Rudick R A, Simonian N A, Alam J A, Campion M, Scaramucci J O, Jones W, Coats M E, Goodkin D E, Weinstock-Guttman B, Herndon R M, Mass M K, Richert J R, Salazar A M, Munschauer F E, Cookfair D L, Simon J H, Jacobs L D
Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, OH 44106, USA.
Neurology. 1998 May;50(5):1266-72. doi: 10.1212/wnl.50.5.1266.
Interferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment.
To determine the incidence and biological significance of NAB to interferon beta-la (IFN-beta-1a; Avonex; Biogen, Cambridge, MA) in MS patients.
A two-step assay for NAB to IFN-beta-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-beta-1a, and from patients in an ongoing open-label study of IFN-beta-1a. The biological significance of NAB to IFN-beta-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and beta-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-beta-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-beta-1a with the incidence in MS patients who had used only IFN-beta-1b.
In patients in the open-label study, development of NAB to IFN-beta-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in beta-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-beta-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-beta-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-beta-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-beta-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB.
NAB directed against IFN-beta have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-beta is significantly greater with IFN-beta-1b therapy compared with IFN-beta-1a therapy. Treatment decisions in MS patients treated with IFN-beta should take into account development of NAB.
干扰素β是复发型多发性硬化症（MS）的一种有效治疗方法。与其他蛋白质药物一样，可能会产生中和抗体（NAB），从而降低治疗效果。
确定MS患者中针对干扰素β-1a（IFN-β-1a；阿沃尼单抗；百健公司，马萨诸塞州剑桥）的NAB的发生率及其生物学意义。
开发了一种针对IFN-β-1a的NAB两步检测法，并用于检测IFN-β-1a III期临床试验参与者以及正在进行的IFN-β-1a开放标签研究患者的血清样本。通过将NAB检测结果与IFN诱导分子新蝶呤和β-2微球蛋白的体内诱导情况相关联，确定针对IFN-β-1a的NAB的生物学意义；通过比较NAB阳性和NAB阴性患者接受IFN-β-1a治疗2年后疾病活动的临床和MRI测量结果，确定其临床意义。比较仅使用IFN-β-1a的MS患者与仅使用IFN-β-1b的MS患者中NAB的发生率。
在开放标签研究的患者中，针对IFN-β-1a的NAB的产生导致干扰素注射后新蝶呤诱导的滴度依赖性降低。在III期研究的患者中，NAB的产生与β-2微球蛋白诱导的降低有关。在III期研究中，观察到NAB阳性与NAB阴性患者相比，IFN-β-1a对MRI活动的益处有降低的趋势。在开放标签研究中，接受IFN-β-1a治疗24个月期间，针对IFN-β-1a的NAB发生率约为5%，但对于仅接受类似时长IFN-β-1b治疗的患者，使用相同检测法时该发生率高出四至六倍。没有临床、MRI或脑脊液特征能够预测哪些患者会产生NAB。
针对IFN-β的NAB在MS患者中具有体内生物学效应。与IFN-β-1a治疗相比，MS患者接受IFN-β-1b治疗时产生针对IFN-β的NAB的频率显著更高。接受IFN-β治疗的MS患者的治疗决策应考虑NAB的产生情况。
