17 results on '"Minkyu Hur"'
Search Results
2. Supplementary figure 1 from GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands
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Jonghwa Won, Hyun-Soo Cho, Dong Geon Kim, Heekyoung Yang, Do-Hyun Nam, Yeup Yoon, Yeon-Gil Kim, Se-Ho Kim, Kwang-Won Hong, YingJin Kang, Kuglae Kim, Ki Hwan Chang, Kyuhyun Lee, Tae Wook Park, Shi-Nai Lee, Jae-Chul Lee, Hyung-Suk Hur, Eun Hee Lee, Minkyu Hur, Min-Soo Kim, Jiho Yoo, and Yangmi Lim
- Abstract
Supplementary Figure 1. Kinetic binding interactions between GC1118 and EGFR as analyzed by SPR. SPR sensorgrams were obtained from injections of (A) GC1118 or (B) cetuximab over an EGFR-immobilized surface at a flow rate of 30 µl/min. The results of a quantitative evaluation of the experimental data are shown in Supplementary Table 2.
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- 2023
3. Supplementary table 1 from GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands
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Jonghwa Won, Hyun-Soo Cho, Dong Geon Kim, Heekyoung Yang, Do-Hyun Nam, Yeup Yoon, Yeon-Gil Kim, Se-Ho Kim, Kwang-Won Hong, YingJin Kang, Kuglae Kim, Ki Hwan Chang, Kyuhyun Lee, Tae Wook Park, Shi-Nai Lee, Jae-Chul Lee, Hyung-Suk Hur, Eun Hee Lee, Minkyu Hur, Min-Soo Kim, Jiho Yoo, and Yangmi Lim
- Abstract
Supplementary Table 1. X-ray data collection and refinement statistics.
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- 2023
4. Supplementary method from GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands
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Jonghwa Won, Hyun-Soo Cho, Dong Geon Kim, Heekyoung Yang, Do-Hyun Nam, Yeup Yoon, Yeon-Gil Kim, Se-Ho Kim, Kwang-Won Hong, YingJin Kang, Kuglae Kim, Ki Hwan Chang, Kyuhyun Lee, Tae Wook Park, Shi-Nai Lee, Jae-Chul Lee, Hyung-Suk Hur, Eun Hee Lee, Minkyu Hur, Min-Soo Kim, Jiho Yoo, and Yangmi Lim
- Abstract
Surface plasmon resonance (SPR)
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- 2023
5. Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts
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Seung Won Choi, Do Hyun Nam, Hye Won Lee, Harim Koo, Eunju Son, Yejin Kim, Heekyoung Yang, Yangmi Lim, Minkyu Hur, Donggeon Kim, and Kyoungmin Lee
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0301 basic medicine ,Cancer Research ,medicine.drug_class ,Cell ,monoclonal ,amplification ,Monoclonal antibody ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Growth factor receptor ,In vivo ,medicine ,Epidermal growth factor receptor ,xenograft ,Cetuximab ,biology ,business.industry ,glioblastoma ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Monoclonal ,Cancer research ,biology.protein ,Biomarker (medicine) ,business ,epidermal growth factor receptor ,medicine.drug - Abstract
We aimed to evaluate the preclinical efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), against glioblastoma (GBM) tumors using patient-derived xenograft (PDX) models. A total of 15 distinct GBM PDX models were used to evaluate the therapeutic efficacy of GC1118. Genomic data derived from PDX models were analyzed to identify potential biomarkers associated with the anti-tumor efficacy of GC1118. A patient-derived cell-based high-throughput drug screening assay was performed to further validate the efficacy of GC1118. Compared to cetuximab, GC1118 exerted comparable growth inhibitory effects on the GBM tumors in the PDX models. We confirmed that GC1118 accumulated within the tumor by crossing the blood&ndash, brain barrier in in vivo specimens and observed the survival benefit in GC1118-treated intracranial models. Genomic analysis revealed high EGFR amplification as a potent biomarker for predicting the therapeutic efficacy of GC1118 in GBM tumors. In summary, GC1118 exerted a potent anti-tumor effect on GBM tumors in PDX models, and its therapeutic efficacy was especially pronounced in the tumors with high EGFR amplification. Our study supports the importance of patient stratification based on EGFR copy number variation in clinical trials for GBM. The superiority of GC1118 over other EGFR mAbs in GBM tumors should be assessed in future studies.
