A potent tetravalent T-cell-engaging bispecific antibody against CD33 in acute myeloid leukemia
A potent tetravalent T-cell-engaging bispecific antibody against CD33 in acute myeloid leukemia
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DOI：
10.1182/bloodadvances.2017014373
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发表时间：
2018-06-12
期刊：
影响因子：
7.5
通讯作者：
Cheung, Nai-Kong V.
中科院分区：
文献类型：
--
作者：
Hoseini, Sayed Shahabuddin;Guo, Hongfen;Cheung, Nai-Kong V.
急性髓性白血病（AML）是成人中最常见的急性白血病，也是儿童中第二常见的癌症，在大多数患者中仍然是一种致命的疾病，但免疫方法已经改善了结果。双特异性抗体（BsAbs）是一种新型的免疫治疗剂，可以使免疫细胞重定向以对抗AML。我们现在报道了免疫球蛋白G轻链单链可变片段[IgG（L）-scFv]形式的四价（2+2）人源化BsAb，其接合多克隆T细胞以杀死CD 33（+）AML靶标。在体外，这种BsAb表现出强的抗原特异性T细胞依赖性细胞介导的细胞毒性（TDCC），50%有效浓度（EC 50）在飞摩尔范围内，转化为体内建立的人AML IV异种移植物的治疗。重要的是，它可以重定向腹腔注射的T细胞，以消融体内建立和快速生长的髓外皮下AML异种移植物。此外，在BsAb结合后，CD 33的内化与二价（1+1）异二聚体的内化相同，两者均显著低于抗CD 33 IgG。与异二聚体相比，四价IgG-scFv BsAb在体外和体内AML细胞的TDCC中的效率高>10倍。该BsAb不与来自脐带血的CD 38（-）CD 34（+）造血干细胞反应，也不杀死来自脐带血的造血干细胞。我们的结论是，本文报道的新型抗CD 33 IgG（L）-scFv BsAb构建体是临床开发的潜在候选者。
Acute myeloid leukemia (AML), the most common acute leukemia in adults and the second most common cancer in children, is still a lethal disease in the majority of patients, but immunologic approaches have improved outcome. Bispecific antibodies (BsAbs) are novel immunotherapeutics that can redirect immune cells against AML. We now report a tetravalent (2+2) humanized BsAb in the immunoglobulin G light chain single chain fragment variable [IgG(L)-scFv] format to engage polyclonal T cells to kill CD33(+) AML targets. In vitro, this BsAb demonstrated strong antigen-specific T-cell-dependent cell-mediated cytotoxicity (TDCC) with an 50% effective concentration (EC50) in the femtomolar range that translated into treatment of established human AML IV xenografts in vivo. Importantly, it could redirect intraperitoneally injected T cells to ablate established and rapidly growing extramedullary subcutaneous AML xenografts in vivo. Furthermore, internalization of CD33 upon BsAb binding was identical to that of a bivalent (1+1) heterodimer, both being substantially less than anti-CD33 IgG. In contrast to the heterodimer, the tetravalent IgG-scFv BsAb was >10-fold more efficient in TDCC of AML cells in vitro and in vivo. This BsAb did not react with and did not kill CD38(-)CD34(+) hematopoietic stem cells from cord blood. We conclude that the novel anti-CD33 IgG(L)-scFv BsAb construct reported here is a potential candidate for clinical development.