Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1.
Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1.
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DOI：
10.1038/nbt.3349
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发表时间：
2015-10
影响因子：
46.9
通讯作者：
Scheinberg DA
中科院分区：
文献类型：
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作者：
Dao T;Pankov D;Scott A;Korontsvit T;Zakhaleva V;Xu Y;Xiang J;Yan S;de Morais Guerreiro MD;Veomett N;Dubrovsky L;Curcio M;Doubrovina E;Ponomarev V;Liu C;O'Reilly RJ;Scheinberg DA
在人白细胞抗原（HLA）分子的背景下，细胞表面上呈递的细胞内肿瘤抗原已经被基于T细胞的疗法靶向，但是在开发针对这些抗原的小分子药物或抗体方面几乎没有进展。在这里，我们描述了一种衍生自T细胞受体（TCR）模拟单克隆抗体（mAb）ESK 1的双特异性T细胞增殖剂（BiTE）抗体，其结合衍生自HLA-A*02：01上呈递的细胞内癌蛋白WT 1的肽。尽管在细胞表面的复合物的密度非常低，ESK 1-BiTE选择性地激活和诱导细胞溶解性人T细胞的增殖，在体外和小鼠中杀死来自多种白血病和实体瘤的细胞。我们还发现，在自体体外环境中，ESK 1-BiTE诱导了对WT 1以外的肿瘤相关抗原具有特异性的稳健的次级CD 8 T细胞应答。我们的研究提供了一种靶向肿瘤特异性细胞内抗原而不使用细胞治疗的方法，并表明表位扩散可能有助于这种BiTE的治疗效果。
Intracellular tumor antigens presented on the cell surface in the context of human leukocyte antigen (HLA) molecules have been targeted by T cell–based therapies, but there has been little progress in developing small-molecule drugs or antibodies directed to these antigens. Here we describe a bispecific T-cell engager (BiTE) antibody derived from a T-cell receptor (TCR)-mimic monoclonal antibody (mAb) ESK1, which binds a peptide derived from the intracellular oncoprotein WT1 presented on HLA-A*02:01. Despite the very low density of the complexes at the cell surface, ESK1-BiTE selectively activated and induced proliferation of cytolytic human T cells that killed cells from multiple leukemias and solid tumors in vitro and in mice. We also discovered that in an autologous in vitro setting, ESK1-BiTE induced a robust secondary CD8 T-cell response specific for tumor-associated antigens other than WT1. Our study provides an approach that targets tumor-specific intracellular antigens without using cell therapy and suggests that epitope spreading could contribute to the therapeutic efficacy of this BiTE.