Advances in Bioscience and Biotechnology, 2013, 4, 18-23 ABB
http://dx.doi.org/10.4236/abb.2013.49A003 Published Online September 2013 (http://www.scirp.org/journal/abb/)
Carbohydrate-associated epitope-based anti-cancer drugs
and vaccines*
Gregory Lee1,2, Cheng-Yuan Huang2, Song-Nan Chow3, Chin-Hsiang Chien4
1UBC Center for Reproductive Health, University of British Columbia, Vancouver, Canada
2Vancouver BioTech Ltd., Vancouver, Canada
3Department of Obstetrics/Gynecology, National Taiwan University Hospital, Taipei, Chinese Taipei
4Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei, Chinese Taipei
Received 27 June 2013; revised 28 July 2013; accepted 15 August 2013
Copyright © 2013 Gregory Lee et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
RP215 is one of the three thousand monoclonal anti-
bodies (Mabs) which were generated against the OC-
3-VGH ovarian cancer cell line. RP215 was shown to
react with a carbohydrate-associated epitope located
specifically on glycoproteins, known as CA215, from
cancer cells. Further molecular analysis by matrix
adsorption laser desorption/ionization time-of-flight
mass spectrometry (MALDI-TOF MS) revealed that
CA215 consists mainly of immunoglobulin super-fa-
mily (IgSF) proteins, including immunoglobulins, T-
cell receptors, and cell adhesion molecules, as well as
several other unrelated proteins. Peptide mappings
and glycoanalysis were performed with CA215 and
revealed high-mannose and complex bisecting struc-
tures with terminal sialic acid in N-glycans. As many
as ten O-glycans, which are structurally similar to
those of mucins, were also identified. In addition, two
additional O-linked glycans were exclusively detected
in cancerous immunoglobulins but not in normal B
cell-derived immunoglobulins. Immunizations of mice
with purified CA215 resulted in the predominant
generation of RP215-related Mabs, indicating the
immunodominance of this carbohydrate-associated
epitope. Anti-idiotype (anti-id) Mabs of RP215, which
were generated in the rat, were shown to contain the
internal images of the carbohydrate-associated epi-
tope. Following immunizations of these anti-id Mabs
in mice, the resulting anti-anti-id (Ab3) responses in
mice were found to be immuno logically similar to that
of RP215. Judging from these observations, anti-id
Mabs, which carry the internal image of the RP215-
specific epitope, may be suitable candidates for anti-
cancer vaccine development in humans.
Keywords: Anti-Cancer Drugs; Anti-Cancer Vaccines;
Anti-Idiotype; CA215; Carbohydrate-Associated Epitope;
Immunodominance; RP215
1. INTRODUCTION
Among the monoclonal antibodies (Mabs) which were
generated against the OC-3-VGH ovarian cancer cell line,
RP215 was shown to react with a carbohydrate-associ-
ated epitope detected in cancerous glycoproteins, known
as CA215. CA215 consists mainly of immunoglobulin
superfamily (IgSF) proteins, including antigen receptors
such as immunoglobulins, T-cell receptors, and several
other related molecules, as well as unrelated mucins [1].
During the last decade, efforts have been made to char-
acterize RP215 Mab and its cognate antigen, CA215.
Cancerous immunoglobulins are the predominant mole-
cules among CA215 that are recognized by RP215
through this specific carbohydrate-associated epitope [2].
Several experimental observations led us to conclude
that the RP215-specific epitope in CA215 is carbohy-
drate-associated. For example, a significant loss of RP-
215 epitope activity was observed when CA215 was
treated with mild sodium periodate solution (10 - 100
mM) at neutral pH, extreme heat (e.g. 100˚C for 5 min),
culturing of cancer cells in serum-free medium, or incu-
bation at extreme pH (≤ 2.0 or ≥12.0) [2-4]. This is in
contrast to normal human immunoglobulin G (IgG), of
which the immunoactivity remained stable under the
above conditions [2-4].
The ability of cancer cells to express immunoglobulins
has been known for decades [5]. These cancerous im-
munoglobulins have been found to be essential for the
growth/proliferation of cancer cells [4,6]. With RP215 as
the unique immunoprobe, numerous biological and im-
munological studies were performed to explore the
mechanisms of the action of cancerous immunoglobulins.
*Conflict of interest: Gregory Lee is a co-founder of Vancouver Bio-
Tech Ltd.

