Biopharmaceuticals (BPs) are drugs that are biological in nature. They are widely used in the treatment of cancer, chronic viral hepatitis and inflammatory and autoimmune diseases. Unfortunately, BPs can have unwanted effects: in some patients, they can cause the immune system to produce anti-drug antibodies (ADAs), which can change the concentration of the drug in the body or even neutralise it. This can decrease the efficacy of the drug, or result in severe side effects such as allergic reactions.
This ADA response, also known as immunogenicity, is not very well understood. The ABIRISK project set out to find a way to predict these unwanted immune responses and thus develop safer and more effective BPs. If it were possible to predict this responses, doctors would be able to identify which patients are likely to develop an adverse reaction, and those who might be non-responsive.
ABIRISK scientists chose five lifelong diseases that are treated with BPs: multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), intestinal bowel diseases (IBD) and haemophilia A (HA). To understand the mechanisms of immunogenicity, they developed standardised assays, as well as new biomarkers that would make it easier to classify patients and to set the threshold of immune response that would indicate when the efficacy of a BP was decreasing.
Large-scale cross-comparison of data
The major achievement of ABIRISK was the creation of the first large prospective cohorts in the study of BP immunogenicity. More than 700 patients, suffering from MS, RA, IBD and JIA, were recruited from more than 70 medical centres across Europe. This allowed bioassays to be cross-compared on a very large scale. For the first time ever, scientists analysed five different diseases at the same time, partially treated with the same BPs. Cross-comparison of the data allowed them to come up with best practices for measuring the immunogenicity of the therapeutic molecules, i.e. their capacity to trigger immune responses.
Standardised assays, human standards
Another important outcome of the project was the standardisation of assays for testing ADA and BP concentrations, as well as the creation of human ADA standards. Until now, assays to detect antibodies used animal standards, but thanks to ABIRISK, project partner Sanofi was able to produce large quantities of human ADA standards, that will, once validated, be available to scientists worldwide through the National Institute for Biological Standards and Control (NIBSC) in the UK.
The availability of these ADA standards allows for the harmonisation of ADA assays for BPs and thus enables researchers and clinicians to publish data that are more consistent. The ADA assays developed by the ABIRISK consortium can help clinicians decide to keep a patient on the BP, switch to another BP with the same mode of action, or to switch to a different class of BP targeting a different part of the disease pathway.
ABIRISK researchers also discovered candidates for biomarkers that can predict early ADA development. These can be explored further by the pharma industry and academia. In cases where several different BPs are available as treatment options, the most appropriate treatment for a patient may be identified by testing for the respective immunogenicity-related biomarkers. This means that patients could receive cost-effective treatment without risking the development of potentially efficacy-limiting anti-BP immunisation.
The ABIRISK database
Another accomplishment of the project was the creation of the ABIRISK database, which brings together immunogenicity data from across Europe. The data includes patients suffering from MS, RA, JIA, IBD and HA who are being treated with various BPs, as well as cohorts of patients from dedicated studies that were part of the ABIRISK program. The database is based on the tranSMART platform, an open-source knowledge management platform for translational science.
- A better understanding of the molecular origin of immunogenicity. This has led to an improvement in the tests that evaluate the immunogenicity potential of new molecules. It also confirmed that therapeutic molecules clumped together as aggregates have higher immunogenic potential than individual molecules, with the structure being preserved.
- New assays for HA for routine analysis. This is expected to reduce false positive ADA results and to improve the detection limit of ADAs, which will considerably improve early and reliable diagnosis of ADA in patients with HA.
- Insight into the immunogenicity of various biological drugs. Translation into clinical use depends on several other factors, such as the persistence of ADA, titres, neutralising capacity and affinity, with the results showing the incidence of ADA in the first year of treatment.
- Immunophenotyping of MS patients, revealing a signature that allows the characterisation of ADA positive and ADA negative patients.
- The development of a common language: terms and definitions related to immunogenicity have been aligned. The paper published in 2015 is used by the industry for reports to evaluate and describe immunogenicity in clinical trials, and it is cited in health authority guidelines.
The ABIRISK consortium brought together a network of clinicians, academic scientists, immunologists, biologists, database experts and statisticians. This ensured that the experimental findings were transferred to biopharmaceutical product development and patient management. The consortium combined industry know-how in clinical trial organisation, data management, new technologies, assay development and validation, as well as experience in regulatory affairs, immunologists from academia, and experts in analysis, patient access and clinical experience. All of this resulted in a better understanding of the immunological events that drive anti-BP immunisation.
Immunogenicity is still not fully understood, and as such, these six years of collaboration between the 38 consortium partners can be considered just the beginning. During the lifetime of ABIRISK, additional immunogenicity research projects were set up between industry and academia and between different academic institutes.
The ABIRISK Sustainability Scientific Committee (ASSC) manages the data collected during the project, and is tasked with stimulating research based on ABIRISK. The Committee is responsible for managing authorisation to access the database, as well as access to samples in biobanks. There are also four new projects linked to ABIRISK goals, funded through various national grants, and an international immunogenicity PhD course to be held every second year at the Karolinska Institute in Stockholm. Following ABIRISK, BIOPIA was founded as a non-profit collaborative effort between a number of European laboratories with expertise in BP pharmacokinetics and immunogenicity. It is an initiative that works on BP immunogenicity awareness raising, with the aim of integrating testing of these factors in order to improve the care and health of patients.