Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium

Abstract

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

Keywords: ABIRISK consortium; anti-drug antibodies; biopharmaceuticals; immunogenicity.

Fig. 1

Typical tiered testing scheme for anti-drug antibody (ADA) testing and characterization. In the first tier, all evaluable samples are run in the screen assay. Samples that score positive in the screen assay are then analysed in a confirmatory assay (tier 2). Samples that score positive in the screen and confirmatory assay are reported as positive, while samples that score negative in either the screen or confirmatory assay are reported as negative. Further tiered testing of positive samples frequently includes analysis of titres and neutralizing activity. In some cases, isotype analysis or epitope mapping may also be performed.

Fig. 2

Interpretation of anti-drug immune response. After sample results have been determined, it will then be possible to categorize the anti-drug antibody (ADA) status of the subjects, and determine whether the positive subjects’ ADA originated from treatment induced, boosted or unaffected ADA responses.