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Abstract: FR-OR32

Chimeric Autoantibody Receptor (CAAR) T Cells as a Precision Therapy for Antigen-Specific B Cell Depletion in PLA2R Membranous Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Payne, Aimee S., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Wang, Baomei, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Manfredo-Vieira, Silvio, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Mao, Xuming, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Gill, Saar, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Hogan, Jonathan, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Background

Primary membranous nephropathy (MN) is an autoimmune disease caused by autoantibodies against podocyte antigens, leading to glomerular damage, nephrotic syndrome, and potentially end-stage renal disease requiring dialysis or transplant. Phospholipase A2 receptor (PLA2R) autoantibodies are found in 70-80% of primary MN patients, co-localize with PLA2R and IgG4 glomerular immune deposits, and correlate with disease activity, supporting their causative role in disease pathogenesis. B cell depletion with rituximab is an effective strategy for treatment of primary MN. However, patients often require repeat treatments for disease relapse or maintenance of remission, and infectious serious adverse events are observed in up to 6.2% of rituximab-treated patients, highlighting the need for therapy that induces durable disease remission without generalized immunosuppression. Chimeric antigen receptor T cells have proven clinical ability to induce long-term remission of B cell cancers. We have shown that autoantigen-based chimeric autoantibody receptor (CAAR) T cells cause DSG3-specific B cell depletion in animal models of mucosal pemphigus vulgaris (mPV) without detectable off-target toxicity, which has led to a phase 1 trial of DSG3-CAART in mPV (NCT04422912). This study extends the CAART approach to PLA2R MN.

Methods

CAARs comprising PLA2R immunodominant epitopes linked to CD137-CD3ζ cytoplasmic domains were expressed in primary human T cells and evaluated for specific cytotoxicity against anti-PLA2R target cells, adsorption of anti-PLA2R MN IgG, and potential off-target binding using luciferase assays, ELISA, and commercial membrane proteome arrays.

Results

PLA2R CAARs directed specific cytolysis of anti-PLA2R cell lines targeting major PLA2R MN epitopes in the cysteine-rich and C-type lectin 1 and 7 domains. PLA2R-CAART cells adsorbed 95-99% of anti-PLA2R IgG from MN patient plasma, indicating that PLA2R CAARs encompass the major autoantibody-binding epitopes in MN patients. Membrane proteome arrays screened with PLA2R CAAR extracellular domains did not identify off-target interactions.

Conclusion

CAAR T cells represent a novel strategy for targeted B cell depletion in PLA2R MN and may ultimately prove to be valuable for the treatment for a broad range of antibody-mediated diseases.

Funding

  • Commercial Support