Tu132 - Identification and Characterization of Inhibitory Receptor Agonists for the Treatment of Autoimmune and Inflammatory Diseases

Stephanie Grebinoski – Seismic Therapeutic; Stephen Lutz – Seismic Therapeutic; Minasri Borah – Seismic Therapeutic; Andre Stanlie – Seismic Therapeutic; Rebecca Goydel – Seismic Therapeutic; Jyothsna Visweswaraiah – 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. Upon activation by antigens, lymphocytes upregulate inhibitory receptors as a feedback mechanism to limit their effector activity. Inhibitory checkpoint receptor deficiency is associated with autoimmunity in mice and humans. Similarly, blockade of inhibitory receptors with antagonist antibodies, that are efficacious for the treatment of cancer, is often associated with new onset of immune-related adverse events. Therefore, if loss or blocking of inhibitory checkpoint receptor pathways can result in inflammation, agonism of these pathways may restore normal immune homeostasis. However, generating agonistic antibodies can present some challenges. For instance, it is known that to elicit strong receptor agonism, super-clustering, typically mediated by the binding of the constant region (Fc) of an antibody to FcγRs, must occur. FcγRs are widely expressed on antigen-presenting cells (APCs) and are classified, based on their function, as activating or inhibitory. Of note, FcγRIIb is the only inhibitory Fc receptor, and dendritic cells derived from mice deficient of this receptor exhibited exaggerated cytokine release. Many agonist antibodies currently in clinical development contain effector-competent Fc and by binding activating Fc receptors can potentially trigger an unwanted production of pro-inflammatory cytokines. To mitigate such a liability, we designed novel agonistic antibodies that selectively bind FcγRIIb. These molecules support superior agonism of checkpoint inhibitory receptors while simultaneously preventing APC activation.