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- 2020
6. Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts
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Jae-Chul Lee, Hye Won Lee, Yangmi Lim, Yeri Lee, Minkyu Hur, Eunju Son, Yejin Kim, Do Hyun Nam, Donggeon Kim, and Kyoungmin Lee
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Colorectal cancer ,Cetuximab ,medicine.disease_cause ,KRAS mutation ,Mice ,Phosphatidylinositol 3-Kinases ,PI3K/mTOR/AKT inhibitor ,Tumor Cells, Cultured ,Epidermal growth factor receptor ,Spectroscopy ,biology ,TOR Serine-Threonine Kinases ,General Medicine ,EGFR-targeting therapeutic antibody ,Computer Science Applications ,ErbB Receptors ,Female ,KRAS ,Colorectal Neoplasms ,medicine.drug ,Signal Transduction ,patient-derived xenograft ,Transplantation, Heterologous ,Mice, Nude ,colorectal cancer ,Antibodies, Monoclonal, Humanized ,Catalysis ,Article ,Inorganic Chemistry ,Proto-Oncogene Proteins p21(ras) ,medicine ,Panitumumab ,Animals ,Humans ,Physical and Theoretical Chemistry ,Autocrine signalling ,Molecular Biology ,Protein kinase B ,neoplasms ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,business.industry ,Organic Chemistry ,medicine.disease ,digestive system diseases ,Mutation ,Cancer research ,biology.protein ,business ,Proto-Oncogene Proteins c-akt - Abstract
Epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies, including cetuximab and panitumumab, are used to treat metastatic colorectal cancer (mCRC). However, this treatment is only effective for a small subset of mCRC patients positive for the wild-type KRAS GTPase. GC1118 is a novel, fully humanized anti-EGFR IgG1 antibody that displays potent inhibitory effects on high-affinity EGFR ligand-induced signaling and enhanced antibody-mediated cytotoxicity. In this study, using 51 CRC patient-derived xenografts (PDXs), we showed that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared with wild-type KRAS. In three KRAS-mutant CRCPDXs, GC1118 was more effective than cetuximab, whereas the two agents demonstrated comparable efficacy against three wild-type KRAS PDXs. Persistent phosphatidylinositol-3-kinase (PI3K)/AKT signaling was thought to underlie resistance to GC1118. In support of these findings, a preliminary improved anti-cancer response was observed in a CRC PDX harboring mutated KRAS with intrinsically high AKT activity using GC1118 combined with the dual PI3K/mammalian target of rapamycin (mTOR)/AKT inhibitor BEZ-235, without observed toxicity. Taken together, the superior antitumor efficacy of GC1118 alone or in combination with PI3K/mTOR/AKT inhibitors shows great therapeutic potential for the treatment of KRAS-mutant mCRC with elevated ratios of high- to low-affinity EGFR ligands and PI3K-AKT pathway activation.
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- 2019
7. Genomic characterization of the porcine CRTC3 and the effects of a non-synonymous mutation p.V515F on lean meat production and belly fat
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Jun Mo Kim, Sunggon Lee, Minkyu Hur, Ki Chang Hong, and Lee Eun A
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0301 basic medicine ,medicine.medical_specialty ,Sus scrofa ,Abdominal Fat ,Single-nucleotide polymorphism ,Biology ,medicine.disease_cause ,Loin ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Exon ,Internal medicine ,medicine ,Animals ,SNP ,Coding region ,Gene ,Abdominal Muscles ,Mutation ,Genome ,0402 animal and dairy science ,04 agricultural and veterinary sciences ,medicine.disease ,CREB-Binding Protein ,040201 dairy & animal science ,Obesity ,Red Meat ,030104 developmental biology ,Endocrinology ,Transcriptome ,Transcription Factors ,Food Science - Abstract
cAMP-responsive element-binding protein (CREB)-regulated transcriptional coactivator 3 (CRTC3) is well known to be related to obesity in humans and mice. However, the effects of CRTC3 have not been studied in pigs. Here, we characterized the structure of the porcine CRTC3 gene and identified single nucleotide polymorphisms (SNPs) in its coding region. Moreover, mRNA expression profiles of CRTC3 in muscle and fat tissues were examined. Of the 40 identified SNPs, the p.V515F mutation, located on exon 16, was genotyped in 368 Yorkshire pigs. The p.V515F mutation was significantly associated with lean meat production ability, including reduced back fat thickness (P = 0.0317) and loin eye area (P = 0.0174). Moreover, the SNP was significantly associated with differences in intermuscular fat (P = 0.0092), total muscle area in the belly (P = 0.0108), and total fat percentage in the belly (P = 0.0298). Taken together, our results suggest that the p.V515F mutation affects to lean meat production ability and amount of belly fat.
