Head of R&D Fapon Biopharma Lexington, Massachusetts, United States
Disclosure(s):
Di LU, PhD: No financial relationships to disclose
Introduction/Rationale: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
