Background/Purpose: Autologous CAR T-cell therapies have remarkable clinical activity in autoimmune disease (AD) via B-cell targeting, with many patients achieving durable, drug-free remission. However, safety concerns persist, including toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Long manufacturing times and complex logistics that limit patient access also limit broader adoption. Allogeneic natural killer (NK) cell therapy may help address these challenges. NKX019 is an allogeneic, CD19-targeted CAR NK-cell therapy derived from healthy donor peripheral blood mononuclear cells (PMBCs) and cryopreserved for off-the-shelf use. NKX019 expresses a humanized anti-CD19 scFv CAR fused to co-stimulatory (OX40) and signaling (CD3ζ) domains to enhance killing, along with membrane-bound interleukin-15 to support persistence. In a Phase 1 clinical trial for relapsed or refractory B-cell malignancies [NCT05020678], NKX019 demonstrated a favorable safety profile, including no ICANS or life-threatening CRS, as well as encouraging anti-tumor activity. In this study, we evaluate the therapeutic potential of NKX019 in AD.

Methods: NHL patient samples and PBMCs obtained from patients with various B-cell mediated AD (SLE, SSc, IIM, MG, RA, MS) were evaluated to assess depletion of CD19+ B cells, B-cell reconstitution and immune repertoire using flow cytometry and genomic analyses (10X Genomics 5’ Single Cell Gene Expression profiling paired with B-Cell Receptor (BCR) sequencing). In vivo studies were performed in NGS mice inoculated with human CD19+ B-cell lymphoma cell lines treated with NKX019 to evaluate activity and biodistribution of NKX019 in tissue samples by bioluminescence imaging (IVIS spectrum) and qPCR, respectively.

Results: NKX019 targets and kills CD19+ cells from patients with NHL and AD. In non-clinical studies, NKX019 potently and selectively depletes B cells from patients with SLE, SSc, IIM, MG, RA, and MS in a dose-dependent manner. In a B-cell lymphoma in vivo efficacy model, NKX019 eliminated CD19+ lymphoma cells and trafficked to several organs including secondary lymphoid tissue, kidneys and lungs. Translational data from patient samples from the NHL trial demonstrated that NKX019 induces potent and sustained depletion of CD19+ cells from circulation. Following treatment, detailed analyses of the BCR repertoire diversity and phenotypic characterization revealed a shift of the B-cell immune repertoire toward a naïve-dominant profile.

Conclusion: In summary, non-clinical in vitro and in vivo data demonstrated that NKX019 effectively depletes CD19+ cells derived from AD patients and in CD19+ lymphoma models, respectively. In NHL patients, NKX019 induced robust B cell depletion followed by reconstitution of the B cell compartment. These data provide compelling support for NKX019 as a novel therapeutic approach for treatment of B-cell driven AD. NKX019 is currently being evaluated in Phase 1 trials for SLE LN (NCT06557265, Ntrust-1); and SSc, IIM, and ANCA-AAV (NCT06733935, Ntrust-2) and investor-sponsored trials for SLE (NCT06518668) and MG.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nkx019-an-allogeneic-off-the-shelf-cd19-targeting-car-nk-cell-therapy-induces-deep-cd19-b-cell-depletion-in-hematological-malignancy-and-models-of-autoimmune-disease/