司库奇尤单抗，一种全人源抗白细胞介素-17A 单克隆抗体，在接受长达 5 年治疗的银屑病患者中表现出低免疫原性。
Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibits low immunogenicity in psoriasis patients treated up to 5 years.
机构信息
Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Skinflammation® Center, Hamburg, Germany.
出版信息
J Eur Acad Dermatol Venereol. 2019 Sep;33(9):1733-1741. doi: 10.1111/jdv.15637. Epub 2019 Jun 20.
BACKGROUND
Secukinumab is a fully human monoclonal antibody that selectively neutralizes IL-17A, a key cytokine involved in psoriasis and psoriatic arthritis development, and has shown rapid and long-lasting efficacy and safety in the complete spectrum of psoriasis manifestations. Monoclonal antibody therapies may be associated with the production of treatment-emergent antidrug antibodies (TE-ADAs) that can affect drug pharmacokinetics, diminish clinical responses via inhibition of target binding or cause hypersensitivity reactions. Secukinumab exhibited minimal immunogenicity up to 52 weeks in patients with moderate-to-severe plaque psoriasis, as evidenced by TE-ADA in <1% patients.
OBJECTIVE
To investigate the immunogenicity of secukinumab treatment up to 5 years in two phase 3 extension studies (NCT01640951 and NCT01365455) in patients with moderate-to-severe plaque psoriasis.
METHODS
Immunogenicity was evaluated up to Week 268 (5 years). TE-ADAs were defined as positive antidrug antibody (ADA) signals detected in post-treatment samples from patients with negative baseline signals. Confirmed positive samples were further analysed for their neutralizing potential.
RESULTS
In total, 1821 patients entered the extension studies. Among patients receiving secukinumab and evaluated for ADAs (n = 1636), 32 developed TE-ADA, which resulted in an incidence of new TE-ADA cases below 1% per year. Neutralizing antibodies were detected in 9/32 (28%) patients with TE-ADA. Half of ADA-positive cases were transient. Among pharmacokinetic samples measured at the times of immunogenicity determination (n = 9992), 544 (5.4%) had secukinumab concentrations higher than the drug tolerance level of 53.8 μg/mL. There was no effect of TE-ADA, including neutralizing antibodies, on efficacy, safety or pharmacokinetics of secukinumab.
CONCLUSION
The yearly secukinumab immunogenicity incidence over 5 years of treatment was consistently below 1% in patients with moderate-to-severe plaque psoriasis. Any TE-ADAs, including neutralizing antibodies, were not associated with loss of secukinumab efficacy or with clinical concerns.
背景
司库奇尤单抗是一种全人源单克隆抗体，能选择性中和白细胞介素 17A（IL-17A），后者是银屑病和银屑病关节炎发展过程中的关键细胞因子，在银屑病的所有表现中都显示出快速和持久的疗效和安全性。单克隆抗体疗法可能会产生治疗中出现的抗药物抗体（TE-ADA），这可能会影响药物的药代动力学，通过抑制靶标结合而降低临床反应，或引起过敏反应。在中重度斑块状银屑病患者中，司库奇尤单抗在长达 52 周的时间内表现出最小的免疫原性，这一点从<1%的患者中出现治疗中出现的抗药物抗体（TE-ADA）得到了证实。
目的
在两项中重度斑块状银屑病的 3 期扩展研究（NCT01640951 和 NCT01365455）中，研究司库奇尤单抗治疗长达 5 年的免疫原性。
方法
免疫原性评估至第 268 周（5 年）。治疗中出现的抗药物抗体（ADA）定义为在基线时无信号的治疗后样本中检测到的阳性抗药物抗体（ADA）信号。对确证阳性的样本进一步进行中和潜力分析。
结果
共有 1821 名患者进入扩展研究。在接受司库奇尤单抗治疗并接受 ADA 评估的 1636 名患者中，有 32 名出现治疗中出现的 ADA，每年新出现的治疗中出现的 ADA 病例发生率低于 1%。在 32 例治疗中出现的 ADA 患者中，有 9 例（28%）检测到了中和抗体。ADA 阳性病例中有一半是一过性的。在免疫原性确定时测量的药代动力学样本中（n=9992），有 544 例（5.4%）的司库奇尤单抗浓度高于 53.8μg/ml 的药物耐受水平。治疗中出现的 ADA，包括中和抗体，对司库奇尤单抗的疗效、安全性或药代动力学没有影响。
结论
在中重度斑块状银屑病患者中，5 年治疗期间每年的司库奇尤单抗免疫原性发生率始终低于 1%。任何治疗中出现的 ADA，包括中和抗体，均不会导致司库奇尤单抗疗效丧失，也不会引起临床关注。
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