Her Cheng, Thacker Seth, Balsamo Joseph, Kelley Baker Logan, Ireland Derek Dc, Pang Eric, Verthelyi Daniela
Laboratory of Immunology, Office of Pharmaceutical Quality Research Division-IV, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA.
Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
AAPS J. 2024 Dec 20;27(1):20. doi: 10.1208/s12248-024-00983-x.
Characterizing and mitigating factors that impact product immunogenicity can aid in risk assessment and/or managing risk following manufacturing changes. For follow-on products that have the same indication, patient population, and active product ingredient, the residual immunogenicity risk resides predominantly on differences in product and process related impurities. Characterizing differences in innate immune modulating impurities (IIRMI), which could act as adjuvants by activating local antigen presenting cells (APCs), can inform the immunogenicity risk assessment potentially reducing the need for clinical trials. To date, assays to detect trace levels of IIRMI are being used to support regulatory decisions by FDA for selected synthetic peptide drug products that refer to reference listed drugs of rDNA origin but not recombinant protein or peptide products where more complex mixtures of trace impurities including host cell proteins are expected. Here we describe an exercise to explore whether or not there are differences in the innate immune response elicited by an insulin glargine (produced in E. coli) and its interchangeable biosimilar insulin (produced in P. pastoris) that could indicate differences in IIRMI. Our results suggest the two products elicit comparable innate immune responses as determined by the expression of 90 immune-related genes, including IL-1α, IL-1β, IL-6, CCL3, CCL2, and CXCL8. The data suggest that these assays can provide useful information when assessing recombinant proteins for the presence of IIRMI.
表征和减轻影响产品免疫原性的因素有助于在生产变更后进行风险评估和/或管理风险。对于具有相同适应症、患者群体和活性产品成分的后续产品，残留免疫原性风险主要在于产品和工艺相关杂质的差异。表征固有免疫调节杂质（IIRMI）的差异，这些杂质可通过激活局部抗原呈递细胞（APC）充当佐剂，可为免疫原性风险评估提供信息，从而可能减少临床试验的需求。迄今为止，检测痕量水平IIRMI的测定方法被用于支持美国食品药品监督管理局（FDA）对选定的合成肽药物产品的监管决策，这些产品参考了重组DNA来源的上市药品，但不包括重组蛋白或肽产品，在后者中预计会有更复杂的痕量杂质混合物，包括宿主细胞蛋白。在此，我们描述了一项实验，以探究甘精胰岛素（由大肠杆菌生产）及其可互换生物类似胰岛素（由巴斯德毕赤酵母生产）引发的固有免疫反应是否存在差异，这可能表明IIRMI存在差异。我们的结果表明，通过90个免疫相关基因（包括IL-1α、IL-1β、IL-6、CCL3、CCL2和CXCL8）的表达确定，这两种产品引发的固有免疫反应相当。数据表明，这些测定方法在评估重组蛋白中IIRMI的存在时可提供有用信息。
