Development of synthetic, self-adjuvanting, and self-assembling anticancer vaccines based on a minimal saponin adjuvant and the tumor-associated MUC1 antigen

Abstract

The overexpression of aberrantly glycosylated tumor-associated mucin-1 (TA-MUC1) in human cancers makes it a major target for the development of anticancer vaccines derived from synthetic MUC1-(glyco)peptide antigens. However, glycopeptide-based subunit...

Synthetic self‐adjuvanted multivalent Mucin 1 (MUC1) glycopeptide vaccines with improved in vivo antitumor efficacy

“…First, one or three Fmoc‐Lys(N 3 )‐OH moieties were installed at the C‐terminus during solid phase peptide synthesis, followed by P30 T‐cell epitope FNNFTVSFWLRVPKVSASHLE installation and Pam 3 CSK 4 lipopeptide attachment. To minimize the potential steric congestion around the different components and favor antigen accessibility and presentation, 12 the 6‐aminohexanoic acid residues were placed to function as flexible spacers as was commonly used for vaccine development 29–31 . The crude peptide was cleaved from the resin using cocktail R solution (trifluoroacetic acid/triisopropylsilane/water = 90:5:5) and then purified on a polar‐CN column for mono‐ and trivalent lipopeptide scaffolding, as previously reported 28 .…”

“…As a result, multicomponent approaches aimed at eliminating the carrier protein and boosting the immune response have been pursued. For example, newly developed vaccines adopted MUC1 glycopeptide as a B‐cell epitope coupled with T‐cell epitopes from different sources and/or toll‐like receptor (TLR) agonists 8,11–16 . These self‐adjuvanted vaccines are state‐of‐the‐art constructs, enabling simultaneous uptake of antigens and agonists by the same antigen presenting cell and leading to enhanced antigen‐directed immune responses 12 .…”

“…For example, newly developed vaccines adopted MUC1 glycopeptide as a B-cell epitope coupled with T-cell epitopes from different sources and/or tolllike receptor (TLR) agonists. 8,[11][12][13][14][15][16] These self-adjuvanted vaccines are state-of-the-art constructs, enabling simultaneous uptake of antigens and agonists by the same antigen presenting cell and leading to enhanced antigen-directed immune responses. 12 Moreover, T helper (Th) cell activation evokes an essential class switch from low-affinity and short-lived immunoglobulin M (IgM) antibodies to high-affinity immunoglobulin G (IgG) antibodies.…”

“…8,[11][12][13][14][15][16] These self-adjuvanted vaccines are state-of-the-art constructs, enabling simultaneous uptake of antigens and agonists by the same antigen presenting cell and leading to enhanced antigen-directed immune responses. 12 Moreover, T helper (Th) cell activation evokes an essential class switch from low-affinity and short-lived immunoglobulin M (IgM) antibodies to high-affinity immunoglobulin G (IgG) antibodies. 12 Numerous studies have shown that glycosylation mode of MUC1 is crucial for immune efficacy.…”

Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses

“…MUC1-based vaccine candidates typically contain the full sequence of MUC1 glycosylated at one or multiple positions with Tn or other TACAs. , Despite the synthetic efforts, − there have been no successful clinical applications to date, which may be a result of the atypical glycosylated proteinsthat express some of these antigensbeing exposed on healthy cells at low concentrations, which may lead to tolerance induction and, consequently, poor immune response in mice . Our research group and others have been working to overcome this issue by using artificial MUC1 derivatives designed in the lab. − These synthetic glycopeptides promise to be more immunogenic and consequently stimulate an effective anti-MUC1 response, as well as being resistant to enzymatic degradation .…”