Bispecific antibodies for the treatment of the autoimmune disease epidermolysis bullosa acquisita

Project: DFG ProjectsDFG Individual Projects

Project Details

Description

Autoimmune diseases have become a major health burden. Despite significant advances in treatment, patients with autoimmune diseases suffer from high (co)-morbidity and increased mortality. General immunosuppression remains the backbone of treatment despite its well-known adverse events that contribute substantially to patients morbidity and mortality. Hence, there is a great need for the development of new treatments for patients with autoimmune diseases. Ideally, these would be causative or, alternatively, directed toward the disease-causing, autoantigen-specific B and/or T cells (targeted treatment). Such a targeted treatment has recently been described in a pre-clinical mouse model of pemphigus, an autoimmune skin blistering disease characterized and caused by autoantibodies against Dsg3. In brief, based on chimeric antigen receptor (CAR) technology, human T cells expressing a chimeric autoantibody receptor (CAAR) consisting of the pemphigus autoantigen Dsg3 fused to the CD137-CD3zeta signaling domains were generated. These Dsg3 CAAR-T cells showed specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expanded, persisted, and specifically eliminated Dsg3-specific B cells in vivo. Thus, the Dsg3 CAAR-T cells prevented the induction of experimental pemphigus in mice, which was induced by injection of lymphoma cells producing anti-Dsg3 antibodies. However, the efficacy of CAAR-T cells remains to be evaluated in a therapeutic experimental setting. Furthermore, given successful evaluation in therapeutic settings, CAAR-T cells would need to be engineered for each patient, which would be a potential hindrance to the broader application of this treatment. To address this translational gap, we aim to develop bispecific T cell engagers (BiTEs) that specifically eliminate autoreactive B cells. We will engineer BiTEs consisting of anti-mouse CD3 fused to an immunodominat fragment of mouse type VII collagen (COL7) (anti-CD3xCOL7 BiTEs). The therapeutic efficacy of the anti-CD3xCOL7 BiTEs will be evaluated in our well-established immunization-induced epidermolysis bullosa acquisita (EBA) mouse model. The advantage of this model is the causal relationship between the presence of autoantibodies against COL7 and the manifestation of clinical disease. We expect that anti-CD3xCOL7 BiTEs will induce a complete and persistent cure for immunization-induced EBA. Confirmation of our hypothesis would open up novel avenues for the treatment of autoimmune diseases with a clear pathogenic link between the autoimmune response and clinical presentation.
Statusfinished
Effective start/end date01.01.1731.12.22

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)
  • Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

  • 205-19 Dermatology
  • 204-05 Immunology

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