Durez Patrick, Vandepapeliere Pierre, Miranda Pedro, Toncheva Antoaneta, Berman Alberto, Kehler Tatjana, Mociran Eugenia, Fautrel Bruno, Mariette Xavier, Dhellin Olivier, Fanget Bernard, Ouary Stephane, Grouard-Vogel Géraldine, Boissier Marie-Christophe
Service et Pole de Rhumatologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Experimentale et Clinique, Universite catholique de Louvain, Rheumatology, Brussels, Belgium.
Neovacs S.A., Paris, France.
PLoS One. 2014 Dec 17;9(12):e113465. doi: 10.1371/journal.pone.0113465. eCollection 2014.
Active immunization, or vaccination, with tumor necrosis factor (TNF)-Kinoid (TNF-K) is a novel approach to induce polyclonal anti-TNF antibodies in immune-mediated inflammatory diseases. This study was performed to transfer the proof of concept obtained in mice model of rheumatoid arthritis (RA) into human. We designed a pilot study to demonstrate the feasibility of therapeutic vaccination in RA.
This was a phase IIa, placebo-controlled, multicenter study in adults with RA who previously experienced secondary failure of TNF antagonists. Patients were immunized intramuscularly with 2 or 3 doses of placebo (n = 10) or 90 (n = 6), 180 (n = 12), or 360 µg TNF-K (n = 12). The primary objective was to identify the best dose and schedule based on anti-TNF antibody titers. Clinical symptoms and safety were assessed during 12 months and solicited reactions for 7 days after each injection.
The highest anti-TNF antibody response was detected in patients immunized with 360 µg TNF-K and with 3 injections, although this difference was not significant with all other groups. Similar proportions of patients receiving TNF-K and placebo reported adverse events up to month 12. Serious adverse events were reported by 4 patients treated with TNF-K (13.3%) and 3 treated with placebo (30.0%), all unrelated to treatment. At month 12, DAS28-CRP, tender and swollen joint counts, and HAQ scores decreased significantly more in patients who exhibited anti-TNF antibody response than in patients who did not.
TNF-K therapeutic vaccination induced dose- and schedule-dependent anti-TNF antibodies in RA patients and was well tolerated. Patients who developed anti-TNF antibodies showed a trend toward clinical improvement. Although the most aggressive dose and schedule, i.e. 360 mg dose administered 3 times, did show a strong trend of higher antibody response, further studies are warranted to examine even higher and more frequent doses in order to establish the best conditions for clinical improvement.
ClinicalTrials.gov NCT01040715.
使用肿瘤坏死因子（TNF）-激肽原（TNF-K）进行主动免疫或疫苗接种，是在免疫介导的炎症性疾病中诱导多克隆抗TNF抗体的一种新方法。本研究旨在将在类风湿关节炎（RA）小鼠模型中获得的概念验证转化到人体。我们设计了一项初步研究，以证明RA治疗性疫苗接种的可行性。
这是一项IIa期、安慰剂对照、多中心研究，纳入之前经历过TNF拮抗剂继发性失效的成年RA患者。患者通过肌肉注射2或3剂安慰剂（n = 10）或90（n = 6）、180（n = 12）或360 μg TNF-K（n = 12）进行免疫接种。主要目标是根据抗TNF抗体滴度确定最佳剂量和接种方案。在12个月期间评估临床症状和安全性，并在每次注射后7天记录即时反应。
在接受360 μg TNF-K且接种3次的患者中检测到最高的抗TNF抗体反应，尽管与所有其他组相比，这种差异并不显著。接受TNF-K和安慰剂的患者中，报告不良事件的比例在第12个月时相似。接受TNF-K治疗的4名患者（13.3%）和接受安慰剂治疗的3名患者（30.0%）报告了严重不良事件，均与治疗无关。在第12个月时，出现抗TNF抗体反应的患者的DAS28-CRP、压痛和肿胀关节计数以及HAQ评分的下降幅度明显大于未出现反应的患者。
TNF-K治疗性疫苗接种在RA患者中诱导了剂量和接种方案依赖性的抗TNF抗体，且耐受性良好。产生抗TNF抗体的患者显示出临床改善的趋势。尽管最激进的剂量和接种方案，即360 mg剂量接种3次，确实显示出抗体反应更高的强烈趋势，但仍需要进一步研究以检查更高和更频繁的剂量，以便确定临床改善 的最佳条件。
ClinicalTrials.gov NCT01040715。
