Generation and preclinical characterization of a novel bispecific CD19-TCRgammadelta antibody for the treatment of B cell acute lymphoblastic leukemia.

Introduction: B-cell acute lymphoblastic leukemia (B-ALL) is characterized by the clonal expansion of immature lymphoblastic cells. Treating patients with disease relapse is challenging, especially after allogeneic stem cell transplantation (aSCT). Although the CD19xCD3 bispecific antibody (bsAb) blinatumomab has improved outcomes for patients with relapsed B-ALL, T cell exhaustion and immune-associated treatment side effects remain problematic. Vγ9Vδ2 T cells constitute a relatively small subset in healthy individuals but their abundance increases after aSCT, and higher numbers correlate with improved outcomes. Unlike ab T cells, Vγ9Vδ2 T cells are not allo-reactive, do not contribute to graft-versus-host disease and release fewer inflammatory cytokines. Methods: Using hybridoma technology, we here generated a panel of hybridoma-derived monoclonal antibodies directed against the Vγ9Vδ2 receptor that specifically activate Vγ9Vδ2 T cells. Subsequently, we generated an IgG-based recombinant CD19xγδ bsAb to activate Vγ9Vδ2 T cells. Results: Our bsAb potently induces Vγ9Vδ2 T cell activation, proliferation, lysis of B-ALL cell lines in vitro in a dose-dependent manner. Additionally, the bsAb mediates lysis of primary leukemic blasts of patients ex vivo and depletion of CD19-positive target cells in an autologous setting. No significant alphabeta T cell activation or proliferation was observed. Discussion: In summary, the selective activation of Vγ9dδ T cells using our novel CD19xγδ bsAb constitutes a promising immunotherapeutic approach for the treatment of B-ALL. Our results warrant further clinical evaluation especially in patients with minimal residual disease after aSCT or CD3-directed bsAb therapy.