Chemistry Reference
In-Depth Information
HO
OH
HO
OH
O
HO
OH
O
HO
Gb
3
Gb
3
Gb
3
O
HO
HO
HO
OH
O
HO
OH
OH
O
HO
OH
OH
O
HO
O
OH
O
HO
HO
O
HO
HO
O
HO
HO
O
O
HO
O
HO
O
HO
O
HO
O
HO
O
MUC5AC
H
N
MUC5AC
N
N
MUC5AC
H
N
TTSTTSAP
SR
H
TTSTTSAP
H
O
TTSTTSAP
O
AcHN
N
H
O
O
68
R = H
69
R =
O
a
O
N
KLH
O
Fig. 7 Clustered Gb3-MUC5AC vaccine construct. (a) 1. Sulfo-MBS, KLH, pH 6.0 buffer,
45 min, RT; 2. pH 6.5-7.0 buffer, N2, 4 h, RT.
In addition to its use as a B-cell epitope for generating anti-MUC1
antibodies, both preclinical and clinical trials have shown MUC1 to be
capable of inducing a Th1 response.
47
Based on these observations and
the promising results of the second-generation unimolecular penta-
valent vaccine, which elicited excellent IgM and IgG antibody titers
against all five carbohydrate antigens, to expand the antigen repertoire
and increase coverage of tumor cells we prepared a hybrid vaccine
construct containing a unimolecular pentavalent glycopeptide domain
covalently linked to the MUC1 peptide.
48
The preparation of the KLH
conjugate of this construct for further preclinical evaluation is currently
underway (Fig. 8).
3.5 Strategies for augmenting the T-cell response in carbohydrate/
glycopeptide-based cancer vaccines
Asdescribedabove,mosteffortsinthedevelopmentofecientstrat-
egies for presentation of these carbohydrate antigens to the immune
system have traditionally relied on the use of a carrier protein, such as
KLH, and a potent immunoadjuvant such as QS-21, to enhance the
T-cell response. However, more recently, in order to produce substantial
levels of both IgM and IgG antibodies capable of reacting with tumor
cell lines, increased attention has been drawn to the development of
approaches to induce T-cell dependent immunogenic pathways,
which either obviate or supplement standard carrier protein-based
approaches.
With this purpose, an even more ambitious work is currently in pro-
gress in our laboratory. We have designed and synthesized a fully syn-
thetic hybrid vaccine construct incorporating the previously synthesized
unimolecular pentavalent carbohydrate domain and the MUC1 peptide
fragment along with an additional, highly immunogenic tumor-
associated peptide antigen.
49
Finally, we highlight below some of the most representative and
successful strategies implemented in other laboratories for the devel-
opment of MUC1 glycopeptide vaccines. These approaches are mainly
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