ISPRI-HCP: CHO protein impurity immunogenicity risk prediction for improving biosimilar product development and assessing product interchangeability

摘要 从生物制品中鉴定和去除宿主细胞蛋白(Hcp)是实现生物相似的关键步骤。 药物开发。虽然生物相似的序列可能与创新者相同，但用于 产生的生物相似将是不同的，因此，新的六氯环己烷可能会被引入到产品中。尽管 最近对纯化工艺的改进，即在不同的细胞系中生产和纯化的生物制品 使用不同的工艺含有可变的hcp杂质，因此有必要对杂质进行鉴定和定量。 对于每种产品，无论是参考创新者产品还是建议的生物相似产品。在这个U01项目中，我们 建议开发一种预测HCP免疫原性的模型，以便于临床评估 生物制品的有意义的免疫原性风险，并评估生物相似物和 创新者产品。我们开发了一个基于Web的工具，名为ISPRI-HCP(以前称为CHOPPI)，它 通过评估T细胞表位计数和密度来预测hCP序列的免疫原性 与人类基因组中其他表位的相对保守性。在以往对单克隆性研究的基础上 用电子计算机方法检测抗体和生物蛋白的免疫原性和我们FDA的通用多肽免疫原性 根据研究经验，我们假设ISPRI-HCP可以准确地对候选HCP杂质进行分类 根据它们的免疫原性风险。为了解决这一假设，我们将训练、测试和交叉验证 基于T细胞免疫原性数据集的中国仓鼠卵巢(CHO)HcP免疫原性预测模型 用我们的方法对授权的单抗产品中的87种常见CHO HCP杂质产生 体外刺激从头T细胞反应，命名为体外免疫方案(AIM 1)。我们还将测试 用于刺激从头T细胞免疫原性数据的抗原刺激策略的质量 开发ISPRI-HCP预测模型(目标2)。这项研究计划将提高 ISPRI-HCP平台，为药物开发商提供了一种快速有效的手段，以减少与HCP相关的 免疫原性风险，以解决生物相似发育中的这一关键质量属性。

ABSTRACT The identification and removal of host cell proteins (HCP) from biologic products is a critical step in biosimilar drug development. While the sequence of a biosimilar may be identical to the innovator, the process used to produce the biosimilar will be different, and as a result, new HCPs may be introduced into the product. Despite recent improvements to purification processes, biologics that are manufactured in different cell lines and purified using different processes contain variable HCP impurities, making it necessary to identify and quantify impurities for each product, be it a reference innovator product or a proposed biosimilar product. In this U01 program, we propose to develop a predictive model for HCP immunogenicity that can facilitate assessment of clinically meaningful immunogenicity risk for biologics and assess interchangeability risk between a biosimilar and an innovator product. We have developed a web-based tool called ISPRI-HCP (formerly called CHOPPI) that predicts the immunogenic potential of HCP sequences by evaluating T cell epitope count and density, and relative conservation with other epitopes in the human genome. Building on previous studies of monoclonal antibody and biologic protein immunogenicity using silico methods and our FDA generic peptide immunogenicity research experience, we hypothesize that ISPRI-HCP can accurately classify candidate HCP impurities according to their immunogenicity risk. To address this hypothesis, we will train, test and cross-validate an immunogenicity prediction model for Chinese hamster ovary (CHO) HCPs using a T cell immunogenicity dataset generated for 87 common CHO HCP impurities in licensed monoclonal antibody products with our method for stimulating de novo T cell responses in vitro, named In Vitro Immunization Protocol (Aim 1). We will also test the quality of the antigen stimulation strategy that is used to stimulate de novo T cell immunogenicity data for development of the ISPRI-HCP predictive model (Aim 2). This research program will improve the accuracy of the ISPRI-HCP platform, providing drug developers with a rapid and efficient means to reduce HCP-associated immunogenicity risk to address this critical quality attribute in biosimilar development.