CLT030, a leukemic stem cell-targeting CLL1 antibody-drug conjugate for treatment of acute myeloid leukemia
CLT030, a leukemic stem cell-targeting CLL1 antibody-drug conjugate for treatment of acute myeloid leukemia
复制标题
CLT 030，一种用于治疗急性髓性白血病的白血病干细胞靶向CLL 1抗体-药物缀合物
DOI：
10.1182/bloodadvances.2018020107
复制
发表时间：
2018-07-24
期刊：
影响因子：
7.5
通讯作者：
Junutula, Jagath R.
中科院分区：
文献类型：
--
作者：
Jiang, Ying-Ping;Liu, Bob Y.;Junutula, Jagath R.
目前急性髓性白血病（AML）的标准治疗在很大程度上是无效的，复发率非常高，生存率很低，主要是由于无法消除罕见的白血病干细胞（LSC）群体，这些细胞启动肿瘤生长并对标准化疗具有抗性。对分离的LSC的RNA测序分析证实C型凝集素结构域家族12成员A（CLL 1，也称为CLEC 12 A）在LSC上高度表达，但在正常造血干细胞（HSC）或其他健康器官组织上不表达。CLL 1的表达在不同类型的AML中是一致的。我们开发了CLT 030（CLL 1-ADC），这是一种基于人源化抗CLL 1抗体的抗体-药物偶联物（ADC），其中2个工程化半胱氨酸残基通过可切割接头与高效DNA结合有效负载共价连接，从而产生位点特异性和均质ADC产物。ADC被设计为在血流中稳定，并且仅在ADC与表达CLL 1的肿瘤细胞结合、内化并且接头在溶酶体隔室中裂解后释放其DNA结合有效载荷。CLL 1-ADC抑制体外LSC集落形成，并在AML细胞肿瘤模型中表现出稳健的体内功效，并在AML患者来源的异种移植物模型中表现出肿瘤生长抑制。与CD 33-ADC相比，CLL 1-ADC对健康正常人CD 34（+）细胞分化为各种谱系的影响降低，如在体外集落形成试验和体内异种移植模型中观察到的。这些结果表明，CLL 1-ADC可能是治疗AML的有效治疗性ADC。
The current standard of care for acute myeloid leukemia (AML) is largely ineffective with very high relapse rates and low survival rates, mostly due to the inability to eliminate a rare population of leukemic stem cells (LSCs) that initiate tumor growth and are resistant to standard chemotherapy. RNA-sequencing analysis on isolated LSCs confirmed C-type lectin domain family 12 member A (CLL1, also known as CLEC12A) to be highly expressed on LSCs but not on normal hematopoietic stem cells (HSCs) or other healthy organ tissues. Expression of CLL1 was consistent across different types of AML. We developed CLT030 (CLL1-ADC), an antibody-drug conjugate (ADC) based on a humanized anti-CLL1 antibody with 2 engineered cysteine residues linked covalently via a cleavable linker to a highly potent DNA-binding payload, thus resulting in a site-specific and homogenous ADC product. The ADC is designed to be stable in the bloodstream and to release its DNA-binding payload only after the ADC binds to CLL1-expressing tumor cells, is internalized, and the linker is cleaved in the lysosomal compartment. CLL1-ADC inhibits in vitro LSC colony formation and demonstrates robust in vivo efficacy in AML cell tumor models and tumor growth inhibition in the AML patient-derived xenograft model. CLL1-ADC demonstrated a reduced effect on differentiation of healthy normal human CD34(+) cells to various lineages as observed in an in vitro colony formation assay and in an in vivo xenotransplantation model as compared with CD33-ADC. These results demonstrate that CLL1-ADC could be an effective ADC therapeutic for the treatment of AML.