Treatment of Autoimmune and Inflammatory Skin Diseases Using Skin-Targeting Bifunctional Antibodies: A Localized Immunomodulation Approach

Abstract Current treatment approaches for autoimmune conditions comprise primarily of systemic immunosuppressants or cytokine blockade. Concentration of therapeutic molecules to the tissues that are the sites of autoimmune and inflammatory diseases is a promising approach with the potential to induce therapeutic benefit and avert risks associated with systemic immunotherapies. Pandion Therapeutics is developing a bifunctional antibody platform that can drive localized immune modulation. The platform combines a “tether antibody” that targets a tissue of choice and “an effector end” that activates specific regulatory immune pathways to restore immune-homeostasis. Here we report the engineering of a skin-tethered PD-1 agonist and a skin-tethered CD39 that inhibit T cell activation and function and deplete local ATP, respectively, modulating different arms of the immune system in a tissue specific manner. These skin-tethered immune effectors were assessed for drug-like properties in biophysical assays and in vitro and in vivo assays for target binding, cellular activity and tissue specific-localization. Moreover, these bifunctionals were tested in pathway-relevant preclinical models such as Vitiligo and Contact Hypersensitivity. Strikingly, a selective accumulation of the tethered bifunctionals to the skin was observed and correlated with a tether-dependent efficacy compared to a non-tether control. We believe that this therapeutic approach has the potential to drive the resolution of cutaneous inflammation, providing an opportunity for developing new targeted therapies for autoimmune and inflammatory skin diseases.