G. Lee et al. / Advances in Bioscience and Biotechnology 4 (2013) 18-23 19
A significant progress has been made regarding our cur-
rent understanding of cancer cell-expressed immu-
noglobulins and their potential roles [7]. By means of
terminal deoxynucleotidyl transferase dUTP nick end
labeling (TUNEL) apoptosis assays, it was clearly dem-
onstrated that RP215 or antibodies against immunog-
lobulins or T-cell receptors, induced apoptosis in all
studied cultured cancer cells, irrespective of their tissue
origins [8]. By immunohistochemical studies, immu-
noglobulins with the RP215 epitope can be readily de-
tected on the surface of cancer cells [9]. Consequently,
complement-dependent cytotoxicity (CDC) reactions can
also be induced by antibodies against a variety of differ-
ent classes or subclasses of immunoglobulins, including
IgG, immunoglobulin M (IgM), immunoglobulin A (IgA),
λ light chain or κ light chain [4,8]. CDC reactions can
also be induced similarly with RP215 [8,9]. This led us
to suggest the possibility that both RP215 and anti-anti-
gen receptor antibodies are involved in affecting similar
gene regulation patterns within cancer cells. This was
indeed the case when gene regulation studies were per-
formed with more than a dozen selected genes which are
essential for the growth and proliferation of cancer cells.
Excellent correlations were obtained between the gene
regulation patterns of these selected genes and treatment
with RP215 or anti-antigen receptors [7]. Furthermore,
both RP215 and anti-antigen receptors exhibited simi-
larly strong influences on the gene expressions of toll-
like receptors [7, 10]. In particular, additional gene regu-
lation studies revealed that genes of selected toll-like
receptors, TLR-2, TLR-3, TLR-4, and TLR-9, were sig-
nificantly affected by RP215 and antibodies against anti-
gen receptors [7]. Since toll-like receptors are key com-
ponents of cellular innate immunity, this observation
strongly suggests the involvement of cancerous immu-
noglobulins or antigen receptors in the innate immune
system of cancer cells [7,10].
Peptide mapping and glycoanalysis of purified CA215
were performed in an attempt to elucidate the molecular
structure of the carbohydrate-associated epitope recog-
nized by RP215 [1] and are highlighted in this review. In
addition, the immunological nature of RP215-specific epi-
tope was also investigated through studies of more anti-
CA215 Mabs and anti-idiotype (anti-id) Mabs against
RP215. The possibility of using carbohydrate epitope-
based anti-cancer vaccines was evaluated based on these
experimental observations [11].
2. BIOCHEMICAL AND
IMMUNOLOGICAL NATURE OF THE
CARBOHYDRATE-ASSOCIATED
EPITOPE
2.1. Structural Analysis of Carbohydrate Epitope
Recognized by RP215
Efforts were made to identify and elucidate the structures
of the RP215-specific carbohydrate-associated epitope.
These included structural analysis of the N-linked and
O-linked oligosaccharides in CA215 [1]. Initially, the
shed media from two cultured cancer cell-lines, OC-3-
VGH (ovarian) and C-33A (cervical), were collected se-
parately and purified for CA215 by RP215-affinity chro-
matography. To obtain affinity-purified cancerous IgG
(designated as CA215-D), affinity-purified CA215 was
further subjected to purification by anti-human IgG af-
finity chromatography (designated as CA215-D). The af-
finity-purified CA215 samples were desalted and clean-
ed of borate, permethylated, and analyzed either by nano
spray ionization-linear ion trap mass spectrometry (NSI-
LTQ/MSn) or by matrix-assisted laser desorption/ ioni-
zation time-of-flight mass spectrometry (MALDI-TOF
MS). N-linked glycan profiling revealed unusually high
mannose structures, as well as terminal N-glycolylnu-
eraminic acids, both of which do not appear in normal
human IgG [12]. On the other hand, several cancer-asso-
ciated mucin-type O-glycans were found in CA215, in-
cluding core 1 to 3 based structures such as sialyl-T, sia-
lyl-Tn, and di-sialyl-T antigens, and Lewis antigens such
as Lea, Leb, Lex, SLex, and Ley. The potential pathways
for the synthesis of the carbohydrate-associated epitope
recognized by RP215 have been elucidated by the studies
of glycosyl-transferases which are involved in O-glycan
synthesis (Gao. Y. and Brockhausen, I., personal com-
munication). Results of the comparative profiles of per-
methylated O-linked glycans from five different CA215
samples are presented in Table 1. From the structural
analysis of O-linked oligosaccharides identified for CA-
215, it can be demonstrated that cancerous IgG (CA215D)
can be attached with two different distinct O-linked oli-
gosaccharides: GalNAc1 Gal1 NeuAc1 and GalNAc1 Gal1
NeuAc2. These two O-linked oligosaccharides are unique
to cancerous IgG, but absent in normal human IgG [12].
