Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, United States.
Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, United States.
J Control Release. 2020 Aug 10;324:317-329. doi: 10.1016/j.jconrel.2020.05.021. Epub 2020 May 16.
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.
FLT3 受体是急性髓系白血病的重要治疗靶点，因为其突变的发生率很高，与不良的临床结局相关。针对 FLT3 受体的靶向治疗，包括小分子 FLT3 酪氨酸激酶抑制剂（TKI）和抗 FLT3 抗体，已经在临床前甚至临床中显示出了有希望的疗效。然而，即使目前 FDA 批准了两种 FLT3 抑制剂，这些治疗方法也未能治愈 AML 或显著延长常见突变（FLT3-ITD）患者的生命。虽然 FLT3 是一个可行的靶点，但抑制其活性的方法还不够完善。为了开发针对 FLT3 的新方法，我们的团队设计了一种由单链可变片段抗体与弹性蛋白样多肽缀合而成的 α-FLT3-A192 融合蛋白。这些融合蛋白组装成多价纳米颗粒，具有极好的稳定性和药代动力学特性，以及在 AML 的细胞和异种移植小鼠模型中的体外和体内药理学活性。总之，α-FLT3-A192 融合蛋白似乎是一种针对 AML 中 FLT3 的可行的新方法，值得进一步进行临床前开发，使其进入临床应用。
