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研究開発


 株式会社先端生命科学研究所では、世界初のHCV抗原測定系をはじめ、HCV抗体診断薬、HBV抗原診断薬などのウイルス性肝炎診断薬の研究開発を行うと共に、それらの知見を活かし、ウイルス感染モデルの研究も行っています。さらに外部研究機関との共同研究等を通して、肺小細胞がんマーカーなどの研究開発や、新規バイオマーカーの研究開発も進めております。
 実際に臨床応用されている当社技術を下にした診断薬及び関連領域を以下に紹介します。



・HCV抗原診断薬
C型肝炎を引き起こすHCVを検出定量する診断薬です。血液を採取し、血清中のHCVコア抗原を測定することにより、ウイルス量を把握することができます。イムノアッセイであるため、PCRなどの核酸増幅系より簡便・安価に測定できます。
世界に先駆け私たちが開発した測定系であり、当社の独創性と技術力が活かされています。


・HCV抗体診断薬
血清中のHCVに対する抗体を検出する診断薬です。遺伝子工学を用いて作製したHCV抗原を使用した製品で、HCVに感染しているかを調べることができます。


・高感度HBV抗原診断薬
B型肝炎を引き起こすHBVを検出定量する診断薬です。PCRなどの核酸増幅系より簡便・安価に測定できます。血清中のHBV表面抗原やコア関連抗原を測定することにより、HBVのスクリーニングや治療モニタリングへの応用が期待されます。変異株に対しても広いスペクトルを有しており当社の独創性が活かされています。


・ProGRP測定診断薬
肺がんの中でも悪性度の高い肺小細胞がんの診断に役立ちます。
ProGRP(ガストリン放出ペプチド前駆体)は、小細胞がんのみで濃度が上昇するため、その他の肺がんとの鑑別に有用です。


・HCV感染モデルの研究
私たちは臨床診断薬分野のみならず、HCV診断薬の研究開発の成果を基に、HCVの治療薬の開発に応用可能なHCV細胞培養系や感染動物モデル系の研究開発を進めています。



■主な投稿論文


Shiotsu Y, Mori Y, Nishimura M, Hatta T, Imada N, Maki N, Iida K, Iwamoto N, Matsuoka E, Tamagaki K, Kosaki A.
Prognostic utility of plasma S100A12 levels to establish a novel scoring system for predicting mortality in maintenance hemodialysis patients: a two-year prospective observational study in Japan.
BMC nephrology 2013; 14: 16.

Iwasaki Y, Mori K, Ishii K, Maki N, Iijima S, Yoshida T, Okabayashi S, Katakai Y, Lee YJ, Saito A, Fukai H, Kimura N, Ageyama N, Yoshizaki S, Suzuki T, Yasutomi Y, Miyamura T, Kannagi M, Akari H.
Long-Term Persistent GBV-B Infection and Development of a Chronic and Progressive Hepatitis C-Like Disease in Marmosets.
Front. Microbiol. 2011; 2: 240.

Shiotsu Y, Mori Y, Hatta T, Maki N, Iida K, Matsuoka E, Kado H, Ishida R, Kishimoto N, Tamagaki K, Nishimura M, Iwamoto N, Ono T, Matsubara H, Kosaki A.
Plasma S100A12 levels and peripheral arterial disease in end-stage renal disease.
Nephron extra 2011; 1: 242-250.

Shiotsu Y, Mori Y, Nishimura M, Sakoda C, Tokoro T, Hatta T, Maki N, Iida K, Iwamoto N, Ono T, Matsuoka E, Kishimoto N, Tamagaki K, Matsubara H, Kosaki A.
Plasma S100A12 level is associated with cardiovascular disease in hemodialysis patients.
CJASN. 2011; 6: 718-723.

Masaki T, Suzuki R, Saeed M, Mori K, Matsuda M, Aizaki H, Ishii K, Maki N, Miyamura T, Matsuura Y, Wakita T, Suzuki T.
Production of infectious hepatitis C virus by using RNA polymerase I-mediated transcription.
J. Virol. 2010; 84: 5824-5835.

Matsubara N, Kusano O, Sugamata Y, Itoh T, Mizuii M, Tanaka J, Yoshizawa H.
A novel hepatitis B virus surface antigen immunoassay as sensitive as hepatitis B virus nucleic acid testing in detecting early infection.
Transfusion 2009; 49: 585-595.

Mori Y, Kosaki A, Kishimoto N, Kimura T, Iida K, Fukui M, Nakajima F, Nagahara M, Urakami M, Iwasaka T, Matsubara H.
Increased plasma S100A12(EN-RAGE) levels in hemodialysis patients with atherosclerosis.
Am. J. Nephrol. 2009; 29(1): 18-24.

Tanaka E, Matsumoto A, Yoshizawa K, Maki N.
Hepatitis B core-related antigen assay is useful for monitoring the antiviral effect of nucleoside analogue therapy.
Intervirology 2008; 51(suppl 1): 3-6.

