TGF-β1 activating antibodies for the immunotherapy of allo- and auto-immune diseases

TGF-β1 is an immunosuppressive cytokine produced as a latent homodimer, in which mature TGF-β1 is encapsulated and kept inactive by the LAP. Tregs activate latent TGF-β1 through the collaboration of transmembrane protein GARP and integrin aVβ8. We derived monoclonal antibodies (mAbs) that activate human or mouse TGF-β1 anchored on cells by a transmembrane protein. Biochemical and structural studies reveal that such mAb-mediated activation requires bivalent binding near LAP dimerization interface and crosslinking of two membrane-bound GARP:TGF-β1 complexes. Administration of mAbs to mice with graft-versus-host-disease reduces disease severity and increases survival. The therapeutic effect requires Tregs. This work demonstrates that in vivo TGF-β1 activation with mAbs is feasible, offering potential new therapeutic options for allo- and auto-immune diseases characterized by deleterious T cell activity insufficiently controlled by Tregs.