Characterization of SGN-CD123A, APotent CD123-Directed Antibody-Drug Conjugate for Acute Myeloid Leukemia
Characterization of SGN-CD123A, APotent CD123-Directed Antibody-Drug Conjugate for Acute Myeloid Leukemia
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DOI：
10.1158/1535-7163.mct-17-0742
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发表时间：
2018-02-01
影响因子：
5.7
通讯作者：
Benjamin, Dennis R.
中科院分区：
文献类型：
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作者：
Li, Fu;Sutherland, May Kung;Benjamin, Dennis R.
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。IL 3受体α（IL 3Ra或CD 123）在大多数AML母细胞上表达，并且有证据表明其在白血病干细胞上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标。在这里，我们报告了SGN-CD 123 A的产生和临床前表征，SGN-CD 123 A是一种使用吡咯并苯并二氮杂卓二聚体（PBD）接头的抗体-药物缀合物，以及具有用于位点特异性缀合的工程化半胱氨酸的人源化CD 123抗体。SGN-CD 123 A在机制上诱导AML细胞中DNA损伤反应途径、细胞周期变化和细胞凋亡的活化。在体外，SGN-CD 123 A介导了11/12个CD 123 thorn AML细胞系和20/23个AML患者的原代样本（包括具有不利细胞遗传学特征或FLT 3突变的样本）的强效细胞毒性。在体内，SGN-CD 123 A治疗在播散性疾病模型中导致AML根除，在皮下异种移植模型中导致缓解，在多药耐药异种移植模型中导致显著生长延迟。此外，SGN-CD 123 A还导致患者来源的异种移植物AML模型的持久完全缓解。当与FLT 3抑制剂quizartinib联合使用时，SGN-CD 123 A增强了quizartinib对两种FLT 3突变异种移植模型的活性。总体而言，这些数据表明SGN-CD 123 A是一种有效的抗白血病药物，支持正在进行的试验，以评估其在AML患者中的安全性和疗效（NCT 02848248）。(C)2017年AACR。
Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Ra, 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 stemcells, 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 CD123thorn 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). (C) 2017 AACR.