MONOCLONAL ANTIBODIES IN IMMUNODIAGNOSIS AND IMMUNOTHERAPY
Volume 36, Number 1, 2017ª Mary Ann Liebert, Inc.
DOI: 10.1089/mab.2016.0045

Short Communications

Antiglycopeptide Mouse Monoclonal Antibody LpMab-21
Exerts Antitumor Activity Against Human Podoplanin
Through Antibody-Dependent Cellular Cytotoxicity
and Complement-Dependent Cytotoxicity
Yukinari Kato,1 Akiko Kunita,2 Masashi Fukayama,2 Shinji Abe,3,4 Yasuhiko Nishioka,4 Hiroaki Uchida,5Hideaki Tahara,5 Shinji Yamada,1 Miyuki Yanaka,1 Takuro Nakamura,1 Noriko Saidoh,1 Kanae Yoshida,1
Yuki Fujii,1 Ryusuke Honma,1,6 Michiaki Takagi,6 Satoshi Ogasawara,1,7,8
Takeshi Murata,7,8 and Mika K. Kaneko1

The interaction between podoplanin (PDPN) and C-type lectin-like receptor 2 (CLEC-2) is involved in tumor
malignancy. We have established many monoclonal antibodies (mAbs) against human podoplanin using thecancer-specific mAb (CasMab) technology. LpMab-21, one of the mouse antipodoplanin mAbs, is of the IgG2a
subclass, and its minimum epitope was determined to be Thr76–Arg79 of the human podoplanin. Importantly,
sialic acid is linked to Thr76; therefore, LpMab-21 is an antiglycopeptide mAb (GpMab). In this study, weinvestigated whether LpMab-21 shows antibody-dependent cellular cytotoxicity (ADCC) and complementdependent cytotoxicity (CDC) against human podoplanin-expressing cancer cell lines in vitro and also studied
its antitumor activities using a xenograft model. LpMab-21 showed high ADCC and CDC activities against not
only podoplanin-expressing Chinese hamster ovary cells but also LN319 glioblastoma cells and PC-10 lungcancer cells, both of which endogenously express podoplanin. Furthermore, LpMab-21 decreased tumor growthin vivo, indicating that LpMab-21 could be useful for antibody therapy against human podoplanin-expressing
cancers.
Keywords: podoplanin, monoclonal antibody, ADCC, CDC, antitumor activity

stimulating domain, and it also binds to the a-2,6-linked sialic
acid linked to Thr52.(24)
Although many antihuman podoplanin monoclonal antibodies (mAbs) are commercially available, almost all themAbs react with the N-terminus of human podoplanin.(6,25–29)
In contrast, we have used the cancer-specific mAb (CasMab)technology to produce antiglycopeptide mAbs (GpMabs)
against human podoplanin.(30–39) Recently, we have successfully developed a novel antihuman podoplanin mAb, LpMab21, which recognizes a sialylated glycopeptide epitope.(40)
LpMab-21 is one of the GpMabs, but not a CasMab.

IntroductionP

odoplanin (PDPN) is expressed in many tumors, suchas brain tumors, esophageal cancers, lung cancers, malignant mesotheliomas, osteosarcomas, fibrosarcomas, testicular cancers, and bladder cancers.(1–15) Importantly, theexpression of human podoplanin in cancer-associated fibroblasts contributes to poor prognosis.(16–21) C-type lectin-likereceptor 2 (CLEC-2) is an endogenous receptor of human podoplanin.(22,23) It binds to human podoplanin throughresidues Glu47 and Asp48 within its platelet aggregation1

Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Clinical Pharmacy Practice Pedagogy, Graduate School of Biomedical Sciences, Tokushima University, Tokushima,
Japan.
4
Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima,
Japan.
5
Division of Bioengineering, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo,
Japan.
6
Department of Orthopaedic Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan.
7
Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan.
8
Molecular Chirality Research Center, Chiba University, Chiba, Japan.
2
320

ANTIHUMAN PODOPLANIN MAB LPMAB-21

Results and Discussion

We have produced several antihuman podoplanin mAbs
using the CasMab technology; however, the isotypes of themAbs are IgG1 (seven clones) and IgG3 (one clone), which do
not induce antibody-dependent cellular cytotoxicity (ADCC)
or complement-dependent cytotoxicity (CDC). The applications of mouse IgG3 mAbs are limited because they often
aggregate.(41) In this case, we have had to convert them tohuman IgG1 to investigate whether these mAbs cause ADCC
and CDC.(33) In contrast, the mouse IgG2a subclass can induce
ADCC and CDC; therefore, we investigated whether LpMab-21
can induce ADCC and CDC against human podoplaninexpressing cancer cell lines. As shown in Figure 1A,
LpMab-21 demonstrated ADCC against LN319, the Chinese hamster ovary (CHO)/human podoplanin, and PC-10
cell lines, whereas it did not induce ADCC against human
podoplanin-negative parental CHO cells. Similarly, LpMab21 induced CDC against LN319 and PC-10 cell lines(Fig. 1B). We previously demonstrated that LN319 expresses
human podoplanin at a higher level than does PC-10(30);therefore, ADCC and CDC might depend on the human podoplanin expression levels in these cell lines.
To investigate the antitumor activity of LpMab-21 on
primary tumor growth in vivo, CHO/human podoplanin cells
were subcutaneously implanted into flanks of nude mice.
LpMab-21 or control mouse IgG (clone PMab-2)(42) was
injected into the peritoneal cavity of the mice once weekly for
4 weeks (n = 6 each). PMab-2 was raised against rat podoplanin and was shown to not cross-react with human podoplanin.(42) Tumor formation was observed in five mice fromthe control group (tumor incidence on day 35: 83.3%, 5/6;
Supplementary Fig. S1). In contrast, LpMab-21 dramaticallyreduced the tumor development (tumor incidence on day 35:
50%, 3/6; Supplementary Fig. S1). The tumor volume wassignificantly reduced by LpMab-21 treatment (Fig. 2). These
results indicate that administration of LpMab-21 inhibitedthe primary tumor growth of CHO/human podoplanin cells.
In our previous study, only CDC of a human–mouse chimericanti-PDPN mAb could show antitumor activity because
human NK cell was not added in this xenograft model.(43) In
contrast, we also showed that ADCC of a human–mousechimeric anti-PDPN mAb is more important than CDC in
another study.(9) Therefore, we think that both ADCC and
CDC are important to induce antitumor activity in the xenograft model.

