Characterization of a Novel FLT3 BiTE® Antibody Construct for the Treatment of Acute Myeloid Leukemia.

Despite advances in the treatment of acute myeloid leukemia (AML), novel therapies are needed to induce deeper and more durable clinical response. Bispecific T cell Engager (BiTE®) molecules, which redirect patient T cells to lyse tumor cells, are a clinically-validated modality for hematologic malignancies. Due to broad AML expression and limited normal tissue expression, FLT3 is proposed to be an optimal BiTE® molecule target. Expression profiling of FLT3 was performed in primary AML patient samples and normal hematopoietic cells and non-hematopoietic tissues. Two novel FLT3 BiTE® molecules, one with a half-life extending (HLE) Fc moiety and one without, were assessed for T-cell dependent cellular cytotoxicity (TDCC) of FLT3-positive cell lines in vitro, in vivo, and ex vivo. FLT3 expression was detected on the surface of most primary AML bulk and leukemic stem cells but only a fraction of normal hematopoietic stem and progenitor cells. FLT3 protein detected in non-hematopoietic cells was cytoplasmic. FLT3 BiTE® molecules induced TDCC of FLT3-positive cells in vitro, reduced tumor growth and increased survival in AML mouse models in vivo. Both molecules exhibited reproducible pharmacokinetic and pharmacodynamic profiles in cynomolgus monkeys in vivo, including elimination of FLT3-positive cells in blood and bone marrow. In ex vivo cultures of primary AML samples, patient T cells induced TDCC of FLT3-positive target cells. Combination with PD-1 blockade increased BiTE® activity. These data support the clinical development of a FLT3 targeting BiTE® molecule for the treatment of AML.