Preclinical evaluation of antigen-specific B-cell depletion for phospholipase A2 receptor membranous nephropathy with chimeric autoantibody receptor T cells
Phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, driven by autoantibodies that target PLA2R on kidney podocytes. Antibody-based therapy with rituximab induces broad B-cell depletion but is associated with risks of serious in...
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| Vydáno v: | Kidney international |
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| Médium: | Journal Article |
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31.10.2025
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| ISSN: | 1523-1755, 1523-1755 |
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| Abstract | Phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, driven by autoantibodies that target PLA2R on kidney podocytes. Antibody-based therapy with rituximab induces broad B-cell depletion but is associated with risks of serious infection and reduced efficacy in patients with high proteinuria. Here, we determined the feasibility of developing chimeric autoantibody receptor T-cell (CAART) therapy for PLA2R-specific B-cell depletion in PLA2R MN.
PLA2R-CAART was produced by T-cell lentiviral transduction. In vitro cytotoxicity and specificity were evaluated against B-cell lines targeting PLA2R immunodominant epitopes and primary PLA2R MN B cells. Adsorption of PLA2R MN IgG was evaluated to determine the extent of pathogenic autoantibody targeting by candidate PLA2R-CAART designs. Specific cytotoxicity, engraftment capability, and off-target toxicity were evaluated in a xenografted anti-PLA2R Nalm-6 preclinical mouse model, with additional toxicology screening by human membrane proteome arrays.
We engineered CAARTs targeting key PLA2R epitopes to selectively deplete autoreactive B cells. C17- and C178-CAART (encompassing CysR, CTLD1, and CTLD7, with/without CTLD8 domains) were successfully expressed on primary T cells and demonstrated specific in vitro cytotoxicity against anti-PLA2R B-cell lines targeting CysR, CTLD1, and CTLD7 epitopes. In co-incubation assays with primary B cells or plasma from patients with MN, C17- and C178-CAART significantly reduced anti-PLA2R B cells and adsorbed 69-97% of plasma anti-PLA2R antibody reactivity. In vivo, C17- and C178-CAART treatment in the Nalm-6 xenograft model resulted in significant reduction in target cell outgrowth with C17-CAART showing slight but consistently increased cytotoxic activity. Specificity testing through comprehensive in vivo pathologic analysis and a high-throughput membrane proteome array analysis showed no significant off-target binding for either C17- or C178-CAART.
Our findings establish preclinical proof-of-concept for the therapeutic potential of antigen-specific B-cell depletion by PLA2R-CAART. Additional studies are required to determine clinical feasibility of PLA2R-CAART for PLA2R MN therapy. |
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| AbstractList | Phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, driven by autoantibodies that target PLA2R on kidney podocytes. Antibody-based therapy with rituximab induces broad B-cell depletion but is associated with risks of serious infection and reduced efficacy in patients with high proteinuria. Here, we determined the feasibility of developing chimeric autoantibody receptor T-cell (CAART) therapy for PLA2R-specific B-cell depletion in PLA2R MN.
PLA2R-CAART was produced by T-cell lentiviral transduction. In vitro cytotoxicity and specificity were evaluated against B-cell lines targeting PLA2R immunodominant epitopes and primary PLA2R MN B cells. Adsorption of PLA2R MN IgG was evaluated to determine the extent of pathogenic autoantibody targeting by candidate PLA2R-CAART designs. Specific cytotoxicity, engraftment capability, and off-target toxicity were evaluated in a xenografted anti-PLA2R Nalm-6 preclinical mouse model, with additional toxicology screening by human membrane proteome arrays.
We engineered CAARTs targeting key PLA2R epitopes to selectively deplete autoreactive B cells. C17- and C178-CAART (encompassing CysR, CTLD1, and CTLD7, with/without CTLD8 domains) were successfully expressed on primary T cells and demonstrated specific in vitro cytotoxicity against anti-PLA2R B-cell lines targeting CysR, CTLD1, and CTLD7 epitopes. In co-incubation assays with primary B cells or plasma from patients with MN, C17- and C178-CAART significantly reduced anti-PLA2R B cells and adsorbed 69-97% of plasma anti-PLA2R antibody reactivity. In vivo, C17- and C178-CAART treatment in the Nalm-6 xenograft model resulted in significant reduction in target cell outgrowth with C17-CAART showing slight but consistently increased cytotoxic activity. Specificity testing through comprehensive in vivo pathologic analysis and a high-throughput membrane proteome array analysis showed no significant off-target binding for either C17- or C178-CAART.
