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Bi-specific autoantigen-T cell engagers as targeted immunotherapy for autoreactive B cell depletion in autoimmune diseases.
- Source :
- Frontiers in Immunology; 2024, p1-14, 14p
- Publication Year :
- 2024
-
Abstract
- Introduction: In autoimmune diseases, autoreactive B cells comprise only the 0.1-0.5% of total circulating B cells. However, current first-line treatments rely on non-specific and general suppression of the immune system, exposing patients to severe side effects. For this reason, identification of targeted therapies for autoimmune diseases is an unmet clinical need. Methods: Here, we designed a novel class of immunotherapeutic molecules, Bispecific AutoAntigen-T cell Engagers (BiAATEs), as a potential approach for targeting the small subset of autoreactive B cells. To test this approach, we focused on a prototype autoimmune disease of the kidney, membranous nephropathy (MN), in which phospholipase A<subscript>2</subscript> receptor (PLA<subscript>2</subscript>R) serves as primary nephritogenic antigen. Specifically, we developed a BiAATE consisting of the immunodominant Cysteine-Rich (CysR) domain of PLA<subscript>2</subscript>R and the single-chain variable fragment (scFv) of an antibody against the T cell antigen CD3, connected by a small flexible linker. Results: BiAATE creates an immunological synapse between autoreactive B cells bearing an CysR-specific surface Ig<subscript>+</subscript> and T cells. Ex vivo, the BiAATE successfully induced T cell-dependent depletion of PLA<subscript>2</subscript>R-specific B cells isolated form MN patients, sparing normal B cells. Systemic administration of BiAATE tomice transgenic for human CD3 reduced anti-PLA<subscript>2</subscript>R antibody levels following active immunization with PLA<subscript>2</subscript>R. Discussion: Should this approach be confirmed for other autoimmune diseases, BiAATEs could represent a promising off-the-shelf therapy for precision medicine in virtually all antibody-mediated autoimmune diseases for which the pathogenic autoantigen is known, leading to a paradigm shift in the treatment of these diseases. [ABSTRACT FROM AUTHOR]
- Subjects :
- AUTOIMMUNE diseases
B cells
CD3 antigen
T cells
IMMUNE system
IMMUNOSUPPRESSION
Subjects
Details
- Language :
- English
- ISSN :
- 16643224
- Database :
- Complementary Index
- Journal :
- Frontiers in Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 176022084
- Full Text :
- https://doi.org/10.3389/fimmu.2024.1335998