Project: Development of a therapeutic antibody to prevent heart failure after myocardial infarction
This project aims to develop a new therapeutic antibody for the prevention of heart failure after acute myocardial infarction (AMI; heart attack). Although AMI treatment has improved significantly and fewer patients die of AMI itself, many patients who survive suffer from heart failure. Heart failure causes a range of debilitating symptoms, including oedema in the abdomen and/or legs, difficulty breathing, nausea, fatigue, confusion, unconsciousness, and cardiovascular complications including subsequent infarction (Fig.1). Ultimately, heart failure can progress to death. Between 25-60% of patients develop heart failure upon AMI[1], which cannot be cured (except with heart transplantation). Current treatment involves drugs to reduce symptoms and limit progression (ACE-inhibitors, beta-blockers, diuretics) and lifestyle changes (diet, exercise, no alcohol/smoking). Ironically, since more patients survive AMI due to improved treatment of the infarction itself, cardiac failure upon AMI is an increasing problem both for individual patients and for healthcare and society as a whole._x000D__x000D_Upon AMI, first the affected blood vessel(s) is unblocked to limit the damage to the heart muscle (e.g. percutaneous coronary intervention; PCI). However, directly following the AMI an inevitable inflammatory response and formation of scar tissue is initiated in the heart, as an attempt of the body to compensate for the damage. This process of non-functional tissue formation (adverse remodeling) leads to heart failure. At the basis of this process are several ‘danger signals’ generated in the heart upon AMI. Production of danger molecules causes attraction and activation of inflammatory cells, which clear damaged heart tissue and cause tissue destruction. In addition, danger molecules signal resident cells to form scar tissue (fibrosis), which impairs the contractile performance of the heart. As a result, the heart is less able to pump blood, leading to cardiac failure. No interventions are available to date to prevent this damaging process to the heart. There is an urgent need for new treatment options._x000D__x000D_Research in the group of Prof. Pasterkamp, UMC Utrecht (UMCU) in the last few years has led to the identification of a new target which plays a central role in adverse remodeling upon AMI (Fig.2). This target is a danger molecule produced in the human heart directly after AMI, during the process of inflammation and adverse remodeling. The target is involved in attraction and activation of inflammatory cells and activates cells which form the scar matrix (fibroblasts). Recently, Bioceros BV has generated a set of mouse antibodies directed against this target in collaboration with the UMCU. Preliminary data show that the lead antibodies block the target and improve both heart function and survival in an accepted in vivo mouse AMI model (Fig.3). These data strongly indicate that derivatives of these target-specific antibodies may be used as therapeutic to prevent heart failure upon AMI in patients. In this project, the selected lead antibody will be further tested and developed into a therapeutic humanized antibody. In parallel, the value of the target as potential companion diagnostic will be determined. Availability of a companion diagnostic allows to optimize antibody treatment in the individual patient and monitor treatment responses. Recent drug development is often accompanied by such companion diagnostics. _x000D__x000D_A strong consortium of SMEs (Bioceros BV, HistologiX Ltd.) and academia (UMCU) from the Netherlands and United Kingdom will use its complementary expertise to perform this ambitious R&D project (Fig.4). The selected lead antibody will be characterized and tested for in vitro efficacy in highly representative cell-based models (Bioceros, UMCU). Potential cross-reactivity will be determined, limiting the chance of side-effects and facilitating future regulatory preclinical studies (HistologiX). The antibody will be humanized and a GMP-ready production cell line will be generated making the antibody available for clinical use after this project (Bioceros). Finally, in vivo Proof-of-Mechanism will be provided for efficacy of the new antibody in an accepted large animal (porcine) AI model (UMCU, Bioceros). In parallel, levels of the target and related surrogate markers will be determined in blood samples from AMI patients (HistologiX, UMCU), providing Proof-of-Principle for these biomarkers for the development of a companion diagnostic. _x000D_At the end of this project, a new therapeutic antibody will be available for the prevention of heart failure upon AMI, with associated data package (in vitro & in vivo efficacy, cross-reactivity), its GMP-ready production cell line, and Proof-of-Principle for its companion diagnostic. This will place the consortium in a good position to initiate further co-development of the therapeutic antibody with a large pharmaceutical company after this project (regulatory studies, clinical trials).
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Acronym
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PREVUMAB
(Reference Number: 8401)
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Duration
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01/10/2013 - 30/09/2016
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Project Topic
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To generate Proof-of-Mechanism for a new target-specific therapeutic antibody to prevent heart failure upon myocardial infarction and validation of its target as companion diagnostic. The selected lead will be tested (efficacy, cross-reactivity), humanized and a production line will be generated.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 10
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Project partner
