Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858.
Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858.
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作者：
Eksioglu EA;Chen X;Heider KH;Rueter B;McGraw KL;Basiorka AA;Wei M;Burnette A;Cheng P;Lancet J;Komrokji R;Djeu J;List A;Wei S
我们最近报道，骨髓源性抑制细胞（MDSC）（定义为CD33+HLA-DR−Lin−）的积累在骨髓增生异常综合征（MDS）的发病机制中发挥直接作用。特别是，CD33 在从 MDS 患者分离的 MDSC 中强烈表达，通过 S100A9 激活，在 MDSC 介导的造血抑制功能中发挥重要作用。因此，我们测试了用全人 Fc 工程单克隆抗体抗 CD33 (BI 836858) 阻断这种相互作用是否会抑制 CD33 介导的信号转导并改善 MDS 中的骨髓微环境。我们观察到 BI 836858 可以通过抗体依赖性细胞毒性 (ADCC) 减少 MDSC，这与颗粒动员和细胞死亡的增加相关。 BI 836858 还可以阻断 CD33 下游信号传导，防止免疫抑制细胞因子的分泌，这与 CFU-GM 和 BFU-E 集落形成的显着增加相关。 CD33 途径的激活可导致活性氧 (ROS) 诱导的基因组不稳定，但 BI 836858 降低了 ROS 以及双链断裂和加合物的水平（通过彗星测定和 γH2AX 测量）。这项工作为开发一组针对 MDSC 的新型 MDS 疗法及其促进疾病的特性奠定了基础，目的是改善患者的造血功能。
We recently reported that the accumulation of myeloid-derived suppressor cells (MDSC), defined as CD33+HLA-DR−Lin−, plays a direct role in the pathogenesis of myelodysplastic syndrome (MDS). In particular, CD33 is strongly expressed in MDSC isolated from patients with MDS where it plays an important role in MDSC-mediated hematopoietic suppressive function through its activation by S100A9. Therefore, we tested whether blocking this interaction with a fully human, Fc-engineered monoclonal antibody against CD33 (BI 836858) suppresses CD33-mediated signal transduction and improves the bone marrow microenvironment in MDS. We observed that BI 836858 can reduce MDSC by antibody-dependent cellular cytotoxicity (ADCC), which correlated with increases in granule mobilization and cell death. BI 836858 can also block CD33 downstream signaling preventing immune-suppressive cytokine secretion, which correlates with a significant increase in the formation of CFU-GM and BFU-E colonies. Activation of the CD33 pathway can cause reactive oxygen species (ROS)-induced genomic instability but BI 836858 reduced both ROS and the levels of double strand breaks and adducts (measured by comet assay and γH2AX). This work provides the ground for the development of a novel group of therapies for MDS aimed at MDSC and their disease-promoting properties with the goal of improving hematopoiesis in patients.
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影响因子：
45.3
作者：
Kristinsson, Sigurdur Y.;Bjorkholm, Magnus;Goldin, Lynn R.
通讯作者：
Goldin, Lynn R.
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DOI：
10.1016/s1470-2045(14)70281-5
发表时间：
2014-08
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Hills RK;Castaigne S;Appelbaum FR;Delaunay J;Petersdorf S;Othus M;Estey EH;Dombret H;Chevret S;Ifrah N;Cahn JY;Récher C;Chilton L;Moorman AV;Burnett AK
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Burnett AK
影响因子：
32.4
作者：
Sade-Feldman, Moshe;Kanterman, Julia;Baniyash, Michal
通讯作者：
Baniyash, Michal
影响因子：
64.8
作者：
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影响因子：
2.1
作者：
Raaijmakers, Marc H. G. P.
通讯作者：
Raaijmakers, Marc H. G. P.