A novel CD34-specific T-cell engager efficiently depletes acute myeloid leukemia and leukemic stem cells <i>in vitro</i> and <i>in vivo</i>
Lucas C. M. Arruda, Arwen Stikvoort, Mélanie Lambert, Liqing Jin, Laura Sánchez Rivera, Renato M. P. Alves, Tales Rocha de Moura, Carsten Mim, Sören Lehmann, Rebecca Axelsson‐Robertson, John E. Dick, Jonas Mattsson, Björn Önfelt, Mattias Carlsten, Michael Uhlin
Abstract
Less than a third of patients with acute myeloid leukemia (AML) are cured by chemotherapy and/or hematopoietic stem cell transplantation, 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, the latter a drug-resistant subpopulation of leukemia cells characterized by the CD34+CD38- phenotype. To target these drug-resistant primitive leukemic cells better, we have designed a CD34/CD3 bi-specific T-cell engager (BTE) and characterized its anti-leukemia potential in vitro, ex vivo and in vivo. Our results show that this CD34-specific BTE 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 singlecell level. Additionally, the BTE triggered efficient T-cell-mediated depletion of CD34+ hematopoietic stem cells from peripheral blood stem cell grafts and CD34+ blasts from AML patients. Using a humanized AML xenograft model, we confirmed that the CD34-specific BTE had in vivo efficacy by depleting CD34+ blasts and leukemic stem cells without side effects. Taken together, these data demonstrate that the CD34-specific BTE has robust antitumor effects, supporting development of a novel treatment modality with the aim of improving outcomes of patients with AML and myelodysplastic syndromes.