The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy
The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy
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DOI：
10.1038/nm.4431
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发表时间：
2017-12-01
期刊：
影响因子：
82.9
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
--
作者：
Hosen, Naoki;Matsunaga, Yukiko;Kumanogoh, Atsushi
癌症特异性细胞表面抗原是基于单克隆抗体（mAb）的免疫治疗的理想靶点，但可能先前已在转录组或蛋白质组分析中鉴定。在这里，我们表明整合素的活性构象可以作为多发性骨髓瘤（MM）的特异性治疗靶点。我们筛选了> 10，000个抗MM mAb克隆，并将MMG 49鉴定为MM特异性mAb，其特异性识别整联蛋白β（7）分子的子集。在β（7）链的N-末端区域中的MMG 49表位被预测在静息整合素构象体中不可接近，但在活性构象中暴露。整合素β（7）的高表达和组成性激活赋予MM细胞高MMG 49反应性，而在其他细胞类型（包括正常整合素β（+）（7）淋巴细胞）中几乎检测不到MMG 49结合。用MMG 49衍生的嵌合抗原受体（CAR）转导的T细胞发挥抗MM作用而不损害正常造血细胞。因此，MMG 49 CAR T细胞疗法对于MM是有希望的，并且具有罕见但生理学相关构象的受体蛋白可以作为癌症免疫治疗靶标。
Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin beta(7) molecules. The MMG49 epitope, in the N-terminal region of the beta(7) chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin beta(7) conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin beta(+)(7) lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.