Generation and evaluation of cancer binding capacity of HLA-A2-WT1 complex-targeting antibody

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
Xue Yao , Sandro Matosevic
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引用次数: 0

Abstract

Wilms’ tumor (WT1), a transcription factor highly expressed in various leukemias and solid tumors, is a highly specific intracellular tumor antigen, requiring presentation through complexation with HLA-restricted peptides.. WT1-derived epitopes are able to assemble with MHC-I and thereby be recognized by T cell receptors (TCR). Identification of new targetable epitopes derived from WT1 on solid tumors is a challenge, but meaningful for the development of therapeutics that could in this way target intracellular oncogenic proteins. In this study, we developed and comprehensively describe methods to validate the formation of the complex of WT1126–134 and HLA-A2. Subsequently, we developed an antibody fragment able to recognize the extracellular complex on the surface of cancer cells. The single chain variable fragment (scFv) of an established TCR-mimic antibody, specifically recognizing the WT1-derived peptide presented by the HLA-A2 complex, was expressed, purified, and functionally validated using a T2 cell antigen presentation model. Furthermore, we evaluated the potential of the WT1-derived peptide as a targetable extracellular antigen in multiple solid tumor cell lines. Our study describes methodology for the evaluation of WT1-derived peptides as tumor-specific antigen on solid tumors, and may facilitate the selection of potential candidates for future immunotherapy targeting WT1 epitopes.

生成和评估 HLA-A2-WT1 复合物靶向抗体的癌症结合能力。
Wilms'torum(WT1)是一种在各种白血病和实体瘤中高度表达的转录因子,是一种高度特异性的细胞内肿瘤抗原,需要通过与 HLA 限制性肽复合来呈现。WT1 衍生的表位能够与 MHC-I 结合,从而被 T 细胞受体 (TCR) 识别。鉴定实体瘤上 WT1 衍生的新靶向表位是一项挑战,但对于开发可通过这种方式靶向细胞内致癌蛋白的疗法来说意义重大。在这项研究中,我们开发并全面描述了验证 WT1126-134 和 HLA-A2 复合物形成的方法。随后,我们开发了一种能够识别癌细胞表面胞外复合物的抗体片段。我们表达、纯化并使用 T2 细胞抗原呈递模型验证了已建立的 TCR 模拟抗体的单链可变片段(scFv),它能特异性识别由 HLA-A2 复合物呈现的 WT1 衍生肽。此外,我们还评估了 WT1 衍生多肽在多种实体瘤细胞系中作为可靶向细胞外抗原的潜力。我们的研究描述了评估 WT1 衍生多肽作为实体瘤肿瘤特异性抗原的方法,并可能有助于为未来靶向 WT1 表位的免疫疗法选择潜在候选者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.20
自引率
4.30%
发文量
567
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