Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk
Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk


Start Date
End Date
IMI1 - Call 3
Grant agreement number

Type of Action: 
RIA (Research and Innovation Action)

IMI Funding
18 170 217
EFPIA in kind
9 573 494
5 107 345
Total Cost
32 851 056


A growing number of medicines are based on biological molecules like proteins and monoclonal antibodies. These novel drugs have resulted in new, more effective treatments for a number of serious conditions. Yet sometimes they trigger a response from the patient’s immune system that can decrease the effectiveness of the drug or cause severe side effects. This is called immunogenicity. The aim of the ABIRISK project was to shed new light on the factors behind immunogenicity and get a better understanding of its molecular origin. The result is an improvement in tests designed to predict the likeliehood that a molecule will trigger an immune response.

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.

Other achievements:

  • 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.

What’s next?

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.

Achievements & News

ABIRISK discovers risks that drive immune response to biopharmaceuticals
December 2016

Biopharmaceuticals have the potential to improve lives, but they can also trigger an immune reaction in some patients. When this happens, the immune system produces antibodies (ADAs) that neutralise the drug, which can reduce the effectiveness of the biopharmaceutical and lead to severe side effects.### In a new study, ABIRISK project scientists discovered that age, gender and even the time of the year can increase the risk of an immune reaction. As part of the study, ABIRISK researchers gathered data from more than 20 000 multiple sclerosis patients who were tested for ADAs in routine clinical testing or research studies in four countries: Sweden, Austria, Denmark and Germany. By analysing the data, scientists discovered that males and older adults are at a higher risk of developing an immune response when receiving the biopharmaceutical called IFNβ. In patients from Sweden and Germany, the start of therapy in April also coincided with a higher likelihood of developing an immune response, indicating that seasonal factors might also play a role. When it comes to a biopharmaceutical called Natalizumab, researchers discovered that females and older people are at a higher risk. According to the scientists in the study, the findings could be used to develop more personalised monitoring programmes and interventions for patients who are at a higher risk. For example, if the seasonal factor behind the higher risk is due to lower vitamin D levels, vitamin D supplementation at the start of therapy could be used to decrease the risk of the immune response. ‘This study was a direct outcome of the collaboration of different research labs, hospitals and industrial partners within the ABIRISK project who shared data from local routine ADA testing labs and research studies’, said Marc Pallardy, the ABIRISK managing entity. ‘The expertise from the industrial partners was essential to coordinate and manage the collaboration between the partners and to build the standardised database, while the academic partners were crucial in data collection and curation, and in the scientific design of the study. It is the first big collaborative achievement of the ABIRISK consortium.’

Join eTRIKS in Amsterdam for its community meeting
September 2015

IMI data management project eTRIKS will hold a community meeting in Amsterdam on 22 October. The event represents an excellent opportunity to learn about the eTRIKS project and the services it offers to IMI and other projects. A highlight of the event will be a review of how eTRIKS works with the IMI project ABIRISK. ###ABIRISK’s goal is to enhance our understanding of safety issues surrounding medicines based on biological molecules such as proteins and monoclonal antibodies. eTRIKS has set up a specific tranSMART tool for ABIRISK partners, onto which ABIRISK data has been curated, uploaded, stored and analysed. The meeting will also mark the launch of the eTRIKS Labs, an online space where new projects will be made available for review and feedback. According to the project, eTRIKS Labs will make it easier to co-create tools, services, training and guidelines for translational research.

ABIRISK issues recommendations for communicating on biopharmaceuticals
June 2015

IMI’s ABIRISK project has published a set of proposals for setting up standards in the field of biopharmaceuticals. Biopharmaceuticals are medicines based on biological molecules such as proteins and antibodies. In some patients, these medicines trigger ‘immunogenicity’, an immune response that may decrease the effectiveness of the drug or cause severe side effects.### ABIRISK is working to shed new light on the causes of these reactions. However, writing in the journal Clinical and Experimental Immunology, the project partners explain that efforts to collaborate across sectors and disciplines are hampered by a ‘lack of agreement on concepts, practices, and standardised terms and definitions related to immunogenicity’. To overcome these challenges and to advance research in this important area, the project has developed and agreed to use a set of common terms and definitions for describing the immunogenicity of biopharmaceuticals. ‘This paper is a major contribution to the field of immunogenicity to set up standards in terms of definitions and common language,’ said ABRISK project leaders Marc Pallardy of Université Paris-Sud and Dan Sikkema of GlaxoSmithKline. ‘Indeed, the lack of common terms across this field hampers the possibility to compare results and introduces confusing factors.’ The terms and definitions are set out in the paper and on the ABIRISK website. The project is keen to receive feedback on its proposals so that it can refine them further.

