The Systems ITD will develop and build highly integrated, high TRL demonstrators in major areas such as power management, cockpit, wing, landing gear, to address the needs of future generation aircraft in terms of maturation, demonstration and Innovation. Integrated Cockpit Environment for New Functions & Operations - D1: Extended Cockpit - D24: Enhanced vision and awareness - D25: Integrated Modular Communications Innovative Cabin and Cargo technologies - D2: Equipment and systems for Cabin & Cargo applications Innovative and Integrated Electrical Wing Architecture and Components - D3: Smart Integrated Wing Demonstrator - D4: Innovative Electrical Wing Demonstrator Innovative Technologies and Optimized Architecture for Landing Gears - D5: Advanced Landing Gears Systems - D6: Electrical Nose Landing Gear System - D7: Electrical Rotorcraft Landing Gear System - D17: Advanced Landing Gear Sensing & Monitoring System High Power Electrical Generation and Conversion Architecture - D8.1: Innovative Power Generation and Conversion for large A/C - D8.2: Innovative Power Generation and Conversion for small A/C Innovative Energy Management Systems Architectures - D9: Innovative Electrical and Control/Command Networks for distribution systems - D10: HVDC Electrical Power Network Demonstrator Innovative Technologies for Environmental Control System - D11: Next Generation EECS for Large A/C - D12: Next Generation EECS Demonstrator for Regional A/C - D13: Next Generation Cooling systems Demonstrators - D16: Thermal Management demonstration on AVANT test rig Ice protection demonstration - D14: Advanced Electro-thermal Wing Ice Protection Demonstrator - D15: Ice Detection System Small Air Transport (SAT) Innovative Systems Solutions - D18, D19, D21: More Electric Aircraft level 0 - D20: Low power de-ice for SAT - D22: Safe and Comfortable Cabin - D23: Affordable future avionic solution for small aircraft ECO Design T2: Production Lifecycle Optimisation Long-term Technologies T1: Power Electronics T3: Modelling and Simulation Tools for System Integration on Aircraft

De novo design and synthesis of affinity ligands mimicking natural biological recognition allows the purification of biopharmaceutical proteins, the resolution of isoforms and the extraction of low abundance proteins from the human proteome. The availability of crystallographic structures of proteins and complexes, together with refined computer-based molecular modelling techniques has lead to the concept of 'intelligent' design of chemically characterised, highly selective and stable affinity ligands for target proteins. Synthetic affinity ligands circumvent the drawbacks of natural IgG-binding ligands, such as resistance to chemical and biological degradation, and offer ease and low cost of production and in situ sterilization. In our previous work, highly selective adsorbents for biopharmaceutical proteins have been developed based on combinatorial libraries using a triazine scaffold. We propose now to concentrate on developing new methods for the purification of engineered antibodies, since it is predicted that by 2008, engineered antibodies will account for >30% of the total revenue in the biotechnology market. This has motivated us to design specific affinity adsorbents for the isolation of whole (IgG), monovalent (Fab, scFv) and engineered variants (diabodies, triabodies, minibodies and single-domain antibodies) for the industrial-scale downstream purification of biomedical and research immunopharmaceuticals. We have recently developed a novel approach to protein fractionation which exploits peptoido-mimetic chemistry based on the 4-component Ugi-Passerini reaction. This multi-component reaction reacts an oxo-component, an aldehyde or ketone, generally immobilised to the solid phase, a primary or secondary amine, an isonitrile and a carboxylic acid in a 'one-pot' reactor to yield a single di-amide scaffold product. Multi-component reactions allow for substantial chemical diversity by incorporating 3, 4 or more reactants, each of which can be varied systematically to produce a variety of subtle changes to the final ligand structure. A particular advantage of the Ugi-Passerini chemistry for affinity ligand design is that this scaffold mimics the native dipeptide bond fairly precisely, with the interatomic distances between the O1-N-O2 in the native dipeptide being divergent from the Ugi scaffold by <1Å in a triangulated pharmacophore diagram. Both the carboxylate and amine substituents are directed away from the scaffold and therefore present an exploitable binding site for target interaction. The current list of commercially available reaction components from the Available Chemicals Directory (ACD) lists of amines, aldehydes, isonitriles and carboxylic acids, gives a potential combinatorial library of 3x1014 elements. We propose to construct limited (~100-200 member) solid-phase libraries of affinity ligands based on these 4-component reactions aimed at creating peptoido-mimetic ligands for binding immunoglobulins via the Fc (Protein A/G), Fab (Protein L) and glycomoiety, differentiating the various classes and sub-classes, binding various immunoglobulin fragments (scFv) and selectively binding immunoglobulins from several sources. We will use beaded Sepharose CL-6B and HyperCel as the aldehyde-substituted component and vary the other three components in an m x n array to generate a library of 'di-amide' type ligands covalently bonded to the matrix support. The binding behaviour of the target proteins will be confirmed by ELISA, small-scale (50microl) liquid chromatography and MS/MS. Those ligands exhibiting favourable IgG-binding characteristics will be re-synthesised using a larger scale suitable for further chromatographic evaluation. An iterative process of chemical synthesis, followed by biological evaluation, and complementation by molecular modelling, will lead to ligands displaying the desired level of specificity for whole and fragmented IgG whilst exhibiting negligible levels of host cell protein binding.

It is now widely accepted that up to ten years are needed to take a drug from discovery to availability for general healthcare treatment. This means that only a limited time is available where a company is able to recover its very high investment costs in making a drug available via exclusivity in the market and via patents. The next generation drugs will be even more complex and difficult to manufacture. If these are going to be available at affordable costs via commercially viable processes then the speed of drug development has to be increased while ensuring robustness and safety in manufacture. The research in this proposal addresses the challenging transition from bench to large scale where the considerable changes in the way materials are handled can severely affect the properties and ways of manufacture of the drug. The research will combine novel approaches to scale down with automated robotic methods to acquire data at a very early stage of new drug development. Such data will be relatable to production at scale, a major deliverable of this programme. Computer-based bioprocess modelling methods will bring together this data with process design methods to explore rapidly the best options for the manufacture of a new biopharmaceutical. By this means those involved in new drug development will, even at the early discovery stage, be able to define the scale up challenges. The relatively small amounts of precious discovery material needed for such studies means they must be of low cost and that automation of the studies means they will be applicable rapidly to a wide range of drug candidates. Hence even though a substantial number of these candidates may ultimately fail clinical trials it will still be feasible to explore process scale up challenges as safety and efficency studies are proceeding. For those drugs which prove to be effective healthcare treatments it will be possible then to go much faster to full scale operation and hence recoup the high investment costs.As society moves towards posing even greater demands for effective long-term healthcare, such as personalised medicines, these radical solutions are needed to make it possible to provide the new treatments which are going to be increasingly demanding to manufature.