I. Delivery of carbohydrate antigens by glycopolymers as potential anti-cancer vaccines : II. A study of the impacts of valency and density on immune response against a tumor associated carbohydrate antigen

Summary

Tumor associated carbohydrate antigens (TACAs) are overexpressed on tumor cells, which renders them attractive targets for anti-cancer vaccines. To overcome the poor immunogenecity of TACAs, a polymer platform was designed for antigen presentation by taking advantage of the polymeric backbone to deliver TACA and helper T (Th) cell epitope on the same chain. The block copolymer was synthesized by cyanoxyl-mediated free radical polymerization followed by conjugation with a TACA Tn antigen and a... Show moreTumor associated carbohydrate antigens (TACAs) are overexpressed on tumor cells, which renders them attractive targets for anti-cancer vaccines. To overcome the poor immunogenecity of TACAs, a polymer platform was designed for antigen presentation by taking advantage of the polymeric backbone to deliver TACA and helper T (Th) cell epitope on the same chain. The block copolymer was synthesized by cyanoxyl-mediated free radical polymerization followed by conjugation with a TACA Tn antigen and a mouse Th-cell peptide epitope derived from poliovirus (PV) to afford the vaccine construct. The glycopolymer vaccine elicited a robust immune response with significant titers of IgG antibodies and the antibodies generated recognized Tn antigens on tumor cell surface. For successful carbohydrate based anti-cancer vaccines, it is critical that B cells are activated to secret antibodies targeting TACAs. Despite the availability of many TACA based constructs, systematic understanding of the effects of structural features on anti-glycan antibody responses is lacking. In this study, a series of defined synthetic glycopolymers bearing a representative TACA, i.e., the Thomsen-nouveau (Tn) antigen, have been prepared to probe the induction of early B cell activation and antibody production via a T cell independent mechanism. Valency and density of the antigen in the polymers turned out to be critical. An average of greater than 6 Tn per chain was needed to induce antibody production. Glycopolymers with 40 antigens per chain and backbone molecular weight of 450 kDa gave the strongest stimulation to B cells in vitro, which correlated well with its in vivo activity. Deviations from the desired valency and density led to decreased antibody production or even antigen specific B cell non-responsiveness. These findings provide important insights on how to modulate anti-TACA immune responses facilitating the development of TACA based anti-cancer vaccines using glycopolymers. Show less