SFB 1192

Projekt B5

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.

Publikationen

  • Purine Release, Metabolism, and Signaling in the Inflammatory Response.

    Linden J, Koch-Nolte F, Dahl G.Annu Rev Immunol. 2019 Jan

  • T RM maintenance is regulated by tissue damage via P2RX7.

    Stark R, Wesselink TH, Behr FM, Kragten NAM, Arens R, Koch-Nolte F, van Gisbergen KPJM, van Lier RAW.Sci Immunol. 2018 Dec

  • CD38-Specific Biparatopic Heavy Chain Antibodies Display Potent Complement-Dependent Cytotoxicity Against Multiple Myeloma Cells.

    Schütze K, Petry K, Hambach J, Schuster N, Fumey W, Schriewer L, Röckendorf J, Menzel S, Albrecht B, Haag F, Stortelers C, Bannas P, Koch-Nolte F.Front Immunol. 2018 Nov

  • Monitoring the Sensitivity of T Cell Populations Towards NAD+ Released During Cell Preparation.

    Rissiek B, Lukowiak M, Haag F, Magnus T, Koch-Nolte F.Methods Mol Biol. 2018 Aug

  • Modulating ion channel function with antibodies and nanobodies.

    Stortelers C, Pinto-Espinoza C, Van Hoorick D, Koch-Nolte F.Curr Opin Immunol. 2018 Jun

  • The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy.

    Seifert L, Hoxha E, Eichhoff AM, Zahner G, Dehde S, Reinhard L, Koch-Nolte F, Stahl RAK, Tomas NMJ Am Soc Nephrol. 2018 May

  • Nanobody-Based Biologics for Modulating Purinergic Signaling in Inflammation and Immunity.

    Menzel S, Schwarz N, Haag F, Koch-Nolte F.Front Pharmacol. 2018 Mar

  • A Heterologous Model of Thrombospondin Type 1 Domain-Containing 7A-Associated Membranous Nephropathy

    Tomas N, Meyer-Schwesinger C, von Spiegel H, Kotb A, Zahner G, Hoxha E, Helmchen U, Endlich N, Koch-Nolte F, Stahl R J Am Soc Nephrol. 2017 Nov

  • Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation. 

    Danquah W, Meyer-Schwesinger C, Rissiek B, Pinto C, Serracant-Prat A, Amadi M, Iacenda D, Knop JH, Hammel A, Bergmann P, Schwarz N, Assunção J, Rotthier W, Haag F, Tolosa E, Bannas P, Boué-Grabot E, Magnus T, Laeremans T, Stortelers C, Koch-Nolte FSci Transl Med. 2016 Nov

  • Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy. 

    Tomas NM, Hoxha E, Reinicke AT, Fester L, Helmchen U, Gerth J, Bachmann F, Budde K, Koch-Nolte F, Zahner G, Rune G, Lambeau G, Meyer-Schwesinger C, Stahl RA.J Clin Invest. 2016 Jul

III. Medizinische Klinik und Poliklinik
Universitätsklinikum Hamburg-Eppendorf

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