The principal goal of this research program is to develop practical synthetic approaches for the modification of a unique capsular zwitterionic polysaccharide (ZPS), PS A1, and conjugate tumor-associated carbohydrate antigens (TACAs) to develop entirely carbohydrate vaccine constructs. PS A1 is a structurally well- characterized polysaccharide containing a repeating tetrasaccharide core isolated from the capsular polysaccharide complex (CPC) of the anaerobe Bacterioides fragilis NCTC 9343. It was determined that PS A1 could coax an immune system to elicit cellular and humoral immune functions via T- and B-cell involvement that influenced helper and memorial response events - a paradigm shifting discovery. What is not entirely clear is the immunogenicity of entirely carbohydrate-based constructs as an alternative approach to glycoprotein conjugates for tumor vaccine development. This research program, therefore, aims to study and assess the innovative vaccine constructs using three specific aims: 1) To develop efficient conjugation methods for the construction of structurally well-defined TACA-PS A1 conjugate vaccines, 2) To study the immunological properties of TACA-PS A1 conjugates in mice and evaluate the specificity and cytotoxicity of TACA-PS A1- raised Abs to human cancer cell lines, and 3) To evaluate, in vivo, the efficacy of TACA-PS A1-invoked immunity to treat tumors. Anti-sera, obtained from murine immunizations will be used to determine total antibody (Ab) titers and Ab isotypes by ELISA, relaying information about immunity. Furthermore, ELISA will be used to determine Ab specificity against conjugated TACAs. Flow cytometry will be used to validate Ab specificity with human cancer cell lines. Complement-mediated cell killing (cytotoxicity) analysis using human tumor cell lines, will reveal Ab function. Finally, assessing and evaluating the efficacy of select TACA-PS A1 constructs to treat cancer will be demonstrated through in vivo experiments utilizing murine models grafted with the TA3/Ha murine breast carcinoma. The broader impact of the proposed research aims to demonstrate how entirely carbohydrate-based vaccines elicit cellular and humoral responses in the immune system. This research program will contribute to improved methodologies for the field of glycoconjugation chemistry, a better understanding of the role of PS A1 as an immunogen in eliciting immune responses, and assessment and evaluation of cancer specific constructs that are rationally designed. This project will, therefore, have an important impact on cancer treatment by providing a novel carbohydrate-based agent for preventive and therapeutic medicine and increase our understanding of glycoimmunology. We also expect this program to be broadly applicable to other areas of vaccine research.
The research proposed in this application will provide unique carbohydrate tumor vaccine constructs with high potential for application in preventive and therapeutic medicine. The proposed work will have important impacts as it will increase our understanding of how carbohydrates are involved in the immune system. Broadly, this project will fundamentally advance our knowledge of humoral and cellular glycoimmunity by evaluating well-defined, semi-synthetic carbohydrate constructs.
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