Gene Delivery Systems of Carbohydrate Mimotopes to Dendritic Cells

碳水化合物模拟表位至树突细胞的基因递送系统

• 批准号: 7574401
• 负责人: Danuta B Kozbor
• 金额: $ 23.06万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574401
• 关键词: Address; Adoptive Cell Transfers; Affinity; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Autoantigens; Carbohydrates; Cells; Chimeric Proteins; Clinical Trials; Complex; Dendritic Cell Vaccine; Dendritic Cells; Effectiveness; Epitopes; Fc Receptor; Future; Ganglioside GD2; Glioma; Glycols; IgG Receptors; IgG1; IgG3; Immune response; Immunity; Immunization; Immunoglobulin G; Immunoglobulin M; Immunotherapy; Lesion; Liposomes; Modified Vaccinia Virus Ankara; Monoclonal Antibodies; Monoclonal Antibody 14G2A; Mus; Neuroblastoma; Patients; Peptides; Physiologic pulse; Proliferating; Recombinant Fusion Proteins; Recombinants; Reporting; T-Lymphocyte; Therapeutic antibodies; Therapy Clinical Trials; Toxic effect; Treatment Protocols; Tumor Antigens; Tumor-Derived; Vaccination; Vaccines; Viral Vector; base; cancer therapy; design; gene delivery system; immunogenic; immunogenicity; in vivo; melanoma; neoplastic cell; next generation; novel strategies; public health relevance; response; sarcoma; trafficking; tumor; tumor immunology

DESCRIPTION (provided by applicant): The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly IgM antibody responses in the immunized host. To overcome the intrinsically weak immunogenicity of carbohydrate antigens and tolerance to self/tumor-associated antigens in a tumor-bearing host, we have generated a mimotope of GD2 ganglioside, designated 47-LDA. Our rational for this immunization strategy is that since the 47-LDA mimotope is structurally similar but not identical to GD2 ganglioside, it may stimulate T cell clones that recognize GD2 but have not been deleted during the establishment of self-identity because of their lower affinity for the antigen. We are proposing to express the 47-LDA mimotope together with universal T helper (Th) epitopes in the context of Fc region of IgG antibodies for targeting the antigenic cassettes to activating Fc gamma receptors (Fc?Rs) on antigen presenting cells. For immunization, the 47-LDA-Fc fusion proteins will be delivered by dendritic cell (DC) vaccination or by our newly developed recombinant modified vaccinia Ankara (rMVA) viral vector/liposomal complex. We hypothesize that targeting the 47-LDA-Fc fusion proteins to activating Fc?Rs on DCs will enhance the magnitude of protective immunity against GD2+ tumors. The Specific Aims are: i) We will generate 47-LDA-Fc fusion proteins with murine IgG1, IgG2a, and IgG3 Fc regions to evaluate their abilities to elicit antitumor immune responses in mice and select the most efficacious construct; ii) We will express the most efficacious 47-LDA Fc-fusion protein by rMVA virus covalently attached to tresylmonomethoxypolyethylene glycol (TMPEG)-modified cationic liposomes (rMVA47-LDAFc/ TMPEG/liposomes) for systemic and mucosal immunizations; and iii) We will compare antitumor efficacy of 47-LDA-Fc fusion protein-pulsed DC vaccine with that of rMVA47-LDA-Fc/TMPEG/liposomes using a combination of adoptive cell transfer (ACT) therapy and vaccination in GD2+ tumor-bearing mice. As the next generation of ACT-based immunotherapies might rely on the ability to endow 'fit' tumor-specific cells that are capable of proliferating and trafficking to tumor lesions, the use of potent vaccines to enhance adoptively transferred T cells may represent a promising new approach for cancer treatment. Public Health Relevance: The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly IgM antibody responses in the immunized host. To overcome the intrinsically weak immunogenicity of carbohydrate antigens and tolerance to self/tumor-associated antigens in a tumor-bearing host, we have generated a mimotope of GD2 ganglioside, designated 47-LDA. We are proposing to express the 47-LDA mimotope together with universal T helper epitopes in the context of Fc region of IgG antibodies for targeting the antigenic cassettes to activating Fc gamma receptors on antigen presenting cells.

