TARGETING IMMUNE INHIBITORY RECEPTORS IN AUTOIMMUNITY: A PROMISING STRATEGY TO TREAT AUTOIMMUNE DISEASE

Abstract

Autoimmune diseases, marked by chronic inflammation and dysregulated immune responses, contribute significantly to global morbidity and mortality. This review explores the potential of agonistic antibodies targeting immune inhibitory receptors (IIRs) as therapeutic tools in autoimmune conditions. Antibodies can be engineered to bind selectively to specific IIRs and deliver the desired intracellular signals necessary to restore immune balance. Among the various agonist formats investigated, only monoclonal antibodies have successfully progressed to clinical trials. Their preferential advancement is largely due to their high specificity, precision, and ability to modulate immune signaling with minimal off-target effects. These antibodies can be engineered to selectively bind IIRs and deliver intracellular signals required to dampen the immune response. Models such as the kinetic-segregation and aggregation models provide insight into how inhibitory signaling occurs and help define the structural and functional features required for agonistic antibody design. For these therapies to be effective, factors such as epitope positioning, binding affinity, receptor clustering signaling capacity, antibody immobilization and Fc receptor engagement must be carefully optimized. These features determine the potency and clinical viability of antibody-based agonists. Agonistic antibodies are especially promising in autoimmune settings, where targeted immune modulation is essential to avoid widespread immunosuppression. While the clinical application of agonists of IIRs in autoimmunity is still in early stages, substantial progress has been made, positioning agonistic antibodies as leading candidates in the development of next-generation immunotherapies.