Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: Clinical Phase I/II trials

Chen, Zhi‐Nan; Li, Mi; Xu, Jing; Song, Fei; Zhang, Qing; Zheng, Zhaohui; Xing, Jinliang; Bian, Huijie; Jiang, Jian‐Li; Wang, Xianhui; Shang, Peng; Qian, Airong; Zhang, Sihe; Li, Ling; Li, Yu; Feng, Qiang; Yu, Xiaoling; Feng, Yong; Yang, Xiang-Min; Tian, Rong; Wu, Zhenbiao; Li, Nan; Mo, Tingshu; Kuang, Anren; Tan, Tianwei; Li, Yun‐Chun; Liang, Daoming; Lu, Wusheng; Miao, Jia; Xu, Guohui; Zhang, Zhihui; Kang, Nan; Han, Jieun; Liu, Qingguang; Zhang, Hongxin; Zhu, Ping

doi:10.1016/j.ijrobp.2005.12.034

Cited by 130 publications

(116 citation statements)

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“…S20050039) in April 2005. It has been proved to be safe and effective in treating primary HCC patients and can effectively prevent the recurrence of tumor and prolong the survival of advanced HCC patients after orthotropic liver transplantation (19,22). In the present study, we further investigated the function of HAb18G/CD147 and its antibodies, HAb18 and LICARTIN, in HCC invasion and metastasis, and evaluated HAb18G/CD147 as a possible anti-HCC metastasis drug target.…”

Section: Introductionmentioning

confidence: 93%

“…HAb18 mAb, the HAb18G/CD147 -specific antibody, and its bivalent fragment HAb18 F(ab ¶) 2 (Metuximab), could bind to HCC cells with high affinity. With flow cytometry analysis, HAb18 mAb exhibited a binding rate of 99.55% to human hepatoma cells, and using immunohistochemistry, it showed a positive HCC staining rate of 75% (39 of 52) with little cross-reaction to normal tissues (14,16,19). We had generated the 131 I-labeled Metuximab [trade name LICARTIN; generic name Iodine ( 131 I) Metuximab Injection] for in vivo injection.…”

Section: Introductionmentioning

confidence: 99%

“…We had generated the 131 I-labeled Metuximab [trade name LICARTIN; generic name Iodine ( 131 I) Metuximab Injection] for in vivo injection. The pharmacokinetic characteristics and safety of the antibody and its radiolabeled conjugate had been determined both in vivo and in clinic (14,16,(19)(20)(21). LICARTIN was approved to be a new drug for clinical therapy of primary HCC patients by China State Food and Drug Administration (no.…”

Section: Introductionmentioning

confidence: 99%

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HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

Xu¹,

Xu²,

Zhang³

et al. 2007

Molecular Cancer Research

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133

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CD147 molecule is reported to be correlated with the malignancy of some cancers; however, it remains unclear whether it is involved in the progression of hepatocellular carcinoma (HCC). Here, we investigated the function of HAb18G/CD147, a member of CD147 family, and its antibodies, HAb18 and LICARTIN, in HCC invasion and metastasis. We observed that HAb18G/CD147 gene silence in HCC cells significantly decreased the secretion of matrix metalloproteinase (MMP) and the invasive potential of HCC cells (P < 0.001). MMP silence in HCC cells also significantly suppressed the invasion of the cells when cocultured with fibroblasts; however, its inhibitory effect was significantly weaker than that of both HAb18G/CD147 silence in HCC cells and that of MMP silence in fibroblasts (P < 0.001). Blocking the HAb18G/CD147 molecule on HCC cells with HAb18 monoclonal antibody resulted in a similar suppressive effect on MMP secretion and cell invasion, but with no significant effects on the cell growth. 131 I-labeled HAb18 F(ab ¶) 2 (LICARTIN), however, significantly inhibited the in vitro growth of HCC cells (P < 0.001). In an orthotopic model of HCC in nude mice, HAb18 and LICARTIN treatment effectively reduced the tumor growth and metastasis as well as the expression of three major factors in the HCC microenviroment (MMPs, vascular endothelial growth factor, and fibroblast surface protein) in the paracancer tissues. Overall, these results suggest that HAb18G/CD147 plays an important role in HCC invasion and metastasis mainly via modulating fibroblasts, as well as HCC cells themselves to disrupt the HCC microenviroment. LICARTIN can be used as a drug targeting to HAb18G/ CD147 in antimetastasis and recurrence therapy of HCC.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

