Rational Design of Epitope Binding Monobodies: New Tools for Autoimmune Therapy

Abstract

Autoimmune Disease is the misguided targeting of self‐proteins or tissues by immune cells and is the number two cause of chronic long‐term disease. Many therapeutic options for autoimmune disease involve the use of immunosuppressive medicines that reduce the immune system's abnormal response. This approach is not specific to the individual autoimmune disorder and as a result these drugs weaken the entire immune system leaving the patient more prone to infection. Therefore, more targeted approaches to treatment of autoimmune disorders is needed. In our work we are developing an antigen specific approach to autoimmune therapy by hiding the epitope (specific auto‐antibody binding site) on the antigen to which an antibody is binding. Using the model system, idiopathic membranous nephropathy (IMN), we have developed epitope binding nanobodies which cover up the epitope region. Twenty‐five epitope binding nanobodies were designed and docked to the epitope region. Binding scores to the epitope regions of the IMN antigen phospholipase A2 receptor were evaluated. Our results show that several prominent interactions lead to improved binding scores compared to the starting nanobody template. Gel analysis of the protein expression of the ySMB, SH13‐M001, and SH13‐M003 epitope binding nanobody candidates, demonstrates successful protein expression and purification. Future studies underway are ELISA assays to confirm binding of epitope binding nanobodies and their ability to inhibit autoantibody binding in vitro.Support or Funding InformationWilliam Randolph Hearst Foundation and Rhodes College department of Chemistry