Immunogenicity risk assessment for tailored mitigation and monitoring of biotherapeutics during development: recommendations from the European Immunogenicity Platform

Abstract

Bringing safe and effective drugs to patients is of utmost importance for the pharmaceutical industry, with immunogenicity (IG) being a critical factor that influences both aspects. Biotherapeutics can elicit unwanted immune responses, potentially leading to (severe) safety implications, reduced patient benefits, and may result in termination of development. Therefore, understanding IG risks throughout drug development is essential for both drug developers and health agencies (HAs). The Immunogenicity Risk Assessment (IRA) facilitates the identification of IG risk factors and allows the establishment of effective mitigation and monitoring strategies. In this publication, the European Immunogenicity Platform (EIP) presents a comprehensive IRA framework aligned across pharmaceutical industry, emphasizing its significance in product development - from early de-risking to bioanalytical monitoring and mitigation measures during clinical trials. The EIP also provides an updated list of IG risks, offers distinct recommendations for assigning overall IG risk levels prior to the start of clinical development and highlights business considerations within this assessment.

Keywords: anti-drug antibody; bioanalysis; biotherapeutics; immunogenicity; immunogenicity de-risking; immunogenicity mitigation; immunogenicity monitoring; immunogenicity risk assessment.

Figure 1

Assignment of overall IG risk level (low, moderate or high) prior to start of clinical development. After risk identification the potential impact of IG is evaluated in relation to the disease status and available alternative medication to assess its potential severity. Since the presence of alternative medications only affects the IG risk category for life-threatening diseases, this differentiation has been excluded for non-life-threatening diseases. This evaluation is influenced by existing knowledge. A high-risk category is assigned when severe safety consequences are anticipated. A low-risk categorization is recommended in case of sufficient certainty that no or little impact of IG will be observed otherwise a moderate category is applicable (as further explained in the box).

Figure 2

Impact of IRA during product development. During concept phase, it is recommended to start the IRA and incorporate the IG risks into the earliest discussions on molecule design. In silico prediction tools are often employed across the industry, to ensure that at minimum there is a de-risking of the amino acid sequence of the potential leads. For high-risk molecules, or new platforms, PE-ADA tests can be implemented. Additional in vitro tests, such as MAPPs, T-cell activation and B-cell epitope prediction assays and tools, can be utilized to confirm observations from the in silico tests, and to gate any de-immunization activities as needed. After candidate selection, the IRA guides the monitoring and mitigation strategy throughout development.