• Journal of Radiopharmaceuticals and Molecular Probes
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• v.7 no.2
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• pp.85-91
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• 2021

Selective amino acid conjugation of bulky antibodies is a valuable asset for real-time diagnosis and therapy. However, selective conjugation incorporating a chelate-bearing radioactive atom into an antibody without affecting its immunoreactivity is a challenging task. A bifunctional chelator (BFC), a selective amino acid-targeting probe, and a linker have been developed to overcome this problem. Here, we report the synthesis of a novel propylene cross-bridged chelator (PCB)-1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane (TE2A)-luminol BFC via a click reaction and radiolabel it with a ⁶⁴Cu ion for tyrosine-selective conjugation of trastuzumab. In the initial optimization study, we tried different oxidative addition conditions such as electro-oxidation, hemin, horseradish peroxidase, iodogen tube, chloramine-T, and iodo beads. In this study, up to 82% of ⁶⁴Cu-PCB-TE2A-luminol was conjugated with the antibody in an iodo bead-catalyzed oxidative addition reaction with an isolated yield of 24.4%.

• Journal of Gastric Cancer
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• v.15 no.2
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• pp.139-142
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• 2015

Hepatic metastasis of early gastric cancer (EGC) following subtotal gastrectomy with lymphadenectomy is rare. We report the case of a 61-year-old male patient who was diagnosed with EGC that was initially treated using endoscopic submucosal dissection (ESD) and subsequently underwent laparoscopic subtotal gastrectomy. Histopathological examination of the patient's ESD specimen showed a moderately differentiated tubular adenocarcinoma invading the submucosa without lymphatic invasion. The deep margin of the specimen was positive for adenocarcinoma, and he subsequently underwent laparoscopic distal gastrectomy. The patient developed liver metastasis 15 months after the operation and then underwent liver resection. Histology of the resected specimen confirmed the diagnosis of two foci of metastatic adenocarcinoma originating from stomach cancer. Immunohistochemical analysis of the specimen demonstrated overexpression of human epidermal growth factor receptor 2. The patient was treated with trastuzumab in combination with chemotherapy consisting of capecitabine and cisplatin. Twenty-four months after the operation, the patient remained free of recurrence.

• Journal of Gastric Cancer
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• v.17 no.1
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• pp.52-62
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• 2017

Purpose: The Trastuzumab for gastric cancer (GC) trial identified human epidermal growth factor receptor 2 (HER2) as a predictor of successful treatment with trastuzumab (HER2 receptor targeting agent) among patients with advanced/metastatic GC. To date, the prevalence of HER2 overexpression in the Korean population is unknown. The present study aimed to assess the incidence of HER2 positivity among GC and gastroesophageal (GE) junction cancer samples and the relationship between HER2 overexpression and clinicopathological characteristics in Korean patients. Materials and Methods: Tumor samples collected from 1,695 patients with histologically proven GC or GE junction enrolled at 14 different hospitals in Korea were examined. After gathering clinicopathological data of all patients, HER2 status was assessed by immunohistochemistry (IHC) at each hospital, and IHC 2+ cases were subjected to silver-enhanced in situ hybridization at 3 central laboratories. Results: A total of 182 specimens tested positive for HER2, whereas 1,505 tested negative. Therefore, the overall HER2-positive rate in this study was 10.8% (95% confidence interval=9.3%-12.3%). The HER2-positive rate was higher among intestinal-type cases (17.6%) than among other types, and was higher among patients older than 70 years and 50 years of age, compared to other age groups. Conclusions: Our evaluation of the HER2 positivity rate (10.8%) among Korean patients with GC and GE junction indicated the necessity of epidemiological data when conducting studies related to HER2 expression in GC and GE junction.

• IMMUNE NETWORK
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• v.9 no.1
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• pp.4-7
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• 2009

Although the success of trastuzumab and rituximab for treatment of breast cancer and non-Hodgkins lymphoma, respectively, suggests that monoclonal antibodies(mAbs) will become important therapeutic agents against a wider range of cancers, useful therapeutic Abs are not yet available for the majority of the human cancers because of our lack of knowledge of which antigens (Ags) are likely to become useful targets. We established a procedure for comprehensive identification of such Ags through the extensive isolation of human mAbs that may be therapeutic. Using the phage-display Ab library we isolated a large number of human mAbs that bind to the surface of tumor cells. They were individually screened by immunostaining, and clones that preferentially and strongly stained the malignant cells were chosen. The Ags recognized by those clones were isolated by immunoprecipitation and identified by mass spectrometry(MS). We isolated 2,114 mAbs with unique sequences and identified 25 distinct Ags highly expressed on several carcinomas. Of those 2,114 mAbs 434 bound to specifically to one of the 25 Ags. I am going to discuss how we could select proper target Ags for therapeutic Abs and candidate clones are therapeutic agents.

