Understanding how aggregation influences the immune response to recombinant protein therapeutic drugs

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Many human diseases, such as multiple sclerosis and cancer, are now treated successfully with drugs which are proteins, rather than small molecules. Protein drugs have the advantage that they are highly specific for a particular target: antibodies are a good example. They can be developed to bind with high affinity to block a specific receptor on the surface of a cell, inhibiting the progress of disease. The use of this new kind of drug in the clinic has grown rapidly over the last two decades, because protein drugs offer the potential for therapeutic intervention which would be difficult or impossible to replicate with small molecule medicines. Although these protein drugs are generally well-tolerated and have opened up exciting new avenues for the treatment of disease, this approach has come with a specific problem. Biotherapeutic proteins (even proteins which are designed to 'look' human) can be recognised as being foreign by the immune system of the patient. This can lead to production of antibodies within the patient which bind to the protein drug and prevent it from functioning effectively. In some cases, the consequences have been more severe, leading to serious adverse health effects in patients undergoing treatment. The origin of this problem lies in the way in which the immune system recognises 'foreign' molecules: a classic question in immunology is, 'why does the immune system not attack its own host's cells?' We now know that there are sophisticated systems for eliminating or inactivating immune cells which would recognise 'self' antigens, to prevent this from happening. This phenomenon is called 'tolerance'. Many protein drugs, although apparently identical to those produced by the host, nevertheless manage somehow to breakdown tolerance and provoke an immune response. It is still unclear exactly how this happens. The aim of this proposal is to investigate this phenomenon and, ultimately, to use the information obtained to inform the design and development of more effective protein drugs in the future. We will focus on one particular aspect which impacts on the immune response to protein drugs- a behaviour known as aggregation. Anyone who has ever boiled an egg is familiar with this behaviour: the white of the egg, after boiling, is solidified. Heat treatment pulls the structure of the protein (albumin) in the egg white apart and the individual protein chains adhere into a dense mesh. This type of behaviour is a general property of proteins, and a version of it can occur in preparations of protein drugs. The presence of aggregates in the preparation is important, as we know that they are very effective at influencing the complex cellular and molecular processes that lead to an immune response. Our proposal will investigate the different immunological responses induced by aggregates from a selection of drug-like proteins. In particular, we seek to determine how these different responses are influenced and modulated by aggregate size, which is the main criterion used to characterise them.