Background/Purpose: B cells and plasma cells are central to the pathogenesis of many autoimmune diseases. While B cell depletion therapies (BCDTs), such as anti-CD20 monoclonal antibodies, have improved outcomes in diseases like systemic lupus erythematosus (SLE), their efficacy is limited by the persistence of plasma cells, leading to disease relapses or refractory cases. Immunotherapies targeting CD19 have revolutionized the treatment of various hematological malignancies. Recently, such therapies have been used in refractory autoimmune diseases with encouraging results. CD19 is a B cell marker expressed from early B cell development through plasma cells, making it an attractive target for broad B cell depletion. However, CD19 targeting BCDT does not address accumulated long-lived plasma cells, leading to persistent autoantibody production despite B cell depletion. B cell maturation antigen (BCMA) is highly expressed on plasma cells, including long-lived plasma cells in lymphoid reservoirs (bone marrow, spleen, lymph nodes). We present a novel TCE designed to target both CD19-positive B cells and BCMA-positive plasma cells. This TCE enables cytotoxic T cells to recognize and eliminate the entire spectrum of B cell lineages, from naïve and memory B cells to plasma blasts and long-lived plasma cells. This dual-targeting approach is designed to overcome a key limitation of current BCDTs by eradicating both the precursors and the ultimate producers of pathogenic autoantibodies.

Methods: Cancer cell lines representing early B cell lineages (CD19+/BCMA-), plasma cells (CD19+/BCMA+), and fully differentiated long-lived plasma cells (CD19-/BCMA+) were co-cultured with isolated T cells and CDR111 for 48h. Peripheral blood mononuclear cells (PBMC) from autoimmune patients and bone marrow (BM) samples from healthy donors were incubated with CDR111. NCG-M mice engrafted with CD34+ human hematopoietic stem cells and treated with toll-like receptor 7 (TLR7) agonist to induce SLE-like symptoms were administered with CDR111.

Results: CDR111 showed potent in vitro killing of all tested cancer cell lines representing the entire B cell compartment. In contrast, CD19-directed control TCE showed no killing of CD19-negative cancer cells, mimicking long-lived plasma cells. Full depletion of B cells and plasma cells was achieved in patient-derived PMBCs. Potent cell killing was observed on plasma cells from BM where BCMA expression is high. CDR111 led to eradication of B cells and plasma cells in peripheral blood, spleen, and bone marrow in the NCG-M mouse model.

Conclusion: CDR111 demonstrates a differentiated approach to treating autoimmune patients. While showing peripheral B cell depletion with controlled cytokine release, it achieves potent plasma cell eradication in lymphoid organs (bone marrow and spleen). CDR111 holds the potential for a true B cell reset, resulting in durable treatment-free disease remission in patients with severe or refractory autoimmune diseases like SLE and rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cdr111-is-a-novel-cd19-and-bcma-dual-targeting-t-cell-engager-tce-for-the-treatment-of-severe-and-refractory-autoimmune-diseases/