Towards a Fully Synthetic Carbohydrate‐Based Anticancer Vaccine: Synthesis and Immunological Evaluation of a Lipidated Glycopeptide Containing the Tumor‐Associated Tn Antigen

Despite the important role of adjuvants for vaccine development, relatively few adjuvants have been successfully incorporated into vaccines intended for human administration. This is in part due to the high toxicity associated with many experimental adjuvants. This lack of choice effectively hinders the ability to produce vaccines against many diseases, or to improve current vaccine formulations. The conjugation of immunostimulatory lipids to peptide antigens, to produce self-adjuvanting lipopeptide vaccines, has been tested in human clinical trials. These systems appear to have a number of advantages over more traditional adjuvants (e.g. alum salts) including the capacity for these vaccines to be administered via mucosal routes (e.g. orally or nasally) instead of by injection, elicitation of antigen-specific cytotoxic T-lymphocytes and mucosal immunity, as well as little-to-no observed toxicity. Several lipopeptide vaccine systems have been described in the literature, ranging from the conjugation of single fatty acid chains, to the conjugation of more complex lipids and glycolipids onto peptide antigens. The following review provides an overview of the most studied lipopeptide vaccine systems grouped into the following categories: 1) bacterial lipopeptides, including tri-palmitoyl-S-glyceryl cysteine (Pam3Cys) and di-palmitoyl-S--glyceryl cysteine (Pam2Cys); 2) the lipid-core peptide (LCP) and multiple antigen lipophilic adjuvant carrier (MALAC) systems; 3) single-chain palmitoylated peptides; and 4) glycolipids (e.g. monophosphoryl lipid A). The review also discusses the potential mechanisms of action for lipopeptide and glycolipopeptide vaccines, as well as structure activity relationships, and provides examples of studies utilising each system.

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“…In addition, bacterial lipopeptides have been studied as adjuvants for anti-tumor [53] and immunocontraceptive [50,54] vaccines.…”

Section: Fig (1)mentioning

confidence: 99%

Self-Adjuvanting Lipopeptide Vaccines

Moyle¹,

Tóth²

2008

CMC

136

113

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“…14.10). A first construction (12) was composed of Pam 3 Cys, the Tn antigen, and the T-cell epitope peptide "YAF" derived from an outer-membrane protein of Neisseria meningitidis [37].…”

Section: Lipid Carriersmentioning

confidence: 99%

Synthetic Vaccines against Cancers

Fiore¹,

Thomas²,

Daskhan³

et al. 2015

Carbohydrate Chemistry: State of the Art and Challenges for Drug Development

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“…Finally, a fully synthetic approach makes it possible to optimize the various components of the candidate vaccine by structure-activity relationship studies. In this respect, proper design of the three-component vaccine is essential, because previously we showed that a compound composed of the inferior adjuvant Pam 3 Cys which lacks the important tetra-lysine moiety and a human Th epitope elicits low titers of IgG antibodies 7,14 . Furthermore, it has been found that covalent attachment of the three components is important for optimal antigenic responses.…”

Section: Online)mentioning

confidence: 99%

“…In addition, foreign carrier proteins such as keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA) and the linker that attach the saccharides to the carrier protein can elicit strong B-cell responses, which may lead to the suppression of antibody responses against the carbohydrate epitope 5,6 . It is clear that the successful development of carbohydrate-based cancer vaccines requires novel strategies for the more efficient presentation of tumor-associated carbohydrate epitopes to the immune system, resulting in a more efficient class switch to IgG antibodies [7][8][9][10][11][12][13][14][15][16][17] .…”

mentioning

confidence: 99%

Robust immune responses elicited by a fully synthetic three-component vaccine

et al. 2007

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The over-expression of saccharides such as Globo-H, Lewis Y and Tn antigen is a common feature of oncogenic transformed cells. Endeavors to exploit this aberrant glycosylation for cancer vaccine development has been complicated by difficulties of eliciting high titers of IgG antibodies against classical conjugates of tumor-associated carbohydrates to carrier proteins. We have designed, chemical synthesized and immunologically evaluated a number of fully synthetic vaccine candidates to establish strategies to overcome the poor immunogenicity of tumor-associated carbohydrates and glycopeptides. We have found that a three-component vaccine composed of a TLR2 agonist, a promiscuous peptide T-helper epitope and a tumor-associated glycopeptide, can elicit in mice exceptionally high titers of IgG antibodies that can recognize cancer cells expressing the tumor-associated carbohydrate. The superior properties of the vaccine candidate are attributed to the local production of cytokines, upregulation of co-stimulatory proteins, enhanced uptake by macrophages and dendritic cells and avoidance of epitope suppression.A broad and expanding body of preclinical and clinical studies [1][2][3][4] demonstrates that naturally acquired, passively administered or actively induced antibodies against carbohydrate-associated tumor antigens are able to eliminate circulating tumor cells and micro-metastases in cancer patients. Tumor-associated saccharides are, however, of low antigenicity, because they are self-antigens and consequently tolerated by the immune system. In addition, foreign carrier proteins such as keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA) and the linker that attach the saccharides to the carrier protein can elicit strong B-cell responses, which may lead to the suppression of antibody responses against the carbohydrate epitope 5,6 . It is clear that the successful development of carbohydrate-based cancer vaccines requires novel strategies for the more efficient presentation of tumor-associated carbohydrate epitopes to the immune system, resulting in a more efficient class switch to IgG antibodies 7-17 .We reasoned that a three-component vaccine composed of a tumor-associated carbohydrate B-epitope, a promiscuous peptide T-helper (Th) epitope and a Toll-like receptor (TLR) ligand will circumvent immune suppression caused by a carrier protein or the linker region of a classical conjugate vaccine. Such a vaccine candidate contains, however, all mediators required for eliciting a strong IgG immune response. In the first instance, vaccine candidates 1 and 2 were designed, which contain as a B-epitope a tumor-associated glycopeptide derived from MUC1 1,18 and the well-documented murine MHC class II restricted Th (Fig. 1). Furthermore, compound 1 contains as an built-in adjuvant the lipopeptide Pam 2 CysSK 4 , which is a potent activator of TLR2/6, whereas compound 2 contains Pam 3 CysSK 4 , which induces cellular activation through TLR1/2 20 .Compound 1 was prepared by a solid-phase peptide synthesis ...

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Towards a Fully Synthetic Carbohydrate‐Based Anticancer Vaccine: Synthesis and Immunological Evaluation of a Lipidated Glycopeptide Containing the Tumor‐Associated Tn Antigen

Cited by 135 publications

References 40 publications

Self-Adjuvanting Lipopeptide Vaccines

Self-Adjuvanting Lipopeptide Vaccines

Synthetic Vaccines against Cancers

Robust immune responses elicited by a fully synthetic three-component vaccine

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