Xu¹,

Xu²,

Zhang³

et al. 2007

Molecular Cancer Research

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141

133

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“…S20050039) in April 2005), has already been proven to be safe and effective for the treatment of primary HCC patients and can effectively prevent the recurrence of tumors and prolong the survival of advanced HCC patients after orthotropic liver transplantation. 34,35 The effects of LICARTIN in overcoming chemoresistance are currently being investigated in our o ongoing investigations.…”

Section: Figurementioning

confidence: 99%

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Tang

Zhang

et al. 2012

Cell Death Differ

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The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1) ( À 82/ À 50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment. The uncontrolled growth and insufficient vascularization of a tumor mass lead to a stressed state in the tumor microenvironment, which includes low oxygen supply, nutrient deprivation and pH changes. Microenvironment stresses directly impinge on the luminal milieu of the endoplasmic reticulum (ER) and might be sufficiently severe to cause ER stress (ERS). 1 These ERS conditions activate a range of cellular stress response pathways, including the unfolded protein response (UPR). 2,3 UPR activation has profound consequences for tumor growth and resistance to radiotherapy and chemotherapy. [4][5][6] Therefore, the UPR might be responsible for the failure of some patients to respond to treatment and is associated with a poor prognosis. 7 Given the observation that UPR is correlated with certain types of aggressive tumors, drug resistance, recurrence and poor survival, 8-11 the inhibition of the UPR pathway may yield more efficient treatments for cancer.Although there is sufficient evidence to indicate that the UPR is generally activated in solid tumors, the UPR remains poorly characterized in cancers. The three major UPR transducers are inositol-requiring enzyme 1 (IRE1), pancreatic kinase-like ER kinase (PERK) and the UPR-specific transcription factor, activating transcription factor 6 (ATF6).These factors all sense the presence of unfolded proteins in the ER lumen and transduce signals to the nucleus that activate the transcription of UPR target genes, such as Bip (also called glucose-regulated protein 78). 12-14 The overexpression of Bip as a result of the three major transducers has been reported in malignant breast disease, colon cancer and gastric and esophageal adenocarcinomas. [15][16][17][18] It has also been...

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“…Immunohistochemistry has shown that HAb18G/ CD147 expression is significantly higher in human HCC tissues than in normal adult and fetal tissues . A radio-immunoconjugate 131 I-labeled antibody HAb18 F(ab') 2 against HAb18G/CD147, registered as Licartin, was performed to treat primary HCC and prevent tumor recurrence of post-orthotopic liver transplantation in advanced HCC patients (Chen et al, 2006;Xu et al, 2007a).…”

Section: Introductionmentioning

confidence: 99%

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

et al. 2011

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Epithelial-mesenchymal transition (EMT) induced by transforming growth factor-b (TGF-b) is implicated in hepatocarcinogenesis and hepatocellular carcinoma (HCC) metastasis. HAb18G/CD147, which belongs to the CD147 family, is an HCC-associated antigen that has a crucial role in tumor invasion and metastasis. The goal of this study was to investigate the role of HAb18G/ CD147 during EMT in hepatocarcinogenesis. Human normal hepatic cell lines QZG and L02, primary mouse hepatocytes and nude mouse models were used to determine the role of HAb18G/CD147 in EMT, and the involvement of the TGF-b-driven pathway. A dualluciferase reporter assay and ChIP were used to investigate the transcriptional regulation of the CD147 gene. Samples from patients with liver disease were assessed to determine the relationship between HAb18G/CD147 and typical markers for EMT. Our results show that upregulation of HAb18G/CD147 is induced by TGF-b coupled with downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The expression of HAb18G/CD147 is controlled by the cell survival PI3K/ Akt/GSK3b signaling pathway, and is directly regulated by the transcription factor Slug. Transfection of CD147 also induces an elevated expression of TGF-b. CD147-transfected hepatocytes have mesenchymal phenotypes that accelerate tumor formation and tumor metastasis in vivo. Immunohistochemistry analysis shows a negative correlation between HAb18G/CD147 and E-cadherin expression (r s ¼ À0.3622, P ¼ 0.0105), and a positive correlation between HAb18G/CD147 and Slug expression (r s ¼ 0.3064, P ¼ 0.0323) in human HCC tissues. Our study uncovers a novel role of HAb18G/CD147 in mediating EMT in the process of HCC progression and showed that CD147 is a Slug target gene in the signaling cascade TGF-b-PI3K/Akt-GSK3b-Snail-Slug-CD147. Our results suggest that CD147 may be a potential target for the treatment and prevention of HCC.

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Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: Clinical Phase I/II trials

Cited by 130 publications

References 17 publications

HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

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