PO.ET02.05 · 实验与分子治疗
GSPT1降解剂抗体偶联物BLB-201用于治疗高危急性髓系白血病
GSPT1 degrader antibody conjugate, BLB-201, for the treatment of high-risk acute myeloid leukemia
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
靶向降解GSPT1（一种翻译终止蛋白）是治疗急性髓系白血病（AML）的一种新方法。我们开发了一种降解剂抗体偶联物（DAC）BLB-201，以（i）改善GSPT1降解剂的全身耐受性，以及（ii）选择性杀伤表达肿瘤抗原CD123/IL3RA的AML原始细胞和白血病干细胞。BLB-201 DAC在活性、安全性、理化性质和稳定性方面均经过优化。BLB-201能快速降解GSPT1，并在AML细胞中引起细胞应激驱动的凋亡，且在血清中表现出高度的均一性、溶解性及连接子-载荷稳定性。评估了BLB-201对一组CD123阳性细胞系以及具有高危异常（如FLT3-ITD突变、TP53突变和MLL1基因重排）的患者AML原始细胞样本的杀伤作用。BLB-201对CD123阳性AML细胞系具有强效作用，但在杀伤实验中不影响CD123阴性细胞的活力。BLB-201对患者AML原始细胞（n=17个样本）和白血病干细胞在离体条件下具有强烈的细胞毒性作用。在体内，BLB-201在低剂量（0.1-0.3 mg/kg）下与临床抗AML药物（venetoclax、azacitidine和quizartinib）在系统性MV-4-11和MOLM-13模型中表现出优异的协同作用。在代表具有高危突变的复发性AML的系统性PDX模型中，BLB-201单药治疗显著抑制了循环CD45+ AML细胞，延长了生存期，并在与venetoclax和azacitidine方案联合使用时产生了完全缓解。作为单一药物，无论在体外还是在CDX AML模型中，BLB-201均表现出优于CD33靶向GSPT1 DAC基准品的疗效。在体外，我们未观察到BLB-201对来自CD34+造血干细胞的正常红系、巨核系和髓系细胞分化的任何影响，而CD33靶向抗体偶联药物gemtuzumab ozogamicin在这些实验中则表现出高度毒性。BLB-201 DAC能够选择性靶向CD123阳性AML原始细胞和白血病干细胞，最大限度地减少GSPT1降解剂对健康组织的直接暴露。这一独特的作用机制在与现有靶向疗法联合使用时，可能改善高危或复发/难治性AML患者的缓解率。
查看英文原文 English abstract
Targeted degradation of GSPT1, a translation termination protein, is a novel approach for Acute Myeloid Leukemia (AML) treatment. We developed a degrader antibody conjugate (DAC) BLB-201 to (i) improve the systemic tolerability of GSPT1 degrader, and (ii) selectively kill AML blasts and leukemia stem cells expressing the tumor antigen, CD123/IL3RA. The BLB-201 DAC was optimized for activity, safety, physiochemical properties, and stability. BLB-201 rapidly degraded GSPT1 and caused cellular stress-driven apoptosis in AML cells, and showed high degree of homogeneity, solubility, and linker-payload stability in serum. A panel of CD123-positive cell lines and patient AML blast samples, with high-risk abnormalities, such as FLT3-ITD mutation, TP53 mutation and MLL1 gene re-arrangements, were evaluated for cell killing by BLB-201. BLB-201 was potent against CD123-positive AML cell lines but did not affect the viability of CD123-negative cells in the cell killing assays. BLB-201 had strong cytotoxic effects on patient AML blasts (n=17 samples) and leukemic stem cells ex vivo . In vivo , BLB-201 exhibited excellent synergy at low doses (0.1-0.3mg/kg) with clinical anti-AML agents (venetoclax, azacitidine and quizartinib) in systemic MV-4-11 and MOLM-13 models. In the systemic PDX models representing relapsed AML with high-risk mutations, BLB-201 monotherapy significantly suppressed circulating CD45+ AML cells, prolonged survival as well as produced complete response in combination with venetoclax and azacitidine regimen. As a single agent both in the in vitro and in CDX AML models, BLB-201 showed better efficacy compared to a CD33-targeted GSPT1 DAC benchmark. We did not observe any effects of BLB-201 on normal erythroid, megakaryocytic and myeloid cell differentiation from CD34+ hematopoietic stem cells in vitro , while the CD33-targeted antibody drug conjugate, gemtuzumab ozogamacin, was highly toxic in these assays. BLB-201 DAC allows selective targeting of CD123-positive AML blasts and leukemia stem cells, minimizing direct exposure of GSPT1 degrader to healthy tissues. This unique mechanism of action may improve response rates when combined with existing targeted therapies for AML patients with high-risk or relapsed/refractory disease.
利益披露 Disclosure
R. Bam, None..
W. Qian, None..
J. Liu, None..
P. Zheng, None..
H. Wang, None..
J. Yu, None..
W. Hou, None..
X. Wei, None..
D. Xue, None..
W. Zhang, None..
D. Yi, None..
A. Chen, None.