Prof. Dr. med. Falk Hiepe
Charité – Universitätsmedizin Berlin
Medizinische Klinik m.S. Rheumatologie
und Klinische Immunologie
Priv.-Doz. Dr. med. Bimba F. Hoyer
Charité – Universitätsmedizin Berlin
Med. Klinik m.S. Rheumatologie und Klinische Immunologie
Selective Plasma Cell Targeting
We previously identified long-lived memory plasma cells secreting pathogenic autoantibodies as a key driver of autoimmune mediated pathology, and demonstrated that they are refractory to conventional immunosuppression or therapies targeting B or T cells. So far, only aggressive therapies including immunoablation with anti-thymocyte globulin (ATG) and proteasome inhibitors can target long-lived memory plasma cells. However, these approaches do not distinguish between plasma cells secreting pathogenic or protective antibodies. In the first funding period, we provided proof of principle that the proposed affinity matrix technology, which labels the plasma cells with the (auto)antigen of interest, is able to deplete long-lived memory bone marrow plasma cells in vivo in an (auto)antigen-specific manner (fig. 1). Moreover, our studies in SLE patients and preclinical lupus models revealed that autoreactive long-lived memory plasma cells can rapidly replenish after their successful depletion.
In the new funding period, we will replace the monoclonal anti-CD138 antibody with a recombinant single-chain fragment variable (scFv) anti-CD138 antibody with a short peptide linker for (auto)antigen conjugation to make the affinity matrix more effective. The anti-CD138 scFv antibody conjugated with the main epitope of the acetylcholine receptor or a polynucleotide, respectively, will be used to study the pathogenic role of autoantibody-secreting plasma cells and the efficacy of their depletion in preclinical models of autoimmune diseases, such as myasthenia gravis and systemic lupus erythematosus. Furthermore, we will investigate mechanisms that contribute to replenishing autoreactive memory plasma cells post-depletion with the aim of identifying therapeutic approaches to prevent this phenomenon. Finally, we will use the affinity matrix technology for functional characterization of autoantigen-specific plasma cells.
Scheibe, F., Pruss, H., Mengel, A.M., Kohler, S., Numann, A., Kohnlein, M., Ruprecht, K., Alexander, T., Hiepe, F., and Meisel, A. (2017). Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology 88, 366-370.
Hiepe, F., and Radbruch, A. (2016). Plasma cells as an innovative target in autoimmune disease with renal manifestations. Nat Rev Nephrol 12, 232-240.
Scheibe, F., Alexander, T., Pruss, H., Wengert, O., Harms, L., Angstwurm, K., Hiepe, F., Arnold, R., and Meisel, A. (2016). Devastating humoral CIDP variant remitted by autologous stem cell transplantation. Eur J Neurol 23, e12-14.
Alexander, T., Sarfert, R., Klotsche, J., Kuhl, A.A., Rubbert-Roth, A., Lorenz, H.M., Rech, J., Hoyer, B.F., Cheng, Q., Waka, A., Taddeo, A., Wiesener, M., Schett, G., Burmester, G.R., Radbruch, A., Hiepe, F.,* and Voll, R.E.* (2015). The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 74, 1474-1478. *contributed equally
Khodadadi, L., Cheng, Q., Alexander, T., Sercan-Alp, O., Klotsche, J., Radbruch, A., Hiepe, F., Hoyer, B.F.*, and Taddeo, A.* (2015). Bortezomib Plus Continuous B Cell Depletion Results in Sustained Plasma Cell Depletion and Amelioration of Lupus Nephritis in NZB/W F1 Mice. PLoS One 10, e0135081. *contributed equally
Taddeo, A., Gerl, V., Hoyer, B.F., Chang, H.D., Kohler, S., Schaffert, H., Thiel, A., Radbruch, A., and Hiepe, F. (2015a). Selection and depletion of plasma cells based on the specificity of the secreted antibody. Eur J Immunol 45, 317-319.
Taddeo, A., Khodadadi, L., Voigt, C., Mumtaz, I.M., Cheng, Q., Moser, K., Alexander, T., Manz, R.A., Radbruch, A., Hiepe, F.*, and Hoyer, B.F.* (2015b). Long-lived plasma cells are early and constantly generated in New Zealand Black/New Zealand White F1 mice and their therapeutic depletion requires a combined targeting of autoreactive plasma cells and their precursors. Arthritis Res Ther 17, 39. *contributed equally
Winter, O., Musiol, S., Schablowsky, M., Cheng, Q., Khodadadi, L., and Hiepe, F. (2015). Analyzing pathogenic (double-stranded (ds) DNA-specific) plasma cells via immunofluorescence microscopy. Arthritis Res Ther 17, 293.
Cheng, Q., Mumtaz, I.M., Khodadadi, L., Radbruch, A., Hoyer, B.F., and Hiepe, F. (2013). Autoantibodies from long-lived 'memory' plasma cells of NZB/W mice drive immune complex nephritis. Ann Rheum Dis 72, 2011-2017.
Kohler, S., Keil, T.O., Swierzy, M., Hoffmann, S., Schaffert, H., Ismail, M., Ruckert, J.C., Alexander, T., Hiepe, F., Gross, C., Thiel, A., and Meisel, A. (2013). Disturbed B cell subpopulations and increased plasma cells in myasthenia gravis patients. Journal of neuroimmunology 264, 114-119.
Mumtaz, I.M., Hoyer, B.F., Panne, D., Moser, K., Winter, O., Cheng, Q.Y., Yoshida, T., Burmester, G.R., Radbruch, A., Manz, R.A., and Hiepe, F.(2012). Bone marrow of NZB/W mice is the major site for plasma cells resistant to dexamethasone and cyclophosphamide: Implications for the treatment of autoimmunity. Journal of autoimmunity 39, 180-188.
Hiepe, F., Dörner, T., Hauser, A.E., Hoyer, B.F., Mei, H., and Radbruch, A. (2011). Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol 7, 170-178.
Yoshida, T., Mei, H., Dörner, T., Hiepe, F., Radbruch, A., Fillatreau, S., and Hoyer, B.F. (2010). Memory B and memory plasma cells. Immunol Rev 237, 117-139.
Alexander, T., Thiel, A., Rosen, O., Massenkeil, G., Sattler, A., Kohler, S., Mei, H., Radtke, H., Gromnica-Ihle, E., Burmester, G.R., Radbruch, A., Arnold, R., and Hiepe, F. (2009). Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 113, 214-223.
Radbruch, A., Muehlinghaus, G., Luger, E.O., Inamine, A., Smith, K.G., Dörner, T., and Hiepe, F. (2006). Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 6, 741-750.
Hoyer, B.F., Moser, K., Hauser, A.E., Peddinghaus, A., Voigt, C., Eilat, D., Radbruch, A., Hiepe, F.*, and Manz, R.A.* (2004). Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J Exp Med 199, 1577-1584. *contributed equally