Validation and Improvement of ISPRI-HCP: An Innovative Platform for Immunogenicity Risk Assessment of Process-related Protein Impurities

摘要 生物制品中工艺相关蛋白质杂质（PRPI）的鉴定和去除是一个关键的 药物开发的一步。尽管最近在生物制品的纯化和加工方面有所改进， 免疫原性PRPI的存在继续引起对药物安全性和有效性的关注。我们提出了一个 使用我们现有的ISPRI-HCP平台评估PRPI免疫原性风险的创新方法。ISPRI- HCP通过利用基于T细胞表位计数的T细胞方法与常规方法不同 和密度。我们假设ISPRI-HCP可以根据以下条件准确分类候选PRPI杂质： 免疫原性风险。为了验证这一假设，我们将测定8个T细胞的免疫原性， 从中国人卵巢细胞（CHO）表达系统中发现了PRPI，从腺病毒疫苗中发现了5个PRPI。 ISPRI-HCP分类的选定PRPI涵盖广泛的免疫原性风险。肽池包括 将制备所选蛋白质的T细胞表位，并测试它们诱导抗原特异性T细胞表位的能力。 在使用外周血单核细胞（PBMC）的测定中分泌INF-γ的T细胞。这个项目的总体目标是 研究旨在提供概念验证，并进一步改进ISPRI-HCP作为预测 PRPI的免疫原性风险。

ABSTRACT The identification and removal of process-related protein impurities (PRPI) from biologic products is a critical step in drug development. Despite recent improvements in the purification and processing of biologics, the presence of immunogenic PRPI continue to raise concerns about drug safety and efficacy. We propose an innovative approach for assessing immunogenicity risk of PRPI using our existing ISPRI-HCP platform. ISPRI- HCP stands apart from conventional methods by utilizing a T cell approach based on the T cell epitope count and density. We hypothesize that ISPRI-HCP can accurately classify candidate PRPI impurities according to their immunogenicity risk. To test this hypothesis, we will determine the T cell immunogenicity of 8 frequently found PRPI from Chinese Hamster Ovary (CHO) cell expression systems and 5 PRPI from adenoviral vaccines. The selected PRPI classified by ISPRI-HCP cover a wide range of immunogenicity risk. Peptide pools comprised of T cell epitopes of the selected proteins will be prepared and tested for their ability to induce antigen-specific INF-g secreting T cells in assays using peripheral blood mononuclear cells (PBMCs). The overall goal of this study is to provide proof-of-concept and further improve ISPRI-HCP as a platform for predicting the immunogenicity risk of PRPI.