Yokota T, Iijima S, Kubodera T, Ishii K, Katakai Y, Ageyama N, Chen Y, Lee YJ, Unno T, Nishina K, Iwasaki Y, Maki N, Mizusawa H, Akari H.
Efficient regulation of viral replication by siRNA in a non-human primate surrogate model for hepatitis C.
Biochem. Biophys. Res. Commun. 2007; 361(2): 294-300.

Ito T, Maki N, Hazeki O, Sasaki K, Nekooki M.
Extracellular and transmembrane region of a podocalyxin-like protein 1 fragment identified from colon cancer cell lines.
Cell Biol. Int. 2007; 31: 1518-1524.

Matsumoto A, Tanaka E, Minami M, Okanoue T, Yatsuhashi H, Nagaoka S, Suzuki F, Kobayashi M, Chayama K, Imamura M, Yotsuyanagi H, Nakaoka S, Maki N, Kawata S, Kumada H, Iino S, Kiyosawa K.
Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy.
Hepatology. Res. 2007; 37: 661-666.

Ishii K, Iijima S, Kimura N, Lee YJ, Ageyama N, Yagi S, Yamaguchi K, Maki N, Mori K, Yoshizaki S, Machida S, Suzuki T, Iwata N, Sata T, Terao K, Miyamura T, Akari H.
GBV-B as a pleiotropic virus: distribution of GBV-B in extrahepatic tissues in vivo.
Microbes Infection. 2007; 9: 515-521.

Misawa N, Matsumoto A, Tanaka E, Rokuhara A, Yoshizawa K, Umemura T, Maki N, Kimura T, Kiyosawa K.
Patients with and without loss of hepatitis B virus DNA after hepatitis B e antigen seroconversion have different virological characteristics.
J. Med. Virol. 2006; 78: 68-73.

Rokuhara A, Matsumoto A, Tanaka E, Umemura T, Yoshizawa K, Kimura T, Maki N, Kiyosawa K.
Hepatitis B virus RNA is measurable in serum and can be a new marker for monitoring lamivudine therapy.
J. Gastroenterol. 2006; 41: 785-790.

Yagi S, Mori K, Shiota K.
Implication of the HCV subgenome discovery for viral pathogenesis, persistence and proliferation.
Future Virol. 2006; 1(4): 425-433.

Tanaka E, Matsumoto A, Suzuki F, Kobayashi M, Mizokami M, Tanaka Y, Okanoue T, Minami M, Chayama K, Imamura M, Yatsuhashi H, Nagaoka S, Yotsuyanagi H, Kawata S, Kimura T, Maki N, Iino S, Kiyosawa K and HBV core-related antigen study group.
Measurement of hepatitis B virus core-related antigen is valuable for identifying patients who are at low risk of lamivudine resistance.
Liver Int. 2006; 26: 90-96.

Yagi S, Mori K, Tanaka E, Matsumoto A, Sunaga F, Kiyosawa K, Yamaguchi K.
Identification of novel HCV subgenome replicating persistency in chronic active hepatitis C patients.
J. Med. Virol. 2005; 77: 399-413.

Iwabata H, Yoshida M, Komatsu Y.
Proteomic analysis of organ-specific post-translational lysine-acetylation and -methylation in mice by use of anti-acetyllysine and -methyllysine mouse monoclonal antibodies.
Proteomics 2005; 5: 4653-4664.

Kimura T, Ohno N, Terada N, Rokuhara A, Matsumoto A, Yagi S, Tanaka E, Kiyosawa K, Ohno S, Maki N.
Hepatitis B virus DNA-negative Dane particles lack core protein but contain a 22-kDa precore protein without C-terminal arginine-rich domein.
J. Bio. Chem. 2005; 280(23): 21713-21719.

Rokuhara A, Sun X, Tanaka E, Kimura T, Matsumoto A, Yao D, Yin L, Wang N, Maki N, Kiyosawa K.
Hepatitis B virus core and core-related antigen quantification in Chinese patients with chronic genotype B and C hepatitis B virus infection.
J. Gastroenterol. Hepatol. 2005; 20: 1726-1730.

Kosaki A, Hasegawa T, Kimura T, Iida K, Hitomi J, Matsubara H, Mori Y, Okigaki M, Toyoda N, Masaki H, Inoue-Shibata M, Nishikawa M, Iwasaka T.
Increased plasma S100A12(EN-RAGE) levels in patients with type 2 diabetes.
J. Clin. Endocrinol. Metab. 2004; 89(11): 5423-5428.


Rokuhara A, Tanaka E, Matsumoto A, Kimura T, Yamaura T, Orii K, , Sun X, Yagi S, Maki N, Kiyosawa K.
Clinical evaluation of a new enzyme immunoassay for hepatitis B virus core-related antigen; a marker distinct from viral
DNA for monitoring lamivudine treatment. J Viral Hepat. 2003 Jul;10(4):324-30.

Kimura T, Rokuhara A, Matsumoto A, Yagi S, Tanaka E, Kiyosawa K, Maki N, New enzyme immunoassay for detection of hepatitis
B virus core antigen (HBcAg) and relation between levels of HBcAg and HBV DNA J Clin Microbiol. 2003 May;41(5):1901-6.


