Relationship between physicochemical properties of protein aggregates and complement activation on safety of biopharmaceuticals

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K15537
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Shibata Hiroko 国立医薬品食品衛生研究所, 生物薬品部, 室長 (60462769)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: バイオ医薬品 / 補体 / 凝集体

Outline of Final Research Achievements

In this study, we attempted to establish ①preparative method of protein aggregates with various physicochemical attributes, ②complement activation assay, and to elucidate the relationship between physicochemical attributes of protein aggregates and their complement activation potency. A preparative method that can constantly provide protein aggregate with various attributes was developed by varying temperature and agitation rate on IVIG and human albumin. Complement activation potency was evaluated by measuring SC5b9, which is an ultimate product of complement pathway. It was suggested that denatured IVIG and aggregated albumin could activate a complement pathway. In the future, improvement of complement activation assay will be needed to get a consistent relationship between attributes of protein aggregates and complement activation potency.

Free Research Field

バイオ医薬品

Academic Significance and Societal Importance of the Research Achievements

抗体以外のタンパク質やFc部分が変性した抗体においても，凝集体が形成されることで補体経路が活性化される可能性が示され，バイオ医薬品における凝集体の管理の重要性を支持する成果である．また，抗体以外のタンパク質の凝集体の補体活性化能に関する報告は極めて少なく，学術的な意義もあると考えられる．引き続き研究を進め，補体活性化の強度や形状による活性化能の違いについて一貫した傾向が得られれば，バイオ医薬品製剤の適切なリスク管理戦略を構築するのに有益な情報となり，バイオ医薬品の品質管理の近代化および安全性向上につながるものと期待される．