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By Robin Marsden

Risk assessment is undeniably complex. All therapeutic proteins have the potential to develop an unwanted immune reaction similar to the desired immune reaction that vaccines elicit. Understanding how frequent that reaction is and the potential association with safety and efficacy is essential to understanding whether the immunogenic response affects the risk-benefit assessment of the drug. The path to a clear risk assessment for immunogenicity is crowded with many roadblocks in the form of a wide range of biological considerations, manufacturing challenges, physiological responses, bioanalytical assay challenges, and requests from health authorities. In addition, if the desired low incidence of immunogenicity is obtained, the ability to detect any subtle clinically meaningful associations becomes more complicated due to the unbalanced analysis sets.

The manner in which antibody response is assessed for risk will vary depending on a number of considerations, such as the therapeutic, the indication, and the route of administration. The number of different types, sizes, and molecular compositions of therapeutics in development requires careful consideration for understanding which bioanalytical assays need to be implemented in order to provide the most relevant data to interpret immunogenicity data in context of pharmacokinetic and pharmacodynamic results. Fundamental to these assays is the approach chosen for the appropriate

calculation of cut point, the value against which all results are compared for positive status. One of the most critical risk factors is the presence of an endogenous counterpart to the chosen therapeutic, which requires a careful risk assessment of the potential for a cross-reactive antibody response to the native protein.

The phrase “case-by-case” is frequently used in describing the approach selected for risk assessments and their impact on bioanalytical and clinical development strategies. This reflects that each molecule of interest needs to be considered independently and that there is no standardized strategy that will work for all molecules. Given the long development cycles for new therapeutics, very few individuals have personal experiences with a wide array of molecules. Inter-departmental discussions and professional societies like AAPS provide the opportunity for colleagues to discuss evolving thought through presented case studies beyond their own personal experience. If someone works for a small company or is new to the field, they do not have access to the same size network of colleagues. With white paper publications lagging behind the rapidly evolving thought, how can we as a professional society increase the shared knowledge across the full industry beyond the connections we have already made?

This blog post is one way—post your thoughts and questions here on challenges and solutions for developing the immunogenicity risk assessment that underpins all of the immunogenicity analyses. What are your worries? Have you had a eureka moment where something just clicked for you on a particular program? How do you integrate the scientific hypotheses that you want to test with the analyses that are feasible to conduct?

Consider joining us on April 29–30 in San Diego at the AAPS Training Course on Immunogenicity Risk Assessment: Theory to Practice to learn from colleagues across the industry to practice immunogenicity risk assessment and associated bioanalytical strategy development for a wide range of case studies.

This blog post was written with the support of Joleen White, Johanna Mora, and Shobha Purushothama.

Robin Marsden is the associate director of bioanalytical at La Jolla Pharmaceutical, and over the last 22 years she has developed and validated assays for small molecules, peptides, PEGylated biotherapeutics, and ADCs, with specialization in the assessment of immunogenicity.