Depleting T regulatory cells by targeting intracellular Foxp3 with a TCR mimic antibody
Depleting T regulatory cells by targeting intracellular Foxp3 with a TCR mimic antibody
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DOI：
10.1080/2162402x.2019.1570778
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发表时间：
2019-04-17
期刊：
影响因子：
7.2
通讯作者：
Scheinberg, David A.
中科院分区：
文献类型：
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作者：
Dao, Tao;Mun, Sung Soo;Scheinberg, David A.
肿瘤微环境中T调节细胞（Tregs）的耗竭是一种很有前途的癌症免疫治疗策略。目前消耗Tregs的方法受到缺乏特异性和同时消耗抗肿瘤效应T细胞的限制。转录因子叉头盒p3 （Foxp3）在Tregs的发育和功能中起着核心作用，是Tregs的理想靶点，但Foxp3迄今为止是一种细胞内的不可药物蛋白。我们已经产生了一种T细胞受体模拟抗体，“Foxp3-#32”，识别HLA-A*02:01背景下Foxp3衍生的表位。mAb Foxp3-#32选择性识别CD4 + CD25 + CD127（低）和Foxp3 + Tregs也表达HLA-A*02:01，并通过抗体介导的细胞毒性消耗这些细胞。Foxp3-#32 mAb在健康供体PBMCs和癌症患者腹水异种移植物中去除Tregs。靶向细胞内Foxp3表位的TCRm mAb代表了一种消耗Tregs的方法。
Depletion of T regulatory cells (Tregs) in the tumor microenvironment is a promising cancer immunotherapy strategy. Current approaches for depleting Tregs are limited by lack of specificity and concurrent depletion of anti-tumor effector T cells. The transcription factor forkhead box p3 (Foxp3) plays a central role in the development and function of Tregs and is an ideal target in Tregs, but Foxp3 is an intracellular, undruggable protein to date. We have generated a T cell receptor mimic antibody, "Foxp3-#32," recognizing a Foxp3-derived epitope in the context of HLA-A*02:01. The mAb Foxp3-#32 selectively recognizes CD4 + CD25 + CD127(low) and Foxp3 + Tregs also expressing HLA-A*02:01 and depletes these cells via antibody-mediated cellular cytotoxicity. Foxp3-#32 mAb depleted Tregs in xenografts of PBMCs from a healthy donor and ascites fluid from a cancer patient. A TCRm mAb targeting intracellular Foxp3 epitope represents an approach to deplete Tregs.