Kimura T, Rokuhara A, Sakamoto Y, Yagi S, Tanaka E, Kiyosawa K, Maki N, Sensitive enzyme immunoassay for hepatitis B virus core-related antigens and their correlation to virus load. J Clin Microbiol. 2002 Feb;40(2):439-45.

Aoyagi K, Iida K, Ohue C, Matsunaga Y, Tanaka E, Kiyosawa K, Yagi S.
Performance of a conventional enzyme immunoassay for hepatitis C virus core antigen in the early phases of hepatitis C infection.
Clin Lab. 2001;47(3-4):119-27.

Shiokawa D, Tanaka M, Kimura T, Hashizume K, Takasawa R, Ohyama H, Fujita K, Yamada T, Tanuma S.
Characterization of two DNase gamma-specific monoclonal antibodies and the in situ detection of DNase gamma in the nuclei of apoptotic rat thymocytes.
Biochem Biophys Res Commun. 2000 Aug 28;275(2):343-9.

Tanaka E, Ohue C, Aoyagi K, Yamaguchi K, Yagi S, Kiyosawa K, Alter HJ.
Evaluation of a new enzyme immunoassay for hepatitis C virus (HCV) core antigen with clinical sensitivity approximating that of genomic amplification of HCV RNA.
Hepatology. 2000 Aug;32(2):388-93.

Iijima A, Tanaka E, Kobayashi M, Yagi S, Mizokami M, Kiyosawa K.
Relationship between histological prognosis of chronic hepatitis C and amount of hepatitis C virus core protein in serum.
J Gastroenterol Hepatol. 2000 Mar;15(3):311-9.

Aoyagi K, Ohue C, Iida K, Kimura T, Tanaka E, Kiyosawa K, Yagi S.
Development of a simple and highly sensitive enzyme immunoassay for hepatitis C virus core antigen.
J Clin Microbiol. 1999 Jun;37(6):1802-8.

Adachi N, Aoyagi K, Saito M, Matsuda I, Yamaguchi K.
Age-related changes of serum progastrin-releasing peptide levels during childhood.
Acta Paediatrica Japonica 1997;39:336-8

Yagi S, Kashiwakuma T, Yamaguchi K, Chiba Y, Ohtsuka E, Hasegawa A.
An epitope chimeric antigen for the hepatitis C virus serological screening test.
Biol Pharm Bull. 1996 Oct;19(10):1254-60.

Tanaka E, Kiyosawa K, Matsumoto A, Kashiwakuma T, Hasegawa A, Mori H, Yanagihara O, Ohta Y.
Serum levels of hepatitis C virus core protein in patients with chronic hepatitis C treated with interferon alfa.
Hepatology. 1996 Jun;23(6):1330-3.

Kashiwakuma T, Hasegawa A, Kajita T, Takata A, Mori H, Ohta Y, Tanaka E, Kiyosawa K, Tanaka T, Tanaka S, Hattori N, Kohara M.
Detection of hepatitis C virus specific core protein in serum of patients by a sensitive fluorescence enzyme immunoassay (FEIA).
J Immunol Methods. 1996 Mar;190(1):79-89.

Yamaguchi K, Aoyagi K, Urakami K, Fukutani T, Maki N, Yamamoto S, Otubo K, Miyake Y, Kodama T.
Enzyme-linked immunosorbent assay of pro-gastrin-releasing peptide for small cell lung cancer patients in comparison with neuron-specific enolase measurement.
Jpn J Cancer Res. 1995 Jul;86:698-705.

Aoyagi K, Miyake Y, Urakami K, Kashiwakuma T, Hasegawa A, Kodama T, Yamaguchi K.
Enzyme immunoassay of immunoreactive progastrin-releasing peptide(31-98) as tumor marker for small-cell lung carcinoma: development and evaluation.
Clin Chem. 1995 Apr;41(4):537-43.

Yamaguchi K, Tanaka E, Higashi K, Kiyosawa K, Matsumoto A, Furuta S, Hasegawa A, Tanaka S, Kohara M.
Adaptation of Hepatitis C virus for persistent infection in patients with acute hepatitis.
Gastroenterology 1994 May;106:1344-8.

Tanaka T, Tsukiyama-Kohara K, Yamaguchi K, Yagi S, Tanaka S, Hasegawa A, Ohta Y, Hattori N, Kohara M.
Significance of specific antibody assay for genotyping of hepatitis C virus.
Hepatology. 1994 Jun;19(6):1347-53.

Tsukiyama-Kohara K, Yamaguchi K, Maki N, Ohta Y, Miki K, Mizokami M, Ohba K, Tanaka S, Hattori N, Nomoto A, et al.
Antigenicities of Group I and II hepatitis C virus polypeptides--molecular basis of diagnosis.
Virology. 1993 Feb;192(2):430-7.

Saito M, Hasegawa A, Kashiwakuma T, Kohara M, Sugi M, Miki K, Yamamoto T, Mori H, Ohta Y, Tanaka E, et al.
Performance of an enzyme-linked immunosorbent assay system for antibodies to hepatitis C virus with two new antigens (c11/c7).
Clin Chem. 1992 Dec;38(12):2434-9.

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