Another promising therapeutic application involving glycodendrimers as functional
antigens with requisite immunochemical abilities recently arose from their molecularly
defined multivalent scaffolds and their abundant architectural variations [36]. Interestingly, although carbohydrates are T-cell-independent antigens with poor immunogenicity, their conjugation to protein carriers serving as T-cell-dependent epitopes generated
glycosylated structures capable of acquiring the requisite immunochemical ability. This
observation triggered numerous efforts directed towards synthetic carbohydrate-based
vaccine candidates. More particularly, early examples of strongly immunogenic
glycoclusters and glycodendrimers bearing critical components of tumor-associated
carbohydrate antigens (TACAs) such as the immune-dominant T N and T F antigens
(α-GalNAc-O-Ser/Thr and β-D-Gal-(1!3)-α-D-GalNAc-O-Ser/Thr, respectively)
have been described as promising antitumor vaccines [37]. More recent investigations
pointed to four optimum structural requirements for constructing successful glycoconjugate vaccines for cancer immunotherapy:
1. The presence of key TACA as recognition motif, acting as B-cell epitope against
which antibodies should be raised.
2. The presence of CD4
+ T-cell peptide epitope and CD8
+ T lymphocyte (CTL) to
trigger both humoral and cytotoxic immunity, respectively.
3. The incorporation of nonimmunogenic and nontoxic lipidic adjuvant targeting
the Toll-like receptor 2 (TLR-2) to provide a self-adjuvanting property to the
construct. Particularly, lipid-bound antigens can be directly recognized by
TLRs, from which they are internalized within the antigen-presenting cells
(APCs), processed, and finally exposed on the surface for CD8
+ natural killer
cell activation [38–40].
4. Multivalency, either insured by the multitask platform used to expose the
epitopes, or naturally generated through the propensity of lipid derivatives to
form liposomes, particularly if glycolipid QS21 adjuvant is co-injected.
Dumy et al. capitalized on these cumulated observations to achieve a fully
synthetic four-component antitumor vaccine, built on a nonimmunogenic cyclodecapeptide template (known as “RAFT” [41] for regioselectively addressable
functionalized template) [42]. The optimized multiepitopic construct incorporated
four copies of a T N antigen analogue as TACAs (B-cell epitope), the universal
CD4
+ helper T-cell peptide from the type I poliovirus protein, together with a CD8
+
CTL from ovalbumin (OVA 257–264 peptide SIINFEKL) to which was covalently
added palmitic acid as lipid adjuvant. The synthetic versatility of the pre-activated
RAFT platform displaying four glyoxoaldehyde functions allowed the efficient
ligation of the aminooxylated sugar (T N ) derivatives on the platform via iterative
oxime ligation. The peptidic epitopes were further combined to the scaffold through
disulfide bridge formation to afford the desired vaccine NPs composed of ovalbumin glycol-lipopeptide (OVA-GLP) 4 (Fig. 4).
The study highlighted both B- and T-cell antigenicity as well as immunogenicity
in vitro and in vivo. The authors first assessed the safety, immunogenicity, and
protective efficacy of 4 using a MO5/BALB/c tumor mouse model. The investigations
revealed the production of tumor-specific antibodies (Abs) developed against the T N
304
N. Kottari et al.
antigens with requisite immunochemical abilities recently arose from their molecularly
defined multivalent scaffolds and their abundant architectural variations [36]. Interestingly, although carbohydrates are T-cell-independent antigens with poor immunogenicity, their conjugation to protein carriers serving as T-cell-dependent epitopes generated
glycosylated structures capable of acquiring the requisite immunochemical ability. This
observation triggered numerous efforts directed towards synthetic carbohydrate-based
vaccine candidates. More particularly, early examples of strongly immunogenic
glycoclusters and glycodendrimers bearing critical components of tumor-associated
carbohydrate antigens (TACAs) such as the immune-dominant T N and T F antigens
(α-GalNAc-O-Ser/Thr and β-D-Gal-(1!3)-α-D-GalNAc-O-Ser/Thr, respectively)
have been described as promising antitumor vaccines [37]. More recent investigations
pointed to four optimum structural requirements for constructing successful glycoconjugate vaccines for cancer immunotherapy:
1. The presence of key TACA as recognition motif, acting as B-cell epitope against
which antibodies should be raised.
2. The presence of CD4
+ T-cell peptide epitope and CD8
+ T lymphocyte (CTL) to
trigger both humoral and cytotoxic immunity, respectively.
3. The incorporation of nonimmunogenic and nontoxic lipidic adjuvant targeting
the Toll-like receptor 2 (TLR-2) to provide a self-adjuvanting property to the
construct. Particularly, lipid-bound antigens can be directly recognized by
TLRs, from which they are internalized within the antigen-presenting cells
(APCs), processed, and finally exposed on the surface for CD8
+ natural killer
cell activation [38–40].
4. Multivalency, either insured by the multitask platform used to expose the
epitopes, or naturally generated through the propensity of lipid derivatives to
form liposomes, particularly if glycolipid QS21 adjuvant is co-injected.
Dumy et al. capitalized on these cumulated observations to achieve a fully
synthetic four-component antitumor vaccine, built on a nonimmunogenic cyclodecapeptide template (known as “RAFT” [41] for regioselectively addressable
functionalized template) [42]. The optimized multiepitopic construct incorporated
four copies of a T N antigen analogue as TACAs (B-cell epitope), the universal
CD4
+ helper T-cell peptide from the type I poliovirus protein, together with a CD8
+
CTL from ovalbumin (OVA 257–264 peptide SIINFEKL) to which was covalently
added palmitic acid as lipid adjuvant. The synthetic versatility of the pre-activated
RAFT platform displaying four glyoxoaldehyde functions allowed the efficient
ligation of the aminooxylated sugar (T N ) derivatives on the platform via iterative
oxime ligation. The peptidic epitopes were further combined to the scaffold through
disulfide bridge formation to afford the desired vaccine NPs composed of ovalbumin glycol-lipopeptide (OVA-GLP) 4 (Fig. 4).
The study highlighted both B- and T-cell antigenicity as well as immunogenicity
in vitro and in vivo. The authors first assessed the safety, immunogenicity, and
protective efficacy of 4 using a MO5/BALB/c tumor mouse model. The investigations
revealed the production of tumor-specific antibodies (Abs) developed against the T N
304
N. Kottari et al.