Due to genetic and/or epigenetic alteration, glycan markers on tumor cells structurally differ from those on the normal cells. These unique glycans, termed tumor associated carbohydrate antigens (TACAs), have been utilized to educate the immune system to specifically recognize and eliminate cancer cells, a concept known as cancer immunotherapy or anticancer vaccine. The major challenge of developing an anti-TACA vaccine is the low immunogenicity of TACAs as they are self-antigens and not sufficiently immunogenic when administered alone. In chapter 1, iron oxide magnetic nanoparticles (NPs) have been evaluated as carriers for glycoconjugate-based anticancer vaccines. With their high biocompatibilities and large surface areas, magnetic NPs were synthesized for TACA delivery. The magnetic NPs were coated with phospholipid-functionalized TACA glycopeptides through hydrophobic−hydrophobic interactions without the need for any covalent linkages. Multiple copies of glycopeptides were presented on NPs, potentially leading to enhanced interactions with antibody-secreting B cells through multivalent binding. Mice immunized with the NPs generated strong antibody responses, and the glycopeptide structures important for high antibody titers were identified. The antibodies produced were capable of recognizing both mouse and human tumor cells expressing the glycopeptide, resulting in tumor cell death through complement-mediated cytotoxicities. These results demonstrate that magnetic NPs can be a new and simple platform for multivalently displaying TACA and boosting anti-TACA immune responses without the need for a typical protein carrier.Besides iron oxide magnetic nanoparticles (NPs), bacteriophage Qβ is another excellent immunogenic carrier able to break self-tolerance to induce strong antibody response against TACA. One potential drawback of bacteriophage Qβ is its strong immunogenicity, which also induces a strong antibody response against itself. This unwanted anti-carrier immune response can lead to carrier-induced epitopic suppression (CIES), which can limits the full potential of the Qβ in inducing maximum desired immune response against TACA. In chapter 2, Qβ viral capsid was engineered to reduce the unwanted immune response against the carrier protein, thus refocusing the immunity towards generating higher potency of desired immune response against TACAs. Non-native disulfide bonds were introduced into the capsid to enhance the stability of the engineered capsids. Our results showed that the new Qβ mutants can reduce the unwanted anti-carrier immune response, yet enhance the wanted titers of antibodies against TACA. The approaches presented in this study provide a fundamental implication for rational design of engineered virus-like-particle-based carrier to maximize the potency of vaccines targeting TACA expressing cancers as well as other diseases.
Read
