The primary objective of this Phase II research proposal is to expand the structure-activity-relationship (SAR) studies which were initiated in Phase I on a novel class of synthetic monosaccharide adjuvants known chemically as aminoalkyl glucosamine phosphates (AGPs). The AGP class of adjuvants significantly enhance cell-mediated immune responses- including cytotoxic T-cells (CTLs)-to vaccine antigens in murine models.
The specific aims of this SAR investigation include the preparation and testing of a series of AGPs possessing structural features which should both increase chemical and metabolic stability, and amplify antigen- dependent T-cell activation and antibody responses. To this end, the AGPs proposed for synthesis will be evaluated for their ability to activate murine macrophage, human peripheral monocytes and other relevant cell types in vitro, and for their ability to induce protective CTLs and neutralizing antibodies in relevant murine models. Part of the study will involve the preparation and evaluation of a synthetic vaccine model comprising an AGP adjuvant covalently linked to a murine CTL epitope of the hepatitis B surface antigen (HBsAg). Murine HBsAg models show relevance to human immune responses to HBsAg and could lead to the design of an AGP-based vaccine for the treatment of hepatitis B virus in humans.
The AGP class of synthetic monosaccharide adjuvants can potentially l) improve the safety and efficacy of existing infectious disease and cancer vaccines, and 2) lead to the development of new wholly synthetic vaccines comprising synthetic adjuvants and antigens.
| Baldridge, Jory R; Cluff, Christopher W; Evans, Jay T et al. (2002) Immunostimulatory activity of aminoalkyl glucosaminide 4-phosphates (AGPs): induction of protective innate immune responses by RC-524 and RC-529. J Endotoxin Res 8:453-8 |