ABIRISK haemophilia paper wins prize
September 2014

A paper by scientists from IMI project ABIRISK won the clinical research award at the Seventh Edition of the Martín Villar Research Awards.### The awards, named after Spanish haematologist Martín Villar, recognise research published by young scientists working in the field of blood coagulation and related disorders, such as haemophilia. Many medicines are based on biological molecules such as proteins and monoclonal antibodies. These novel drugs have resulted in new, more effective treatments for many conditions including haemophilia, a serious disease in which the blood fails to clot following injury. Yet sometimes these medicines trigger a response from the patient’s immune system, and this can decrease the effectiveness of the drug or cause severe side effects. The ABIRISK project is investigating the causes of this immune response. In this paper, the researchers identify for the first time variations in a specific gene that are associated with a strong immune response to the haemophilia treatment Factor VIII. Around 30% of haemophilia A patients develop an immune response to Factor VIII treatment, and the researchers suggest that their findings could pave the way for new ways of preventing the immune system from blocking the action of Factor VIII.

Genes could influence effectiveness of MS treatment, ABIRISK reveals
April 2014

The effectiveness of one of the main drugs used to treat multiple sclerosis (MS) could be influenced by patients’ genes, according to new research from IMI’s ABIRISK project published in PLoS ONE.### The findings could influence treatment decisions in the future. MS is a neurological disease in which the immune system attacks the protective coating around nerve cells. The frontline treatment for MS is beta interferon (IFNβ), which comes in two types – IFNβ-1a and IFNβ-1b. However, around a fifth of patients develop high levels of antibodies that neutralise the drug, reducing its effectiveness. In this study, the researchers reveal that patients carrying certain genetic variants are at greater risk of developing high levels of antibodies, and suggest that this could help determine treatment decisions in the future. However they caution that their results should be confirmed in additional studies, and emphasise that the factor with the strongest influence on the risk of developing antibodies is the way the drug is prepared and administered. Patients who receive IFNβ-1a as an intramuscular injection are at the lowest risk (under 10%) of developing neutralising antibodies, while patients who receive it as a subcutaneous injection face a much higher risk (around 30%). Patients taking IFNβ-1b face the greatest risk (almost 50%).

Participants Show participants on map

EFPIA companies
  • Bayer Pharma AG, Berlin, Germany
  • Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
  • Ipsen Innovation SAS, Les Ulis, France
  • Merck Kommanditgesellschaft Auf Aktien, Darmstadt, Germany
  • Novartis Pharma AG, Basel, Switzerland
  • Novo Nordisk A/S, Bagsvaerd, Denmark
  • Pfizer Limited, Sandwich, Kent , United Kingdom
  • Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
  • UCB Pharma SA, Brussels, Belgium
Universities, research organisations, public bodies, non-profit groups
  • Academisch Medisch Centrum Bij De Universiteit Van Amsterdam, Amsterdam, Netherlands
  • Academisch Ziekenhuis Leiden, Leiden, Netherlands
  • Assistance Publique Hopitaux De Paris, Paris, France
  • Bundesinstitut Fur Impfstoffe Und Biomedizinische Arzneimittel, Langen, Germany
  • Centre National De La Recherche Scientifique Cnrs, Paris, France
  • Commissariat A L Energie Atomique Et Aux Energies Alternatives, Paris, France
  • Fondazione Per L'Istituto Di Ricerca In Biomedicina, Bellinzona, Switzerland
  • Fundacio Hospital Universitari Vall D'Hebron - Institut De Recerca, Barcelona, Spain
  • Groupe D'Etudes Therapeutiques Desaffections Inflammatoires Digestives Association, Paris, France
  • Heinrich-Heine-Universitaet Duesseldorf, Düsseldorf, Germany
  • Institut National De La Sante Et De La Recherche Medicale, Paris, France
  • Istituto Giannina Gaslini, Genova, Italy
  • Johann Wolfgang Goethe-Universitaet Frankfurt Am Main, Frankfurt am Main, Germany
  • Karolinska Institutet, Stockholm, Sweden
  • Klinikum Rechts Der Isar Der Technischen Universitat Munchen, Muenchen, Germany
  • Medical Research Infrastructure Development And Health Services Fund By The Sheba Medical Center, Ramat Gan, Israel
  • Medizinische Universitat Innsbruck, Innsbruck, Austria
  • Queen Mary University Of London, London, United Kingdom
  • Region Hovedstaden, Hilleroed, Denmark
  • The Health Corporation - Rambam, Haifa, Israel
  • Universita Degli Studi Di Firenze, Florence, Italy
  • Universitatsklinikum Bonn, Bonn, Germany
  • Universitatsspital Basel, Basel, Switzerland
  • University College London, London, United Kingdom
  • Univerzita Karlova, Prague 1, Czech Republic
Small and medium-sized enterprises (SMEs)
  • Alta Ricerca E Sviluppo In Biotecnologie Srlu, Siena, Italy
  • Biomonitor A/S, Copenhagen, Denmark
  • Scicross AB, Skovde, Sweden
Patient organisations
  • Drk-Blutspendedienst Baden-Wurttemberg-Hessen Ggmbh, Mannheim, Germany
Third parties
  • Universite De Tours, Tours - BP12050, France
  • Universite Paris-Sud, Orsay, France
Project coordinator
Sebastian Spindeldreher
Novartis Pharma AG
Managing entity
Marc Pallardy
Institut National de la Santé et de la Recherche Médicale