Precision Targeting of Lupus-Associated IGHV4-34+ Pathogenic B Cells Using Chimeric Antigen Receptor T Cells

Developing CART4-34, a novel CAR T cell therapy that selectively eliminates IGHV4-34+ pathogenic B cells in lupus while sparing healthy B cells and avoiding broad immunosuppression.
Completed Systemic Diseases Systemic Lupus Erythematosus (SLE) Autoantibodies B Cell Biology Biological & Mechanistic Experimental Platforms & Models In Vitro Models Precision Medicine T Cell Biology Therapeutic Development Translational & Clinical

Funding Year: 2024

Project Overview

Current CAR T cell therapies for SLE target CD19, which eliminates all B cells — including healthy ones — leading to profound immunosuppression. This project develops a more precise alternative: CART4-34, engineered to target IGHV4-34, an antigen highly enriched in pathogenic B cells and strongly associated with disease severity in SLE. Key findings demonstrate that IGHV4-34+ autoantibodies compose multiple autoantibodies associated with aggressive lupus characteristics, form immune complexes in glomerulonephritis, and can be effectively targeted and depleted by CART4-34 in patient-derived B cells. Soluble IGHV4-34 antibodies affect CART4-34 function but antibody removal restores it, and a novel IGHV4-34+ transgenic mouse model has been developed to test whether B cell depletion reduces autoantibody production and alleviates disease symptoms in vivo.

Impact & Innovation

CAR T precision medicine for lupus — without broad immunosuppression.

 

By targeting IGHV4-34 rather than CD19, CART4-34 eliminates the pathogenic B cells and autoantibodies most strongly linked to severe SLE while preserving healthy B cells and plasma cells — a fundamentally safer approach to CAR T therapy in autoimmune disease.

  • Identifies IGHV4-34+ B cells and their autoantibodies as specific, high-value targets in aggressive SLE, with demonstrated depletion efficacy in patient-derived B cells using CART4-34
  • Introduces a previously unexplored CAR T target in SLE with a novel IGHV4-34+ transgenic mouse model for in vivo mechanistic and therapeutic validation
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by moving a precision B cell targeting strategy from antigen discovery through CAR T engineering and preclinical validation toward clinical development in SLE
Research Approach

A framework designed for discovery

This project combines B cell immunology, CAR T cell engineering, and preclinical disease modeling to develop and validate CART4-34 as a precision therapy targeting IGHV4-34+ pathogenic B cells in SLE. The work moves from antigen characterization through CAR T construction, patient-derived B cell testing, and in vivo transgenic mouse model validation.

Characterization of serum IGHV4-34+ antibodies and immune complex formation in SLE and lupus glomerulonephritis; development of CART4-34 targeting IGHV4-34+ B cells; co-culture assays measuring CART4-34 cytotoxicity against patient-derived B cells activated with cytokines and differentiated into plasmablasts; IGHV4-34 Ig depletion studies assessing effects on NK cell-mediated ADCC and CAR T function; and development of a novel IGHV4-34+ transgenic mouse model for in vivo testing.

Serum samples from 52 healthy donors and 105 SLE patients quantifying IGHV4-34+ Ig levels; patient-derived B cell co-culture datasets measuring CART4-34 efficacy; glomerulonephritis tissue staining datasets; IGHV4-34 Ig depletion and CAR T functional restoration datasets; and the novel IGHV4-34+ transgenic mouse model for in vivo mechanistic validation.

Validation of IGHV4-34 as a precision CAR T target in SLE, with demonstration of selective pathogenic B cell depletion while sparing healthy B cells and plasma cells. In vivo validation using the transgenic mouse model will test whether IGHV4-34+ B cell depletion reduces autoantibody production and alleviates disease symptoms, supporting advancement toward clinical development.

Investigators & Institutions

Powering the science

Principal Investigator

Marco Ruella, MD, Colton Consortium Member

Associate Professor, Department of Medicine, Perelman School of Medicine, University of Pennsylvania

Colton Centers & Institutions

Colton Center for Autoimmunity at the University of Pennsylvania

Perelman School of Medicine

Research Outputs

From insight to impact

Publications

Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells

Science Translational Medicine
Cohen, IJ; Bochi-Layec, AC; Lemoine, J; Jenks, S; Bayat, P; Kim, KH; Zhao, H; Ugwuanyi, O; Stella, F; Ghilardi, G; Gabrielli, G; McCuaig, S; Iatrou, A; Vlachonikola, E; Karipidou, M; Bouziani, E; Espie, D; Ramasubramanian, R; Agathangelidis, A; Bhosale, A; Paruzzo, L; Medico, G; Kolar, B; Bugrovsky, R; Guruprasad, P; Wang, LP; Harris, J; Arons, E; Zhang, Y; Pajarillo, R; Kreiger, PA; Day, CP; Sahinalp, SC; Wu, CH; Santi, A; Fulmer, B; Cases, M; Palmer, MB; Porazzi, P; Wherry, EJ; Kreitman, RJ; Tiacci, E; Apostolidis, SA; Behrens, EM; Bhoj, V; Sanz, I; Inghirami, G; Schuster, SJ; Ghia, P; Stamatopoulos, K; Ruella, M February 2026
Adaptive ImmunityAnimal ModelsAutoantibodiesB Cell BiologyBiological & MechanisticExperimental Platforms & ModelsIn Vitro ModelsPrecision MedicineTherapeutic DevelopmentTranslational & ClinicalOtherSystemic DiseasesSystemic Lupus Erythematosus (SLE)University of Pennsylvania

Spatial atlas of diabetic kidney disease reveals a B cell-rich subgroup

Nature
Dumoulin, B; Levinsohn, J; Klötzer, KA; Li, C; Mao, L; Ha, E; Mohandes, S; Nguyen, T; Paruzzo, L; Hirohama, D; Fang, V; Bhoj, VG; Parhiz, H; Andrade-Silva, M; Abedini, A; Bergeson, A; Traum, D; May, MJ; Kaestner, K; Ruella, M; McAllister, FE; Hakimi, AA; Li, M; Palmer, M; Wherry, EJ; Hunter, CA; Cancro, MP, TRIDENT Consortium; Susztak, K April 2026
Adaptive ImmunityB Cell BiologyBioinformaticsBiological & MechanisticBiomarker DiscoveryCytokine SignalingData-Driven & QuantitativeDisease SubtypingExperimental Platforms & ModelsHuman CohortsImmune ProfilingInnate ImmunityMulti-omics IntegrationSingle Cell TechnologiesSpatial BiologyTherapeutic DevelopmentTranslational & ClinicalEndocrine DiseasesOtherType 1 DiabetesUniversity of Pennsylvania

Additional Outputs

Publication resubmitted to Science Translational Medicine: Cohen IJ et al. Chimeric Antigen Receptor T Cells (CART) against the IGHV4-34 B cell Receptor Eliminate Neoplastic and Autoimmune B Cells while Sparing Healthy B cells.