Nanobody-based treatment strategies in glomerulonephritis
Nanobodies, single domain antibodies derived from camelid heavy chain antibodies, are emerging as a promising and highly specific new class of biologicals. Since context-, mechanism-, and cell specific treatment options are still missing for most glomerular diseases, we aim to devise nanobody-based treatment strategies for glomerulonephritis. Therefore, we selected plasmamembrane proteins of immune cells (P2X7, CD 38) as well as kidney resident cells (THSD7A, PLA2R1) that are potential checkpoints of glomerular disease initiation and progression: More specifically, P2X7 ion channel recognizes extracellular ATP as a danger signal and drives sterile inflammation; autoantibodies directed against the podocyte membrane proteins THSD7A and PLA2R are the key pathogens in membranous nephropathy and the CD38 ecto-enzyme is upregulated by antibody-producing plasma cells. Nanobodies directed against these membrane proteins will be engineered to reach the following specific aims: (1) To ameliorate inflammation mediated by kidney resident T cells with P2X7-blocking nanobodies, (2) to block the binding of pathogenic autoantibodies to podocytes with PLA2R1- and THSD7Aspecific nanobodies, and (3) to deplete autoantibody secreting plasma cells with engineered CD38-specific heavy chain antibodies. Furthermore, the different levels and sites of interference will also allow for a synergistic combination of these treatment options. All treatment strategies will be functionally, structurally, and outcome based analyzed in established cell culture systems and animal models of antibody-mediated glomerulonephritis. Collectively, we here suggest and evaluate a novel nanobody based treatment strategy for glomerular diseases, which might fundamentally change our current treatment conception for immune mediated glomerular diseases. We expect that the results of our project will pave the way for new, nanobody-based therapeutics of glomerulonephritis.
Molecular consequences of SARS-CoV-2 liver tropism
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