Clinical Immunogenicity Risk Assessment for a Fusion Protein.

This document highlights some relevant factors in the assessment of immunogenicity risk of fusion protein therapeutics. Our aim is to highlight specific risks associated with this type of molecule, while also aligning with general risk assessment factors, through a hypothetical case study, where the therapeutic molecule of interest is a Receptor-Fc Fusion protein (RFF) expressed within a typical manufacturing process in Chinese Hamster Ovary Cells (CHO). Given that the components are comprised of endogenous sequences, the risk of developing an ADA response to this molecule is generally considered to be low. However, the consequences of such an immune response may be more severe, specifically, if there is cross reactivity with the endogenous receptor, inducing cell lysis, or if any ADA act as an agonist to trigger receptor signaling. The risk factors described below are not meant to provide a comprehensive list, but rather a framework for factors that should be considered. Immunogenicity risk is difficult to quantify and relies on a comprehensive analysis of both product and patient-related factors. The goal is not necessarily to quantify risk, but rather to demonstrate an understanding of factors that may pose a risk, implement a strategy to minimize risk factors and then align overall risk with a bioanalytical immunogenicity monitoring strategy. The consequences resulting from unexpected outcome will likely depend on severity and impact on patient safety. An immunogenicity risk assessment is an ongoing and continuous process throughout clinical development with the goal of maximizing the safety of patients.