Anti-Biopharmaceutical Immunization: prediction
and analysis of clinical relevance to minimize the RISK
Project focus
ABIRISK Project aims to provide an integrated approach to AD immunization, bringing together, in an extensive and coordinated manner, a large network of clinicians from various specialties with broad experience in the care of patients treated with various type of BPs and developing ADA, biologists familiar with the immune monitoring of patients, scientists specialized in the mechanisms of immunogenicity, methodologists and biostatisticians. In addition the collaboration with a large network of private pharmaceutical industries under European Federation of Pharmaceutical Industries and Associations (EFPIA), will ensure direct transfer of the experimental findings into BP development and patient management.
Collectively, this group will critically evaluate the immunogenicity of existing BPs for Hemophilia A, Multiple Sclerosis, and Inflammatory Diseases, and develop standardized ADA assays, including Neutralizing Antibody (NAb) Assays, for each BP. Novel integrated approaches to characterize AD lymphocyte responses will be used to provide insight into the basic mechanisms by which BPs drive immune cell activation. The predictive value of existing as well as new tools used for prediction of protein drug immunogenicity will be explored and evaluated, including T cell assays, in silico prediction, in vitro generated BP-derived agretopes generated by processing in human dendritic cells, measurement of peptide affinity for HLA class II molecules, modulation of dendritic cell function and activation by BPs, human in vitro mononuclear leukocytes assays, use of artificial lymph nodes, animal models, and generation of post-translational modifications and aggregates and characterizing them in various models.
Collection and integration of immunogenicity-related data and clinical relevance will be assembled into a single immunogenicity databank that will be used to describe the natural history of the occurrence of ADA, identify common and disease-specific/drug-specific variables associated with immunogenicity/outcomes, develop models that will predict occurrence of ADA, presence or absence of subsequent clinical outcomes, derive predictive signatures for immunogenicity phenotypes (ADA or NAb) and immunogenicity-related-events, and evaluate the operating characteristics of the predictive signatures.
For all of this work to be successful, robust and standardized assay methods are required. Key members from EFPIA in conjunction with academic scientists will work together to establish standardized reagents and protocols that will be shared as an outcome of this research. It is hoped that an understanding of the basic mechanisms of immunogenicity can be broadly applied to new BPs as they are developed, thus enabling the development of new drugs for those in need.
Over the past several years, immunogenicity was one reason for the failure of several BPs in clinical development. Currently, it is not possible to predict the likelihood of a patient to develop an unwanted immune response to a BP. Even of detected ADA, the consequences for the patient outcome are not well defined.
ABIRISK Project will investigate the correlation between patient and clinical factors and the incidence of immunogenicity. A major goal is to further elucidate the underlying mechanisms of immunogenicity and this may result in more science-based regulatory guidelines, which may reduce the regulatory burden for immunogenicity testing and save time and resources in the BP drug development process. A better understanding of the physico-chemical characteristics such as aggregates and impurities will enable us to better define the product specifications. Finally, data dissemination of the information generated by ABIRISK Project will be made available to other relevant stakeholders world-wide through the Consortium website and database, reports at European Immunogenicity Platform (EIP), presentations at scientific meetings, publications and White Papers, Standard Operating Procedures, and dedicated meetings with regulatory bodies. Regulations for the monitoring of immunogenicity to BPs continue to evolve, and maintenance of state-of-the-art knowledge of global regulations with the possibility to influence their evolution through introduction of innovative scientific information, will be of key interest to all participants.
Abbreviations : AD = anti-drug; ADA = anti-drug antibodies; BPs = biopharmaceuticals products; EFPIA: European Federation of Pharmaceutical Industries and Associations; EIP: European Immunogenicity Platform; NAb = neutralizing antibody.