Chimeric autoantibody receptor cell therapy for the treatment of membranous nephropathy

We read with interest the research letter by Seifert et al.1 Seifert L. Riecken K. Zahner G. et al. An antigen-specific chimeric autoantibody receptor (CAAR) NK cell strategy for the elimination of anti-PLA2R1 and anti-THSD7A antibody-secreting cells. Kidney Int. 2024; 105: 886-889 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar recently published in Kidney International. They demonstrated the basic efficacy of PLA2R1- and THSD7A-based chimeric autoantibody receptor (CAAR) natural killer (NK) and T cells for the antigen-specific elimination of antibody-secreting target cells. This is undoubtedly a step forward for a new immunotherapy in membranous nephropathy. However, there is a need to improve the efficacy of current therapy. The cytotoxicity assays showed that an effector:target ratio greater than 1:1 appears necessary to achieve significant activity. In our opinion, the extracellular domain, the hinge, the transmembrane domain, and the membrane-proximal immunoreceptor tyrosine-based activation motif (ITAM) domain could be modified to increase efficacy. In addition, CD8 T-cell sorting should be considered before transduction for more potent target cell elimination. Additionally, NK92 cells must be irradiated before administration, and this procedure may also reduce their efficacy, so other sources of NK cells should be tried. In our lab, we also engineered PLA2R- and THSD7A-CAAR T cells (preliminary data presented in last Kidney Week 2 Garcia-Busquets A. Matilla M. Arana C. et al. Adoptive cellular immunotherapy for the control of primary membranous nephropathy. J Am Soc Nephrol. 2023; 34: 45-46 Google Scholar ). Our approach is based on lentiviral vectors that are more easily moved to clinical studies. In addition, we have developed a chimeric anti–human leukocyte antigen antibody receptor (CHAR) 3 Betriu S. Rovira J. Arana C. et al. Chimeric HLA antibody receptor T cells for targeted therapy of antibody-mediated rejection in transplantation. HLA. 2023; 102: 449-463 Crossref PubMed Scopus (0) Google Scholar in the setting of transplantation, in parallel with, and independently of a group in Leiden, the Netherlands. 4 Gille I. Hagedoorn R.S. van der Meer-Prins E.M.W. et al. Chimeric HLA antibody receptor T cells to target HLA-specific B cells in solid organ transplantation. HLA. 2023; 102: 436-448 Crossref PubMed Scopus (0) Google Scholar Both groups are now closely collaborating on the chimeric antibody receptor approach, including CAAR and CHAR, and we would like to call for close collaboration between academia research teams to evaluate and eventually bring this innovative therapeutic approach to the patient. An antigen-specific chimeric autoantibody receptor (CAAR) NK cell strategy for the elimination of anti-PLA2R1 and anti-THSD7A antibody-secreting cellsKidney InternationalVol. 105Issue 4PreviewMembranous nephropathy (MN) is an antibody-mediated disease of the kidney, typically resulting in nephrotic syndrome with urinary loss of high amounts of albumin and other plasma proteins. Phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing protein 7A (THSD7A) were the first kidney autoantigens identified in adult patients with MN.1,2 Importantly, we and others could demonstrate that autoantibodies in MN are not only excellent biomarkers to monitor immunologic disease activity, but also cause the disease through the direct interaction with the autoantigen expressed on podocytes in the kidney. Full-Text PDF Open AccessThe authors replyKidney InternationalVol. 105Issue 6PreviewWe thank Rovira et al.1 for their interest in our recent work.2 We fully agree that the use of chimeric autoantibody receptor (CAAR) cells, which specifically target pathogenic B-cell clones, represents a highly innovative therapeutic strategy for antibody-mediated diseases. In this direction, we demonstrated the principal feasibility of this approach for membranous nephropathy, a prototypical antibody-mediated disease with known target antigens.3,4 Certainly, we agree with Rovira et al. that there is always potential for improvements, particularly in the early stages of such developments. Full-Text PDF