Background: Autoimmune diseases arise from breakdowns in immune tolerance that lead to inappropriate production of autoantibodies and chronic tissue inflammation. Although current therapies, including biologics and targeted small molecules, can suppress broad immune pathways, many patients fail to achieve durable disease control or experience dose-limiting toxicities, underscoring the need for additional treatment options. Recently, administration of CAR T cell therapies targeting CD19 and/or BCMA have resulted in long-term, drug-free remission of patients with autoimmune disorders [1,2]. CD19 and BCMA are complementary targets and early clinical data with dual targeting CAR-T cells has demonstrated superior autoantibody clearance [3]; however, these therapies carry significant safety risks and patient access challenges. Dual targeted T cell engager molecules are poised to enter the clinic and show promise in achieving a safe and accessible treatment option for patients with refractory autoimmune disorders.

Objectives: To analyze the effects of treatment with a trispecific antibody targeting CD3, CD19, and BCMA in non-human primates.

Methods: LBL-051 is a novel, next-generation, trispecific T cell engager antibody which binds CD3, CD19, and BCMA with optimized affinity to minimize cytokine release while maximizing B and plasma cell depletion. LBL-051 lacks cross-reactivity with analogous cynomolgus targets, requiring the use of a surrogate molecule, LBL-051-S3 in cynomolgus monkey studies. LBL-051-S3 was administered to animals subcutaneously in a single or two-dose step up regimen, and animals were followed for a minimum of 28 days.

Results: Treatment with LBL-051-S3 resulted in rapid and complete depletion of CD19+ B cells at all dose levels in the peripheral blood and tissue (bone marrow, lymph nodes, and spleen) and depletion was maintained for ≥28 days. Additionally, CD38+CD138+ plasma cells were completely depleted in the bone marrow of cynomolgus monkeys as assessed by flow cytometry. As a surrogate for plasma cell function, IgA levels were measured in the peripheral blood. Dose-dependent decreases in immunoglobulins were observed following administration of LBL-051-S3, with IgA becoming undetectable at the “medium” dose and higher by day 28.

A dose-dependent increase in serum cytokines was observed with evidence of clinical cytokine release syndrome (CRS) observed only at the highest single dose, but not at lower doses. Subsequent groups were dosed in a step-up fashion beginning with a “medium” priming dose followed by a “high” to “very high” step-up dose, with no CRS observed, despite the cumulative dosage exceeding the highest primary dose level.

Conclusions: The surrogate molecule LBL-051-S3 rapidly and completely depletes both peripheral and tissue CD19+ B cells and plasma cells in cynomolgus monkeys with minimal cytokine release. To our knowledge, this is the first NHP study showing complete tissue depletion of both cell types with a T cell engager molecule.

REFERENCES: [1] Muller, F., Taubman, J. Bucci, L. et al. CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up. N Engl J Med, 390:687-700 (2024). DOI: 10.1056/NEJMoa2308917.

[2] Müller, F., Wirsching, A., Hagen, M. et al. BCMA CAR T cells in a patient with relapsing idiopathic inflammatory myositis after initial and repeat therapy with CD19 CAR T cells. Nat Med 31 , 1793–1797 (2025). DOI: 10.1038/s41591-025-03718-3.

[3] Wang, W., He, S., Zhang, W., et al. BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: a phase 1 open-label clinical trial. Ann Rheum Dis , 83(10):1304 (2024). DOI: 10.1136/ard-2024-225785.

Acknowledgments: NIL.

Disclosure of Interests: Angie Hertz Obenio Bio, I am employed by Aditum Bio, the sole investor in Oblenio Bio, Oblenio Bio, Chris Daige Shares of Oblenio Bio, I am employed by Aditum Bio, the sole investor in Oblenio Bio, Simon Wong Oblenio Bio, I am employed by Aditum Bio, the sole investor in Oblenio Bio, Tapan Maniar Oblenio Bio, I am employed by Aditum Bio, the sole investor in Oblenio Bio, Samantha Truex Oblenio Bio, I am employed by Aditum Bio, the sole investor in Oblenio Bio, Scott Plevy Oblenio Bio, I am employed by Aditum Bio, the sole investor in Oblenio Bio, Vicki Sung Oblenio Bio, I am employed by Aditum Bio, the sole investor in Oblenio Bio.