Tu181 - Chimeric Autoantigen-t Cell Receptor (CATCR)-T Cell Therapies to Selectively Target Autoreactive B Cells

Brian Mog – The Johns Hopkins University School of Medicine; Elana Shaw – The Johns Hopkins University School of Medicine; Michael Hwang – The Johns Hopkins University School of Medicine; Sze Tan – The Johns Hopkins University School of Medicine; Alexander Pearlman – The Johns Hopkins University School of Medicine; Sarah DiNapoli – The Johns Hopkins University School of Medicine; Suman Paul – The Johns Hopkins University School of Medicine; Sandra Gabelli – The Johns Hopkins University School of Medicine; Chetan Bettegowda – The Johns Hopkins University School of Medicine; Nickolas Papadopoulos – The Johns Hopkins University School of Medicine; Michelle Petri – The Johns Hopkins University School of Medicine; Antony Rosen – The Johns Hopkins University School of Medicine; Shibin Zhou – The Johns Hopkins University School of Medicine; Kenneth Kinzler – The Johns Hopkins University School of Medicine; Bert Vogelstein – The Johns Hopkins University School of Medicine

Abstract Text: All currently available drugs to treat autoimmune diseases are indiscriminate, suppressing both self-directed and protective immune responses. This lack of precision results in opportunistic infection, poor vaccine responses, and excess mortality. Precision immunotherapies that selectively eliminate autoreactive B cells, while sparing normal B cells, could treat autoimmunity without increasing the risk of infection, revolutionizing the management of patients with autoimmune diseases. Here, we developed such a precision therapy for the treatment of antiphospholipid syndrome (APS), an autoimmune disease caused by pathogenic antibodies against beta-2-glycoprotein I (β2GPI) that promote recurrent thrombosis and fetal loss. This was achieved by reprogramming primary human T cells to selectively eliminate anti-β2GPI B cells. To this end, we used CRISPR/Cas12a editing to express chimeric autoantigen-T-cell receptors (CATCRs), which incorporate the autoantigen β2GPI into different parts of the TCR-CD3 complex, on engineered T cells. By expressing β2GPI-CATCRs, T cells acquired the ability to selectively bind anti-β2GPI B cell receptors (BCRs) on the surface of autoreactive B cells in APS, inducing immune synapse formation and killing target B cells via the perforin–granzyme pathway. In co-culture experiments, β2GPI-CATCR-T cells selectively eliminated anti-β2GPI B cells and abolished anti-β2GPI autoantibodies —pathogenic drivers of thrombosis and fetal loss in APS— in a dose-dependent manner, providing an opportunity to treat and prevent APS. Complete target cell killing was observed at physiologically relevant effector:target cell ratios. Beyond APS, CATCR-T-cell therapies have the potential to treat autoimmunity without increasing the risk of infection, promising a future of antigen-specific immunotherapy for autoimmune and rheumatic diseases.