Prof. Dr. med. Falk Hiepe
Charité – Universitätsmedizin Berlin
Medizinische Klinik m.S. Rheumatologie
und Klinische Immunologie
Charitéplatz 1
10117 Berlin
Tel. +49 (0) 30 450 513026
falk.hiepe@charite.de
Priv.-Doz. Dr. med. Bimba F. Hoyer
Charité – Universitätsmedizin Berlin
Med. Klinik m.S. Rheumatologie und Klinische Immunologie
Charitéplatz 1
10117 Berlin
Tel. +49 (0) 30 450 613266
bimba.hoyer@uksh.de
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.
Ostendorf, L., Burns, M., Durek, P., Gitta, A.E., Heinrich, F., Garantziotis, P., Enghard, P., Richter, U., Biesen, R., Schneider, U., Knebel, F., Burmester, G., Radbruch, A., Mei H.E., Mashreghi, F., Hiepe F., Alexander, T. Targeting CD38 in Systemic Lupus Erythematosus. (2020). N. Engl. J. Med. 383, 1149-1155.
Cheng, Q., Pelz, A., Taddeo, A., Khodadadi, L., Klotsche, J, Hoyer, B.F., Alexander, T., Thiel, A., Burmester, G.R., . Radbruch A., and Hiepe, F. (2020). Selective depletion of plasma cells in vivo based on the specificity of their secreted antibodies. Eur. J. Immunol. 50, 284-291.
Cornelis, R., Hahne, S., Taddeo, A., Petkau, G., Malko, D., Durek, P., Thiem, M., Heiberger, L., Peter, L., Mohr, E., Klaeden, C., Tokoyoda, K., Siracusa, F., Hoyer, B. F., Hiepe, F., Mashreghi, M. F., Melchers, F., Chang, H. D., and Radbruch, A. (2020). Stromal Cell-Contact Dependent PI3K and APRIL Induced NF-kappaB Signaling Prevent Mitochondrial- and ER Stress Induced Death of Memory Plasma Cells. Cell Rep. 32, 107982.
Männe, C., A. Takaya, Y., Yamasaki, M., Mursell, S., Hojyo, T. Y., Wu, J., Sarkander, M. A., McGrath, R., Cornelis, S., Hahne, S., Cheng, Q., Kawamoto, T., Hiepe, F., Kaufmann, S. H. E., Yamamoto, T., Radbruch, A., and K. Tokoyoda. (2019). Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG(+) plasma cell persistence in the bone marrow. Proc. Natl. Acad. Sci. USA 116, 7425-7430.
Chang, H. D., Tokoyoda, K., Hoyer, B.F., Alexander, T., Khodadadi, L., Mei, H., Dörner, T., Hiepe, F., Burmester, GR., and Radbruch, A. (2019). Pathogenic memory plasma cells in autoimmunity. Curr. Opin. Immunol. 61, 86-91.
Cheng, Q., Khodadadi, L., Taddeo, A., Klotsche, J., Hoyer, B.F., Radbruch, A. and Hiepe, F. (2018). CXCR4-CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice. Eur. J. Immunol. 48, 1020-1029.
Alexander, T., Q. Cheng, J. Klotsche, L. Khodadadi, A. Waka, R. Biesen, Hoyer, B.F., Burmester, G.R., Radbruch, A. and Hiepe, F. (2018). Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors. Eur. J. Immunol. 48, 1573-1579.
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., Voll, R.E. (2015). The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann. Rheum. Dis. 74, 1474-8.
Mei, H.E., Wirries, I., Frölich, D., Brisslert, M., Giesecke, C., Grün, J.R., Alexander, T., Schmidt, S., Luda, K., Kühl, A.A., Engelmann, R., Dürr, M., Scheel, T., Bokarewa, M., Perka, C., Radbruch, A., Dörner, T. (2015). A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood 125, 1739-48.