It remains to be elucidated to see if these two O-linked
oligosaccharides are structurally linked to the RP215-
specific carbohydrate-associated epitope.
Following further analysis with glycosylation site pep-
tide mapping, the potential N-glycosylation and O-gly-
cosylation sites along the peptides sequences were iden-
tified by Protein BLAST service. Among the ten glyco-
peptides which were detected from CA215, eight were
shown to be homologous to the Fab and/or Fc fragments
of human immunoglobulin heavy chains. All the analyti-
cal results of the ten glycopeptides are summarized in
Table 2. These experimental analyses strongly suggested
that immunoglobulin heavy chains are the predominant
molecular species in CA215 [1,2]. In addition, the RP215-
specific epitope activity of CA215 was found to be
pH-dependent. At pH 12, deglycosylation of CA215 may
esult in loss of RP215 epitope activity. r

G. Lee et al. / Advances in Bioscience and Biotechnology 4 (2013) 18-23 20
Table 1. Comparative profiles of permethylated O-linked glycans of human IgG and five different CA215 samples.
Observed Mass Proposed
Sample ID m/z [M + Na]+ structure Structure
CA215 (lots: A, B, and C)a 534 GalNAc1Gal1
CA215 (lots: A and B) 708 GalNAc1Gal1Fuc1
CA215 (lots: A, B, D, C, E, and F)b896 GalNAc1Gal1NeuAc1
CA215 (lots: C, E, and F) 926 GalNAc1Gal1NeuGc1
CA215C 940c GalNAc1GlcNAc1NeuAc1
CA215(lots: A, B, and C) 1140 GalNAc1GlcNAc1Gal1NeuAc1
CA215 (lots: C, D, E, and F) 1257 GalNAc1Gal1NeuAc2
CA215 (lots: C, E, and F) 1317 GalNAc1Gal1NeuGc2
CA215 (lots: A, B, C, E, and F) 1345 GalNAc1GlcNAc1Gal2NeuAc1
CA215 (lots: C, E, and F) 1375 GalNAc1GlcNAc1Gal2NeuGc1
aCA215 lots A, B and C were from OC-3-VGH ovarian cancer cells (CA215-OC-3) lots A and B were obtained through acid elution, whereas lots C, D, E and F
were obtained through elution with 3M urea. bLot CA215D was obtained by an additional purification of urea-eluted CA215 (S15K-100425) with goat
anti-human. IgG affinity column followed by the same analysis (CA215D is designated as affinity-purified cancerous IgG). CA215 lots E and F were from
C-33A cervical cancer cells (CA215-C33A). cDetected by MALDI-TOF MS method but not found by NSI-MS method. dN-acetylgalactosamine (□),
N-acetylglucosamine (■), Fucose (▲), Galactose (●), N-acetylneuraminic acid (♦) and N-glycolylneuraminic acid (♦). [Obtained from reference #1 with per-
mission].
Table 2. N-linked and O-linked glycosylation site mappings of CA215. Fc refers to the constant region of the immunoglobulins. Fab
represents the variable region of the immunoglobulins. Lot CA215C (urea-eluted) was used for this analysis. The source protein
BLAST service was: http://blast.ncbi.nlm.nih.gov/Blast.cgi.
Accession number Peptide detecteda Peptide sequence homology of proteins (%)
I. CAC12842.1 1. EEQFNSTFR Immunoglobulin heavy chain (Fc) (100%)
II. CAA04843.1 2. EEQFNSTYR Immunoglobulin heavy chain (Fc) (100%)
III. AAB60643.2 3. LSVPTSEWQR Cathepsin S (100%)
IV. AAK68690.1 4. FTCLATNDAGDSSK Hemicentin (100%)
Titin (100%)
Palladin isoform 4 (92%)
LRN4 (78%)
(IgSF proteins)
V. AAD38158.1 5. DTLMISR Immunoglobulin heavy chain (Fc) (100%)
VI. AAC39746.2 6. GYLPEPVTVTWNSGTLTNGVR Immunoglobulin heavy chain (Fab) (90%)
VII. AAN76042.1 7. SVSLTCMINGFYPSDISVEWEK Immunoglobulin heavy chain (Fc) (90%)
VIII. CAJ75462.1 8. QSSGLYSLSSVVSVTSSSQPVTCNV Immunoglobulin heavy chain (Fab and Fc) (100%)
IX. ABY48864.2 9. VYTMGPPREELSSR Immunoglobulin heavy chain (Fc) (98%)
IgA variable region (89%)
IgM (98%)
X. NP_001139647.1 10. TFPSVR Zinc finger protein 414 isoform I (100%)
Forkhead box protein C2 (100%)
Immunoglobulin heavy chain variable region (83%)
a
; Bold letters indicate glycosylation sites [Obtained from reference #1 with permission].

