6 个月至 5 岁）的度普利尤单抗治疗患者出现治疗后 ADAs。在度普利尤单抗治疗患者中，≤3.7%的患者存在持续性应答，<1%的患者存在高滴度（≥10000），≤5.1%的患者为 NAb 阳性。中度和高滴度 ADA 应答患者中 NAb 更为常见。高滴度 ADAs 虽然罕见，但与血清中度普利尤单抗浓度降低和疗效丧失的相关性最强，与 NAb 状态无关。在 ADA 阳性和阴性患者中，疗效通常相似。对于大多数高或中度滴度 ADAs 患者，随着度普利尤单抗治疗的继续，滴度下降，疗效改善。ADA 阳性和阴性患者的治疗后新发和严重治疗后新发不良事件发生率相似。1 例高滴度 ADAs 患者发生血清病。
在 AD 患者中，ADAs 和 NAbs 对度普利尤单抗的浓度、疗效和安全性影响极小，除了少数患者中高滴度 ADAs 外。
ClinicalTrials.gov，标识符（NCT02277743、NCT02277769、NCT02260986、NCT02395133、NCT01949311、NCT03054428、NCT03345914、NCT02612454 和 NCT03346434）。