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- 2018
8. GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands
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Jiho Yoo, Min Soo Kim, Yeup Yoon, Tae Wook Park, Jonghwa Won, Yangmi Lim, Kwang Won Hong, Jae-Chul Lee, Yeon Gil Kim, Minkyu Hur, Do-Hyun Nam, Shi Nai Lee, Eun-Hee Lee, Se-Ho Kim, Donggeon Kim, Kyuhyun Lee, Hyung Suk Hur, Kuglae Kim, Yingjin Kang, Ki Hwan Chang, Hyun Soo Cho, and Heekyoung Yang
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Models, Molecular ,0301 basic medicine ,Cancer Research ,medicine.drug_class ,Antineoplastic Agents ,Pharmacology ,Biology ,Antibodies, Monoclonal, Humanized ,Ligands ,Monoclonal antibody ,Epitope ,Epitopes ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Panitumumab ,Cell Proliferation ,Tumor microenvironment ,Cetuximab ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,ErbB Receptors ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Monoclonal ,biology.protein ,Female ,Antibody ,Colorectal Neoplasms ,Protein Binding ,medicine.drug - Abstract
The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR–GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251–63. ©2015 AACR.
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- 2016
9. GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer
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Yung-Jue Bang, Ju Hee Bang, Mei Hua Jin, Ji Eun Park, Minkyu Hur, Do Youn Oh, Ah Rong Nam, and Jonghwa Won
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Cancer Research ,Cetuximab ,Mice, Nude ,Apoptosis ,medicine.disease_cause ,Antibodies, Monoclonal, Humanized ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Stomach Neoplasms ,medicine ,Tumor Cells, Cultured ,Cytotoxic T cell ,Panitumumab ,Animals ,Humans ,MTT assay ,Cell Proliferation ,Cisplatin ,business.industry ,Gastroenterology ,Cancer ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,ErbB Receptors ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,030211 gastroenterology & hepatology ,Female ,KRAS ,Growth inhibition ,business ,medicine.drug - Abstract
EGFR overexpression in gastric cancer (GC) has been reported in about 30% of patients. However, the anti-EGFR antibodies cetuximab and panitumumab have failed to improve overall survival of GC patients in combination with cytotoxic chemotherapy compared with chemotherapy alone. GC1118, a novel anti-EGFR antibody with a distinct binding epitope compared with cetuximab or panitumumab, has not been tested in GC. GC cell lines, SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719, AGS, MKN-45, NCI-N87, and KATO-III, were employed to test the effect of cetuximab or GC1118 alone, and combined with the cytotoxic agent cisplatin or 5-fluorouracil (5-FU). Cells were also treat with or without high-affinity ligands EGF 20 ng/ml or HB-EGF 100 ng/ml. GC1118 exhibited a more potent growth inhibition effect in the majority of cell lines than cetuximab in MTT assay, regardless of the KRAS mutation status of cell lines. Co-treatment of GC1118 and cisplatin or 5-FU inhibited colony formation and migration to a greater extent, even following EGFR ligand stimulation. Ligand-induced p-AKT and p-ERK upregulation were more potently inhibited by combination treatment with GC1118 and chemotherapeutic agents compared with cetuximab plus chemotherapeutic agents. GC1118 also showed more potent anti-tumor effects compared with cetuximab in a mouse xenograft model. Taken together, GC1118 alone or in combination with cytotoxic chemotherapeutic agents exerted more potent anti-tumor effects than cetuximab in GC cells, regardless of KRAS status. These findings support the further clinical development of GC1118 for the treatment of GC.
