Synthesis of Glycopeptide-Based Cancer Antigen Vaccines

 描述(申请人提供)：肿瘤相关碳水化合物抗原(TACA)是在癌细胞上表现出高度限制性表达的糖和寡糖。由于TACAs是癌细胞所特有的，因此产生针对TACAs的主动免疫反应作为一种减少癌症转移或复发的手段引起了人们的极大兴趣。在主动免疫治疗中使用TACA的两个主要挑战是它们的抗原性差，以及通过化学手段合成寡糖和相关糖偶联物的固有困难。过去的工作表明，含有TACA多肽的脂质体疫苗可以产生对TACA的免疫反应。如果脂质体含有异种碳水化合物，如鼠李糖，则针对该碳水化合物的天然抗体将极大地增强免疫反应的产生，可能是通过Fc介导的抗原摄取。这项建议的第一个具体目标是通过研究纯化的人抗鼠李糖抗体及其在野生型和FC人源化小鼠的抗原摄取中的作用来更详细地确定增强的机制。第二个特定目的将决定特定的Fc区域是否可以作为该疫苗的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的小鼠身上进行测试，以更好地预测其对人类的效果。某些神经酰胺刺激不变的自然杀伤T细胞可作为疫苗佐剂。第三个具体目标是合成鼠李糖修饰的神经酰胺，并确定它们除了为天然抗体提供识别位点外，是否还可以通过与CD1d结合作为改进的疫苗佐剂。这项提议利用了 受过有机化学和免疫学培训的研究人员之间的合作互动，以便所有疫苗的结构和抗原性将在野生型小鼠和具有人源化免疫细胞的小鼠中得到很好的表征。

 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.