Anti-FLT3 nanoparticles for acute myeloid leukemia: Preclinical pharmacology and pharmacokinetics.

FLT3 receptor is an important therapeutic target in acute myeloid leukemia due to high incidence of mutations associated with poor clinical outcome. Targeted therapies against the FLT3 receptor, including small-molecule FLT3 tyrosine kinase inhibitors (TKIs) and anti-FLT3 antibodies, have demonstrated promising preclinical and even clinical efficacy. Yet, even with the current FDA approval for two FLT3 inhibitors, these modalities were unable to cure AML or significantly extend the lives of patients with a common mutation called FLT3-ITD. While FLT3 is a viable target, the approaches to inhibit its activity were inadequate. To develop a new modality for targeting FLT3, our team engineered an α-FLT3-A192 fusion protein composed of a single chain variable fragment antibody conjugated with an elastin-like polypeptide. These fusion proteins assemble into multi-valent nanoparticles with excellent stability and pharmacokinetic properties as well as in vitro and in vivo pharmacological activity in cellular and xenograft murine models of AML. In conclusion, α-FLT3-A192 fusions appear to be a viable new modality for targeting FLT3 in AML and warrant further preclinical development to bring it into the clinic.