Biomedical Engineering Reference
In-Depth Information
candidates having low molecular weight and based on well-defined dendrimeric-
type structures are attractive scaffolds for assembling multiple epitopes. The
essential feature of this new generation of vaccine model consists in combining
both immunostimulant peptide fragments and TACAs as T-cell and B-cell
epitopes respectively. In addition, mucin carbohydrate markers should
preferentially be presented in a multivalent form to mimic the native structures
expressed on the tumor cell surface. By comparison with monovalent conjugates,
the multivalent presentation of mucin antigens, indeed favours the efficient
delivery of the vaccine prototype to APCs by virtue of cell receptor cross-linking
and endocytosis [52]. Secondly, the cluster formation also results in a high
density of carbohydrate antigens at the surface of a small peptidic scaffold, thus
eliciting the production of high titre of antibodies that are specific to tumors
expressing the same carbohydrate antigens. Moreover, unlike the few methods
available for carbohydrate conjugation to proteins and despite their relative
structural complexity, the synthesis of homogenous branched glycoconjugates in
good quantities relies on reproducible methods comparable to those described in
paragraph 3.
4.1.
Multiple Antigen Glycopeptide (MAG) using a polylysine core
On the basis of the multiple antigen peptides described earlier by Tam [53],
Leclerc and co-workers designed multiple antigen glycopeptide (MAG) [51,54].
This MAG is composed of a polylysine core which was assembled on the Wang
resin
26
pre-loaded with a βAla linker using the Fmoc strategy (Figure 11).
K-L-F-A-V-W-K-I-T-Y-K-D-T
K
K
K-L-F-A-V-W-K-I-T-Y-K-D-T
K-
β
A-
K-
β
A-
Wan g re sin
26
K-L-F-A-V-W-K-I-T-Y-K-D-T
K
K
OH
H O
27
K-L-F-A-V-W-K-I-T-Y-K-D-T
O
HO
A cH N
O
X
-K-L-F-A-V-W-K-I-T-Y-K-D-T
28
OH
O H
O H
HO
H O
HO
K
O
O
O
FmocH N
CO
2
H
H O
HO
H O
X
-K-L-F-A-V-W-K-I-T-Y-K-D-T
K-
β
A
AcHN
AcHN
A cH N
X
-K-L-F-A-V-W-K-I-T-Y-K-D-T
O
O
O
O
29
: X =
K
N
X
-K-L-F-A-V-W-K-I-T-Y-K-D-T
H
2
N
H
2
N
N
H
O
O
O
30
: X =
B- ce ll epitope
Th ep itope (PV pep tide)
Lysine cor e
O
NHAc
OH
O
OH
HO
Fig. 11. Structure of the MAG displaying Tn and PV epitopes.
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