Background/Purpose: Immune reset, achieved through profound and sustained depletion of B cells and/or plasma cells, has demonstrated significant clinical efficacy in patients with severe and refractory autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Therapies targeting CD19 and/or BCMA, such as CAR-T, have shown promise in inducing immune reset, potentially enabling drug-free remission. However, these strategies face substantial logistical hurdles and safety concerns. T cell engager (TCE), a drug modality well-validated in oncology, offers an alternative approach to achieve robust B cell and plasma cell depletion with enhanced safety profiles as well as off-the-shelf availability. Here, we describe the development and characterization of a next generation TCE therapy, designed to induce immune reset via dual targeting of B cells and plasma cells.

Methods: The activity of IAR130 was evaluated via flow cytometry to quantify target cell killing and T cell activation in vitro. CD8 T cells isolated from human peripheral blood mononuclear cells (PBMCs) were co-cultured with cells expressing CD19 or BCMA. The in vivo efficacy of IAR130 was evaluated in humanized CD3/CD19/BCMA triple knock-in mice and cynomolgus monkeys, to assess the depletion of B cells, antibody-secreting cells, and immunoglobulin.

Results: IAR130, a 2+1 format tri-specific TCE targeting CD19, BCMA, and CD3, was designed and engineered to achieve depletion of both B cells and plasma cells. The 2+1 TCE design, via steric hindrance mediated masking of CD3 binder, enables minimized target-independent T cell binding and activation, possibly leading to improved safety and pharmacokinetics (PK) profile. in vitro, IAR130 elicited robust T cell activation and potent cytotoxicity against CD19- and BCMA-expressing cells. In mouse models, IAR130 deeply depleted B cells and antibody-secreting cells across tissues (blood, lymph nodes, and bone marrow), and reduced circulating immunoglobulin levels, outperforming benchmark CD19 TCE and BCMA TCE. IAR130 also exhibited favorable drug developability and compatibility with subcutaneous administration. In non-human primates, IAR130 elicited deep and prolonged depletion of circulating B cells, antibody-secreting cells, and immunoglobulin.

Conclusion: IAR130 is positioned as a next-generation, off-the-shelf TCE designed to induce immune reset through dual depletion of B cells and plasma cells. Its optimized 2+1 format, robust pre-clinical efficacy, and developability support its potential as a versatile therapy for diverse autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-and-characterization-of-iar130-a-21-format-cd19-and-bcma-dual-targeting-t-cell-engager-for-autoimmune-diseases/