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Masafumi Ikeda, Shinichi Ohkawa, Takuji Okusaka, Shuichi Mitsunaga, Satoshi Kobayashi, Chigusa Morizane, Ikue Suzuki, Shunsuke Yamamoto, Junji Furuse
GC33 is a humanized mAb against human glypican-3 (GPC3). In the first-in-human study carried out in the USA, GC33 was well tolerated and showed preliminary antitumor activity in patients with advanced hepatocellular carcinoma. This study aimed to assess the safety, tolerability, and pharmacokinetic characteristics of GC33 in Japanese patients with advanced hepatocellular carcinoma. The study design was a conventional 3 + 3 dose-escalation design to determine the maximum tolerated dose of GC33 given i.v. at 5, 10, or 20 mg/kg weekly...
April 2014: Cancer Science
Mingqian Feng, Mitchell Ho
Glypican-3 (GPC3) is an emerging therapeutic target in hepatocellular carcinoma (HCC), even though the biological function of GPC3 remains elusive. Currently human (MDX-1414 and HN3) and humanized mouse (GC33 and YP7) antibodies that target GPC3 for HCC treatment are under different stages of preclinical or clinical development. Humanized mouse antibody GC33 is being evaluated in a phase II clinical trial. Human antibodies MDX-1414 and HN3 are under different stages of preclinical evaluation. Here, we summarize current evidence for GPC3 as a new target in liver cancer, discuss both its oncogenic function and its mode of actions for current antibodies, and evaluate potential challenges for GPC3-targeted anti-cancer therapies...
January 21, 2014: FEBS Letters
Andrew X Zhu, Philip J Gold, Anthony B El-Khoueiry, Thomas A Abrams, Hideo Morikawa, Norihisa Ohishi, Toshihiko Ohtomo, Philip A Philip
PURPOSE: GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The antitumor activity of GC33 was shown in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic characteristics, and preliminary efficacy of GC33 in patients with advanced HCC. EXPERIMENTAL DESIGN: Patients with measurable, histologically proven, advanced HCC were enrolled to a dose-escalation study of GC33 (2...
February 15, 2013: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Wei Gao, Mitchell Ho
Glypican-3 (GPC3) is highly expressed in human hepatocellular carcinoma (HCC) and a growing body of evidence supports the role of GPC3 in HCC pathogenesis. In this review, we discuss recent developments regarding the regulation of GPC3 in HCC and provide insight about GPC3 as a potential therapeutic target in liver cancer. One of the most well studied pathways related to the biological functions of GPC3 is the Wnt signaling pathway. GPC3 may form a complex with Wnt and stimulates HCC growth. GPC3 does this by facilitating and/or stabilizing the interaction between Wnt and Frizzled, leading to the activation of downstream signaling pathways...
2011: Cancer Reports
Kenji Yorita, Nobuyasu Takahashi, Hirotake Takai, Atsuhiko Kato, Masami Suzuki, Takahiro Ishiguro, Toshihiko Ohtomo, Koki Nagaike, Kazuhiro Kondo, Kazuo Chijiiwa, Hiroaki Kataoka
BACKGROUND: GC33 is a recently developed monoclonal antibody against human glypican-3 (GPC3), which is significantly upregulated in hepatocellular carcinoma (HCC). GC33 recognizes a GPC3 ectodomain and shows significant antitumour activity in vivo. Thus, humanized GC33 antibody may be a promising tool for treating HCC having cell surface GPC3 expression. AIMS: This study aims to determine the specificity, subcellular localization and prognostic impact of GPC3 immunoreactivity detected by GC33 in HCC clinical specimens...
January 2011: Liver International: Official Journal of the International Association for the Study of the Liver
Kiyotaka Nakano, Takahiro Ishiguro, Hiroko Konishi, Megumi Tanaka, Masamichi Sugimoto, Izumi Sugo, Tomoyuki Igawa, Hiroyuki Tsunoda, Yasuko Kinoshita, Kiyoshi Habu, Tetsuro Orita, Masayuki Tsuchiya, Kunihiro Hattori, Hisafumi Yamada-Okabe
Glypican 3 (GPC3), a glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan, is expressed in a majority of hepatocellular carcinoma tissues. The murine monoclonal antibody GC33 that specifically binds to the COOH-terminal part of GPC3 causes strong antibody-dependent cellular cytotoxicity against hepatocellular carcinoma cells and exhibits strong antitumor activity in the xenograft models. To apply GC33 for clinical use, we generated a humanized GC33 from complementarity-determining region grafting with the aid of both the hybrid variable region and two-step design methods...
