A novel CD34-specific T-cell engager efficiently depletes acute myeloid leukemia and leukemic stem cells in vitro and in vivo

Abstract

Less than a third of acute myeloid leukemia (AML) patients are cured by chemotherapy and/or hematopoietic stem cell transplantation (HSCT), highlighting the need to develop more efficient drugs. The low efficacy of standard treatments is associated with inadequate depletion of CD34+ blasts and leukemic stem cells (LSCs), the latter a drug-resistant subpopulation of leukemia cells characterized by the CD34+CD38- phenotype. To better target these drug-resistant primitive leukemic cells, we have designed a CD34/CD3 bispecific T-cell engager (BiTE) and characterized its anti-leukemia potential in vitro, ex vivo and in vivo. Our results show that this CD34-specific BiTE induces CD34-dependent T-cell activation and subsequent leukemia cell killing in a dose-dependent manner, further corroborated by enhanced T-cell-mediated killing at the single-cell level. Additionally, the BiTE triggered efficient T-cell-mediated depletion of CD34+ HSCs from peripheral blood stem cell grafts and CD34+ blasts from AML patients. Using a humanized AML xenograft model, we confirmed that the CD34-specific BiTE had in vivo efficacy by depleting CD34+ blasts and LSCs without side effects. Taken together, these data demonstrate robust antitumor effects of the CD34-specific BiTE supporting development of a novel treatment modality with the aim of improving outcomes of patients with AML and myelodysplastic syndromes.