Towards the manipulation of the UPR in mammalian cells to orchestrate cellular re-organization for enhanced monoclonal antibody production

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We have developed a defence mechanism to respond to infection when our body recognises a foreign 'invader'. We have a type of cell known as a B cell in our body, which in response to infection changes into an antibody-producing cell. This is necessary to allow us to fight off infections that would otherwise be very harmful. The antibodies work by attacking the foreign invader and destroying it, thereby clearing the infection and removing the foreign agent. In order for the B cells to change into antibody producing cells (a process known as differentiation), they must adjust the organization of themselves so that they have the required pieces of cellular machinery to make large amounts of antibody. As antibodies are the bodies natural defence against disease, many new antibody type drugs are being developed to help treat human diseases such as cancer and AIDS. However, in order to produce these next generation antibody-based therapeutic 'drugs' we must use mammalian cells to make them. The types of cells we use to make these drugs are not as efficient at producing antibodies as the modified B cell and as a result we are not able to produce enough of these drugs and the cost and demand for them is therefore high. It is thought that this will become even more of a problem as more antibody based drugs are developed. The research proposed here will examine whether we can find mammalian cells with more of the required machinery to produce high-levels of antibodies, or alternatively, if we can manipulate these mammalian cells to produce more of this machinery so that higher yields or amounts of these drugs can be produced more quickly at less cost. At present it is unknown if this is possible, and the process is poorly understood in the mammalian cells used to produce these antibodies. Advanced technology known as proteomics and inducible expression technology will be used to study the differences in the levels of the proteins known to be important for antibody production in differentiated B cells and compare the levels of these proteins in the mammalian cells used for commercial antibody production. We will look for proteins that become either more or less abundant (by altered gene expression, protein synthesis and/or protein degradation) and for subtle molecular modifications to pre-existing proteins known to be able to modify their function (e.g., switch them on or off). Information from current genomics projects will be mined and used in combination with our protein data to identify ways of improving the amount of therapeutic protein 'drug' we can manufacture using these mammalian cells. As stated above, this is extremely important as it is expected that with an increasing number of protein 'drugs' being developed we will lack the capability of producing large enough amounts to meet the required demand for these new drugs.