Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice.
Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice.
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防护性表位发现和基于MUC1的疫苗在免疫耐药小鼠中有效肿瘤保护。
DOI：
10.1021/jacs.8b08473
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发表时间：
2018-12-05
影响因子：
15
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Wu X;Yin Z;McKay C;Pett C;Yu J;Schorlemer M;Gohl T;Sungsuwan S;Ramadan S;Baniel C;Allmon A;Das R;Westerlind U;Finn MG;Huang X
人类粘蛋白-1 (MUC1) 是抗癌疫苗开发中极具吸引力的抗原。然而，在多种基于MUC1的疫苗的人类临床试验中，尽管产生了抗MUC1抗体，但这些抗体通常未能表现出与肿瘤的大量结合，这可能是由于在免疫耐受环境中诱导保护性免疫应答的挑战。为了设计在免疫耐受宿主中有效的基于 MUC1 的疫苗，首先通过将强大的噬菌体 Qβ 载体与含有 20-22 个氨基酸残基的 MUC1 糖肽共价连接来合成疫苗构建体，覆盖 MUC1 串联重复区域的一个全长。然而，这些第一代构建体在耐受性人类 MUC1 转基因 (Tg) 小鼠中引发的 IgG 抗体并未与肿瘤细胞强烈结合。为了克服这个问题，合成了肽阵列。通过分析抗体的结合选择性，发现长 MUC1 糖肽含有免疫显性但非保护性表位。对关键保护性表位的身份获得了重要的见解。针对保护性表位的疫苗重新设计产生了新的 Qβ-MUC1 构建体，与含有金标准蛋白载体（即匙孔血蓝蛋白）的构建体相比，该构建体能够在 MUC1.Tg 小鼠中诱导更高水平的抗 MUC1 IgG 抗体，与多种肿瘤细胞发生强烈反应并杀死多种肿瘤细胞。使用这种新的 Qβ-MUC1 缀合物进行疫苗接种可以在转移性肿瘤和实体瘤模型中对 MUC1.Tg 小鼠产生显着的保护。这些抗体对人类乳腺癌组织表现出显着的选择性，表明其具有很高的转化潜力。
Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUCl antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qβ carrier with MUC1 glycopeptides containing 20–22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qβ-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qβ-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential.
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作者：
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