Synthesis of Glycopeptide-Based Cancer Antigen Vaccines

糖肽癌抗原疫苗的合成

• 批准号: 8878565
• 负责人: KATHERINE A WALL
• 金额: $ 42.08万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878565
• 关键词: Active Immunotherapy; Adjuvant; Affinity Chromatography; Antibodies; Antibody Response; Antigen Presentation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Binding; CD8B1 gene; Cancer Vaccines; Carbohydrates; Cells; Ceramides; Chemicals; Chimera organism; Cross Presentation; Cytolysis; Effectiveness; Engineering; Enhancing Antibodies; Environment; Fc Receptor; Fc domain; Ficoll; Generations; Glycoconjugates; Glycolipids; Glycopeptides; Health; Human; Immune; Immune response; Immunization; Immunology; Individual; Interferons; KRN7000; Ligands; Lipids; Liposomes; Malignant Neoplasms; Mediating; Mucin-1 Staining Method; Mus; Neoplasm Metastasis; Oligosaccharides; Organic Chemistry; Peptides; Production; Property; Recombinants; Research Personnel; Rhamnose; Role; Site; Structure; Synthetic Vaccines; T-Lymphocyte; Testing; Training; Tumor Antibodies; Tumor Immunity; Tumor-Associated Carbohydrate Antigens; Ursidae Family; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Wild Type Mouse; Work; Xenobiotics; base; cancer cell; cancer recurrence; carbohydrate structure; cytokine; improved; interest; killer T cell; mouse model; neoplastic cell; response; tumor; uptake; vaccine candidate; vaccine development; vaccine effectiveness

 DESCRIPTION (provided by applicant): Tumor-associated carbohydrate antigens (TACAs) are saccharides and oligosaccharides which show highly restricted expression on cancer cells. Since TACAs are unique to cancer cells, there is a great interest in generating an active immune response against TACAs as a means of reducing cancer metastasis or recurrence. Two major challenges to using TACAs in active immunotherapy are their poor antigenicity and the inherent difficulty of synthesizing oligosaccharides and related glycoconjugates by chemical means. Past work demonstrated that liposomal vaccines with a TACA- bearing peptide can generate immune responses to TACAs. If the liposome contains a xenobiotic carbohydrate such as rhamnose, natural antibodies against the carbohydrate will greatly enhance the generation of an immune response, presumably through Fc mediated antigen uptake. The first specific aim of this proposal seeks to determine in more detail the mechanism of enhancement by studying purified human anti-rhamnose antibodies and their role in antigen uptake in wild type and Fc humanized mice. The second specific aim will determine if a specific Fc region can serve as a more generally effective targeting ligand than rhamnose for this vaccine. The most effective vaccine formulation will be tested in humanized mice to better predict its efficacy in humans. Stimulation of invariant natural killer T cells by certain ceramides can serve as a vaccine adjuvant. The third specific aim involves synthesis of rhamnose-modified ceramides and determining if they can serve as improved vaccine adjuvants through binding to CD1d in addition to providing a recognition site for natural antibodies. This proposal takes advantage of a collaborative interaction between researchers trained in organic chemistry and immunology so that the structure and antigenicity of all vaccines will be well characterized in wild type mice an in mice bearing humanized immune cells.

 描述（由申请人提供）：肿瘤相关糖抗原（TACA）是糖类和寡糖，在癌细胞上表现出高度受限的表达。由于 TACA 是癌细胞所独有的，因此人们对产生针对 TACA 的主动免疫反应作为减少癌症转移或复发的一种手段非常感兴趣。在主动免疫治疗中使用 TACA 的两个主要挑战是其抗原性差以及通过化学方法合成寡糖和相关糖缀合物的固有困难。过去的工作表明，带有 TACA 肽的脂质体疫苗可以产生针对 TACA 的免疫反应。如果脂质体含有异生碳水化合物，例如鼠李糖，针对碳水化合物的天然抗体将大大增强免疫反应的产生，大概是通过 Fc 介导的抗原摄取。该提案的第一个具体目标旨在通过研究纯化的人抗鼠李糖抗体及其在野生型和 Fc 人源化小鼠中抗原摄取中的作用，更详细地确定增强机制。第二个具体目标将确定特定 Fc 区是否可以作为该疫苗比鼠李糖更有效的靶向配体。最有效的疫苗配方将在人源化小鼠中进行测试，以更好地预测其在人类中的功效。某些神经酰胺刺激不变的自然杀伤 T 细胞可以用作疫苗佐剂。第三个具体目标涉及鼠李糖修饰的神经酰胺的合成，并确定它们除了为天然抗体提供识别位点之外，是否可以通过与 CD1d 结合来作为改进的疫苗佐剂。该提案利用了 受过有机化学和免疫学培训的研究人员之间的协作互动，以便在野生型小鼠和携带人源化免疫细胞的小鼠中很好地表征所有疫苗的结构和抗原性。

项目成果

Mixed-phase synthesis of glycopeptides using a N-peptidyl-2,4-dinitrobenzenesulfonamide-thioacid ligation strategy.

• DOI: 10.1021/ol202163e
• 发表时间: 2011-10-07
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Karmakar P;Talan RS;Sucheck SJ
• 通讯作者: Sucheck SJ

Synthesis of β-Glycosyl Amides from N-Glycosyl Dinitrobenzenesulfonamides.

• DOI: 10.1080/07328303.2012.663431
• 发表时间: 2012-01-01
• 期刊: Journal of carbohydrate chemistry
• 影响因子: 1
• 作者: Gaitonde V;Sucheck SJ
• 通讯作者: Sucheck SJ

Development of a Bioconjugate Platform for Modifying the Immune Response of Autoreactive Cytotoxic T Lymphocytes Involved in Type 1 Diabetes.

开发用于改变 1 型糖尿病相关自身反应性细胞毒性 T 淋巴细胞免疫反应的生物共轭平台。

• DOI: 10.1021/acs.bioconjchem.9b00332
• 发表时间: 2019
• 期刊: Bioconjugate chemistry
• 影响因子: 4.7
• 作者: Nandedkar-Kulkarni,Neha;Vartak,AbhishekR;Sucheck,StevenJ;Wall,KatherineA;Quinn,Anthony;Morran,MichaelP;McInerney,MarciaF
• 通讯作者: McInerney,MarciaF

Augmenting Vaccine Immunogenicity through the Use of Natural Human Anti-rhamnose Antibodies.

• DOI: 10.1021/acschembio.8b00312
• 发表时间: 2018-08-17
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Hossain MK;Vartak A;Karmakar P;Sucheck SJ;Wall KA
• 通讯作者: Wall KA

Synthesis of Oligosaccharide Components of the Outer Core Domain of P. aeruginosa Lipopolysaccharide Using a Multifunctional Hydroquinone-Derived Reducing-End Capping Group.

• DOI: 10.1021/acs.orglett.7b03590
• 发表时间: 2018-01-19
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Vartak A;Hefny FM;Sucheck SJ
• 通讯作者: Sucheck SJ