Anti-tumor effect against human cancer xenografts by a fully human monoclonal antibody to a variant 8-epitope of CD44R1 expressed on cancer stem cells

Kazue Masuko, Shogo Okazaki, Mayumi Satoh, Goh Tanaka, Tatsuya Ikeda, Ryota Torii, Eri Ueda, Takashi Nakano, Masaaki Danbayashi, Tomoyo Tsuruoka, Yoshiya Ohno, Hideki Yagi, Noritsugu Yabe, Hideaki Yoshida, Tomoyuki Tahara, Shiro Kataoka, Taichi Oshino, Takayuki Shindo, Shin ichiro Niwa, Takatsugu IshimotoHideo Baba, Yoshiyuki Hashimoto, Hideyuki Saya, Takashi Masuko

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background: CD44 is a major cellular receptor for hyaluronic acids. The stem structure of CD44 encoded by ten normal exons can be enlarged by ten variant exons (v1-v10) by alternative splicing. We have succeeded in preparing MV5 fully human IgM and its class-switched GV5 IgG monoclonal antibody (mAb) recognizing the extracellular domain of a CD44R1 isoform that contains the inserted region coded by variant (v8, v9 and v10) exons and is expressed on the surface of various human epithelial cancer cells. Methods and Principal Findings: We demonstrated the growth inhibition of human cancer xenografts by a GV5 IgG mAb reshaped from an MV5 IgM. The epitope recognized by MV5 and GV5 was identified to a v8-coding region by the analysis of mAb binding to various recombinant CD44 proteins by enzyme-linked immunosorbent assay. GV5 showed preferential reactivity against various malignant human cells versus normal human cells assessed by flow cytometry and immunohistological analysis. When ME180 human uterine cervix carcinoma cells were subcutaneously inoculated to athymic mice with GV5, significant inhibition of tumor formation was observed. Furthermore, intraperitoneal injections of GV5markedly inhibited the growth of visible established tumors from HSC-3 human larynx carcinoma cells that had been subcutaneously transplanted one week before the first treatment with GV5. From in vitro experiments, antibody-dependent cellular cytotoxicity and internalization of CD44R1 seemed to be possible mechanisms for in vivo anti-tumor activity by GV5. Conclusions: CD44R1 is an excellent molecular target for mAb therapy of cancer, possibly superior to molecules targeted by existing therapeutic mAb, such as Trastuzumab and Cetuximab recognizing human epidermal growth factor receptor family.

Original languageEnglish
Article numbere29728
JournalPLoS One
Volume7
Issue number1
DOIs
Publication statusPublished - 2012 Jan 17

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Neoplastic Stem Cells
Stem cells
Heterografts
epitopes
stem cells
Tumors
Epitopes
monoclonal antibodies
Monoclonal Antibodies
Cells
neoplasms
Exons
Neoplasms
Immunoglobulin M
exons
Immunoglobulin G
Recombinant proteins
Immunosorbents
Flow cytometry
carcinoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Anti-tumor effect against human cancer xenografts by a fully human monoclonal antibody to a variant 8-epitope of CD44R1 expressed on cancer stem cells. / Masuko, Kazue; Okazaki, Shogo; Satoh, Mayumi; Tanaka, Goh; Ikeda, Tatsuya; Torii, Ryota; Ueda, Eri; Nakano, Takashi; Danbayashi, Masaaki; Tsuruoka, Tomoyo; Ohno, Yoshiya; Yagi, Hideki; Yabe, Noritsugu; Yoshida, Hideaki; Tahara, Tomoyuki; Kataoka, Shiro; Oshino, Taichi; Shindo, Takayuki; Niwa, Shin ichiro; Ishimoto, Takatsugu; Baba, Hideo; Hashimoto, Yoshiyuki; Saya, Hideyuki; Masuko, Takashi.

In: PLoS One, Vol. 7, No. 1, e29728, 17.01.2012.

