Abstract: FR-OR60
Adoptive Cellular Immunotherapy for the Control of Primary Membranous Nephropathy
Session Information
- Kidney Pathology: From Classic Clinicopathologic Studies to Computational Pathology
November 03, 2023 | Location: Room 109, Pennsylvania Convention Center
Abstract Time: 05:51 PM - 06:00 PM
Category: Pathology and Lab Medicine
- 1800 Pathology and Lab Medicine
Authors
- Garcia Busquets, Ainhoa, FRCB-IDIBAPS, Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Barcelona, Spain
- Matilla, Marina, FRCB-IDIBAPS, Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Barcelona, Spain
- Arana, Carolt, Clinic Barcelona, Department of Nephrology and Kidney Transplantation, Barcelona, Spain
- Betriu Méndez, Sergi, Clinic Barcelona, Department of Immunology, Barcelona, Spain
- Ramirez-Bajo, Maria Jose, FRCB-IDIBAPS, Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Barcelona, Spain
- Bañón-Maneus, Elisenda, FRCB-IDIBAPS, Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Barcelona, Spain
- Xipell Font, Marc, Clinic Barcelona, Department of Nephrology and Kidney Transplantation, Barcelona, Spain
- Campistol Plana, Josep Maria, Clinic Barcelona, Department of Nephrology and Kidney Transplantation, Barcelona, Spain
- Juan, Manel, Clinic Barcelona, Department of Immunology, Barcelona, Spain
- Quintana, Luis F., Clinic Barcelona, Department of Nephrology and Kidney Transplantation, Barcelona, Spain
- Palou, Eduard, Clinic Barcelona, Department of Immunology, Barcelona, Spain
- Diekmann, Fritz, Clinic Barcelona, Department of Nephrology and Kidney Transplantation, Barcelona, Spain
- Rovira, Jordi, FRCB-IDIBAPS, Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Barcelona, Spain
Background
Primary membranous nephropathy (PMN) is an autoimmune podocytopathy caused by subepithelial immune deposits that thicken the glomerular basal membrane and fusion of podocyte processes, causing proteinuria. It is the most common cause of non-diabetic nephrotic syndrome in adults. It is caused in 80% of cases by antibodies targeting podocytes' M-type receptor of phospholipase A2 (PLA2R), in 5% against thrombospondin 7A type-1 (THSD7A), or other recently described antigens. A third of affected patients evolve into terminal kidney disease. Immunotherapy based on chimeric antigen receptors (CAR)-T cells has been an extraordinary advance in the fight against cancer. The current proposal aims to generate a chimeric anti-PLA2R autoantibody receptor (PLA2R-CAAR) and anti-THSD7A autoantibody receptor (THSD7A-CAAR) to target antibody-producing B cells.
Methods
In this pre-clinical study, human T lymphocytes were obtained from healthy volunteers. The design, generation, and production of PLA2R-CAAR and THSD7A-CAAR will be carried out, with subsequent evaluation of their cytotoxic properties and cytokine production, through an in vitro model.
Results
We have identified and cloned the genetic sequence corresponding to PLA2R and THSD7A. The PLA2R-CAAR construct has been generated from domain binding, leader peptide, extracellular domain (either PLA2R or THSD7A), and intracellular domains from A2-CHAR (developed in our laboratory). We produced lentiviral particles with the construct in HEK-293T cells. After the isolation of CD3+ cells from healthy volunteers, transduction and production of PLA2R-CAAR and THSD7A-CAARs is performed. CAAR-T cell’s cytotoxic properties were assessed using serum samples containing anti-PLA2R or anti-THSD7A antibodies from patients with membranous nephropathy.
Conclusion
This strategy may be the prelude to a new immunotherapy for patients with membranous nephropathy who have anti-PLA2R or anti-THSD7A antibodies in circulation.
Funding
- Private Foundation Support