DNA vaccine expressing the mimotope of GD2 ganglioside induces protective GD2 cross-reactive antibody responses
DNA vaccine expressing the mimotope of GD2 ganglioside induces protective GD2 cross-reactive antibody responses
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DOI：
10.1158/0008-5472.can-04-2164
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Kozbor, D
中科院分区：
文献类型：
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作者：
Bolesta, E;Kowalczyk, A;Kozbor, D
GD2神经节苷脂在神经外胚层衍生的肿瘤（包括神经母细胞瘤和黑色素瘤）上表达，在荷瘤患者中具有弱免疫原性，并在免疫宿主中主要诱导免疫球蛋白（Ig）-M抗体反应。在这里，我们研究了 GD2 相互转化为肽模拟形式是否会在小鼠中诱导 GD2 交叉反应 IgG 抗体反应。使用抗 GD2 单克隆抗体 (mAb) 14G2a 筛选 X-15 噬菌体展示肽库，分离出模拟肽 47，其抑制 14G2a 抗体与 GD2 阳性肿瘤细胞的结合。该肽也被神经母细胞瘤患者的 GD2 特异性血清抗体识别，表明它具有肿瘤细胞上表达的 GD2 神经节苷脂的内部图像。通过分子建模和诱变研究建立的 GD2 模拟肽抗原性的分子基础，导致产生了对 GD2 的模拟性增强的 47-LDA 突变体。用肽 47-LDA 编码的质粒 DNA 对小鼠进行免疫接种，引发 GD2 交叉反应 IgG 抗体反应，该反应在随后使用 GD2 神经节苷脂加强免疫后增强。疫苗诱导的抗体识别 GD2 阳性肿瘤细胞，介导补体依赖性细胞毒性，并表现出针对皮下注射的保护作用。严重联合免疫缺陷小鼠异种移植模型中人 GD2 阳性黑色素瘤的生长。我们的研究结果为通过使用 GD2 神经节苷脂保护性表位进行小基因疫苗接种来增强 GD2 交叉反应 IgG 抗体反应的方法提供了见解。
The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly immunoglobulin (Ig)-M antibody responses in the immunized host. Here, we investigated whether interconversion of GD2 into a peptide mimetic form would induce GD2 cross-reactive IgG antibody responses in mice. Screening of the X-15 phage display peptide library with the anti-GD2 monoclonal antibody (mAb) 14G2a led to isolation of mimetic peptide 47, which inhibited the binding of 14G2a antibody to GD2-positive tumor cells. The peptide was also recognized by GD2-specific serum antibodies from a patient with neuroblastoma, suggesting that it bears an internal image of GD2 ganglioside expressed on the tumor cells. The molecular basis for antigenicity of the GD2 mimetic peptide, established by molecular modeling and mutagenesis studies, led to the generation of a 47-LDA mutant with an increased mimicry to GD2. Immunization of mice with peptide 47-LDA-encoded plasmid DNA elicited GD2 cross-reactive IgG antibody responses, which were increased on subsequent boost with GD2 ganglioside. The vaccine-induced antibodies recognized GD2-positive tumor cells, mediated complement-dependent cytotoxicity, and exhibited protection against s.c. human GD2-positive melanoma growth in the severe combined immunodeficient mouse xenograft model. The results from our studies provide insights into approaches for boosting GD2 cross-reactive IgG antibody responses by minigene vaccination with a protective epitope of GD2 ganglioside.