‰

Importantly, LpMab-21 is the first mouse antihuman podoplanin mAb of the IgG2a subclass, which was generated using
the CasMab technology.(30–36,38,39)

21

FIG. 1. Antibody-dependent cellular cytotoxicity (ADCC)
and complement-dependent cytotoxicity (CDC) of LpMab-21
against human podoplanin-expressing cell lines. (A) ADCC
activity of LpMab-21. Mouse splenocytes were harvested fromsevere combined immunodeficiency mouse spleens. Spleens
were homogenized in RPMI 1640 and centrifuged. To deplete
red blood cells, the cell pellet was suspended in red blood cell
lysis buffer (Sigma–Aldrich). After washing and resuspension
in cRPMI1640, splenocytes were used as effector cells. ADCC
was determined using the 51Cr release assay. Target cells wereincubated with 0.1 mCi of [51Cr]sodium chromate at 37C for
1 hour. After washing with cRPMI1640 three times, 51Crlabeled target cells were placed in 96-well plates in triplicate.
Effector cells and LpMab-21 or control mouse IgG were added
to the plates. After 6 hours of incubation, 51Cr release wasmeasured in the supernatant (100 mL) from each well using a
gamma counter (PerkinElmer). The percentage of cytotoxicity
was calculated using the following formula: specific lysis(%) = (E - S)/(M - S) · 100, where E is the 51Cr release in thetest sample, S is the spontaneous release, and M is the maximum release. Statistical significance of the differences inin vitro data was analyzed by the standard Student’s t-test. In
this study, p values of <0.05 were considered statistically significant in all experiments. **p < 0.01 (B) CDC was evaluatedwith the 51Cr release assay. Target cells were incubated with
[51Cr]sodium chromate (0.1 mCi) for 1 hour at 37C. The cells
were then washed with cRPMI1640. The 51Cr-labeled cells
were incubated with a baby rabbit complement (Cedarlane) at adilution of 1:32 (Chinese hamster ovary [CHO] and CHO/
human podoplanin) or 1:4 (LN319 and PC-10) in the presenceof LpMab-21 (1 mg/mL) or control mouse IgG (1 mg/mL) for
3 hours (CHO and CHO/human podoplanin) or 6 hours (LN319
and PC-10) in 96-well plates. After the incubation, the 51Cr
radioactivity was measured in the supernatants using a gamma
counter. The percentage of cytotoxicity was calculated as described previously. **p < 0.01.

22

KATO ET AL.

FIG. 2. Antitumor effects of LpMab-21 on primary tumor
development. CHO/human podoplanin cells (3 · 106 cells/
100 mL) were subcutaneously inoculated into BALB/c nude
mice. After 1 day, 100 mg of LpMab-21 or control mouse
IgG (clone PMab-2) was injected into the peritoneal cavityof the mice. The antibodies were injected once weekly for 4
weeks (control group: n = 6; LpMab-21 group: n = 6). The
tumor diameter was measured at intervals of 3 to 4 days andwas calculated using the following formula: tumor volume = W2 · L/2, where W is short diameter and L is long
diameter. *p < 0.05; **p < 0.01 with two-way analysis ofvariance.
Taken together, LpMab-21 could be useful for antibody
therapy against human podoplanin-expressing cancers. Ourdeveloped CasMabs as well as LpMab-21 could be applied to
the novel antitumor reagents, including T cells and viruses,(44) to give strict specificity against tumor cells.
Acknowledgments

This work was supported, in part, by project for utilizing
glycans in the development of innovative drug discovery
technologies from Japan Agency for Medical Research anddevelopment, AMED (Y.K.), by the Basic Science and Platform Technology Program for Innovative Biological Medicine
from AMED (Y.K.), by the Platform for Drug Discovery, Informatics, and Structural Life Science (PDIS) from AMED
(Y.K., T.M.), by Translational Research Network Programfrom AMED (Y.K.), by JSPS KAKENHI Grant Number
26440019 (M.K.K.) and 16K10748 (Y.K.), and by the Regional Innovation Strategy Support Program from the Ministryof Education, Culture, Sports, Science and Technology(MEXT) of Japan (Y.K.). This work was performed, in part,
under the Cooperative Research Program of Institute for Protein Research, Osaka University, CR-16–05, and by the Grant
for Joint Research Project of the Institute of Medical Science,
the University of Tokyo. The authors would like to thankEnago (www.enago.jp) for the English language review.
Author Disclosure Statement

No competing financial interests exist.
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Address correspondence to:
Dr. Yukinari Kato
Tohoku University Graduate School of Medicine
2-1 Seiryo-machi
Aoba-ku
Sendai
Miyagi 980-8575
JapanE-mail: yukinari-k@bea.hi-ho.ne.jp
Received: November 14, 2016
Accepted: December 19, 2016