Enhanced immunogenicity of multivalent MUC1 glycopeptide antitumour vaccines based on hyperbranched polymers

Abstract

Enhancing the immunogenicity of an antitumour vaccine still poses a major challenge. It depends upon the selected antigen and the mode of its presentation. We here describe a fully synthetic antitumour vaccine, which addresses both aspects. For the antigen, a tumour-associated MUC1 glycopeptide as B-cell epitope was synthesised and linked to the immunostimulating T-cell epitope P2 derived from tetanus toxoid. The MUC1-P2 conjugate is presented multivalently on a hyperbranched polyglycerol to the immune system. In comparison to a related vaccine of lower multivalency, this vaccine exposing more antigen structures on the hyperbranched polymer induced significantly stronger immune responses in mice and elicited IgG antibodies of distinctly higher affinity to epithelial tumour cells.

Just a spoonful of sugar: Short glycans affect protein properties and functions

“…Multivalency is also important in antibody recognition, as shown, for example, in the case of the H. influenzae HMW1 adhesin that, when glycosylated with at least four N‐glucosyl moieties on its C‐terminal fragment, specifically binds to antibodies in multiple sclerosis patients serum . The multivalent nature of glycan‐antibody interaction is also exploited in vaccine developments, both for infectious diseases and cancer, where the multivalent display of the glycan antigens is essential for enhancing the immunogenic properties of the vaccine …”

Peer Review #3 of "Application of built-in adjuvants for epitope-based vaccines (v0.1)"

“…Multi-alkyne-functionalized hyperbranched polyglycerol (hbPG) is a globular polymer with multiple branches that displays good biocompatibility and is not immunogenic; its multi-functional dendrimer-like structure provides sufficient space to present multivalent antigens (Glaffig et al, 2014). Based on these characteristics, B cell epitopes of the tumor-associated antigen, MUC1, glycopeptide, and the T cell epitopes of the tetanus toxin, P2, can be coupled in series to each branch of the hbPG; moreover, these nanoscale branched spheres can express the glycopeptide on its surface, resulting in enhanced exposure of the antigens to the immune system (Glaffig et al, 2014;Glaffig et al, 2015). Currently, various vaccines based on polymer nanoparticles are being tested in preclinical and clinical trials, including those for tuberculosis, cancer, and HIV (Table 5).…”

Immunological Evaluation of Recent MUC1 Glycopeptide Cancer Vaccines

“…The antibodies showed notable binding to tumor cell MCF-7. Instead of using HPMA, Glaffig et al used hyper-branched polyglycerol (HPG), an inert polymer which is water soluble and non-linear unlike HPMA and has a dendrimer-like structure that allows it to bind with multiple antigens and prevent entanglement of bound antigen [ 76 ]. In this case, a higher valency and more glycosylation gave better anti-tumor antibody responses.…”