Development of cancer vaccines from fully synthetic mucin-based glycopeptide antigens. A vision on mucins from the bioorganic chemistry perspective - Carbohydrate Chemistry: Chemical and Biological Approaches - page 554

clinical trial in ovarian cancer patients at MSKCC, and the study is
nearing completion. Full evaluation of promising preliminary serological
data must await completion of the trial.

3.4 Strategies for enhancing the carrier protein response in
mucin-related glycopeptide-based cancer vaccines.
3.4.1 Incorporation of additional immunoenhancing elements:
dual-acting KLH-conjugated vaccines. In a futher refinement and logical
progression of our vaccine program, we sought to incorporate an
additional immunogenic component, i.e. an antigenic peptide marker,
into the glycopeptide backbone of our multiantigenic constructs,
with the aim of augmenting the effect of the carrier protein, and
eliciting a B- and/or T-cell response. Following the lead of the mucin
family of O-linked glycoproteins, with the hope of exploiting the
immunogenicity of the mucin peptides, we designed a new type of
antitumor vaccine construct featuring both a carbohydrate-based anti-
gen and a mucin-derived peptide marker in an alternating pattern.
Again, this type of design seeks to mimic the molecular architecture of
the tumor cell surface, thus provoking a more realistic and effective
immune response. We reasoned that inclusion of a tumor-associated
mucin sequence on the peptide backbone could enable an augmented,
long-lived IgG antibody response. This type of vaccine construct with
clustered carbohydrate-peptide fragments could have three potential
advantages. First, a mucin-derived peptide marker may act not only as a
B-cell epitope for the generation of antibodies against mucins, but also
as a T-helper cell epitope to activate T-cells. Moreover, the tandem
repeats of both carbohydrate and peptide would maximize the exposure
oftheseB-cellandTcellepitopesonthesurfaceofthecarrierprotein.
Finally, vaccines comprised of several carbohydrate and peptide anti-
gens associated with a particular type of cancer may provide an in-
creased and more diverse antibody response, thus improving the
e ciency of binding to target tumor cells.
As a proof of principle, we designed and synthesized a KLH-conjugated
vaccine construct 40 targeting ovarian cancer, which contains alternating
repeat domains of the Gb 3 carbohydrate antigen (globotriaosyl cer-
amide) 41 and MUC5AC peptide marker (Fig. 7). 42 Structurally, MUC5AC
consists of tandem repeat domains of an eight-amino acid sequence
(TTSTTSAP), which are potentially responsible for the activation of T
cells. Synthesis of this dual-acting vaccine construct was accomplished by
standard peptide ligation methods, using a Gb 3 -MUC5AC thioester as a
key building block, followed by final conjugation to KLH. Preliminary
immunological evaluation of this construct suggests a moderate IgM and
IgG response to both the Gb 3 and MUC5AC antigens.
Furthermore, it is well-known that the overexpression of MUC1
is correlated with the progression of breast, 43 ovarian 44 and colon 45
cancers. For this reason, it has emerged as an attractive antigen in
the design of antitumor vaccines. From a structural standpoint, MUC1
contains repeating units of a 20-amino acid sequence (HGVTSAPDTR-
PAPGSTAPPA)

this glycoprotein. 46 in the extracellular portion of