- Published
- 2018
10. Abstract 2266: Efficacy of CEACAM1-targeting immunoglobulin in combination with pembrolizumab in lung cancer
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Minkyu Hur, Jae Hwan Kim, Kyoung Ho Pyo, Jonghwa Won, Min-Jee Jung, and Byoung Chul Cho
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0301 basic medicine ,Cancer Research ,Tumor microenvironment ,biology ,business.industry ,Cancer ,Pembrolizumab ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Humanized mouse ,medicine ,Cancer research ,biology.protein ,Adenocarcinoma ,Antibody ,Lung cancer ,business ,CD8 ,030215 immunology - Abstract
Background: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) as an immune check point molecule is expressed in lung cancer cells. The homophilic interaction of CEACAM1 inhibits killing effect of T cells by co-inhibitory signal transduction. Thus, up-regulated CEACAM1 in the tumor microenvironment is considered as a promising therapeutic target for cancer. In this study, anti-cancer effect of anti-CEACAM1 monoclonal antibody (MG1124, from GC Pharma, Yongin, South Korea) was investigated with lung cancer-xenograft humanized mice. Materials & Methods: Multispectral image analysis using Vectra polaris system was performed in 49 of human lung cancers (36 adenocarcinoma; 13 squamous cell carcinoma) to evaluate the expressions of CEACAM1, PD-L1 and CD8. Four tumors (YHIM-01, YHIM-02, YHIM-03 and YHIM-04) with high CEACAM1 expression were subcutaneously implanted into humanized mice (hu-CD34 NSG) matched with HLA-A. Efficacy of MG1124 was performed by the single mouse trial format. Humanized mice were treated with MG1124 (q2w, 20 mpk, i.p. injection) with or without pembrolizumab (q2w, 10 mpk, i.p. injection). Findings: Among 49 lung cancers evaluated, proportion of tumor cells expressing CEACAM1 and PD-L1 with any intensity ranged 0.1- 89.2% (median, 15.4%) and 0.2% - 95.6% (median, 6.8%) respectively, and TIL counts ranged 0 - 1,200 cells/mm2 (median, 129 cells/mm2). Four tumors with high CEACAM1(14.5% in YHIM-01, 81.2% in YHIM-02, 23.8% in YHIM-03 and 36.7% in YHIM-04) were selected to establish humanized mouse models. MG1124 as a monotherapy demonstrated antitumor activity and also was superior to pembrolizumab in 1 (YHIM-02, TGI=63.4±1.7% for combination vs. TGI=58.7±9.1% for pembrolizumab alone) out of 4 humanized mouse models. Combination of MG1124 with pembrolizumab also demonstrated synergic anti-tumor effect in 3 models (YHIM-01, TGI= 39.6±19.7% vs. 0.6±11.4% for pembrolizumab alone, vs. 16.5±33.3% for MG1124 alone; YHIM-02, TGI=58.7±9.1% vs. 38.2±14.9% for pembrolizumab, vs. 63.4±1.7% for MG1124 alone; YHIM-03, TGI= 35.6±13.2% vs. TGI=0.0±13.2% for pembrolizumab alone, vs. TGI=3.1±13.3% for MG1124 alone). PD-L1 expression was not associated with MG1124 alone or in combination with pembrolizumab (PD-L1, 2.5% in YHIM-01, 0.5% in YHIM-02 and 14.0% in YHIM-03 respectively). Interestingly, however, combinational effects of MG1124 and pembrolizumab were shown only in 3 models showing high CD8+ T cell infiltration in the tumors (209, 432, 362 vs. 46 in a model without combination synergy). Conclusion: CEACAM1-targeting monoclonal antibody, MG1124, exhibits promising anti-cancer effects in CEACAM1-expressing lung cancers. Tumoral CEACAM1 expression and high intratumoral CD8+ T cell infiltration could serve as a predictive biomarker to MG1124 monotherapy or in combination with pembrolizumab and need to be further investigated. Citation Format: Jae-Hwan Kim, Kyoung-Ho Pyo, Min-Jee Jung, Minkyu Hur, Jonghwa Won, Byoung Chul Cho. Efficacy of CEACAM1-targeting immunoglobulin in combination with pembrolizumab in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2266.
