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.

摘要 生物制品中宿主细胞蛋白（HCP）的鉴定和去除是生物类似药的关键步骤 药物开发虽然生物类似药的序列可能与创新药相同，但用于 生产生物仿制药的不同厂家可能会有所不同，因此，可能会在产品中引入新的HCP。尽管 纯化工艺的最新改进，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，因此有必要对杂质进行鉴别和定量 对于每种产品，无论是参考创新产品还是拟议的生物类似药产品。在U 01项目中，我们 建议开发HCP免疫原性的预测模型，以便于临床评估 生物制品的有意义的免疫原性风险，并评估生物类似药与 创新产品。我们开发了一个基于Web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预测HCP序列的免疫原性潜力，和 与人类基因组中其他表位的相对保守性。基于以前的单克隆抗体研究 抗体和生物蛋白免疫原性，使用计算机模拟方法和我们的FDA通用肽免疫原性 根据研究经验，我们假设ISPRI-HCP可以准确分类候选HCP杂质 根据它们的免疫原性风险。为了解决这个假设，我们将训练，测试和交叉验证一个 使用T细胞免疫原性数据集建立中国仓鼠卵巢（CHO）HCP免疫原性预测模型 使用我们的方法生成许可单克隆抗体产品中87种常见CHO HCP杂质 体外刺激从头T细胞应答，称为体外免疫方案（Aim 1）。我们还将测试 用于刺激新生T细胞免疫原性数据的抗原刺激策略的质量， ISPRI-HCP预测模型的开发（目标2）。这项研究计划将提高 ISPRI-HCP平台，为药物开发人员提供快速有效的方法，以减少HCP相关的 免疫原性风险，以解决生物类似药开发中的这一关键质量属性。