• Journal of Gastric Cancer
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• v.18 no.1
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• pp.1-19
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• 2018

Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant diseases. While continued efforts have been focused on GC treatment, the introduction of trastuzumab marked the beginning of a new era of target-specific treatments. Considering the diversity of mutations in GC, satisfactory results obtained from various target-specific therapies were expected, yet most of them were unsuccessful in controlled clinical trials. There are several possible reasons underlying the failures, including the absence of patient selection depending on validated predictive biomarkers, the inappropriate combination of drugs, and tumor heterogeneity. In contrast to targeted agents, immuno-oncologic agents are designed to regulate and boost immunity, are not target-specific, and may overcome tumor heterogeneity. With the successful establishment of predictive biomarkers, including Epstein-Barr virus pattern, microsatellite instability status, and programmed death-ligand 1 (PD-L1) expression, as well as ideal combination regimens, a new frontier in the immuno-oncology of GC treatment is on the horizon. Since the field of immuno-oncology has witnessed innovative, practice-changing successes in other cancer types, several trials on GC are ongoing. Among immuno-oncologic therapies, immune checkpoint inhibitors are the mainstay of clinical trials performed on GC. In this article, we review target-specific agents currently used in clinics or are undergoing clinical trials, and highlight the future clinical application of immuno-oncologic agents in inoperable GC.

• Journal of Gastric Cancer
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• v.19 no.2
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• pp.148-156
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• 2019

Esophagogastric junction (EGJ) cancer is a solid tumor entity with rapidly increasing incidence in the Western countries. Given the high proportion of advanced cancers in the West, treatment strategies routinely employed include surgery and chemotherapy perioperatively, and chemoradiation in neoadjuvant settings. Neoadjuvant chemoradiation and perioperative chemotherapy are mostly performed in esophageal cancer that extends to the EGJ and gastric as well as EGJ cancers, respectively. Recent trials have tried to combine both strategies in a perioperative context, which might have beneficial outcomes, especially in patients with EGJ cancer. However, it is difficult to recruit patients for trials, exclusively for EGJ cancers; therefore, the results have to be carefully reviewed before establishing a standard protocol. Trastuzumab was the first drug for targeted therapy that was positively evaluated for this tumor entity, and there are several ongoing trials investigating more targeted drugs in order to customize effective therapies based on tissue characteristics. The current study reviews the multimodal treatment concept for EGJ cancers in the West and summarizes the latest reports.

• Mass Spectrometry Letters
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• v.12 no.3
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• pp.85-92
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• 2021

The therapeutic antibody drug market has experienced explosive growth as mAbs become the main therapeutic modality for a variety of diseases. Characterization of glycosylation that directly affects the efficacy and safety of therapeutic monoclonal antibodies (mAbs) is critical for therapeutics development, bioprocess system optimization, lot release, and comparability evaluation. The LC/MS approach has been widely used to structurally characterize mAbs, and recently attempts have been made to obtain comprehensive information on the primary structure and post-translational modifications (PTMs) of mAbs through intact protein analysis. In this study, we performed state-of-the-art LC/MS based intact protein analysis to readily identify and characterize glycoforms of various mAbs. Different glycoforms of mAbs produced in different expression cell lines including CHO, SP2/0 and HEK cells were monitored and compared. In addition, the comparability of protein molecular weight, glycoform pattern, and relative abundances of glycoforms between the commercialized trastuzumab biosimilar and the original product was determined in detail using the given platform. Intact mAb analysis allowed us to gain insight into the overall mAb structure, including the complexity and diversity of glycosylation. Furthermore, our analytical platform with high reproducibility is expected to be widely used for biopharmaceutical characterization required at all stages of drug development and manufacturing.

