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Synthetically-defined glycoconjugate vaccine candidates against cancer
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Cancer is a major cause of death worldwide and despite the several treatments currently available (such as chemotherapy and hormonal treatments), these are often associated with severe side effects and often have poor results. Thus, more effective strategies are needed.
In the las years anti-cancer vaccines have gained a lot of interest, as these can act as preventive or therapeutic treatments, by triggering the immune system to attack the cancer cells, hence being a promising approach to fight cancer.
Importantly, as a result of its overexpression and shorter glycans in cancer cells, MUC1 is currently a drug target for many cancers, including its use as an antigen for the development of anticancer vaccines. However, therapeutic vaccines based on MUC1 face several challenges, as the natural tumor-associated MUC1 (taMUC1) is poorly immunogenic, and these derivatives can act as self-antigens, which can lead to immunosuppression.
Additionally, polysaccharide-based vaccines fail to generate memory, as polysaccharide antigens only interact with specific B-cells promoting low-affinity humoral responses. Hence, when conjugated, glycoconjugate vaccines have some advantages over traditional polysaccharide-based vaccines, such as triggering T cell dependent responses leading to the establishment of B-cell memory and longerlasting immune responses.
To overcome these issues, an artificial MUC1 was synthesized and conjugated to gold nanoparticles to be used as anti-cancer vaccine. The construct was tested for its ability to promote an immune response against human tumor associated MUC1 in mice.
With ELISA assays, we found that the synthetic MUC1 was able to trigger the production of specific antibodies against human tumor-associated MUC1. Furthermore, the anti-sera from the immunized mice were able to bind to the natural MUC1 antigen in human breast cancer cell lines and in tumor samples from breast cancer patients, and also were able to elicit antibody-dependent cell mediated cytotoxicity towards breast cancer cells.
Having obtained these promising results with the unnatural MUC1, another vaccine candidate was prepared using the same artificial MUC1 antigen conjugated with the highly immunogenic protein carrier CRM197, as the protein carrier was expected to trigger T-cell responses on its own, hence leading to a stronger immune response. Once again, specific antibodies against human MUC1 were detected, and these were able to specifically bind to the MUC1 expressed in human breast cancer cells and to promote cytotoxic T Lymphocyte responses. As predicted, antibodies against the protein carrier were also detected in high levels. Additionally, when tumors were induced in mice immunized with this second vaccine candidate, a delay in tumor growth was observed.
These encouraging results will lead to further studies on the potential therapeutic effect of these vaccine candidates.
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MUC1 Glicopéptido Vacinas Cancro Modificação seletiva de proteínas