Steinbeis experts conduct research into diagnostic and treatment processes for lysosomal storage diseases
Lysosomal storage diseases (LSDs) are a group of metabolic diseases in which defects in a specific enzyme lead to severe pathological changes in organs. Although individual types of LSD are rare, general incidence levels are relatively high (roughly 1 in 8,000). Depending on the defective enzyme, LSDs can cause damage to organisms in a variety of ways through conditions such as liver or kidney damage, heart attacks, and neurological damage. In recent times, of all the different treatment methods available, enzyme replacement therapy (ERT) has proven particularly successful. ERT involves delivering missing or defective enzymes through an infusion of human recombinant proteins. ERT works for a variety of LSDs, but unfortunately it is extremely expensive: The costs of treatment per patient per annum can be as high as €300,000. The Steinbeis Transfer Center for Biopolymer Analysis and Biomedical Mass Spectrometry is conducting research into alternative treatment methods.
A major problem with ERT is that antibodies form against synthetic enzymes, and this can lead to severe allergic reactions (see reference literature, 1-6). Antibodies bind with the therapeutic enzyme, and this neutralizes and hinders therapeutic effects. In many cases, treatment can only be continued if patients are administered powerful immunosuppressives, but these also cause severe side effects. There is therefore strong interest in alternative therapies for blocking or removing antibodies in enzyme replacement therapy, in the same way that there is strong general interest in protein therapy.
Antibodies work by only binding to short, specific peptide segments of a protein. These sections are called epitopes, and their structure and binding affinity are decisive when it comes to the specific nature of an antibody. It is crucial to identify the structure of epitopes and their binding affinity, partly for medical advancement and the development of diagnostic and therapeutic biomarkers, but unfortunately this is currently not possible using conventional methods. To identify the epitopes of antibodies, the experts at the Rüsselsheim-based Steinbeis Transfer Center for Biopolymer Analysis and Biomedical Mass Spectrometry have developed a method which combines surface plasmon resonance (SPR) biosensor analysis with mass spectrometry (MS). For the first time, this makes it possible to identify molecules while simultaneously determining antibody epitope affinity. The success of the work speaks for itself: The applicability and efficiency of the new combined method have already been validated by successfully identifying epitopes in a series of antibody protein complexes (reference 7).
The Steinbeis experts in Rüsselsheim recently performed an epitope analysis of antibodies following enzyme replacement therapy for Fabry’s disease (FD). FD is a lyposomal storage disease that affects the skin, kidneys, and cardiovascular system and has other pathological effects. The disease, which has only been identified in around 5,000 patients in Europe until now, is caused by mutations in a gene in the X chromosome. The company Genzyme, which has been working with the Steinbeis experts for a number of years, has recently made successful advancements in the treatment of FD by using enzyme replacement therapy, and in 2010 its work was honored with the Steinbeis Foundation Transfer Award. Patients are given infusions of the recombinant human enzyme during enzyme replacement therapy. Although therapy can be successful, there are significant drawbacks due to reactions in the immune system and immunoglobulin antibody formation, and this can even result in life-threatening complications. The identification, chemical synthesis, and optimization of epitope affinity and the stability of antibody epitopes open up new possibilities to avoid reactions of the immune system and increase the therapeutic effectiveness of ERT in lysosomal storage diseases. There are two treatment options. The first involves pretreating patients with the epitope peptide in order to neutralize antibodies. The second is to remove antibodies by using special blood cleansing techniques. Both methods are designed to significantly enhance the efficacy of therapeutic procedures with proteins, paving the way for new developments and new clinical applications involving epitope peptides as therapeutic guidance frameworks and specific diagnostic options.