Targeting AML with Long-Lasting Bispecific Antibodies: A Promising Immunotherapeutic Approach

A novel bispecific antibody has been developed to target CD123+ acute myeloid leukemia (AML) stem and blast cells, leveraging T cell immunotherapy's strength while maintaining the dosing simplicity of therapeutic antibodies. This antibody, unlike others, can stimulate T cells to kill CD123+ AML cells regardless of the T cells' antigen specificity through a mechanism called "redirected T cell-cytotoxicity" (RTCC). It features a full Fc domain that forms stable heterodimers and is engineered to prevent nonselective T cell activation while ensuring a long serum half-life.

The antibody, XmAb14045, was selected from a library of optimized bispecific antibodies for its high affinity for human CD123 and CD3. It demonstrated potent T cell-mediated killing of CD123+ AML cell lines with high specificity and efficacy. In animal models, XmAb14045 showed a prolonged serum half-life and rapidly activated T cells, leading to a significant depletion of CD123+ cells in circulation and bone marrow, with sustained T cell activation.

The study suggests that basophil and plasmacytoid dendritic cell counts could serve as biomarkers for clinical efficacy, and the findings support the clinical evaluation of anti-CD123 × anti-CD3 bispecific antibodies for treating AML. The authors are affiliated with Xencor, Inc., with various disclosures including employment and equity ownership.