Opportunities and challenges for TCR mimic antibodies in cancer therapy.
Opportunities and challenges for TCR mimic antibodies in cancer therapy.
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DOI：
10.1080/14712598.2016.1176138
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发表时间：
2016-08
影响因子：
4.6
通讯作者：
Scheinberg DA
中科院分区：
文献类型：
--
作者：
Chang AY;Gejman RS;Brea EJ;Oh CY;Mathias MD;Pankov D;Casey E;Dao T;Scheinberg DA
单克隆抗体（mAb）是有效的癌症治疗剂，但仅识别细胞表面靶标，而大多数癌症相关蛋白质存在于细胞内。因此，潜在的癌症治疗靶点，如过表达的自身蛋白、激活的癌基因、突变的肿瘤抑制因子和易位的基因产物，是传统mAb治疗无法达到的。一种新兴的靶向这些表位的方法是使用识别与T细胞受体（TCR）的表位相似的表位的TCR模拟mAb（TCRm）。TCRm抗原由来源于降解蛋白质并在细胞表面MHC分子的背景下呈递的线性肽序列组成。我们讨论了TCRm表位的性质如何为传统mAb治疗提供优势（绝对肿瘤特异性和获得新的重要靶点）和劣势（低密度，MHC限制，MHC下调和交叉反应性线性表位）。我们还将讨论这些障碍的潜在解决方案。TCRm联合收割机将TCR识别的特异性与mAb的效力、药理学性质和多功能性相结合。TCRm表位的结构和呈递具有与靶标的选择、mAb设计、可用肽和MHC亚型限制、可能的交叉反应性和治疗活性相关的重要后果。
Monoclonal antibodies (mAbs) are potent cancer therapeutic agents, but exclusively recognize cell-surface targets whereas most cancer-associated proteins are found intracellularly. Hence, potential cancer therapy targets such as overexpressed self-proteins, activated oncogenes, mutated tumor suppressors, and translocated gene products are not accessible to traditional mAb therapy. An emerging approach to target these epitopes is the use of TCR mimic mAbs (TCRm) that recognize epitopes similar to those of T cell receptors (TCR). TCRm antigens are comprised of a linear peptide sequence derived from degraded proteins and presented in the context of cell-surface MHC molecules. We discuss how the nature of the TCRm epitopes provides both advantages (absolute tumor specificity and access to a new universe of important targets) and disadvantages (low density, MHC restriction, MHC down-regulation, and cross-reactive linear epitopes) to conventional mAb therapy. We will also discuss potential solutions to these obstacles. TCRm combine the specificity of TCR recognition with the potency, pharmacologic properties, and versatility of mAbs. The structure and presentation of a TCRm epitope has important consequences related to the choice of targets, mAb design, available peptides and MHC subtype restrictions, possible cross-reactivity, and therapeutic activity.