Project: Bicyclic Anti-Inflammatory Therapeutics
The complement system plays an essential role in innate immunity, our first line of defence. Activation occurs via different pathways and supports rapid clearance of invading pathogens. Unfortunately, the complement system also has a dark side and gets activated in cases where it should not. This leads to tissue damage and acute (or chronic) inflammatory disorders in a variety of clinical conditions (e.g. cardiovascular (stroke), ocular (AMD), allograft/xenograft rejection, ischemia/reperfusion injuries, autoimmune diseases, and neurological disorders (a.o. Alzheimer)). Currently, there is no effective treatment for the majority of these diseases, which emphasizes the urgent medical need for efficient complement inhibitors and so the enormous commercial and societal impact of this project. Approaches to develop small molecular weight inhibitors have failed to deliver safe and effective treatments. Monoclonal antibody therapy has so far proven the only successful strategy and FDA approval of eculizumab (Soliris), targetting the C5 component of the complement cascade, for treatment of the orphan diseases Paroxysmal Nocturnal Hemoglobinuria (2007) and atypical Hemolytic Uremic Syndrome (2011) has established a landmark for complement component inhibitors. This treatment is, however, extremely expensive (>400,000 USD/year) and Soliris is reportedly the world’s most expensive drug. _x000D_Recent discoveries by the UMCU-P of this project showed that Gram-positive bacteria, like Staphylococcus aureus, produce very potent and specific complement inhibitor proteins (SSL7, SCIN and Efb) to shut down the complement pathway and protect themselves from immune eradication (Rooijakkers et al., Nat. Immunol. 2005; Serruto et al., Nat. Rev. Microbiol. 2010). This provides compelling evidence that effective complement-inhibition strategies can be developed and these natural inhibitors guide us to the most effective points of intervention. This project aims at developing bicyclic peptides as potent inhibitors of the activated forms of central complement components (C3b, C5b and Bb) using an evolutionary strategy much like that of bacteria. Mild chemical synthesis (neutral pH in water at room temperature) in combination with phage-display technology (~10^11 diversity) makes these constrained peptides readily available for therapeutic development (Timmerman et al., Chembiochem 2005; Heinis et al., Nat. Chem. Biol. 2009). Such bicyclic peptide inhibitors have recently emerged as potential therapeutics and shown exceptionally high binding affinities and selectivities that are fully comparable with those of monoclonal antibodies. Moreover, they exhibit ideal drug-like properties (in vivo half lifes ~1-6 hours, excellent proteolytic stabilities in blood) for candidate drugs to treat acute inflammatory diseases. Furthermore, they have the potential to inhibit protein-protein interactions in a similar fashion as described for bacterial complement inhibitors (SSL7, SCIN and Efb), which makes them ideally suited for development as potent and selective complement inhibitors, a target class for which still hardly any drug exist. _x000D__x000D_The project consortium consists of 3 participants:_x000D_1. PEPSCAN THERAPEUTICS (NL)_x000D_R&D-performing SME in Therapeutic Peptide Development. Research with special focus on development of scaffold technologies (e.g. CLIPS) & Peptide Array Synthesis (Identification of Protein-Protein Interactions). Participant owns IP on Bicycle Peptides in general. Participant has granted non-exclusive licence to BICYCLE THERAPEUTICS for the use of CLIPS-technology in genetically-encoded libraries._x000D_2. BICYCLE THERAPEUTICS (UK)_x000D_R&D-performing SME active in Therapeutic Peptides Development. Participant has developed unique technology of bicycle peptide screening in phage display. Participant focuses on developing a pipeline of bicycle peptide products for clinical development. Participant has developed a range of bicycle libraries with different drug-like characteristics and introduced a high level of automation into the process of selection of target binding bicycle peptides. Participant owns IP on the use of bicycle peptides in phage display libraries and on the use of the selection technology to develop drug products. _x000D_3. UNIVERSITY MEDICAL CENTRE UTRECHT (UMCU)_x000D_Research facility of UMCU within the department of Medical Microbiology with a focus on host-pathogen interactions. Special focus on innate immunity and complement activation, bacterial inhibition of complement activation and development of therapeutic complement inhibitors. Participant owns IP on a diversity of (bacterial) complement modulators. _x000D__x000D_Complementarity between the participants is unique in terms of i) technological facilities and infrastructure, ii) scientific background & expertise, and iii) know-how & intellectual property. The team is of very high quality and indispensable for carrying out the work as described in this proposal._x000D_
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Acronym
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BAIT
(Reference Number: 7679)
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Duration
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01/04/2013 - 31/03/2016
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Project Topic
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Unwanted complement activation is part of the root cause of >50 diseases (a.o. several Acute Inflammatory Diseases)) for which currently no effective therapies exist. This proposal describes discovery and development of bicyclic peptide drugs as inhibitors of key complement factors (C3b, C5b, Bb).
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Network
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Eurostars
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Call
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Eurostars Cut-Off 9
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Project partner
