Design of Novel Antigen-Specific Immunotherapies for the Treatment of Autoimmune Disorders

Abstract

Autoimmune disorders are a challenging problem for both afflicted patients and pharmaceutical scientists, since they involve one of the most complex biological systems – the immune system. A dysregulation of antigen recognition is at the center of autoimmune disorders, and can occur in a variety of host tissues throughout the body. Further complicating these diseases is the high degree of variability in terms of clinical manifestation. Traditional therapies for autoimmune disorders, such as corticosteroids or immunomodulators, generally focus on symptom suppression or slowing disease progression rather than treating the underlying cause, which is rarely fully understood. New approaches to treatments in which a disease-causing autoantigen is known seek to leverage antigen specificity through the development of antigen-specific immunotherapies (ASIT). In this research, we explore different novel approaches to ASIT focused on chemical conjugation, including the design and development of a new therapeutic class, antigen-drug conjugates (AgDCs). By reversing the paradigm of antibody-drug conjugates (ADCs), AgDCs exploit the directing effect of the autoantigen towards diseased cell populations, coupled with the immunomodulatory effects of a small molecule drug. Soluble Antigen Arrays (SAgAs) focus on disrupting immune recognition at the immunological synapse by conjugating autoantigen on a multivalent polymer support. Polymer-drug conjugates also present a unique opportunity as a depot delivery system with the potential for targeted applications. The strategies presented here carry an overarching goal to increase therapeutic specificity while limiting off-target effects, in an attempt to develop improved treatments with better efficacy and safety profiles for patients.