Multivalent glycidic constructs toward anti-cancer therapeutics - Carbohydrate Chemistry: Chemical and Biological Approaches - page 493

recent years several reports provided evidence that carbohydrate-based
vaccines do result in a T-cell response. 19 Moreover, additional studies
establish the feasibility of tumour-associated carbohydrate antigen-
presenting glycopeptides as CD8 þ T-cell-based vaccines. 20,21
There are different strategies in order to pursue an immune response,
such as the conjugation of glycans to immunogenic carrier proteins,
peptides or polysaccharides, hence making them more 'foreign'. More-
over a second idea is to mimic the cancer cell surface by displaying
vaccine glycans in a multivalent context. A multivalent glycan can display
high-avidity interaction with protein binding sites, often reaching nM
dissociation constant values. The so-called 'cluster glycoside effect'
operates in protein-carbohydrate interactions in living cells, and can be
reproduced in synthetic multivalent carbohydrate ligands. 22
It is clear that multiple simultaneous interactions have unique collective
properties that are quantitatively and also qualitatively different from
those displayed by their constituents, that interacts in a monovalent way.
2 Multivalent glycidic constructs
Each type of cancer is characterized by a distinct set of changes in glycan
expression. The first generation of carbohydrate vaccine, displayed only
multiple copies of one TACA. Hence it did not take into account the
degree of heterogeneity of carbohydrates expressed on malignant cell
surfaces. However, even within a particular cancer type, there is a
considerable amount of variation in the level and nature of cell-surface
carbohydrates expressed. 18 A vaccine that targets several cancer-
associated glycans should, in principle, lead to a stronger and more
specific immune response than one that targets a single cancer glycan. 23
In multivalent glycidic structures, different carbohydrate antigens are
displayed on a single carrier structure; these constructs are designed in
order to imitate the heterogeneous nature of cancer-cell surface glycans.
Danishefsky and co-workers prepared multiantigenic vaccines containing
several different glycan structures, 24 closely associated with a specific
cancer on a single molecule (unimolecular multivalent construct).
Inspired by the way of presentation in natural mucins, multiple
tumour antigens were included into a single polypeptide construct. Non-
natural amino acids have been used for the conjugation of the glycans,
with the idea that such unnatural linkages might result in an enhanced
immune response. Furthermore, the use of amino acids containing long,
aliphatic side chains may serve to space the glycosides from the peptide
backbone facilitating glycopeptide synthesis.
An unimolecular trivalent 25 (Fig. 1A), and a pentavalent 26 vaccine
(Fig. 1B), employing non-natural amino acids as linkers to carbohydrate
domains have been prepared. The trivalent construct containing as
carbohydrate epitopes Tn, Lewis y, and Globo H has shown promising
levels of immunogenicity in preclinical investigation. The observed
antibody responses, against each individual carbohydrate antigen,
demonstrated proof of principle for a unimolecular multivalent vaccine
construct with a non-natural amino acid linker.