Laboratory of Immunology, Division of Biotechnology Review and Research III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Building 52-Room 2112, 10903 New Hampshire Av., Silver Spring, Maryland, 20993, USA.
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Laboratorio de Cultivos Celulares, FBCB, UNL, Santa Fe, Argentina.
AAPS J. 2019 Feb 8;21(2):26. doi: 10.1208/s12248-019-0300-7.
Recombinant human interferon-β (rhIFN-β) therapy is the first-line treatment in relapsing-remitting forms of multiple sclerosis (MS). The mechanism of action underlying its therapeutic activity is only partially understood as IFN-βs induce the expression of over 1000 genes modifying multiple immune pathways. Currently, assessment of potency for IFN-β products is based on their antiviral effect, which is not linked to its therapeutic effect. Here, we explore the use of a multiplexed gene expression system to more broadly characterize IFN-β bioactivity. We find that MM6 cells stimulated with US-licensed rhIFN-βs induce a dose-dependent and reproducible pattern of gene expression. This pattern of gene expression was used to compare the bioactivity profile of biosimilar candidates with the corresponding US-licensed rhIFN-β products, Rebif and Betaseron. While the biosimilar candidate for Rebif matched the pattern of gene expression, there were differences in the expression of a subset of interferon-inducible genes including CXCL-10, CXCL-11, and GBP1 induced by the biosimilar candidate for Betaseron. Assessment of product impurities in both products suggested that the difference was rooted in the presence of innate immune response modulating impurities (IIRMIs) in the licensed product. These studies indicate that determining the expression levels for an array of reporter genes that monitor different pathways can be informative as part of the demonstration of biosimilarity or comparability for complex immunomodulatory products such as IFN-β, but the sensitivity of each gene to potential impurities in the product should be examined to fully understand the results.
重组人干扰素-β（rhIFN-β）治疗是复发缓解型多发性硬化症（MS）的一线治疗方法。其治疗活性的作用机制仅部分了解，因为 IFN-βs 诱导表达超过 1000 种基因，修饰多种免疫途径。目前，IFN-β 产品效力的评估基于其抗病毒作用，而与治疗作用无关。在这里，我们探索使用多重基因表达系统更广泛地描述 IFN-β 的生物活性。我们发现，用美国许可的 rhIFN-β 刺激 MM6 细胞会诱导剂量依赖性和可重复的基因表达模式。该基因表达模式用于比较生物类似候选物与相应的美国许可 rhIFN-β 产品 Rebif 和 Betaseron 的生物活性特征。虽然 Rebif 的生物类似候选物与基因表达模式匹配，但在干扰素诱导基因的一部分表达上存在差异，包括由 Betaseron 的生物类似候选物诱导的 CXCL-10、CXCL-11 和 GBP1。对两种产品中产品杂质的评估表明，差异源于许可产品中存在先天免疫反应调节杂质（IIRMIs）。这些研究表明，确定监测不同途径的一系列报告基因的表达水平可以作为证明生物相似性或复杂免疫调节产品（如 IFN-β）可比性的一部分，但应检查每个基因对产品中潜在杂质的敏感性，以充分理解结果。
