抗体依赖性细胞介导的细胞毒性
癌症研究
诱导多能干细胞
生物
白细胞介素12
干细胞
单克隆抗体
细胞毒性T细胞
抗体
化学
体外
细胞生物学
免疫学
生物化学
胚胎干细胞
基因
作者
Zhu Huang,Robert Blum,Ryan Bjordahl,Svetlana Gaidarova,Paul Rogers,Tom Tong Lee,Ramzey Abujarour,G. Bonello,Jianming Wu,Ping-Huei Tsai,Jeffrey S. Miller,Bruce Walcheck,Bahram Valamehr,Dan S. Kaufman
出处
期刊:Blood
[American Society of Hematology]
日期:2020-02-06
卷期号:135 (6): 399-410
被引量:156
标识
DOI:10.1182/blood.2019000621
摘要
Antibody-dependent cellular cytotoxicity (ADCC) is a key effector mechanism of natural killer (NK) cells that is mediated by therapeutic monoclonal antibodies (mAbs). This process is facilitated by the Fc receptor CD16a on human NK cells. CD16a appears to be the only activating receptor on NK cells that is cleaved by the metalloprotease a disintegrin and metalloproteinase-17 upon stimulation. We previously demonstrated that a point mutation of CD16a prevents this activation-induced surface cleavage. This noncleavable CD16a variant is now further modified to include the high-affinity noncleavable variant of CD16a (hnCD16) and was engineered into human induced pluripotent stem cells (iPSCs) to create a renewable source for human induced pluripotent stem cell-derived NK (hnCD16-iNK) cells. Compared with unmodified iNK cells and peripheral blood-derived NK (PB-NK) cells, hnCD16-iNK cells proved to be highly resistant to activation-induced cleavage of CD16a. We found that hnCD16-iNK cells were functionally mature and exhibited enhanced ADCC against multiple tumor targets. In vivo xenograft studies using a human B-cell lymphoma demonstrated that treatment with hnCD16-iNK cells and anti-CD20 mAb led to significantly improved regression of B-cell lymphoma compared with treatment utilizing anti-CD20 mAb with PB-NK cells or unmodified iNK cells. hnCD16-iNK cells, combined with anti-HER2 mAb, also mediated improved survival in an ovarian cancer xenograft model. Together, these findings show that hnCD16-iNK cells combined with mAbs are highly effective against hematologic malignancies and solid tumors that are typically resistant to NK cell-mediated killing, demonstrating the feasibility of producing a standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies that are otherwise refractory.
科研通智能强力驱动
Strongly Powered by AbleSci AI