PDF(Pubmed)
Abstract：
While conventional chimeric antigen-receptor (CAR)-T therapies have shown remarkable clinical activity in some settings, they can induce severe toxicities and are rarely curative. To address these challenges, we developed a controllable cell therapy where synthetic D-domain-containing proteins (soluble protein antigen-receptor X-linker [SparX]) bind one or more tumor antigens and mark those cells for elimination by genetically modified T cells (antigen-receptor complex [ARC]-T). The chimeric antigen receptor was engineered with a D-domain that specifically binds to the SparX protein via a unique TAG, derived from human alpha-fetoprotein. The interaction is mediated through an epitope on the TAG that is occluded in the native alpha-fetoprotein molecule. In vitro and in vivo data demonstrate that the activation and cytolytic activity of ARC-T cells is dependent on the dose of SparX protein and only occurs when ARC-T cells are engaged with SparX proteins bound to antigen-positive cells. ARC-T cell specificity was also redirected in vivo by changing SparX proteins that recognized different tumor antigens to combat inherent or acquired tumor heterogeneity. The ARC-SparX platform is designed to expand patient and physician access to cell therapy by controlling potential toxicities through SparX dosing regimens and enhancing tumor elimination through sequential or simultaneous administration of SparX proteins engineered to bind different tumor antigens.
摘要：
虽然传统的CAR-T疗法在某些情况下显示出显著的临床活性，它们可以引起严重的毒性，很少治愈。为了应对这些挑战，我们开发了一种可控的细胞疗法,其中合成的含D结构域的蛋白(SparX)结合一种或多种肿瘤抗原,并标记这些细胞被基因修饰的T细胞(ARC-T)消除.嵌合抗原受体通过独特的TAG与SparX蛋白特异性结合的D结构域进行工程改造，来源于人类甲胎蛋白.相互作用是通过TAG上的表位介导的,该表位被封闭在天然甲胎蛋白分子中。体外和体内数据表明，ARC-T细胞的活化和溶细胞活性取决于SparX蛋白的剂量，并且仅在ARC-T细胞与SparX蛋白结合时发生。通过改变识别不同肿瘤抗原的SparX蛋白以对抗固有或获得性肿瘤异质性,ARC-T细胞特异性也在体内被重新定向。ARC-SparX平台旨在通过SparX给药方案控制潜在的毒性，并通过连续或同时施用设计为结合不同肿瘤抗原的SparX蛋白来增强肿瘤消除，从而扩大患者和医师对细胞治疗的访问。
