Tu131 - Identification and Characterization of PD-1 Agonists for the Treatment of Autoimmune and Inflammatory Diseases

Marisella Panduro – Seismic Therapeutic; Minasri Borah – Seismic Therapeutic; Stephanie Grebinoski – Seismic Therapeutic; Joshua Vitlip – Seismic Therapeutic; Stephen Lutz – Seismic Therapeutic; Ishan Sharma – Seismic Therapeutic; Elliot Wittenberg – Seismic Therapeutic; Allison Colthart – Seismic Therapeutic; Jyothsna Visweswaraiah – Seismic Therapeutic; Ryan Peckner – Seismic Therapeutic; Nathan Higginson-Scott – Seismic Therapeutic; Kevin Otipoby – Seismic Therapeutic; Daniela Cipolletta – Seismic Therapeutic

Abstract Text: 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. Given that loss or blockade of IR pathways can result in autoimmunity, we hypothesized that agonism of these pathways should restore normal immune homeostasis. However, the generation of agonistic antibodies presents 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. While FcgRs are widely expressed on antigen-presenting cells (APCs), they can be functionally classified as activating or inhibitory. Of note, FcgRIIb is the only inhibitory Fc receptor, and APCs derived from mice deficient in this receptor exhibit 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, prevent APC activation and limit immune responses in vivo.