Antibodies specific for disease-causing mutant proteins

The consequences of changing a single nucleotide in one of our approximately 25.000 genes can reach from an even increased fitness of the organism (increased malaria resistance of heterozygotes for sickle cell anemia), over an increased susceptibility for the development of diseases to manifestation of severe disease (e.g. missense mutations causing autosomal dominant inherited diseases). It is, however, not the nucleotide change itself that causes potentially damage but rather the change in the gene product, a protein, whose building plan is encoded by the gene carrying the mutation. Whereas the detection of a single nucleotide change in a gene is a relatively easy task with modern methods, the detection of small changes like the substitution of a single amino acid in a protein sequence is not. How such a change affects the mutant protein`s function in the context of the cellular protein network, the proteome, is mostly unknown due to the lack of tools that allow to differentiate between the normal "wild-type" protein and its mutant variant that are often present in the same cell. Therefore it is the major goal of our project to generate antibodies, in particular monoclonal antibodies, which recognize specifically the mutant, disease-causing variant or the wild-type protein. For this project, which represents a proof-of-principle study, we will produce antibodies against human lamin A and lamin associated protein 2a (LAP2a) mutants, which are linked to human genetic disorders, so called laminopathies. No antibodies with such specificities have been reported yet. We are, however, very confident that this goal can be achieved based on the results and expertise we gained during our basic research studies on protein phosphatase 2A (PP2A). We were able to generate not only monoclonal antibodies specific for post-translationally modified amino acids of PP2A subunits but also others, which recognize differences as small as a single amino acid substitution in the primary protein sequence. For the commercialisation of these antibodies we concluded licensing agreements with international companies like Upstate/Chemicon-USA and Alexis Corporation. By capitalizing on our scientific and commercial expertise, we therefore want to set out on the generation of antibodies specific for disease-causing mutant proteins. We envision such antibodies to be of great value for both, basic research as well as clinical applications like the prognosis of etiopathology of genetic disorders, and potentially even therapeutic measures in the future.