Development of cell-free protein synthesis platforms for discovery and/or production of biologicals

Cell-Free Protein Synthesis (CFPS) has been employed in fundamental biological research for decades, however, interest for the approach as a viable means for drug development and production has only emerged in recent years. The advantages that CFPS provides in terms of efficiency, simplicity, flexibility, cost- and time savings outweigh the hurdles that are still to be overcome for CFPS to become a routine manufacturing system for peptide- or protein-based biologicals. Currently, there are several CFPS systems used that are either based on prokaryotic or eukaryotic cell lysates (including mammalian) or fully synthetic systems consisting of all the molecular machinery necessary to create functional proteins. The choice of a specific lysate is dictated by the target protein and the end-use application. Proteins that require post-translational modification are generally produced using lysates of mammalian cells. Hence systems based on mammalian cells are of particular interest as they combine properties inherent to eukaryotic cells and their ability to produce human-like glycosylated proteins with the advantages of cell-free synthesis. These proteins include antibody fragments, antigens, virus-like particles, cytokines, enzymes, antimicrobial peptides and proteins containing non-natural amino acids. The benefits of CFPS are manifold, from ease of handling and scalability, on-demand launch of production, ability to rapidly switch products, simplified purification to facilitated standardisation and quality control. CFPS needs less energy resources, the manufacturing footprint is less complex and smaller than in cell cultivation and it enables production of proteins that have toxic effects on cells. In addition, CFPS has the potential as an enabling technology for personalised medicines and is amenable to decentralised manufacturing. CFPS has gained even more interest in the recent past owing to advances in synthetic biology and thanks to the rise of Machine-Learning/Artificial Intelligence (ML/AI). The use of generative deep learning and artificial intelligence has high potential in the de-novo design of biomolecules with specific properties of therapeutic and/or preventive nature. CFPS offers here great opportunities to increase the throughput in screening of the de-novo created biomolecules. The application of synthetic biology, potentially also combined with generative AI, and cell-free biosynthesis open up new avenues for the design, discovery and manufacture of therapeutics not only against infectious diseases, but also non-communicable diseases and equally for vaccines. Proposals should address at least two of the following elements: Address the bottlenecks that currently hamper the large-scale deployment of CFPS, i.e. the lack of a quality-by-design approach, the need to fully characterise the underlying cell lysates and their critical quality attributes and the need for better understanding of the correlations between specific cell lysate properties and CFPS process parameters, specific product quality attributes (such as protein folding), and CFPS platform performance. Use synthetic biology techniques for the design of de-novo biomolecules with specific desired properties (antimicrobial, immunogenic, angiogenic, etc.) and develop suitable cell-free systems for the high-throughput screening of the designed biomolecules. Develop novel or optimise existing CFPS platforms for the production of the targeted biomolecule to a Good Manufacturing Practices (GMP) conform process, producing clinical-grade material that can be tested in clinical trials. The demonstration of the superiority of the developed CFPS platform as compared to the current state-of-the art production system for a specific therapeutic peptide or protein would be an asset and participation of start-ups, micro, small and medium-sized enterprises (SMEs) is encouraged. Applicants envisaging to include clinical studies should provide details of their clinical studies in the dedicated annex using the template provided in the submission system. https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32003H0361 Please note that the definition of clinical studies (see introduction to this Work Programme part) is broad and it is recommended that you review it thoroughly before submitting your application.