Advanced personalized diagnostics to overcome severe side effects of protein therapeutics

Therapeutic protein drugs have been widely used to treat a variety of diseases including cancer, autoimmune diseases, neurological diseases, metabolic diseases, bleeding disorders and others. The global protein drug market reached nearly $174.7 billion in 2015 and should reach nearly $248.7 billion by 2020. Although most protein drugs offer a favourable benefit-risk ratio, one key hurdle for the maintenance of clinical efficacy and safety has been the development of unwanted immune responses against protein drugs, in particular the development of anti-drug antibodies. Some patients develop pathogenic antibodies which neutralize the biologic activity of the protein drug or cause devastating health problems such as anaphylaxis or autoimmune pathologies. Currently, there is no diagnostic tool which can predict and distinguish the development of harmless or pathogenic antibodies in an individual patient. Therefore, basic research efforts are required to better understand immune regulation and nature of harmless and pathogenic anti-drug antibodies and to create the scientific basis for the development of novel diagnostics. Early diagnosis of evolving pathogenic antibodies would provide a window of opportunity for early immune intervention which could prevent pathogenic immune responses. One prominent example of pathogenic anti-drug antibodies is the development of neutralizing antibodies against factor VIII (FVIII) following replacement therapy of hemophilia A patients with human FVIII products. The antibodies neutralize the biological activity of FVIII and render replacement therapies ineffective which can result in life-threatening bleeding complications. In this project application, we propose to close a major gap in current understanding of the nature and evolution of pathogenic antibodies against FVIII and their differentiation from non-pathogenic antibodies in patients with severe hemophilia A. We generated novel data on the temporal association between epitope specificity (protein epitopes versus carbohydrate epitopes), affinity, isotype/IgG subclass profiles and functional activities of antibodies against FVIII which develop in patients following replacement therapy with FVIII products. The possibility to combine basic research with the analysis of longitudinal samples obtained from patients undergoing FVIII therapy provides a unique opportunity to directly translate novel research findings into clinical application. The data coming out of this project can provide the scientific basis for the development of novel diagnostic tools, such as FVIII-specific microarrays, which will allow physicians to differentiate patient-specific characteristics and design personalized treatment approaches, and ultimately improve patient outcomes.