November 2010: Anti-cancer Drugs
Hirotake Takai, Atsuhiko Kato, Yasuko Kinoshita, Takahiro Ishiguro, Yayoi Takai, Yoshimi Ohtani, Masamichi Sugimoto, Masami Suzuki
Previously, we demonstrated the antitumor efficacy of the anti-glypican-3 (GPC3) antibody GC33 in several human liver cancer xenograft models and the important role of antibody-dependent cellular cytotoxicity (ADCC) in the antitumor mechanism of GC33. Involvement of other mechanisms such as modulation of the functions of GPC3 in antitumor activity remains to be elucidated. In this study, we investigated histopathologically time-course changes in xenografts in mice following a single administration of GC33 to clarify the morphological changes contributing to the tumor growth inhibition of GC33, including the changes in GPC3-related factors/components [proliferation, extracellular matrices (ECMs) and macrophage]...
May 2009: Cancer Biology & Therapy
Takahiro Ishiguro, Masamichi Sugimoto, Yasuko Kinoshita, Yoko Miyazaki, Kiyotaka Nakano, Hiroyuki Tsunoda, Izumi Sugo, Iwao Ohizumi, Hiroyuki Aburatani, Takao Hamakubo, Tatsuhiko Kodama, Masayuki Tsuchiya, Hisafumi Yamada-Okabe
Human glypican 3 (GPC3) is preferentially expressed in the tumor tissues of liver cancer patients. In this study, we obtained a monoclonal antibody (mAb) against the COOH-terminal part of GPC3, which induced antibody-dependent cellular cytotoxicity (ADCC). The mAb, designated GC33, exhibited marked tumor growth inhibition of s.c. transplanted Hep G2 and HuH-7 xenografts that expressed GPC3 but did not inhibit growth of the SK-HEP-1 that was negative for GPC3. GC33 was efficacious even in an orthotopic model; it markedly reduced the blood alpha-fetoprotein levels of mice intrahepatically transplanted with Hep G2 cells...
December 1, 2008: Cancer Research
Kiyotaka Nakano, Tetsuro Orita, Junichi Nezu, Takeshi Yoshino, Iwao Ohizumi, Masamichi Sugimoto, Koh Furugaki, Yasuko Kinoshita, Takahiro Ishiguro, Takao Hamakubo, Tatsuhiko Kodama, Hiroyuki Aburatani, Hisafumi Yamada-Okabe, Masayuki Tsuchiya
Glypican 3 (GPC3), a GPI-anchored heparan sulfate proteoglycan, is expressed in the majority of hepatocellular carcinoma (HCC) tissues. Using MRL/lpr mice, we successfully generated a series of anti-GPC3 monoclonal antibodies (mAbs). GPC3 was partially cleaved between Arg358 and Ser359, generating a C-terminal 30-kDa fragment and an N-terminal 40-kDa fragment. All mAbs that induced antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC) against cells expressing GPC3 recognized the 30-kDa fragment, indicating that the C-terminal region of GPC3 serves as an epitope for mAb with ADCC and/or CDC inducing activities...
January 9, 2009: Biochemical and Biophysical Research Communications
J Stoye
An improved algorithm for the simultaneous alignment of multiple protein and nucleic acid sequences, the Divide-and-Conquer Alignment procedure (DCA), is presented. The basic method described in Tönges,et al. (1996) (Tönges, U., Perrey, S.W., Stoye, J., Dress, A.W.M., 1996. A general method for fast multiple sequence alignment. Gene, 172, GC33-GC41) is generalized to align any number of sequences to work arbitrary (e.g. affine linear) gap penalty functions. Also, the practical efficiency of the method is improved so that families of more than 10 sequences can now be aligned simultaneously within a few seconds or minutes...
May 12, 1998: Gene
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