• Journal of Digestive Cancer Research
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• v.10 no.1
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• pp.22-30
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• 2022

Immune checkpoint inhibition has been established as a new treatment option for various types of carcinoma, and many clinical trials are being actively conducted as a treatment for advanced or metastatic gastric cancer, either as a monotherapy with an immune checkpoint inhibitor or as a combination therapy with standard chemotherapy. In the CheckMate-649 clinical trial to confirm the efficacy of the combination of nivolumab and chemotherapy (FP) in advanced gastric cancer and gastroesophageal junction cancer, nivolumab group showed improvement in overall survival in programmed death ligand 1-positive cancer patients compared with placebo group. Also, the combination therapy of pembrolizumab, trastuzumab and chemotherapy (FP) in first-line treatment was tested through the KEYNOTE-811 trial. The pembrolizumab group showed 22.7% of improvement in objective response rate compared with placebo group. Accordingly, the combination of nivolumab/pembrolizumab with standard chemotherapy was approved for the first-line treatment. In KEYNOTE-059 trials for patients with progressive disease after at least two lines of chemotherapy, pembrolizumab monotherapy showed improvement in objective response rate and overall survival, and the use of pembrolizumab was approved for the third-line or more treatment. In this article, we review the result of clinical trials related to immune checkpoint inhibitors that have been recently introduced in the treatment of gastric cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.5
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• pp.2593-2596
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• 2016

Background: Male breast cancer (MBC) is a rare disease that accounts for less than 1% of all cancers in men and less than 1% of all diagnosed breast cancers. In this study, we retrospectively evaluated the clinicopathological features, treatment options and overall survival in Kurdish MBC cases. Materials and Methods: Seventeen MBC were referred to Department of Radiation Oncology in Imam Reza Hospital, Kermanshah, Iran, between 2010 and 2016. Immunohistochemical analysis was performed for ER, PR and Her2 biomarkers and FISH for those with Her2 2+. Median follow-up period was 30 months (2-65 months). We excluded from the study patients who did not have follow-up after initial diagnosis. Treatment methods were chemotherapy, radiotherapy, hormonal therapy, target therapy and palliative care. Survival was estimated by the Kaplan Meier method (Prism 5). Results: The mean age at diagnosis was $49.24{\pm}17$ years (range, 24-85 years). Grade II was the most grade in MBC (65%). Fourteen patients (82%) had invasive ductal carcinoma, one (6%) had ductal carcinoma in situ and 2 (12%) had invasive papillary. ER, PR and Her2 were significantly positive in 14/17, 8/17 and 2/17 cases, respectively. The treatment included modified radical mastectomy for most patients. Chemotherapy with TAC and CEF regimens was delivered to 15/17 cases. Tamoxifen therapy was delivered to 14/17 cases. Three stage IV patients received Avestin and two with Her2 3+ were given Trastuzumab (Herceptin). Patients received adjuvant radiotherapy following surgery and chemotherapy. The site of metastasis was the bone in 2 cases, lung in 1 case and liver in 1 case. Zoledronic acid (Zometa) was prescribed for patients with bone metastasis. Five-year overall survival rate was 64%. Conclusions: MBC is rare. Thus, we need larger studies are in collaboration with several research centers in the field of breast cancer. ER positive, grade II of invasive ductal carcinoma, stage II and right side happened more with MBC. Overall survival is similar to other studies.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7695-7700
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• 2015

Background: HER2/neu overexpression on cell membranes of breast cancer cells is due to HER2/neu gene amplification and it is important to identify potential candidates for anti HER2 therapy with trastuzumab. IHC, FISH and CISH are standard FDA approved assays currently used to determine HER2 status in routine practice. The aim of this study was to determine HER2 gene amplification, using the CISH method in breast carcinoma samples which had IHC +2 reactions. Materials and Methods: This study was conducted from 2008-2010 using 334 consecutive breast carcinoma samples referred from local laboratories to Mehr Hospital. CISH assays were performed for all cases, and IHC tests were also done for determining efficacy and accuracy of local labs. HER2 status in local IHC tests was compared with central IHC and CISH results. Results: Of 334 breast cancer patients, 16 were negative for HER2 IHC (0, +1), 201 cases were equivocal (+2), and 31 positive (+3). Of 334 referral cases, 88 were CISH positive (26.3%) and 246 were CISH negative (73.7%). Of 201 IHC +2 cases, HER2 gene amplification was observed in 42 cases (kappa: 0.42). A 29.9% concordance was found between local IHC and central IHC. Sensitivity and specificity of local IHC were 90% and 53.8%, respectively. Conclusions: Low accuracy of IHC results in local labs was associated with the following factors: using former FDA-approved criteria for HER2 interpretation, utilizing non-validated kits, and lack of any quality assurance program. Therefore, following the new 2014 ASCO/CAP guideline and comprehensive quality assurance should be implemented to ensure accuracy of HER2 testing.