FLT3 (FMS-like tyrosine kinase 3), expressed on the surface of acute myeloid leukemia (AML) blasts, is a promising AML target, given its role in the development and progression of leukemia, and its limited expression in tissues outside the hematopoietic system. Small molecule FLT3 kinase inhibitors have been developed, but despite having clinical efficacy, they are effective only on a subset of patients and associated with high risk of relapse. A durable therapy that can target a wider population of AML patients is needed. Here, we developed an anti-FLT3-CD3 immunoglobulin G (IgG)-based bispecific antibody (7370) with a high affinity for FLT3 and a long half-life, to target FLT3-expressing AML blasts, irrespective of FLT3 mutational status. We demonstrated that 7370 has picomolar potency against AML cell lines in vitro and in vivo. 7370 was also capable of activating T cells from AML patients, redirecting their cytotoxic activity against autologous blasts at low effector-to-target (E:T) ratio. Additionally, under our dosing regimen, 7370 was well tolerated and exhibited potent efficacy in cynomolgus monkeys by inducing complete but reversible depletion of peripheral FLT3+ dendritic cells (DCs) and bone marrow FLT3+ stem cells and progenitors. Overall, our results support further clinical development of 7370 to broadly target AML patients.

中文翻译：

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一种优化的全长FLT3 / CD3双特异性抗体可证明有效的抗白血病活性和可逆的血液毒性。

在急性髓样白血病（AML）原始细胞表面表达的FLT3（类似于FMS的酪氨酸激酶3），由于其在白血病的发生和发展中的作用以及在造血系统以外组织中的有限表达，因此是有希望的AML靶标。 。已经开发了小分子FLT3激酶抑制剂，但尽管具有临床疗效，但它们仅对部分患者有效，并且与复发风险高相关。需要一种能够针对更广泛的AML患者的持久疗法。在这里，我们开发了一种基于抗FLT3-CD3免疫球蛋白G（IgG）的双特异性抗体（7370），该抗体对FLT3具有高亲和力并具有较长的半衰期，以靶向表达FLT3的AML母细胞，而与FLT3突变状态无关。我们证明了7370在体外和体内对AML细胞株具有皮摩尔效价。7370还能够激活AML患者的T细胞，从而以低的效应物与靶标（E：T）比率重定向其对自体胚细胞的细胞毒活性。此外，在我们的给药方案下，通过诱导外周FLT3 +树突状细胞（DC）以及骨髓FLT3 +干细胞和祖细胞的完全但可逆的耗竭，7370在食蟹猴中具有良好的耐受性并显示出强大的功效。总体而言，我们的结果支持7370进一步针对广泛AML患者的临床开发。7370具有良好的耐受性，并通过诱导外周FLT3 +树突状细胞（DC）和骨髓FLT3 +干细胞和祖细胞的完全但可逆消耗而在食蟹猴中显示出有效功效。总体而言，我们的结果支持7370进一步针对广泛AML患者的临床开发。7370具有良好的耐受性，并通过诱导外周FLT3 +树突状细胞（DC）和骨髓FLT3 +干细胞和祖细胞的完全但可逆消耗而在食蟹猴中显示出有效功效。总体而言，我们的结果支持7370进一步针对广泛AML患者的临床开发。