Laboratory of Precision Medicine and Biopharmaceutics & Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Int J Mol Sci. 2019 Aug 12;20(16):3912. doi: 10.3390/ijms20163912.
Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.
Wilms 肿瘤 1 基因（WT1）癌蛋白是一种细胞内致癌转录因子，在正常成人组织中几乎不表达，但在各种白血病和实体瘤中过度表达。WT1 衍生的 HLA-A02:01 T 细胞表位 RMFPNAPYL（RMF）是一种经过验证的基于 T 细胞免疫治疗的靶点。我们针对 WT1 RMF/HLA-A02:01 复合物生成了两种亲和力不同的 T 细胞受体模拟抗体药物偶联物（TCRm-ADC），ESK-MMAE 和 Q2L-MMAE，介导特异性抗肿瘤活性。虽然 ESK-MMAE 在体内显示出更高的肿瘤生长抑制率，但它们的疗效并不那么理想，这可能是由于肽/HLA 靶标的低表达。因此，我们探索了一种双特异性 TCRm-ADC，与 TCRm-ADC 相比，它能发挥更强的肿瘤细胞毒性。因此，我们的研究结果验证了将细胞内肽作为 ADC 靶点的可行性，这拓宽了抗体药物的抗原选择范围，并为肿瘤治疗的精准医学提供了新策略。
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