Project: Generation & optimization of anti-FCGR2B antibodies to create tolerizing vaccines for autoimmune diseases and severe allergy
The human body is susceptible to invasion by pathogens or other harmful substances in the environment, and the immune system acts as the body’s natural defence to clear away these ‘invaders’. By doing so, the immune system prevents disease and restores health in case of disease. While it is a highly powerful protective function, a delicate balance exists between identifying a truly noxious agent and innocuous molecules. This process of eliminating immune reactions against innocuous agents is called ‘immune tolerance’, which prevents the immune system from unwanted reactions against self-proteins (e.g. of the body’s own tissues) or external non-harmful molecules. Failure of this process can lead to reactions against one’s own body which can result in autoimmune disorders and allergies. These diseases are affecting millions of people worldwide with symptoms ranging from mild discomfort to severe physical disability and death. _x000D_
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Autoimmune disorders consist of a wide spectrum of, mostly, chronic diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis and type I diabetes. These disorders arise when the immune system attacks its own tissues, and can affect various or multiple organs – for example the skin, joints, kidneys, muscles, adrenal glands and pancreas. Commonly, patients suffer from the malfunction of the organs, and progression towards disabilities and, in some cases, death. In the US alone, approximately 8% of the population is affected by one or more forms of autoimmune diseases. These diseases represent one of the largest challenges facing the healthcare sector; currently, there is no cure and effective treatments are lacking in most cases. Nevertheless, the spending on this health issue has been enormous; a recent NIH [1] (US) report suggests that the annual healthcare costs associated are close to 100 billion dollars in the US alone [2]. _x000D_
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Allergies are a more common form of health issues relating to immune responses. They arise from the immune system’s exaggerated response towards common environmental factors, for example grass or plant pollen, or foods. Despite a wide range of manifestations, certain forms of allergies can be debilitating or life-threatening, such as allergic asthma, certain food allergies (e.g. peanut) and anaphylactic shock. It has been reported that 180,000 people die of allergic asthma annually world-wide [3]. Anaphylactic shock requires clinical emergency procedures, and delayed and inappropriate intervention will result in fatality. _x000D_
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The aetiology of these diseases justifies an approach to reset the immune system and reestablishment of immune tolerance in these conditions. For the development of novel therapies, understanding of the molecular mechanisms of tolerance is essential. Our recent exciting discoveries led us to the identification of an antibody binding receptor, the Fc gamma receptor 2B (FCGR2B), which plays a central role in establishing and the COtenance of immune tolerance. In vivo animal studies have demonstrated that a lack of this receptor can lead to failure in the induction of tolerance and an increased susceptibility to autoimmune diseases. On the contrary, FCGR2B over-expression alleviates the symptoms from experimentally induced autoimmunity. Our aim is to develop therapeutics that allow re-induction of tolerance towards allergens and auto-antigens. To investigate the therapeutic potential, we have generated monoclonal antibodies against murine FCGR2B that activate the receptor thereby inducing tolerance when simultaneously administrated with an antigen. A similar antibody in humans would offer a complete new treatment strategy for patients with auto-immune diseases and allergies. _x000D_
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To achieve this, our strategy involves modelling of the interaction between target and antibody using state-of-the art in silico technology for our mouse and recently selected human anti-FCGR2B antibodies. This approach further allows modelling of amino acid modifications throughout the variable doCOs of the antibody to improve its overall performance. Modelled amino acid substitutions are introduced at large scale using a recently developed highly accurate gene synthesis technology. Antibodies variants will be screened on enhanced biological activity in our human and mouse model systems. _x000D_
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For this effort, Immunaffect BV (NL), VU Medical Center (NL) and Selvita S.A (PL) will join forces. These Ps bring their own unique and complementary expertise in immunology, antibody binding receptor, antigen-antibody interactions, epitope mapping, protein engineering technologies, and in-vitro and in-vivo testing models. In this project, the consortium aims to achieve Proof of Principle (PoP) for this platform technology in the treatment of Multiple Sclerosis (MS)._x000D_
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Acronym
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VACIMMUNE
(Reference Number: 5307)
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Duration
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01/03/2010 - 01/03/2013
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Project Topic
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The aim of the current project is to achieve Proof of Principle for the use of fully human agonistic antibodies targeted at the antibody binding receptor FCGR2B for use in tolerizing vaccines, using Multiple Sclerosis as a model.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 3
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Project partner
