Targeting C-type lectins on dendritic cells using carbohydrate-analogs for the specific delivery of tumor vaccines

使用碳水化合物类似物将 C 型凝集素靶向树突状细胞以特异性递送肿瘤疫苗

• 批准号: 213952189
• 负责人: Professor Dr. Christoph Rademacher
• 金额: --
• 依托单位: Research group Clinical Pharmacy and Diagnostics
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/213952189?language=en
• 关键词: Targeting; type; lectins; dendritic; cells

The tumor microenvironment is immune suppressive and as a consequence immune cells become tolerant over tumor cells. In order to develop anti-cancer vaccines that activate the immune system against the tumor, it is essential to overcome this tolerance. Dendritic cells are the most important antigen presenting cells in the body and orchestrate the interplay between various immune cells. Therefore, dendritic cells are attractive targets for the activation of the immune response against cancer. Certain C-type lectins are uniquely expressed on the cell surface of dendritic cells. Thus in principle, these receptors are ideal targets for delivery of immunomodulatory agents to dendritic cells. Natural carbohydrate ligands of these lectin receptors resemble well-suited precursors to develop analogs for specific targeting. Biophysical techniques will be combined with computer-aided design of specific ligands that are then chemically synthesized. Finally, these ligands are coupled to liposomes, which are long-lived stealth vehicles that are able to carry tumor antigens as cargo to dendritic cells. The success of this design process is evaluated in three stages. First, the liposomal vehicles will be tested for binding to mammalian model cells expressing specific C-type lectins. Then, isolated immune cells will serve to analyze the efficient delivery of tumor antigens in vitro. Finally, the targeted liposomes are applied in vivo to ensure effective delivery and activation in a murine cancer model.

肿瘤微环境是免疫抑制的，因此免疫细胞对肿瘤细胞具有耐受性。为了开发能够激活免疫系统对抗肿瘤的抗癌疫苗，克服这种耐受性是必不可少的。树突状细胞是体内最重要的抗原提呈细胞，协调各种免疫细胞之间的相互作用。因此，树突状细胞是激活抗癌免疫反应的有吸引力的靶点。某些C型凝集素在树突状细胞的细胞表面有独特的表达。因此，原则上，这些受体是向树突状细胞输送免疫调节剂的理想靶点。这些凝集素受体的天然碳水化合物配体类似于非常适合的前体，以开发用于特定靶向的类似物。生物物理技术将与特定配体的计算机辅助设计相结合，然后通过化学合成。最后，这些配体被连接到脂质体上，脂质体是一种长寿的隐形载体，能够将肿瘤抗原作为货物运送到树突状细胞。这一设计过程的成功分三个阶段进行评估。首先，将测试脂质体与表达特定C型凝集素的哺乳动物模型细胞的结合。然后，分离的免疫细胞将用于分析肿瘤抗原在体外的有效传递。最后，靶向脂质体在体内应用，以确保在小鼠癌症模型中有效的传递和激活。

项目成果

Microbe-focused glycan array screening platform

• DOI: 10.1073/pnas.1800853116
• 发表时间: 2019-02-05
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Geissner, Andreas;Reinhardt, Anika;Seeberger, Peter H.
• 通讯作者: Seeberger, Peter H.

A Liposomal Platform for Delivery of a Protein Antigen to Langerin-Expressing Cells

• DOI: 10.1021/acs.biochem.9b00402
• 发表时间: 2019-05-28
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Schulze, Jessica;Rentzsch, Mareike;Rademacher, Christoph
• 通讯作者: Rademacher, Christoph

Carbohydrates as Drugs

碳水化合物作为药物

• DOI: 10.1007/978-3-319-08675-0
• 发表时间: 2014
• 期刊: Carbohydrates as Drugs
• 作者: Seeberger PH;Rademacher C (Eds.)
• 通讯作者: Rademacher C (Eds.)

(19)F NMR-Guided Design of Glycomimetic Langerin Ligands.

(19)F NMR 指导的糖模拟 Langerin 配体的设计

• DOI: 10.1021/acschembio.6b00561
• 发表时间: 2016
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Wamhoff EC;Hanske J;Schnirch L;Aretz J;Grube M;Varon Silva D;Rademacher C
• 通讯作者: Rademacher C

CellFy: A Cell-Based Fragment Screen against C-Type Lectins.

• DOI: 10.1021/acschembio.8b00875
• 发表时间: 2018-11
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: J. Schulze;H. Baukmann;Robert Wawrzinek;Felix F. Fuchsberger;E. Specker;Jonas Aretz;M. Nazaré;C. Rademacher