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

ISPRI-HCP：CHO 蛋白杂质免疫原性风险预测，用于改进生物仿制药产品开发和评估产品互换性

• 批准号: 10620080
• 负责人: Anne Searls DeGroot
• 金额: $ 200万
• 依托单位: EPIVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620080
• 关键词: ISPRI; HCP; CHO; protein; impurity

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.

抽象的 从生物制品中鉴定并去除宿主细胞蛋白 (HCP) 是生物仿制药的关键步骤 药物开发。虽然生物仿制药的序列可能与创新药相同，但所用的过程 生产生物仿制药会有所不同，因此，可能会在产品中引入新的 HCP。尽管 最近对纯化工艺的改进，在不同细胞系中生产并纯化的生物制剂 使用不同的工艺含有不同的 HCP 杂质，因此有必要识别和量化杂质 对于每种产品，无论是参考创新产品还是拟议的生物仿制药产品。在这个U01计划中，我们 提议开发 HCP 免疫原性预测模型，以促进临床评估 有意义的生物制剂免疫原性风险，并评估生物仿制药和生物仿制药之间的互换性风险 创新产品。我们开发了一种基于网络的工具，称为 ISPRI-HCP（以前称为 CHOPPI）， 通过评估 T 细胞表位计数和密度来预测 HCP 序列的免疫原性潜力，以及 与人类基因组中其他表位的相对保守性。以先前的单克隆研究为基础 使用计算机模拟方法测定抗体和生物蛋白的免疫原性以及我们的 FDA 通用肽免疫原性 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 根据其免疫原性风险。为了解决这个假设，我们将训练、测试和交叉验证 使用 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 使用我们的方法针对许可的单克隆抗体产品中的 87 种常见 CHO HCP 杂质生成 在体外刺激从头 T 细胞反应，称为体外免疫方案（目标 1）。我们也会测试 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）。该研究计划将提高 ISPRI-HCP平台，为药物开发商提供快速有效的方法来减少HCP相关 免疫原性风险，以解决生物仿制药开发中的这一关键质量属性。