Pandion Therapeutics, Inc. announced the presentation of preclinical data highlighting the potential of its modular biologics pipeline for the treatment of autoimmune diseases at the Federation of Clinical Immunology Societies (FOCIS) 2020 virtual annual meeting. Pandion utilizes its TALON (Therapeutic Autoimmune reguLatOry proteiN) drug design and discovery platform to create antibody-based candidates that target known control nodes in the immune system. These drug candidates are modularly engineered to either work systemically or to be targeted to specific tissues via tethering modules, potentially enabling a precision medicine approach to treating autoimmune diseases. The posters presented at FOCIS showed in vivo proof of concept for gut- and skin-tethered immune effectors, the potential broad biological effects of PD-1 agonism, as well as an introduction to Pandion’s emerging kidney research program. Key findings presented at FOCIS: Title: A MAdCAM-tethered PD-1 Agonist Inhibits T Cell Activation and Ameliorates Intestinal Inflammation. Authors: L.J. Edwards, B. Larkin, S. Alioto, D. Cluckey, D.C. Rios, E. Lurier, P. Halvey, K. Kis-Toth, N. Higginson-Scott, J.L. Viney and K.L. Otipoby. Background: PD-1 is a critical immune regulator found on activated conventional T cells. Inhibition of PD1 in the treatment of cancer can result in autoimmune diseases, including colitis. In contrast, activating, or agonizing, PD-1 results in the attenuation of overactive T cells, providing a new potential treatment approach for autoimmune diseases. Pandion has created PT001, a PD-1 agonist tethered to the gut-selective molecule, MAdCAM. Findings: PT001 demonstrated tethered agonism of PD-1 without blocking the normal receptor and ligand interaction of either MAdCAM or PD-1. In an animal model of graft versus host disease, PT001 treatment resulted in prolonged survival beyond the dosing period. In an animal model of graft versus host disease, PT001 treatment reduced conventional T cell infiltration of the colon, demonstrating localized effect of the tethered molecule. Title: Localized Immunomodulation of T cells for Treatment of Autoimmune and Inflammatory Skin Diseases. Authors:P. Mande, D. Rios, S. Borthakur, A. Boisvert, M. Rowe, P. Halvey, J.L. Viney, K. Kis-Toth, I. Mascanfroni, N. Higginson-Scott and K.L. Otipoby. Background: Pathogenic T cells are found in the majority of chronic immune-mediated skin diseases. Pandion has created PD-1 agonists, including a skin-tethered version, designed to regulate and attenuate the activity of pathogenic T cells. In addition, Pandion has created skin-tethered CD39 effector modules designed to convert a proinflammatory environment to an anti-inflammatory environment. Pandion is currently evaluating these candidates in various models of skin autoimmune diseases. Findings: Skin-tethered effectors localized to the skin. In an animal model of vitiligo, the skin-tethered PD-1 agonist reduced skin depigmentation and reduced skin-specific conventional T cells with no systemic effects on T cells. In an animal model of contact hypersensitivity, the skin-tethered CD39 significantly inhibited ear inflammation. All of the observed effects were tether-dependent, showing the localized effect of the tethered molecules. Title: Generation of Kidney-Targeted IL-2 Mutein for Prevention of Graft Rejection in Renal Transplantation. Authors: B. Li, B. Larkin, T. Kiprono, M. Rowe, J. Visweswaraiah, N. Willardsen, J. Allen, K.L. Otipoby, J.L. Viney, H.H. Shaheen and N. Higginson-Scott. Background: Kidney transplant can be a life-saving procedure for many people with end-stage renal disease, but current long-term treatments to prevent rejection of the donor kidney can have serious side effects. Findings: Pandion has created a kidney-tethered IL-2 mutein, which selectively binds to kidney tubular epithelium in vivo. Work is ongoing understand the potential of this tethered molecule to expand regulatory T cells in the kidney as an approach for the treatment of kidney inflammation. Title: Molecular Profiling Reveals Anti-PD-1 Agonist Antibody-Induced Changes to Key Immune Pathways. Authors: P.J. Halvey, E.B. Lurier, M. Cianci, J.L. Viney, K.L. Otipoby and K. Kis-Toth. Background: PD-1 is a critical immune regulator found on activated conventional T cells. Inhibition of PD1 in the treatment of cancer can result in autoimmune diseases, including colitis. Activating, or agonizing, PD-1, results in the inhibition of the conventional T cells, and affords a potential treatment approach for autoimmune diseases. Pandion has created PT001, a gut-tethered PD-1 agonist, and PT627, a systemic PD-1 agonist. PD-1 agonism is a promising treatment approach for autoimmune diseases. Findings: In cell-based assays, PD-1 agonism with PT001 and PT627 resulted in the suppression of many known immune activation pathways, including Th1/Th2 and Th17 differentiation and chemokine signalling.