Our findings establish preclinical proof-of-concept for the therapeutic potential of antigen-specific B-cell depletion by PLA2R-CAART. Additional studies are required to determine clinical feasibility of PLA2R-CAART for PLA2R MN therapy. Phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, driven by autoantibodies that target PLA2R on kidney podocytes. Antibody-based therapy with rituximab induces broad B-cell depletion but is associated with risks of serious infection and reduced efficacy in patients with high proteinuria. Here, we determined the feasibility of developing chimeric autoantibody receptor T-cell (CAART) therapy for PLA2R-specific B-cell depletion in PLA2R MN.INTRODUCTIONPhospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, driven by autoantibodies that target PLA2R on kidney podocytes. Antibody-based therapy with rituximab induces broad B-cell depletion but is associated with risks of serious infection and reduced efficacy in patients with high proteinuria. Here, we determined the feasibility of developing chimeric autoantibody receptor T-cell (CAART) therapy for PLA2R-specific B-cell depletion in PLA2R MN.PLA2R-CAART was produced by T-cell lentiviral transduction. In vitro cytotoxicity and specificity were evaluated against B-cell lines targeting PLA2R immunodominant epitopes and primary PLA2R MN B-cells. Adsorption of PLA2R MN IgG was evaluated to determine the extent of pathogenic autoantibody targeting by candidate PLA2R-CAART designs. Specific cytotoxicity, engraftment capability, and off-target toxicity were evaluated in a xenografted anti-PLA2R Nalm-6 preclinical mouse model, with additional toxicology screening by human membrane proteome arrays.METHODSPLA2R-CAART was produced by T-cell lentiviral transduction. In vitro cytotoxicity and specificity were evaluated against B-cell lines targeting PLA2R immunodominant epitopes and primary PLA2R MN B-cells. Adsorption of PLA2R MN IgG was evaluated to determine the extent of pathogenic autoantibody targeting by candidate PLA2R-CAART designs. Specific cytotoxicity, engraftment capability, and off-target toxicity were evaluated in a xenografted anti-PLA2R Nalm-6 preclinical mouse model, with additional toxicology screening by human membrane proteome arrays.We engineered CAARTs targeting key PLA2R epitopes to selectively deplete autoreactive B-cells. C17- and C178-CAART (encompassing CysR, CTLD1, CTLD7, with/without CTLD8 domains) were successfully expressed on primary T-cells and demonstrated specific in vitro cytotoxicity against anti-PLA2R B-cell lines targeting CysR, CTLD1, and CTLD7 epitopes. In co-incubation assays with primary B-cells or plasma from patients with MN, C17- and C178-CAART significantly reduced anti-PLA2R B-cells and adsorbed 69-97% of plasma anti-PLA2R antibody reactivity. In vivo, C17- and C178-CAART treatment in the Nalm-6 xenograft model resulted in significant reduction in target cell outgrowth with C17-CAART showing slight but consistently increased cytotoxic activity. Specificity testing through comprehensive in vivo pathologic analysis and a high-throughput membrane proteome array analysis showed no significant off-target binding for either C17- or C178-CAART.RESULTSWe engineered CAARTs targeting key PLA2R epitopes to selectively deplete autoreactive B-cells. C17- and C178-CAART (encompassing CysR, CTLD1, CTLD7, with/without CTLD8 domains) were successfully expressed on primary T-cells and demonstrated specific in vitro cytotoxicity against anti-PLA2R B-cell lines targeting CysR, CTLD1, and CTLD7 epitopes. In co-incubation assays with primary B-cells or plasma from patients with MN, C17- and C178-CAART significantly reduced anti-PLA2R B-cells and adsorbed 69-97% of plasma anti-PLA2R antibody reactivity. In vivo, C17- and C178-CAART treatment in the Nalm-6 xenograft model resulted in significant reduction in target cell outgrowth with C17-CAART showing slight but consistently increased cytotoxic activity. Specificity testing through comprehensive in vivo pathologic analysis and a high-throughput membrane proteome array analysis showed no significant off-target binding for either C17- or C178-CAART.Our findings establish preclinical proof-of-concept for the therapeutic potential of antigen-specific B-cell depletion by PLA2R-CAART. Additional studies are required to determine clinical feasibility of PLA2R-CAART for PLA2R MN therapy.CONCLUSIONSOur findings establish preclinical proof-of-concept for the therapeutic potential of antigen-specific B-cell depletion by PLA2R-CAART. Additional studies are required to determine clinical feasibility of PLA2R-CAART for PLA2R MN therapy. |
| Author | Manfredo-Vieira, Silvio Payne, Aimee S Hogan, Jonathan J Patel, Darshil R Altun, Burcin Wong, Steven Radaelli, Enrico Gill, Saar I Mao, Xuming Cottman-Thomas, Ebony Goodman, Emma E Willis, Elinor Wang, Baomei Zhao, Gexin Boesteanu, Alina C |
| Author_xml | – sequence: 1 givenname: Burcin surname: Altun fullname: Altun, Burcin organization: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 2 givenname: Gexin surname: Zhao fullname: Zhao, Gexin organization: Department of Dermatology, Columbia University, New York, New York, USA – sequence: 3 givenname: Baomei surname: Wang fullname: Wang, Baomei organization: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 4 givenname: Xuming surname: Mao fullname: Mao, Xuming organization: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 5 givenname: Silvio surname: Manfredo-Vieira fullname: Manfredo-Vieira, Silvio organization: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 6 givenname: Elinor surname: Willis fullname: Willis, Elinor organization: Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 7 givenname: Enrico surname: Radaelli fullname: Radaelli, Enrico organization: Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 8 givenname: Emma E surname: Goodman fullname: Goodman, Emma E organization: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 9 givenname: Alina C surname: Boesteanu fullname: Boesteanu, Alina C organization: Center for Cellular Immunotherapies and Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 10 givenname: Saar I surname: Gill fullname: Gill, Saar I organization: Center for Cellular Immunotherapies and Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 11 givenname: Darshil R surname: Patel fullname: Patel, Darshil R organization: Cabaletta Bio, Philadelphia, Pennsylvania, USA – sequence: 12 givenname: Steven surname: Wong fullname: Wong, Steven organization: Cabaletta Bio, Philadelphia, Pennsylvania, USA – sequence: 13 givenname: Ebony surname: Cottman-Thomas fullname: Cottman-Thomas, Ebony organization: Cabaletta Bio, Philadelphia, Pennsylvania, USA – sequence: 14 givenname: Jonathan J surname: Hogan fullname: Hogan, Jonathan J organization: Cabaletta Bio, Philadelphia, Pennsylvania, USA – sequence: 15 givenname: Aimee S surname: Payne fullname: Payne, Aimee S email: asp2261@cumc.columbia.edu organization: Department of Dermatology, Columbia University, New York, New York, USA. Electronic address: asp2261@cumc.columbia.edu |
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