描述（由申请人提供）：在神经外胚层来源的肿瘤（包括神经母细胞瘤和黑色素瘤）上表达的GD2神经节苷脂在荷瘤患者中具有弱免疫原性，并且在免疫宿主中主要诱导IgM抗体应答。为了克服碳水化合物抗原本质上较弱的免疫原性和荷瘤宿主对自身/肿瘤相关抗原的耐受性，我们生成了 GD2 神经节苷脂的模拟表位，命名为 47-LDA。我们对这种免疫策略的合理性是，由于 47-LDA 模拟表位与 GD2 神经节苷脂在结构上相似但不相同，因此它可能会刺激识别 GD2 的 T 细胞克隆，但由于其亲和力较低，因此在建立自我同一性期间未被删除。为抗原。我们建议在 IgG 抗体 Fc 区的背景下表达 47-LDA 模拟表位和通用 T 辅助表位 (Th)，用于靶向抗原盒以激活抗原呈递细胞上的 Fc γ 受体 (Fc?R)。对于免疫接种，47-LDA-Fc 融合蛋白将通过树突状细胞 (DC) 疫苗接种或通过我们新开发的重组修饰安卡拉痘苗 (rMVA) 病毒载体/脂质体复合物来递送。我们假设靶向 47-LDA-Fc 融合蛋白来激活 DC 上的 Fc?R 将增强针对 GD2+ 肿瘤的保护性免疫的程度。具体目标是： i) 我们将生成具有鼠 IgG1、IgG2a 和 IgG3 Fc 区的 47-LDA-Fc 融合蛋白，以评估它们在小鼠中引发抗肿瘤免疫反应的能力，并选择最有效的构建体； ii) 我们将通过与三磺基单甲氧基聚乙二醇（TMPEG）修饰的阳离子脂质体（rMVA47-LDAFc/TMPEG/脂质体）共价连接的rMVA病毒表达最有效的47-LDA Fc融合蛋白，用于全身和粘膜免疫； iii) 我们将使用过继细胞移植（ACT）疗法和疫苗接种相结合，比较 47-LDA-Fc 融合蛋白脉冲 DC 疫苗与 rMVA47-LDA-Fc/TMPEG/脂质体的抗肿瘤功效，使用过继细胞移植（ACT）疗法和疫苗接种在 GD2+ 荷瘤中老鼠。 由于下一代基于 ACT 的免疫疗法可能依赖于赋予“适合”肿瘤特异性细胞的能力，这些细胞能够增殖并运输到肿瘤病灶，因此使用强效疫苗来增强过继转移的 T 细胞可能代表一种有前途的新疗法。癌症治疗的方法。 公共健康相关性：在神经外胚层来源的肿瘤（包括神经母细胞瘤和黑色素瘤）上表达的 GD2 神经节苷脂在荷瘤患者中具有弱免疫原性，并在免疫宿主中主要诱导 IgM 抗体反应。为了克服碳水化合物抗原本质上较弱的免疫原性和荷瘤宿主对自身/肿瘤相关抗原的耐受性，我们生成了 GD2 神经节苷脂的模拟表位，命名为 47-LDA。我们建议在 IgG 抗体 Fc 区的背景下表达 47-LDA 模拟表位以及通用 T 辅助表位，以靶向抗原盒以激活抗原呈递细胞上的 Fc γ 受体。

项目成果

Targeting a mimotope vaccine to activating Fcgamma receptors empowers dendritic cells to prime specific CD8+ T cell responses in tumor-bearing mice.

• DOI: 10.4049/jimmunol.0900364
• 发表时间: 2009-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Gil M;Bieniasz M;Wierzbicki A;Bambach BJ;Rokita H;Kozbor D
• 通讯作者: Kozbor D

Immunization with a mimotope of GD2 ganglioside induces CD8+ T cells that recognize cell adhesion molecules on tumor cells.

• DOI: 10.4049/jimmunol.181.9.6644
• 发表时间: 2008-11-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Wierzbicki A;Gil M;Ciesielski M;Fenstermaker RA;Kaneko Y;Rokita H;Lau JT;Kozbor D
• 通讯作者: Kozbor D