Immunogenicity risk mitigation of therapeutic proteins with translational immunogenicity, analytical...

The immunogenicity of therapeutic proteins remains a key challenge, leading to early and late-stage clinical failures, posing a significant hurdle in the development of safe and efficacious biopharmaceuticals. This review highlights the main categories of factors influencing the immune response-mediated impacts of biotherapeutics: 1) patient-related factors, 2) product-related factors, and 3) administration-related factors. It provides a comprehensive overview of these immune response-mediated impacts, ranging from the development of anti-drug antibody (ADA) responses, injection site reactions (ISR), and injection site pain (ISP). Using immune response-mediated impacts as a focal point, the review discusses tools and strategies that can be used to evaluate the potential critical quality attributes (pCQAs) of therapeutic proteins as they have an impact on immunogenicity. These tools include various immunogenicity assessment assays spanning in silico, in vitro, ex vivo, in vivo animal models, and clinical tools. It also highlights a comprehensive repertoire of analytical characterization methods. Emphasis is placed on the importance of combined stage-appropriate use of these tools to minimize the risk of immunogenicity. Additionally, regulatory guidance, forums, and consortium landscapes are outlined to inform immunogenicity risk assessment strategy for therapeutic proteins. Ultimately, this integrated comprehensive immunogenicity testing strategy aims to advance the field of immunogenicity risk assessment to develop safe and efficacious protein therapeutics.