A CD19/BCMA Dual-targeting VHH format T-cell Engager with Novel CD3 Binder for Enhanced Potency and Safety Profile 2329221
B-cell depletion therapies targeting CD19 or BCMA have shown significant therapeutic potential in systemic lupus erythematosus (SLE) and other autoimmune diseases (AID). However, CD19-directed approaches alone may be insufficient, as long-lived plasma cells lacking CD19 but expressing BCMA can sustain disease activity. Therefore, a dual-targeting strategy addressing both CD19-positive B cells and BCMA-positive plasma cells may enable more complete elimination of pathogenic immune cells and improve treatment durability. We developed FPE024, a CD19/BCMA dual-targeting T-cell engager (TCE) designed to enhance B-cell and plasma cell depletion. All components, including the CD3 nanobody, exhibit cross-species binding to both human and cynomolgus monkey antigens, enabling translational evaluation. In vitro cytotoxicity and cytokine release were assessed using tumor cells with varying CD19 and BCMA expression. B-cell killing was evaluated in PBMCs from healthy donors and SLE patients. In vivo efficacy was examined in NSG mouse xenograft models and cynomolgus monkeys. FPE024 induced potent cytotoxicity against CD19- and/or BCMA-expressing cells, with cytokine release comparable to approved TCEs, indicating a favorable safety profile. Similar B-cell depletion was observed in PBMCs from healthy donors and SLE patients. In NSG mice, FPE024 effectively eliminated target-expressing tumor cells at low doses. In cynomolgus monkeys, FPE024 achieved robust depletion of B cells and plasma cells at 0.1 mg/kg. FPE024 is a potent CD19/BCMA dual-targeting T-cell engager that enables broad depletion of pathogenic B cells and plasma cells. Its strong preclinical efficacy and translational relevance support further development for autoimmune diseases requiring comprehensive B-cell depletion. n/a Therapeutic Approaches to Autoimmunity (THER)