0010: XmAb657, a CD19 x CD3 T-Cell Engaging Bispecific Antibody for Autoimmune Disease

Background/Purpose: B cell depletion is a validated therapeutic strategy in autoimmune disease, but current approaches targeting CD20 may only partially eliminate disease-driving subsets such as early lineage B cells and plasma cells. T-cell engagers (TCEs) that redirect cytotoxic T cells to B-lineage targets offer a promising path to achieve deeper and more durable depletion. XmAb657 is a CD19 x CD3 bispecific antibody specifically engineered for autoimmune indications. CD19 is broadly expressed across the B cell lineage, including on subsets not addressed by CD20-targeted therapies. XmAb657 incorporates a bivalent CD19-binding arm to enhance avidity and improve engagement of CD19+ B cells, while the TCE format facilitates potent T cell–mediated cytotoxicity, including in tissue compartments where conventional therapies may have limited activity. XmAb657 was designed using a clinically validated 2+1 bispecific format and an Fc domain engineered for extended half-life.

Methods: XmAb657 was tested in a human PBMC-based redirected T cell cytotoxicity (RTCC) assay to assess B cell killing, cytokine production (IFNγ), and T cell activation (CD69, CD25). In vivo pharmacokinetics, pharmacodynamics, and tissue depletion were evaluated in cynomolgus monkeys following a single intravenous (IV) or subcutaneous (SC) dose. Peripheral blood, bone marrow, and lymph node B cells and plasma cells were measured for up to 42 days. Extent of lymph node B cell depletion was also assessed by IHC using a non-competing anti-CD19 antibody.

Results: In vitro, XmAb657 induced potent B cell cytotoxicity and T cell activation at low nanomolar concentrations. In cynomolgus monkeys, a single IV or SC dose of XmAb657 led to rapid and sustained depletion of peripheral B cells, and B cell counts were suppressed to levels below reliable quantitation (< 5 B cells/µL blood) for at least 42 days. Tissue analysis confirmed marked reductions in CD19+ B cells as well as CD19+ plasma cells in both lymph nodes and bone marrow. Serum half-life was approximately 15 days. XmAb657 was well tolerated in cynomolgus monkeys, with no clinical signs consistent with cytokine release.

Conclusion: XmAb657, a CD19 x CD3 bispecific antibody engineered for treatment of autoimmune disease, demonstrated potent in vitro activity and deep, durable depletion of circulating and tissue-resident B cells in cynomolgus monkeys after a single dose. Targeting CD19 may complement other B-lineage–directed approaches by extending depletion to a broader range of B cell subsets. These findings support the ongoing advancement of XmAb657 into first-in-human clinical studies.