Targeted Degradation of Antigen-Specific Pathogenic Autoantibodies That Cause Heart Failure

Autoantibodies are the causative agents in a wide range of autoimmune diseases. Existing approaches to the depletion of such autoantibodies include therapies that deplete the whole antibody repertoire or immunoadsorption, which although antigen-specific is costly and time-consuming. Here, we report the first pharmacological strategy for the antigen-specific depletion of autoantibodies. Specifically, we synthesized a synthetic bifunctional molecule (β-MoDE-A) capable of selectively depleting antibodies against the beta-1 adrenergic receptor (β1AR) in vitro and in vivo. β-MoDE-A contains a motif that mimics the anti-β1AR binding epitope linked to a ligand for the asialoglycoprotein receptor, which re-routes pathogenic autoantibodies to the liver for degradation. We demonstrate that β-MoDE-A is effective in mediating ternary complex formation and endocytosis of anti-β1AR antibodies in vitro and depletes these antibodies in vivo in a mouse model. The novel drug platform represented by this approach provides the first example of an antigen-specific extracellular degrader of an individual pathogenic IgG species of any isotype or subclass, but without any potential for broad-based immunosuppression.