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 such as proteins and monoclonal antibodies. These novel drugs have resulted in new, more effective treatments for a number of serious conditions. Yet sometimes these medicines trigger a response from the patient’s immune system, which can decrease the effectiveness of the drug or cause severe side effects. The aim of the IMI-funded ABIRISK project is to shed new light on the factors behind this immune response. The project, which represents the first concerted effort to solve this problem, will aid in the creation of new, safer biopharmaceuticals and also generate tools to determine how individual patients are likely to respond to them both in clinical trials and after release to the market.

Biopharmaceuticals are drugs that are biological in origin (i.e. are made of proteins or DNA for example) and are manufactured using biotechnology. A number of biopharmaceuticals are already in use and have dramatically improved quality of life for patients with serious, hard to treat conditions such as multiple sclerosis, Crohn’s disease, diabetes, rheumatoid arthritis, haemophilia A and some cancers. However, in some patients, biopharmaceuticals can trigger an immune reaction, a phenomenon known as immunogenicity. When this happens, the immune system produces antibodies (ADAs) that neutralise the drug, which can reduce the effectiveness of the biopharmaceutical. In some patients, the immune response causes side effects such as a rash, chest pains, or a fall in blood pressure. In the most severe cases, it can trigger anaphylactic shock and even prove fatal.

Immunogenicity – the known unknowns
Diverse factors appear to be involved in immunogenicity. On the drug side, both the compound and the route and duration of administration seem to play a role, while on the patient side, the type of disease, age, genetic background and interactions with other medicines may be risk factors.  Therefore it is extremely hard to predict which biopharmaceuticals will have immunogenicity problems; although many tests exist, these are not always accurate. Furthermore, knowing which patients are at greatest risk of mounting an immune response to a given biopharmaceutical is extremely difficult.

Reducing the risks
Even though immunogenicity continues to pose a problem in the development of new drugs, until now there has been no major effort to solve the problem. Enter the ABIRISK project, which aims to give biopharmaceuticals a much-needed boost and represents the first concerted effort to tackle the immunogenicity problem by bringing together leading experts from hospitals, academia, industry and small companies. The project will set up laboratory tests to probe the immunogenicity of several biopharmaceuticals that are already used on patients. The scientists will then match their test findings with the effect the drug actually has on patients. This will help the team to develop tools that are better at predicting immunogenicity during drug development.

Many pharmaceutical companies, academic institutions and patient registries have large amounts of data on biopharmaceuticals and patients’ responses to them. In ABIRISK, these diverse databases will be assembled into a single immunogenicity databank that will help researchers pinpoint the factors that influence a drug’s immunogenicity and patients’ risk of it. This will allow the researchers to generate tools that will accurately predict whether a patient will mount an immune response to a biopharmaceutical and how that immune response will affect the efficacy and safety of the drug.

Safer, more effective drugs for patients
Immunogenicity means many patients today are denied the life-changing benefits of biopharmaceuticals. ABIRISK will ultimately result in a new generation of biopharmaceuticals with lower immunogenicity that can be safely and effectively used by more patients. In addition, the project will allow clinicians to determine which patients will respond best to which biopharmaceutical, thereby preventing patients from suffering the side effects of a drug that does not suit them.

For Europe’s pharmaceutical industry, better tests will help companies identify the safest, most effective biopharmaceuticals and weed out those that pose a high immunogenicity risk earlier in the drug development process. This will save companies both time and money. Finally, by adding to our knowledge of the mechanisms behind immunogenicity, the project will help to improve regulatory guidelines for the approval of biopharmaceuticals.

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 Biopharma SPRL, 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 Ricerc A 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-Universitatfrankfurt Am Main, Frankfurt am Main, Germany
  • Karolinska Institutet, Stockholm, Sweden
  • Klinikum Rechts Der Isar Der Technischen Universitat Munchen, Muenchen, Germany
  • Medizinische Universitat Innsbruck, Innsbruck, Austria
  • Queen Mary University Of London, London, United Kingdom
  • Region Hovedstaden, Hilleroed, Denmark
  • Sheba Medical Center, Ramat Gan, Israel
  • The Health Corporation - Rambam, Haifa, Israel
  • Universita Degli Studi Di Firenze, Florence, Italy
  • Universitaetsklinikum Bonn, Bonn, Germany
  • University College London, London, United Kingdom
  • University Hospital Basel, Basel, Switzerland
  • Univerzita Karlova, Prague 1, Czech Republic
Small and medium-sized enterprises (SMEs)
  • ALTA Ricerca e Sviluppo in Biotecnologie S.r.l.u., Siena, Italy
  • Biomonitor A/S, Copenhagen, Denmark
  • SciCross AB, Skovde, Sweden
Patient organisations
  • DRK-Blutspendedienst Baden-Württemberg – Hessen gemeinnützige GmbH, Mannheim, Germany
Third parties
  • Université François Rabelais de Tours, Tours - BP12050, France
  • Université Paris-Sud, Orsay, France


Project coordinator
Sebastian Spindeldreher
Novartis Pharma AG
+41 61 6963291
Managing entity
Marc Pallardy
Institut National de la Santé et de la Recherche Médicale