Anti-Biopharmaceutical Immunization: prediction
and analysis of clinical relevance to minimize the RISK
Analyses of the mechanisms and consequences of immunization against biopharmaceutical products (BPs) require extensive post-marketing follow-up of patients, with comparisons of several BPs and various clinical conditions treated with the same BP. Sufficient numbers of patients must be included in each subgroup for the reliable evaluation of independent parameters. There is also a need for high-quality data generated by centers familiar with clinical research. The ABIRISK consortium has been designed to meet all of these requirements in order to target three types of disorders:
- Hemophilia A
- Multiple sclerosis
- Inflammatory diseases: inflammatory rheumatisms (including rheumatoid arthritis) and inflammatory bowel diseases
ABIRISK Project will collect data both retrospectively from patients suffering from various types of diseases and treated with various BPs at European centers with a high level of experience in clinical research and will prospectively recruit additional patients in dedicated studies during the 5 years of this program. Guidelines and Standard Operating Protocols (SOPs) for the study of anti-drug (AD) immunization will be established and used to standardize the collection of prospective data from these patients. ABIRISK Project thus represents a unique opportunity to create an interdisciplinary task force of clinical centers especially designed to study immune responses against BPs.
For each BP, standardized anti-drug antibodies (ADA) and neutralizing antibody (NAb) assays are needed in order to accurately assess a subject’s antibody status and to compare antibody incidence and characteristics across cohorts. For some compounds, standardized ADA assays are already available and successfully performed at different laboratories across Europe. Indeed, for other compounds, immunogenicity assays are either not available, or multiple versions of an assay are run at different labs, making data interpretation and comparisons between laboratories difficult. ABIRISK consortium will evaluate currently available assays and reagents, and will develop and validate standardized assays for ADA measurement. Development of these assays will help to improve the routine clinical assessment of patients and to support the clinical studies conducted as part of this project. Various assay formats and platforms will be considered to determine the most suitable methodology and read-out for a particular product (i.e., ADA or NAb).
A SOP will be written for each assay. A universal assay validation protocol will be prepared for ADA and NAb assays and each assay will be validated according to the procedures outlined in this validation protocol. The validation protocol will be prepared by following guidelines and recommendations set out in the various white papers and guidance documents for immunogenicity assay validation and testing. A full validation procedure will be performed for all ADA assays that will be developed during this program. A validation report will be prepared for each assay after completion of the validation procedure.
Additional methodology may be developed in order to further characterize ADA responses. These methods may include isotype and affinity determinations to determine the predominant isotype(s) produced. ADA affinity and the isotypes/affinities and avidity characterization most correlated to adverse events/loss of response can then be determined.
One of the original and important aspects of the ADA assay section of ABIRISK project is the generation of universal and unlimited ADA internal standards for each BP, possible due to the unique expertise of this consortium.
The availability of robust, sensitive and specific ADA assays is of utmost importance because ADA positive (ADA+) and negative (ADA-) patient cohorts will be selected using these assays for cohort stratification.
To minimize the risk of ADA induction and improve sustainable BP efficacy, we need to gain insight into the mechanisms by which BPs drive immune cell activation. This includes understanding the molecular structures of antibodies inducing BP immunogenicity, the role of inflammation in driving ADA responses and the importance of underlying patient characteristics associated with ADA development. Different approaches will be used to assess the cellular, antibody and genetic characteristics of patients treated with a range of different BPs in different diseases. Results will be correlated with clinical outcomes for selected diseases and with development of ADA responses. We will use samples collected both retrospectively and prospectively from a range of cohorts across Europe. To ensure high quality and timeliness of experimental procedures, external assessment of each laboratory will be made.
The following objectives are: i)Understand the cellular mechanisms leading to AD responses; ii) Characterize ADA functionally and structurally; iii) Identify genetic risk factors that determine the individual’s risk of developing ADA and eventually might influence the selection of immune-therapies in disease.
ADA+ and ADA- patient groups will be compared to control groups. A phenotypical, functional and genetic signature will be generated and made available across the consortium.
For this objective ABIRISK project will evaluate the predictive value of a broad spectrum of technologies that have been developed or used as tools for prediction of protein drug immunogenicity, develop and assess novel predictive immunogenicity methodologies and explore the effects of formulation and aggregation on immunogenicity prediction.
The following approaches will be tested: 1) Evaluation of different T cell assay approaches with regard to their predictive value for clinical immunogenicity; 2) Evaluation of in silico prediction methods; 3) Identification of in vitro generated BP-derived agretopes generated by natural processing in human dendritic cells; 4) Modulation of dendritic cell function and activation by BP; 5) Development of artificial lymph nodes for assessment of immunogenicity of BP; 6) Relevance of new animal models.
All these approaches are complementary and represent state of the art technology.
ABIRISK project will, in a single “immunogenicity databank”, collect the information selected on the basis of its potential value for immunogenicity prediction and safety gathered during the program. This will involve the standardization of information originating from many sources (both prospective and retrospective investigations) and relating to different BPs, different diseases (hemophilia A, multiple sclerosis, rheumatoid arthritis and inflammatory bowel diseases) and different cohorts for a given disease. This will also include the integration of various preclinical, clinical and immune monitoring factors. The immunogenicity databank will be designed together with an appropriate external organization with proven expertise, which will then set up, manage and maintain the databank. The structure will ensure that research methods can be systematically applied to produce meaningfully comparable results across disparate data sources.
To obtain (specific or common) predictive signatures for immunogenicity phenotypes and immunogenicity-related clinical events, the generated ABIRISK databank will be used to (i) describe the natural history of the occurrence of ADAs in a “real world” setting (proportion of patients affected, time course, occurrence of subsequent clinical outcomes); (ii) identify common and disease-specific/drug-specific variables that are associated with immunogenicity and immunogenicity-related outcomes; (iii) develop models that will predict: a) the occurrence of ADAs and b) the occurrence or absence of subsequent clinical outcomes; (iv) derive (specific or common) predictive signatures for immunogenicity phenotypes (ADAs, NAbs) and immunogenicity-related events; (v) evaluate the operating characteristics of the predictive signatures.
Abbreviations : AD = anti-drug; ADA = anti-drug antibodies; BPs = biopharmaceuticals products; NAb = neutralizing antibody; SOP = Standard Operating Protocol.