Preparation Of Antiangiogenic DNA Vaccine Based On Flk-1_ECD-C3d3 And Research Of Its Anti-Bladder Tumor Effects

The close relationship between tumor progression and its angiogenesis was first hypothesized by Folkman in 1971. Accumulating evidence has clearly shown that angiogenesis played an essential role in the development of various solid tumors and affected its growth and metastasizing dramatically. Therefore, tumor angiogenesis is potentially an important therapeutic target which has been actively studied during the last decade.The strategy of inhibition of tumor angiogenesis has been proved to be extremely effective in animal experiments. However, translation of these strategies to a clinical setting has proven difficult, in part due to toxicities of the drugs. Another obstacle is the delivery of sufficient amounts of bioavailable drugs. In most cases, chronic long-term delivery of high doses is necessary to achieve a clinical response.One strategy to circumvent the hurdles has been to take advantage of inherent immune response to selectively target tumor neovascularization, thereby eliminating the need for long-term expensive delivery of high doses of potentially toxic agents. Appropriate target antigen is the key factor to the success of this strategy. Vascular endothelial growth factor(VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR-2, also known as Flk-1) play a critical role in the regulation of normal and pathological angiogenesis. Flk-1, which has a more restricted expression on proliferating tumor endothelial cells, provides an optimization selection. But Flk-1 is self-antigen. A major challenge is to break the immune tolerance and induce a robust, long-lived T cell-mediated immunity which leads to an effective suppression of tumor angiogenesis. Luckily, in 90s of the last century, an important discover in the research area of complement provided a novel approach to solve this tough question. This discover was that C3d, a fragment of complement C3 component, can influence the acquired immune response by binding to its receptor CR2/CD21, on B lymphocytes and other antigen-presenting cells (APC). Dempsey et al. found that the fusion of three copies of C3d (C3d3) to hen egg lysozyme, a model antigen, increased the efficiency of immunizations by more than 1000-fold. The development of vaccines containing the...