Identifying next generation Ig selective cleaving enzymes for treatment of autoimmune diseases using IMPACT platform

Abstract

Abstract Dysregulated humoral immune mechanisms result in immunoglobulin production that is pathogenic and contributes to a wide range of autoimmune diseases and transplant rejection. Proteases derived from human pathogens can specifically cleave these immunoglobulins (Ig) and can potentially eliminate circulating, cell-surface and immune-complex Ig classes and modulate Ig-mediated autoimmunity and inflammation, providing a novel opportunity to treat antibody-mediated diseases. We describe here the discovery, generation, and functional characterization of Ig specific proteases. These proteases were identified using Seismic Therapeutic’s IMPACT platform and tested for their ability to cleave intact Ig subclasses and Ig isotypes in a high-throughput CE-SDS cleavage assay. Additionally, we found that these enzymes cleave soluble and cell bound Ig in human blood, dramatically reducing effector function. We believe that these subclass and isotype specific cleaving proteases will provide an opportunity to develop novel targeted therapies for various autoimmune diseases where autoantibodies are the key drivers of the disease. In addition, we believe that they will be potentially better tolerated compared to current therapeutic interventions such as plasma exchange and other immunosuppressive therapies.