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）是在癌细胞上表达高度限制的糖和低聚糖。由于TACA对癌细胞是独特的，因此产生针对TACA的主动免疫应答作为减少癌症转移或复发的手段具有很大的兴趣。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和通过化学手段合成寡糖和相关糖缀合物的固有困难。过去的工作表明，含有TACA-承载肽的脂质体疫苗可以产生对TACA的免疫应答。如果脂质体含有外源性碳水化合物如鼠李糖，则针对碳水化合物的天然抗体将极大地增强免疫应答的产生，推测是通过Fc介导的抗原摄取。本提案的第一个具体目的是通过研究纯化的人抗鼠李糖抗体及其在野生型和Fc人源化小鼠中的抗原摄取中的作用，更详细地确定增强机制。第二个具体目标将确定特异性Fc区是否可以作为该疫苗的比鼠李糖更普遍有效的靶向配体。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。通过某些神经酰胺刺激不变的自然杀伤T细胞可以作为疫苗佐剂。第三个具体目标涉及合成鼠李糖修饰的神经酰胺，并确定它们是否可以通过与CD 1d结合以及为天然抗体提供识别位点来作为改进的疫苗佐剂。该提案利用了 在有机化学和免疫学方面受过训练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。

 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.