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Synthesis, conformational analysis and in vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
Chemical Science ( IF 7.6 ) Pub Date : 2020-03-27 , DOI: 10.1039/c9sc06334j Iris A. Bermejo 1, 2, 3, 4, 5 , Claudio D. Navo 1, 2, 3, 4, 5 , Jorge Castro-López 5, 6, 7, 8 , Ana Guerreiro 9, 10, 11, 12, 13 , Ester Jiménez-Moreno 1, 2, 3, 4, 5 , Elena M. Sánchez Fernández 5, 14, 15, 16, 17 , Fayna García-Martín 18, 19, 20, 21, 22 , Hiroshi Hinou 18, 19, 20, 21, 22 , Shin-Ichiro Nishimura 18, 19, 20, 21, 22 , José M. García Fernández 5, 23, 24, 25 , Carmen Ortiz Mellet 5, 14, 15, 16, 17 , Alberto Avenoza 1, 2, 3, 4, 5 , Jesús H. Busto 1, 2, 3, 4, 5 , Gonçalo J. L. Bernardes 9, 10, 11, 12, 13 , Ramón Hurtado-Guerrero 5, 6, 7, 8, 26 , Jesús M. Peregrina 1, 2, 3, 4, 5 , Francisco Corzana 1, 2, 3, 4, 5
Chemical Science ( IF 7.6 ) Pub Date : 2020-03-27 , DOI: 10.1039/c9sc06334j Iris A. Bermejo 1, 2, 3, 4, 5 , Claudio D. Navo 1, 2, 3, 4, 5 , Jorge Castro-López 5, 6, 7, 8 , Ana Guerreiro 9, 10, 11, 12, 13 , Ester Jiménez-Moreno 1, 2, 3, 4, 5 , Elena M. Sánchez Fernández 5, 14, 15, 16, 17 , Fayna García-Martín 18, 19, 20, 21, 22 , Hiroshi Hinou 18, 19, 20, 21, 22 , Shin-Ichiro Nishimura 18, 19, 20, 21, 22 , José M. García Fernández 5, 23, 24, 25 , Carmen Ortiz Mellet 5, 14, 15, 16, 17 , Alberto Avenoza 1, 2, 3, 4, 5 , Jesús H. Busto 1, 2, 3, 4, 5 , Gonçalo J. L. Bernardes 9, 10, 11, 12, 13 , Ramón Hurtado-Guerrero 5, 6, 7, 8, 26 , Jesús M. Peregrina 1, 2, 3, 4, 5 , Francisco Corzana 1, 2, 3, 4, 5
Affiliation
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The Tn antigen (GalNAc-α-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp2-iminosugar-type α-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines.
中文翻译：
具有基于sp2-亚氨基糖片段的非天然抗原的抗癌疫苗的合成，构象分析和体内测定
Tn抗原（GalNAc-α-1- O -Thr / Ser）是众所周知的与肿瘤相关的碳水化合物决定簇。由于糖肽作为抗癌疫苗的潜在用途，因此使用具有这种结构的糖肽已成为重要而有希望的研究领域。本文中，具有非天然Tn抗原的糖肽的构象偏好，其特征在于苏氨酸修饰有sp 2-亚氨基糖型α-GalNAc模拟物已在溶液中通过结合NMR光谱学和分子动力学模拟进行了研究，并通过X射线晶体学研究了与抗mucin-1（MUC1）抗体结合的固态。Tn替代物可以模拟溶液中天然抗原取样的主要构象体，并且对抗MUC1抗体表现出高亲和力。受这些数据的鼓励，已经制备了基于这种非天然糖肽并与载体蛋白Keyhole Limpet血蓝蛋白（KLH）偶联的癌症疫苗候选物，并已在小鼠中进行了测试。重要的是，体内实验业已证明，与带有天然Tn抗原的类似物相比，这种疫苗能引起更高水平的抗MUC1 IgG特异性抗体，并且所产生的抗体能够高度选择性地识别人乳腺癌细胞。总之，我们收集了证据以确认抗原的呈递状态（无论是溶液状态还是处于结合状态）在设计的癌症疫苗的功效中都起着至关重要的作用。而且，从这种疫苗得到的结果证明，仍有空间探索碳水化合物水平的进一步调整，这可能有助于设计更有效的癌症疫苗。
更新日期：2020-04-24
中文翻译：
具有基于sp2-亚氨基糖片段的非天然抗原的抗癌疫苗的合成，构象分析和体内测定
Tn抗原（GalNAc-α-1- O -Thr / Ser）是众所周知的与肿瘤相关的碳水化合物决定簇。由于糖肽作为抗癌疫苗的潜在用途，因此使用具有这种结构的糖肽已成为重要而有希望的研究领域。本文中，具有非天然Tn抗原的糖肽的构象偏好，其特征在于苏氨酸修饰有sp 2-亚氨基糖型α-GalNAc模拟物已在溶液中通过结合NMR光谱学和分子动力学模拟进行了研究，并通过X射线晶体学研究了与抗mucin-1（MUC1）抗体结合的固态。Tn替代物可以模拟溶液中天然抗原取样的主要构象体，并且对抗MUC1抗体表现出高亲和力。受这些数据的鼓励，已经制备了基于这种非天然糖肽并与载体蛋白Keyhole Limpet血蓝蛋白（KLH）偶联的癌症疫苗候选物，并已在小鼠中进行了测试。重要的是，体内实验业已证明，与带有天然Tn抗原的类似物相比，这种疫苗能引起更高水平的抗MUC1 IgG特异性抗体，并且所产生的抗体能够高度选择性地识别人乳腺癌细胞。总之，我们收集了证据以确认抗原的呈递状态（无论是溶液状态还是处于结合状态）在设计的癌症疫苗的功效中都起着至关重要的作用。而且，从这种疫苗得到的结果证明，仍有空间探索碳水化合物水平的进一步调整，这可能有助于设计更有效的癌症疫苗。
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