- Published
- 2019
11. Preclinical characterization and efficacy of 4R9, a novel immune checkpoint blockade targeting CEACAM1 for cancer therapy
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Jae Chul Lee, Byoung Chul Cho, Hye-mi Nam, Eun Hee Lee, Hye In Yum, Hye-Young Park, Jonghwa Won, Yangmi Lim, Minkyu Hur, Mi-Young Oh, Jae Hwan Kim, and Hyung-Suk Choi
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Cancer Research ,Oncology ,business.industry ,Cancer therapy ,Cancer research ,Medicine ,business ,T cell response ,Receptor ,Immune checkpoint ,Blockade - Abstract
e14155 Background: CEACAM1 is one of the several immune checkpoint receptors expressed on T cells that mediate suppression of inflammatory T cell response. It is known that CEACAM1-CEACAM1 homophilic interaction induces downregulation of ZAP70 phosphorylation in response to T cell receptor (TCR) stimulation. Also, CEACAM1 is highly expressed on non-small cell lung cancer (NSCLC) and its expression correlated with cancer progression and poor prognosis. We developed a fully human monoclonal antibody 4R9, human CEACAM1-targeting antibody. Methods: T cell activation of 4R9 was determined by NFAT-luciferase reporter assay with CEACAM1 overexpressing Jurkat stable cells. In vitro efficacy of 4R9 was examined using NK-mediated tumor cell killing assay. The anti-tumor efficacy of 4R9 alone or in combination was studied in vivo in a humanized mouse model engrafted with NSCLC patient-derived tumor xenografts. Results: Anti-CEACAM1 antibody 4R9 binds to CEACAM1 overexpressed in HEK293 or Jurkat cells but not to other CEA family members. 4R9 blocks CEACAM1-CEACAM1 homophilic interaction by binding to N domain of CEACAM1. CEACAM1-CEACAM1 homophilic interaction induced downregulation of ZAP70 phosphorylation in response to TCR stimulation in CEACAM1 overexpressing Jurkat stable cell line, which was rescued by 4R9 resulting in augmentation of NFAT activity and IL-2 expression. NK cell-mediated tumor lysis was increased by 4R9 in a CEACAM1 expression-dependent manner. Out of 49 NSCLC tumor tissues, 20 cases exhibited dominant expression of CEACAM1 over PD-L1 with 6 cases showing > 50% of CEACAM1 positivity. In a single mouse trial using NSCLC PDX-huNSG mouse model, 4R9 (20 mpk, 2qW) suppressed tumor progression more than 30% as monotherapy (10/19) as well as in combination (16/22) with pembrolizumab (5 mpk, 2qW). Moreover, PDX of adenocarcinoma origin with more than 50% of CEACAM1 expression were more efficiently prohibited for progression with 4R9, suggesting potential therapeutic use of 4R9 in patients with NSCLC. Conclusions: Anti-CEACAM1 antibody blocked CEACAM1-mediated negative regulation and restored T/NK cell activities. Different expression patterns of CEACAM1 compared with PD-L1 and efficacies in a single mouse trial support the rationale for developing anti-CEAEAM1 antibody as cancer therapeutics.
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- 2019
12. GC1118, a novel EGFR-targeted monoclonal antibody, exhibits potent growth and migration inhibitory efficacies in gastric cancer cell lines
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Shi-Nai Lee, hee Lee Dae, Jonghwa Won, Eun Hee Lee, Jae-Chul Lee, Cheul Oh Sang, Jun Cho Hyung, Yangmi Lim, Minkyu Hur, and Lim Kim Jung
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Oncology ,business.industry ,medicine.drug_class ,Medicine ,Hematology ,Inhibitory postsynaptic potential ,business ,Monoclonal antibody ,Molecular biology ,Gastric cancer cell - Published
- 2017
13. Abstract LB-113: Enhanced anti-tumor efficacy of CEACAM1-targeting antibody after affinity maturation
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Hye-mi Nam, Hye-Young Park, Hye In Yum, Hyun-Jung Cho, Minkyu Hur, Eun Hee Lee, Byoung Chul Cho, Mijung Lee, Jae Hwan Kim, So-Young Eun, Aerin Yoon, Jonghwa Won, Sungtae Yun, and Mi-Young Oh
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Antitumor activity ,Affinity maturation ,Cancer Research ,Oncology ,biology ,Chemistry ,biology.protein ,Cancer research ,Antibody - Abstract
