Abstract
Abstract The development of autoimmune diseases is the result of a dysregulated immune response against self-antigens, resulting in cell dysregulation and tissue damage. Upon chronic exposure to antigens, inhibitory receptors (IR) are upregulated as a feedback mechanism to limit T-cell effector activity. IR deficiency is associated with autoimmunity in mice and humans. Similarly, blockade of IR is efficacious for the treatment of cancer but is often associated with new onset of immune-related adverse events. Therefore, if loss or blocking of IR pathways can result in autoimmunity, agonism of these pathways should restore normal immune homeostasis. However, the generation of agonistic antibodies present some challenges. For instance, to elicit strong receptor agonism, super-clustering mediated by the binding of the constant region (Fc) of an antibody to FcgRs, must occur. However, while FcgRs are widely expressed on antigen-presenting cells (APCs), they are not the same and are classified, based on their function, as activating or inhibitory. Of note, FcgRIIb is the only inhibitory Fc receptor, and APCs derived from mice deficient in this receptor exhibited exaggerated cytokine release. Most PD-1 agonist antibodies in clinical development contain a wild-type Fc and can trigger unwanted production of pro-inflammatory cytokines by engaging activating FcgRs. To mitigate such liability, we designed novel PD-1 agonistic antibodies that selectively bind FcgRIIb and prevent APC activation.
Published Version
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