Project Details
Projekt
Preclinical development of antibody-specific novel immunotherapies
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 504745852
Antibody-mediated neurological diseases such as NMDAR encephalitis or myasthenia gravis are currently treated with broad immunosuppression or non-selective antibody removal, resulting in often treatment-limiting side effects or insufficient responses. Thus, there is a strong medical need for the highly selective depletion of monospecific antibody-producing cells, e.g. those releasing NMDAR or acetylcholine receptor (AChR) autoantibodies. In NMDAR encephalitis, autoantibodies are produced by a pool of short-lived plasmablasts, which is continuously replenished by ongoing differentiation of memory B cells. Elimination of NMDAR -specific memory B cells should therefore lead to a depletion of all NMDAR autoantibody-producing cells. Currently, this goal is achieved by removal of all CD20-positive B cells using the monoclonal anti-CD20 antibody rituximab. To selectively target NMDAR -specific B cells, we developed NMDAR -specific Chimeric AutoAntibody Receptor (CAAR) T cells. Similarly, selective removal of ACachR-reactive B cells is a promising strategy in achR-antibody positive myasthenia gravis, for which we developed ACachR-specific CAAR T cells. In this project, we want to address the next steps necessary to translate the promising preclinical results into clinical application. CAAR T cell safety and function will be assessed in a variety of in vitro and in vivo assays paving the road to prepare the first clinical trial. Investigating two antibody-mediated autoimmune diseases acting centrally (brain; NMDAR encephalitis) or peripherally (neuromuscular junction; myasthenia gravis) will allow us to better understand possible compartment effects of CAAR T cell therapy. Positive results in this project will provide an entirely novel way of highly specific “personalized” immunotherapy in patients with antibody-mediated neurological disorders and can be expanded to a broader spectrum of antibody-mediated diseases.
DFG Programme
Clinical Research Units