Since the huge success of PD-1 blocking antibodies in clinical studies, anti-cancer therapy has changed its strategic gear to immunotherapy, which showed the strongest potential to eradicate cancer without detrimental side effects. Antibodies targeting similar immune checkpoint proteins with immunosuppressive functions have started to surge into clinical trials. CEACAM1 (CCM1) is also a potential target for anti-cancer immunotherapy because it is an ITIM-containing inhibitory molecule expressed on activated T cells and NK cells, on which it suppresses T/NK cell-mediated pro-inflammatory immune responses. CCM1-CCM1 homophilic interaction inhibits ZAP-70 phosphorylation in the TCR proximal signaling complex, thereby suppressing T cell activation. The anti-cancer therapeutic potential of CCM1-blockade has already been demonstrated in mouse models and one of the anti-human CCM1 antibodies entered into a phase I clinical trial once. As previously reported, our clone C25 (an anti-CCM1 monoclonal antibody) activated T cells and enhanced T/NK cell-mediated tumor cell-killing in a CCM1-dependent manner. The clone C25 was further engineered to have higher efficacies through mutagenesis within the variable regions of heavy and light chains. Here, we describe mutated variants of C25 with improved in vitro tumor-killing efficacies as well as higher binding affinities while maintaining fundamental characteristics of their parental clone C25. Most importantly, C25 and its variants exclusively bind to CCM1, but not to any other homologs of the CCM family. Such strong target-specificity will be a crucial point that distinguishes our clones from the other anti-CCM1 antibodies having off-target binding activities. We are currently investigating the CCM1-dependent anti-cancer therapeutic efficacy of our final clone on the patient-derived tumor xenografts implanted in a humanized mouse model. The target-ligand expression profiling on tumor tissues from lung cancer patients revealed strong clues for patient selection criteria and co-treatment options. Citation Format: So-Young Eun, Mijung Lee, Hye-Young Park, Miyoung Oh, Hye In Yum, Aerin Yoon, Eunhee Lee, Hyemi Nam, Sungtae Yun, Hyunjung Cho, Minkyu Hur, Jaehwan Kim, Byoung Chul Cho, Jonghwa Won. Enhanced anti-tumor efficacy of CEACAM1-targeting antibody after affinity maturation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-113.
- Published
- 2018
14. GC1118, an anti-EGFR monoclonal antibody, blocks irinotecan-induced EGFR activation and exhibits synergistic tumor regression in gastric cancer model
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Jae-Chul Lee, Hyung Jun Cho, Minkyu Hur, Yangmi Lim, Shi-Nai Lee, Eun Hee Lee, and Jonghwa Won
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Oncology ,Irinotecan ,medicine.medical_specialty ,business.industry ,Internal medicine ,Cancer Model ,Tumor regression ,Medicine ,Hematology ,Anti-EGFR Monoclonal Antibody ,business ,medicine.drug - Published
- 2017
15. Abstract LB-114: GC1118, a new anti-EGFR antibody overcome acquired resistance to cetuximab in colorectal cancer xenograft model
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Hyun-Jung Cho, Kyuhyun Lee, Jonghwa Won, Eun Hee Lee, Yangmi Lim, Minkyu Hur, Shi-Nai Lee, Jae-Chul Lee, and Sujeong Kim
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030213 general clinical medicine ,Cancer Research ,Tumor microenvironment ,Cetuximab ,Colorectal cancer ,business.industry ,Cancer ,medicine.disease ,030226 pharmacology & pharmacy ,digestive system diseases ,Epiregulin ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Growth factor receptor ,Immunology ,medicine ,Cancer research ,Panitumumab ,Progression-free survival ,business ,neoplasms ,medicine.drug - Abstract
Purpose: Anti-epidermal growth factor receptor (EGFR) antibodies such as cetuximab and panitumumab are widely used to treat patients with metastatic colorectal cancer (mCRC). However, patients eventually develop resistance to these drugs, which is one of the biggest challenges of EGFR-targeted therapy. Retrospective clinical studies revealed that mCRC patients with higher expression of low-affinity EGFR ligands such as amphiregulin and epiregulin had longer median progression free survival. On the contrary, patients refractory to cetuximab tended to have higher level of TGF-α expression according to the gene expression analysis. Recently, we demonstrated that GC1118 is a prominent blocker of both high- and low-affinity EGFR ligands induced signaling while cetuximab is limited to low-affinity ligands. In this study, we generated and characterized cetuximab-resistant CRC cell line and tested anti-tumor efficacy of GC1118 on cetuximab-resistant CRC tumor models. Experimental Design: To develop cetuximab-resistant SW48 colon cancer cell line (SW48CR) in