Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Rα, or CD123) is expressed on the majority of AML blasts, and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGN-CD123A, an antibody–drug conjugate using the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A–mediated potent cytotoxicity of 11/12 CD123+ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248). Mol Cancer Ther; 17(2); 554–64. ©2017 AACR.

中文翻译：

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SGN-CD123A 的表征，一种针对急性髓系白血病的有效 CD123 导向的抗体药物偶联物

对常规化疗耐药的急性髓性白血病 (AML) 患者的治疗选择有限，需要新的治疗药物。IL3 受体 α（IL3Rα 或 CD123）在大多数 AML 原始细胞上表达，并且有证据表明其在白血病细胞中的表达相对于正常造血干细胞增加，这使其成为基于抗体的治疗的有吸引力的靶点。在这里，我们报告了 SGN-CD123A 的生成和临床前表征，SGN-CD123A 是一种使用吡咯并苯二氮卓二聚体 (PBD) 接头的抗体-药物偶联物，以及具有工程化半胱氨酸的人源化 CD123 抗体，用于位点特异性偶联。从机制上讲，SGN-CD123A 诱导 AML 细胞中 DNA 损伤反应通路的激活、细胞周期变化和细胞凋亡。体外，SGN-CD123A 介导的 11/12 CD123+ AML 细胞系和 20/23 来自 AML 患者的原始样本的强细胞毒性，包括那些具有不利细胞遗传学特征或 FLT3 突变的样本。在体内，SGN-CD123A 治疗导致播散性疾病模型中的 AML 根除、皮下异种移植模型中的缓解以及多药耐药异种移植模型中的显着生长延迟。此外，SGN-CD123A 还导致患者来源的异种移植 AML 模型的持久完全缓解。当与 FLT3 抑制剂 quizartinib 结合使用时，SGN-CD123A 增强了 quizartinib 对两种 FLT3 突变异种移植模型的活性。总体而言，这些数据表明 SGN-CD123A 是一种有效的抗白血病药物，支持正在进行的评估其在 AML 患者中的安全性和有效性的试验 (NCT02848248)。摩尔癌症治疗; 17(2); 554-64。©2017 AACR。