G. Lee et al. / Advances in Bioscience and Biotechnology 4 (2013) 18-23 21
2.2. Molecular and Immuno-Characteristics of
Cancerous Immunoglobulins
The molecular and immunological nature of cancerous
immunoglobulins was further investigated initially through
reverse transcription polymerase chain reaction (RT-PCR)
to determine the primary structures of cancerous IgG and
IgA at the DNA and protein levels. In the constant re-
gions of the heavy chains, the IgG and IgA detected in
cancer cells were identical to those of normal human B
cells with homology greater than 98% [2,13]. Studies
were conducted to investigate if the glycosylations in
cancerous immunoglobulins have any alterations in their
biochemical and immunological properties as compared
to those of normal human IgG. As stated previously,
cancerous IgG was isolated by two-step affinity chroma-
tography from the OC-3-VGH ovarian cancer cell line.
Unexpectedly, the isolated cancerous IgG (CA215D in
Table 1) exhibits extremely low immunoactivity when
compared to that of normal human IgG. Apparently, the
aberrant glycosylations have altered the tertiary structure
of the cancerous IgG and subsequently its immunological
properties [3].
2.3. Immunodominance of RP215-Specific
Epitope in CA215
Attempts were made to generate additional Mabs against
affinity-purified CA215. Some of the epitopes recogni-
zed by the new Mabs were conformational, while others
were linear, similar to that recognized by RP215. When
compared with Mabs against CA215, the amino acid
sequence homology to RP215’s Fab regions ranged from
100% to 65% for the five generated Mabs which were
designated as RCA-10, RCA-100, RCA-104, RCA-110
and RCA-111, respectively [14]. Unexpectedly, all of the
five generated Mabs were shown to recognize epitopes
similar or identical to the RP215-specific epitope. All of
the generated RCA Mabs and RP215 were shown to
induce apoptosis and CDC of cancer cells in culture [14].
These Mabs were categorized into three distinct groups
according to their sequence homology and epitope spe-
cificity. All of these Mabs could be paired with RP215 in
a typical sandwich enzyme immunoassay [14]. These ex-
perimental observations strongly suggest the immunodo-
minance of the RP215-specific carbohydrate-associated
epitope. The immunological basis of the immunodomi-
nance of RP215-specific “sugar” epitope remains to be
explained. It also remains to be demonstrated if differen-
tial anti-cancer efficacy exists among the three distinct
groups of these biosimilar anti-CA215 Mabs. Due to the
existence of the immunodominance of the RP215-asso-
ciated carbohydrate epitope, we are encouraged to use
these RP215 unique epitope(s) or glycolpeptide com-
ponents for the development of anti-cancer vaccines or
antibody-based anti-cancer drugs in humans [14].
2.4. Anti-Idiotype Monoclonal Antibodies against
RP215 as Anti-Cancer Vaccines
RP215 was shown to inhibit the growth of a variety of
cancer cells in vitro and in vivo [9,11]. Anti-idiotype
(anti-id) Mabs against RP215 were generated in the rat
and characterized for future development of epitope-
specific anti-cancer vaccines in humans. These rat anti-id
Mabs were generated by using F(ab’)2 fragments of
RP215 as the immunogen. Anti-id Mabs were then util-
ized for subsequent immunizations in mice to induce
anti-anti-id (Ab3) antibody responses. By using TUNEL
apoptosis assay, both RP215 and Ab3 were shown to
induce apoptosis in cultured cancer cells [4, 7-9,11,13].
Ab3 and RP215 were shown to react similarly with can-
cer cells from cell lines of different human tissue origins
by immunohistochemical staining assay and by Western
blot assay [15].
Results of this study suggest that anti-id Mabs bear the
properties of the internal image of RP215-specific car-
bohydrate-associated epitope [11]. Ab3 immune respon-
ses can be induced upon immunization of rat anti-id Mab
in mice. Ab3 were shown to have immunological proper-
ties similar to that of RP215 in terms of the efficacy to
induce apoptosis to cancer cells. Therefore, anti-id Mabs
against RP215 could be a good candidate for the devel-
opment of anti-cancer vaccines in the future [11].
