Chemistry Reference
In-Depth Information
An alternative strategy to enhance the immunogenicity of
glycopeptide antigens consists in their conjugation to a built-in
adjuvant, for example the previously described Toll-like receptor 2
(TLR2) ligand Pam
3
CysSer, which stimulates the generation of cytokines
and chemokines that activate antigen presenting cells.
56
Kunz and co-
workers have also pioneered the preparation of the two-component
Pam
3
Cys-glycopeptide conjugates. In one example, a Tn antigen
MUC4 glycopeptide derived from the tandem repeat of the human
epithelial mucin MUC4, was coupled to Pam
3
CysSer to give the MUC4-
glycopeptide-TLR2 ligand vaccine.
57
MUC4, which is larger in size than
MUC1, has been found to be overexpressed in 50% of cancers of colon
and pancreatic origin, and is the only tumor-associated mucin
specifically occurring on pancreatic adenocarcinoma cells. More
recently, the synthesis of a MUC1-glycopeptide
Pam
3
CysSerK
4
-
lipopetide conjugate, which contains sialylated carbohydrate antigens
was developed.
58
Immunization of mice with this vaccine induced a
rather low MUC1-specific antibody response, with antibodies mainly of
the IgM type.
In order to potentiate the generation of a stronger immune response,
Boons et al. have synthesized a series of three-component vaccines, de-
signed to incorporate orthogonal immunogenic elements. The re-
searchers combined a short sequence of the MUC1 tandem repeat
containing the Tn antigen as B-cell epitope, with both a T-cell epitope
peptide derived from Polio virus (polio
103-115
) and the Pam
3
CysSerK
4
lipopeptide as a built-in adjuvant (Fig. 10).
59
These three building blocks
were sequentially coupled to each other through liposome-mediated
native chemical ligation (NCL).
60
Applied in a liposome preparation,
the resulting three-component vaccine elicited remarkably high levels
of IgG antibodies in mice, which effectively recognized MCF-7 breast
cancer cells.
Recently, the authors modified the synthetic strategy for the
preparation of a similar three-component vaccine which contains only
one cysteine as reacting linker for NCL.
61
Thus,anextendedglycopep-
tide containing both the MUC1-Tn B-cell epitope at the C-terminus and
the polio
103-115
T-cell epitope at the N-terminal part was subjected to
liposome-mediated native chemical ligation through its N-terminal
cysteine with a Pam
3
CysSerK
4
lipopeptide glycine thioester. The
obtained three-component vaccine was administered in a liposomal
Built-in adjuvant
(TLR ligand)
OH
HO
O
HO
AcHN
OH
O
O
KKKK
GC
KLFAVWKITYKDT
GC
TSAPDTRPAP
OH
S
H
O
HN
O
O
O
T-cell epitope
(Polio
103-115
)
B epitope
(Tn antigen)
O
O
14
14
14
Fig. 10 Three-component vaccine construct comprising a MUC1 glycopeptide antigen, a
helper T-cell epitope from Polio virus and the Toll-like receptor 2 ligand lipopeptide.
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