Development of cell-based therapies targeting DNA-reactive B cells in SLE

Laura Belver, Ph.D., Josep Carreras Leukaemia Research Institute 

B cells produce antibodies that recognize pathogens—foreign invaders like bacteria—and coordinate their elimination, protecting us from infections. Each B cell makes a unique antibody so we can be protected against nearly every pathogen we could come across. In systemic lupus erythematosus (SLE), B cells can become self-reactive, making autoantibodies that mistakenly recognize a person’s own cell contents as invaders. Autoantibodies can recognize many targets- even a person’s own DNA. Anti-DNA autoantibodies, found in more than 70% of people with SLE, can build up in organs like the kidney, where they cause inflammation and tissue damage. Dr. Belver will develop the first cell-based therapy to directly target and eliminate B cells that produce anti-DNA autoantibodies. 

Chimeric antigen receptor (CAR)-T cell therapy—re-engineering a person’s T cells to target and destroy specific cell types—has shown promising effects in people with lupus. However, many CAR-T cell therapies developed to date target both healthy and disease-causing B cells, leaving the treated person at a higher risk for infections. Chimeric autoantibody receptor (CAAR)-T cells are another type of cell therapy — like CAR-T cells — that specifically target B cells that produce autoantibodies. Dr. Belver will design a CAAR-based approach with re-engineered T cells to remove anti-DNA autoantibody-producing B cells. She will then test these CAARs in mouse models of lupus to determine if targeting anti-DNA autoantibody-producing B cells can reduce SLE features like high levels of inflammatory molecules, proteinuria (increased protein in the urine), and kidney damage. 

What this study means for people with lupus 

The standard of care for SLE involves broad anti-inflammatory and immunosuppressive drugs, which can cause short- and long-term adverse effects. CAAR-based approaches offer a unique opportunity to get rid of disease-causing B cells while sparing healthy B cells, preventing side effects and improving the quality of life for people with SLE. 

The success of cell-based therapies relying on chimeric antigen receptor T cells (CAR-T) for the treatment of B cell malignancies has increased the interest in finding new applications for this technology beyond the field of oncology. In the context of autoimmune disorders, the development of chimeric autoantibody receptors (CAARs) comprising autoantigens fused to T cell signaling domains has shown promising results in preclinical models of different autoimmune diseases, and are currently being tested in clinical trials for pemphigus vulgaris and myasthenia gravis. This highlights the potential of CAAR-based approaches to revert autoimmunity and holds promise for the development of new therapeutic strategies for the treatment of other autoimmune disorders. More than 70% of Systemic Lupus Erythematosus (SLE) patients express anti-double-stranded DNA (dsDNA) antibodies, which are directly associated with the development of some of the most aggressive manifestations of the disease. The main objective of this research proposal is to develop CAAR-based strategies to target dsDNA-recognizing B cells in SLE. While CAARs designed to date use protein autoantigens as antigenic baits to target self-reactive B cells, this approach entails some difficulties when the autoantigen driving the disease is a nucleic acid instead of a protein. To bridge this gap, we will design dsDNA-targeting CAARs using DNA mimics, which are naturally-occurring peptides that simulate DNA surface charge distribution and 3D structure. We will first evaluate the binding affinity of anti-dsDNA antibodies to a collection of 16 DNA mimics by enzyme-linked immunosorbent assays (ELISA) and glomerular binding assays (GBA), using SLE patient sera. DNA mimics that show high cross-reactivity in these settings will be selected for CAAR design. Then, we will use a logic gate strategy to develop CAAR-T cells that specifically target autoreactive B cells with affinity for dsDNA. This system will consist of a suboptimal DNA mimic CAAR, which is insufficient to trigger T cell activation and requires the simultaneous engagement of a B cell-specific CD19 CAR costimulatory receptor. Using this system, our CAAR-CAR-T cells will be only activated by B cells expressing anti-dsDNA B cell receptors, but not by serum antibodies recognizing dsDNA or off-target cells from other lineages. We will evaluate our CAAR-CAR-T cells in in vitro killing assays and in humanized lupus mouse models to determine which designs provide the best on-target therapeutic effects. Although the pathogenic role of anti-dsDNA antibodies is well-known, there are not available therapeutic interventions to efficiently block their activity. Our innovative and clinically relevant research program will approach this challenge by delivering a novel therapeutic strategy specifically directed against anti-dsDNA antibody-producing cells that will provide a specific, safe and efficient treatment for SLE patients.