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Am J Transl Res 2012;4(4):415-421
Original Article
Soluble heparin-binding EGF-like growth factor (HB-EGF) detected by
newly developed immuno-PCR method is a clear-cut serological
biomarker for ovarian cancer
Noriyuki Kasai, Kazuhiro Kobayashi, Shinobu Shioya, Yukitaka Yoshikawa, Fusanori Yotsumoto, Shingo
Miyamoto, Eisuke Mekada, Junichi Enokizono
Pharmacokinetic Research Laboratories, Kyowa Hakko Kirin Co. Ltd., 1188, Shimotogari, Nagaizumi-cho,
Sunto-gun, Shizuoka, 411-8731, Japan; Department of Obstetrics and Gynecology, School of Medicine, Fukuoka
University, 45-1, 7-Chome Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan; Research Institute for Microbial
Diseases, Osaka University, 3-1, Yamadaoka, Suita, Osaka, 565-0871, Japan
Received August 6, 2012; accepted September 23, 2012; Epub October 10, 2012; Published October 30, 2012
Abstract: Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of growth factors that
bind to and activate the EGF receptor. HB-EGF is synthesized as a membrane-anchored protein (proHB-EGF),
and then proteolytically cleaved, resulting in the mitogenically active soluble form. HB-EGF plays pivotal roles in
pathophysiological processes such as development and cell proliferation. In this study, we developed an
immuno-PCR system for the determination of soluble HB-EGF concentrations in human serum. Utilizing a
monoclonal antibody with neutralizing activity against HB-EGF as a capture antibody resulted in increasing
selectivity for an active form of HB-EGF in serum, and immuno-PCR system improved its sensitivity compared to
the currently available methods. As a result of measurement of HB-EGF in 20 ovarian cancer patients and 20
healthy volunteers, ovarian cancer patients showed significantly higher concentrations than healthy volunteers
(P<0.05), which indicates that soluble HB-EGF detected by newly developed immuno-PCR system can be useful
serological biomarkers such as a diagnostic biomarker for ovarian cancer, and a predictive and
pharmacodynamic biomarker for anti-HB-EGF targeted therapies under development. (AJTR1208002).
Keywords: HB-EGF, ovarian cancer, serological biomarker, immuno-PCR
Address all correspondence to:
Dr. Noriyuki Kasai, Pharmacokinetic Research Laboratories, Kyowa Hakko Kirin Co. Ltd., 1188, Shimotogari,
Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan. Tel: +81-55-989-4289; Fax: +81-55-989-2073; E-mail:
noriyuki.kasai@kyowa-kirin.co.jp
Original Article
Soluble heparin-binding EGF-like growth factor (HB-EGF) detected by
newly developed immuno-PCR method is a clear-cut serological
biomarker for ovarian cancer
Noriyuki Kasai, Kazuhiro Kobayashi, Shinobu Shioya, Yukitaka Yoshikawa, Fusanori Yotsumoto, Shingo
Miyamoto, Eisuke Mekada, Junichi Enokizono
Pharmacokinetic Research Laboratories, Kyowa Hakko Kirin Co. Ltd., 1188, Shimotogari, Nagaizumi-cho,
Sunto-gun, Shizuoka, 411-8731, Japan; Department of Obstetrics and Gynecology, School of Medicine, Fukuoka
University, 45-1, 7-Chome Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan; Research Institute for Microbial
Diseases, Osaka University, 3-1, Yamadaoka, Suita, Osaka, 565-0871, Japan
Received August 6, 2012; accepted September 23, 2012; Epub October 10, 2012; Published October 30, 2012
Abstract: Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of growth factors that
bind to and activate the EGF receptor. HB-EGF is synthesized as a membrane-anchored protein (proHB-EGF),
and then proteolytically cleaved, resulting in the mitogenically active soluble form. HB-EGF plays pivotal roles in
pathophysiological processes such as development and cell proliferation. In this study, we developed an
immuno-PCR system for the determination of soluble HB-EGF concentrations in human serum. Utilizing a
monoclonal antibody with neutralizing activity against HB-EGF as a capture antibody resulted in increasing
selectivity for an active form of HB-EGF in serum, and immuno-PCR system improved its sensitivity compared to
the currently available methods. As a result of measurement of HB-EGF in 20 ovarian cancer patients and 20
healthy volunteers, ovarian cancer patients showed significantly higher concentrations than healthy volunteers
(P<0.05), which indicates that soluble HB-EGF detected by newly developed immuno-PCR system can be useful
serological biomarkers such as a diagnostic biomarker for ovarian cancer, and a predictive and
pharmacodynamic biomarker for anti-HB-EGF targeted therapies under development. (AJTR1208002).
Keywords: HB-EGF, ovarian cancer, serological biomarker, immuno-PCR
Address all correspondence to:
Dr. Noriyuki Kasai, Pharmacokinetic Research Laboratories, Kyowa Hakko Kirin Co. Ltd., 1188, Shimotogari,
Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan. Tel: +81-55-989-4289; Fax: +81-55-989-2073; E-mail:
noriyuki.kasai@kyowa-kirin.co.jp
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