3. DISCUSSION
When RP215 Mab was initially generated against the
OC-3-VGH ovarian cancer cell extract in 1987, it was
initially used as for diagnostic applications to monitor
serum levels of CA215, a pan cancer biomarker among
cancer patients [16,17]. It was later shown that the epi-
tope recognized by RP215 was carbohydrate-associated
and reacts with CA215, which consists mainly of IgSF
proteins. Cancerous immunoglobulins are widespread
among all cancer cells and have been demonstrated to be
essential for the growth/proliferation of cancer cells
[4,8,11]. Therefore, RP215 may become a unique probe
to target surface bound immunoglobulins and serve as
antibody-based anti-cancer drugs for therapeutic applica-
tions [11]. In this review, efforts were made to summa-
rize the characteristics of this carbohydrate-associated
“sugar” epitope recognized by RP215 Mab, through pep-
tide mappings and glycoanalysis, demonstration of im-
munodominance, and generation of anti-id Mabs against
RP215 [1,11]. The progress of this research is briefly
described in this review for the potential development of
“sugar” epitope-based anti-cancer vaccines. With RP215
and anti-human IgG as the affinity ligands in two-step
immunoaffinity chromatography, cancerous IgG was

G. Lee et al. / Advances in Bioscience and Biotechnology 4 (2013) 18-23 22
purified from the shed media of two separate cancer cell
lines, OC-3-VGH (ovary) and C33A (cervix). Two O-
linked oligosaccharides were identified from the purified
cancerous IgG, but were absent in normal human IgG
[1,12]. It was assumed that these O-linked oligosaccha-
rides may be related to the RP215-specific carbohydra-
te-associated epitope in cancerous IgG. However, this
assumption can be verified only when the primary struc-
ture of the carbohydrate moiety is completely elucidated
[1].
The immunodominance of the RP215-specific carbo-
hydrate-associated epitope is an interesting phenomenon
[14,18]. When mixtures of purified CA215 glycoproteins,
each of which carries the RP215-specific epitope, were
used as immunogen to generate Mabs, all the recovered
clones were found to secrete Mabs recognizing epitope(s)
similar to that of RP215 [14]. This observation indicates
the immunodominance of the RP215-specific “sugar”
epitope, which may have potential application in future
cancer vaccine development [14,18].
Attempts were made to demonstrate the generations of
rat generated anti-id Mabs against RP215 for cancer vac-
cine development [11]. Following generations of mono-
clonal anti-id antibodies in the rat, anti-id antibodies can
be mass-produced and serve as the immunogen in ani-
mals or humans to induce Ab3 responses. Experimental
evidence has indicated that Ab3 antiserum is similar to
RP215 in recognizing the RP215-specific epitope of
CA215, with the anti-cancer efficacy demonstrated in our
studies, such as through induced apoptosis assays [4,11].
Therefore, monoclonal anti-id antibodies can serve as the
immunogen for anti-cancer vaccinations to induce Ab3
responses in humans for the therapeutic applications of
human cancer [11]. Cancer treatment with anti-id anti-
bodies through active immunizations in vaccinations has
been reported previously for leukemia, but with limited
efficacy [19]. Vaccination can elicit strong and specific
humoral responses to relevant tumor associated antigens,
but clinical implications of these results remain fully
elucidated. Judging from numerous on-going preclinical
studies, the RP215-specific carbohydrate-associated epi-
tope in cancerous immunoglobulins appears to be a suit-
able candidate for cancer vaccine development [8,11].
Furthermore, the carbohydrate-associated epitope-based
anti-cancer vaccines can potentially target cancer cells of
many tissue origins in humans [11].
4. CONCLUSION
There is no doubt that cancerous immunoglobulins play
an important role in the growth/proliferation of cancer
cells. The carbohydrate-associated epitope(s) on CA215
exhibit their universal expression in different cancer cell
lines and the unique characteristic of immunodominance.
The experimental results also suggested the concept of
developing a vaccine based on either a humanized RP215
Mab or its internal image (anti-id Mab). More effort is
still required to elucidate the structures of the carbohy-
drate-associated epitope on CA215. These updated ex-
perimental observations should advance our current un-
derstanding in cancer immunology and provide a novel
strategy for the development of cancer vaccines.
5. ACKNOWLEDGEMENTS
This work was supported in parts by NRC-IRAP program (#794354) of
Canada. Proof readings and preparations of this manuscript by summer
research student, Suefay Liu of McGill University, are acknowledged.
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