Research output: Contribution to journalArticle

Masuko, K, Okazaki, S, Satoh, M, Tanaka, G, Ikeda, T, Torii, R, Ueda, E, Nakano, T, Danbayashi, M, Tsuruoka, T, Ohno, Y, Yagi, H, Yabe, N, Yoshida, H, Tahara, T, Kataoka, S, Oshino, T, Shindo, T, Niwa, SI, Ishimoto, T, Baba, H, Hashimoto, Y, Saya, H & Masuko, T 2012, 'Anti-tumor effect against human cancer xenografts by a fully human monoclonal antibody to a variant 8-epitope of CD44R1 expressed on cancer stem cells', PLoS One, vol. 7, no. 1, e29728. https://doi.org/10.1371/journal.pone.0029728
Masuko, Kazue ; Okazaki, Shogo ; Satoh, Mayumi ; Tanaka, Goh ; Ikeda, Tatsuya ; Torii, Ryota ; Ueda, Eri ; Nakano, Takashi ; Danbayashi, Masaaki ; Tsuruoka, Tomoyo ; Ohno, Yoshiya ; Yagi, Hideki ; Yabe, Noritsugu ; Yoshida, Hideaki ; Tahara, Tomoyuki ; Kataoka, Shiro ; Oshino, Taichi ; Shindo, Takayuki ; Niwa, Shin ichiro ; Ishimoto, Takatsugu ; Baba, Hideo ; Hashimoto, Yoshiyuki ; Saya, Hideyuki ; Masuko, Takashi. / Anti-tumor effect against human cancer xenografts by a fully human monoclonal antibody to a variant 8-epitope of CD44R1 expressed on cancer stem cells. In: PLoS One. 2012 ; Vol. 7, No. 1.
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AU - Masuko, Kazue

AU - Okazaki, Shogo

AU - Satoh, Mayumi

AU - Tanaka, Goh

AU - Ikeda, Tatsuya

AU - Torii, Ryota

AU - Ueda, Eri

AU - Nakano, Takashi

AU - Danbayashi, Masaaki

AU - Tsuruoka, Tomoyo

AU - Ohno, Yoshiya

AU - Yagi, Hideki

AU - Yabe, Noritsugu

AU - Yoshida, Hideaki

AU - Tahara, Tomoyuki

AU - Kataoka, Shiro

AU - Oshino, Taichi

AU - Shindo, Takayuki

AU - Niwa, Shin ichiro

AU - Ishimoto, Takatsugu

AU - Baba, Hideo

AU - Hashimoto, Yoshiyuki

AU - Saya, Hideyuki

AU - Masuko, Takashi

PY - 2012/1/17

Y1 - 2012/1/17

N2 - Background: CD44 is a major cellular receptor for hyaluronic acids. The stem structure of CD44 encoded by ten normal exons can be enlarged by ten variant exons (v1-v10) by alternative splicing. We have succeeded in preparing MV5 fully human IgM and its class-switched GV5 IgG monoclonal antibody (mAb) recognizing the extracellular domain of a CD44R1 isoform that contains the inserted region coded by variant (v8, v9 and v10) exons and is expressed on the surface of various human epithelial cancer cells. Methods and Principal Findings: We demonstrated the growth inhibition of human cancer xenografts by a GV5 IgG mAb reshaped from an MV5 IgM. The epitope recognized by MV5 and GV5 was identified to a v8-coding region by the analysis of mAb binding to various recombinant CD44 proteins by enzyme-linked immunosorbent assay. GV5 showed preferential reactivity against various malignant human cells versus normal human cells assessed by flow cytometry and immunohistological analysis. When ME180 human uterine cervix carcinoma cells were subcutaneously inoculated to athymic mice with GV5, significant inhibition of tumor formation was observed. Furthermore, intraperitoneal injections of GV5markedly inhibited the growth of visible established tumors from HSC-3 human larynx carcinoma cells that had been subcutaneously transplanted one week before the first treatment with GV5. From in vitro experiments, antibody-dependent cellular cytotoxicity and internalization of CD44R1 seemed to be possible mechanisms for in vivo anti-tumor activity by GV5. Conclusions: CD44R1 is an excellent molecular target for mAb therapy of cancer, possibly superior to molecules targeted by existing therapeutic mAb, such as Trastuzumab and Cetuximab recognizing human epidermal growth factor receptor family.

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