vivo, mice bearing SW48 xenograft colorectal tumors were continuously exposed to cetuximab for several months. K-Ras mutation was analyzed by PCR and EGFR ligand expression was determined by ELISA assay. Results: First, we determined K-Ras mutation status and EGFR expression to characterize SW48CR cell line. K-Ras mutation is one of the most well-known cetuximab resistance mechanisms in CRC. There was no difference in EGFR expression level between SW48 and SW48CR. K-Ras expression was slightly increased and constitutively activated in SW48CR without mutation. Cetuximab resistance was confirmed by measuring proliferation and EGFR signaling inhibition by cetuximab in vitro. As expected, cetuximab was incapable of inhibiting cell proliferation and EGFR downstream signals in SW48CR cell line. Using SW48CR xenograft mouse model, we found that GC1118 suppressed SW48CR tumor growth by 80% while cetuximab inhibited less than 35%. Despite of this potent anti-tumor efficacy of GC1118 in vivo, GC1118 had no effect on SW48CR proliferation in vitro. This indicated GC1118 anti-tumor effect on SW48CR may be related to tumor microenvironment. In addition, EGFR ligand expression analysis indicated that HB-EGF, one of the high-affinity EGFR ligands was significantly increased in SW48CR compared with SW48, as previously reported by others. Since high-affinity EGFR ligands such as HB-EGF and TGF-α were implicated in tumor microenvironment, we are currently investigating GC1118 effects on tumor vasculature of SW48CR xenograft by immunohistochemical staining. Conclusion: These results suggest that overexpression of HB-EGF may contribute to cetuximab resistant CRC and GC1118 could be rational strategy to treat patients who acquired cetuximab resistance. Citation Format: Shi-Nai Lee, Hyun-Jung Cho, Yangmi Lim, Minkyu Hur, Eun Hee Lee, Jae-Chul Lee, Kyuhyun Lee, Sujeong Kim, Jonghwa Won. GC1118, a new anti-EGFR antibody overcome acquired resistance to cetuximab in colorectal cancer xenograft model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-114.
- Published
- 2016
16. Oral administration of 1,4-aryl-2-mercaptoimidazole inhibits T-cell proliferation and reduces clinical severity in the murine experimental autoimmune encephalomyelitis model
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Ho Kyun Han, Jeongmin Kim, Heon Jin Park, Min Woo Lee, Young Lim Kim, Minkyu Hur, Jonghwa Won, Eun Joo Jung, Ge Hyeong Lee, Yeup Yoon, Ikyon Kim, Sejin Hwang, Mi Soon Kim, A. Mi Woo, and Sungjoo Kim
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,T cell ,Encephalomyelitis ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Administration, Oral ,Pharmacology ,Lymphocyte Activation ,Jurkat cells ,Severity of Illness Index ,Myelin oligodendrocyte glycoprotein ,Jurkat Cells ,Mice ,Antigen ,Oral administration ,Medicine ,Animals ,Humans ,Immunologic Factors ,Hypersensitivity, Delayed ,Cell Proliferation ,Mice, Inbred BALB C ,biology ,Molecular Structure ,NFATC Transcription Factors ,business.industry ,Experimental autoimmune encephalomyelitis ,Imidazoles ,Thiones ,NFAT ,medicine.disease ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Spinal Cord ,Immunology ,biology.protein ,Molecular Medicine ,Interleukin-2 ,Female ,Lymph Nodes ,business - Abstract
T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC(50) of 5 microM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kappaB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRM-III reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRM-III as a potential lead compound for the treatment of T-cell-driven autoimmune diseases.
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- 2009
17. Clinical characteristics of triple-negative breast cancer
- Author
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Suyeon Lee, Hyunna Lee, R. J. Im, Jinseon Lee, Chan Seok Yoon, Seung Sang Ko, Minkyu Hur, Jun-Ran Kim, and Sung-Soo Kang
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Response to therapy ,business.industry ,medicine.disease ,Breast cancer ,Internal medicine ,medicine ,skin and connective tissue diseases ,business ,human activities ,Triple-negative breast cancer - Abstract
e11565 Background: Breast cancer represent a heterogenous group of tumors that are diverse in behavior, outcome, and response to therapy. To reduce mortality from breast cancer, there is a desire t...
- Published
- 2011
Catalog
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