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Elimination of melanoma by sortase A-generated TCR-like antibody-drug conjugates (TL-ADCs) targeting intracellular melanoma antigen MART-1
Biomaterials ( IF 12.8 ) Pub Date : 2018-06-15 , DOI: 10.1016/j.biomaterials.2018.06.017
Jun Lai , Yun Wang , Shan-Shan Wu , Ding Ding , Ze-Yu Sun , Ying Zhang , Jie Zhou , Zhan Zhou , Ying-Chun Xu , Li-Qiang Pan , Shu-Qing Chen

Most tumor-associated proteins are located inside tumor cells and thus are not accessible to current marketed therapeutic monoclonal antibodies or their cytotoxic conjugates. Human leukocyte antigen (HLA) class I can present peptides derived from intracellular tumor-associated proteins and somatically mutated proteins on the cell's surface, forming an HLA/peptide complex as tumor-specific antigens for T cell receptor (TCR) recognition. Therefore, HLA-mediated presentation of intracellular tumor antigen peptides provides a viable way to distinguish tumor cells from normal cells, which is important for broadening antigen selection, especially for antibody-drug conjugates (ADCs) regarding their highly cytotoxic payload. We applied sortase A-mediated conjugation to develop TCR-like ADCs (i.e., EA1 HL-vcMMAE) targeting intracellular MART-1 protein, a melanocyte-differentiating antigen specific for metastatic melanomas, via the cell surface HLA-A2/MART-126-35 peptide complex. Homogenous EA1 HL-vcMMAE (drug to antibody ratio of 4) efficiently eliminated melanoma cells in xenograft mouse models with no obvious toxicity at the therapeutic dosage. Trametinib, an MEK inhibitor serving as an HLA expression enhancing agent, augmented the TL-ADCs’ efficacy both in vitro and in vivo by upregulating MART-126-35 peptide presentation, thus providing a strategy for overcoming the limitation of antigen presentation level for TL-ADCs. Hence, our findings validate the strategy of using sortase A-generated TL-ADCs to target tumor-specific intracellular proteins, with or without agents present, to increase presenting TCR epitope peptides.



中文翻译:

通过分选酶A生成的靶向细胞内黑色素瘤抗原MART-1的TCR样抗体-药物偶联物(TL-ADC)消除黑色素瘤

大多数与肿瘤相关的蛋白质位于肿瘤细胞内部,因此当前市售的治疗性单克隆抗体或其细胞毒性偶联物无法获得。I类人类白细胞抗原(HLA)可以在细胞表面呈递源自细胞内肿瘤相关蛋白和体细胞突变蛋白的肽,形成HLA /肽复合物,作为T细胞受体(TCR)识别的肿瘤特异性抗原。因此,HLA介导的细胞内肿瘤抗原肽的呈递提供了一种区分肿瘤细胞与正常细胞的可行方法,这对于拓宽抗原选择非常重要,尤其是对于抗体-药物缀合物(ADC)而言,具有很高的细胞毒性有效载荷。我们应用分选酶A介导的结合来开发针对细胞内MART-1蛋白的TCR样ADC(即EA1 HL-vcMMAE),26-35肽复合物。在异种移植小鼠模型中,同质的EA1 HL-vcMMAE(药物与抗体之比为4)可有效消除黑色素瘤细胞,在治疗剂量下无明显毒性。曲美替尼(一种用作HLA表达增强剂的MEK抑制剂)通过上调MART-1 26-35肽的呈递,从而在体外和体内增强TL-ADC的功效,从而为克服抗原呈递水平的局限提供了一种策略。 TL-ADC。因此,我们的发现验证了使用分选酶A生成的TL-ADCs靶向肿瘤特异性细胞内蛋白质(有或无药剂存在)以增加呈递的TCR表位肽的策略。

更新日期:2018-06-15
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