ABSTRACT
OBJECTIVE: To synthesize mesoporous silica-core-shell magnetic nanoparticles (MNPs) encapsulated by liposomes (Lipo [MNP@m-SiO2]) in order to enhance their stability, allow them to be used in any buffer solution, and to produce trastuzumab-conjugated (Lipo[MNP@m-SiO2]-Her2Ab) nanoparticles to be utilized in vitro for the targeting of breast cancer. MATERIALS AND METHODS: The physiochemical characteristics of Lipo[MNP@m-SiO2] were assessed in terms of size, morphological features, and in vitro safety. The multimodal imaging properties of the organic dye incorporated into Lipo[MNP@m-SiO2] were assessed with both in vitro fluorescence and MR imaging. The specific targeting ability of trastuzumab (Her2/neu antibody, Herceptin(R))-conjugated Lipo[MNP@m-SiO2] for Her2/neu-positive breast cancer cells was also evaluated with fluorescence and MR imaging. RESULTS: We obtained uniformly-sized and evenly distributed Lipo[MNP@m-SiO2] that demonstrated biological stability, while not disrupting cell viability. Her2/neu-positive breast cancer cell targeting by trastuzumab-conjugated Lipo[MNP@m-SiO2] was observed by in vitro fluorescence and MR imaging. CONCLUSION: Trastuzumab-conjugated Lipo[MNP@m-SiO2] is a potential treatment tool for targeted drug delivery in Her2/neu-positive breast cancer.
Subject(s)
Animals , Female , Humans , Mice , 3T3 Cells , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents/administration & dosage , Breast Neoplasms/chemistry , Cell Line, Tumor , Drug Delivery Systems/methods , Ferric Compounds/chemistry , Liposomes , Magnetite Nanoparticles/administration & dosage , Molecular Targeted Therapy/methods , Nanoconjugates/administration & dosage , Nanoparticles/chemistry , Receptor, ErbB-2/immunology , Silicon Dioxide/administration & dosageABSTRACT
To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-alpha, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-alpha have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-alpha, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.
Subject(s)
Animals , Humans , Antibodies, Monoclonal/pharmacology , Antigens, CD20/immunology , Drug Discovery , Immune System Diseases/drug therapy , Immunotherapy/trends , Molecular Targeted Therapy , Neoplasms/drug therapy , ErbB Receptors/immunology , Receptor, ErbB-2/immunology , Tumor Necrosis Factor-alpha/immunology , United States , United States Food and Drug Administration , Vascular Endothelial Growth Factor A/immunologyABSTRACT
To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-alpha, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-alpha have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-alpha, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.
Subject(s)
Animals , Humans , Antibodies, Monoclonal/pharmacology , Antigens, CD20/immunology , Drug Discovery , Immune System Diseases/drug therapy , Immunotherapy/trends , Molecular Targeted Therapy , Neoplasms/drug therapy , ErbB Receptors/immunology , Receptor, ErbB-2/immunology , Tumor Necrosis Factor-alpha/immunology , United States , United States Food and Drug Administration , Vascular Endothelial Growth Factor A/immunologyABSTRACT
Breast cancer is one of the most common cancers in the world and is on the increase. Vaccines are new hopes for primary prevention of this cancer. In the breast cancer case, HER2 is a focus as a target for vaccine development. Here, preliminary data from a computation analysis of this outer membrane protein to find potential B-cell epitopes are described using a new bioinformatics tool. According to the results, 947SRMARDPQRFVVIQNE262 is the peptide with the best binding affinity. These data may be useful for further vaccine development because promiscuous peptide binders allow the total number of predicted epitopes to be minimized without compromising the population coverage required in the design of vaccines.
Subject(s)
Algorithms , Breast Neoplasms/prevention & control , Cancer Vaccines/immunology , Computational Biology , Epitopes, B-Lymphocyte/immunology , Humans , Peptide Fragments/chemistry , Receptor, ErbB-2/immunology , SoftwareABSTRACT
BACKGROUND/AIMS: The aim of this study was to investigate the immunohistochemical overexpression of c-erbB-2 and c-met proteins according to the histopathological parameters such as grade of dysplasia, histological type, depth of invasion, lymph node metastasis, and TNM stage in gastric adenoma and gastric adenocarcinoma. METHODS: Immunohistochemical staining using monoclonal c-erbB-2 and c-met antibodies was performed on paraffin embedded specimens in 43 adenomas and 44 adenocarcinomas. RESULTS: The expression rate of c-erbB-2 was higher in adenomas (91%) than adenocarcinomas (30%). The expression rate of c-met was higher in adenocarcinomas (77%) than adenomas (49%). In adenoma, the expression rate of c-met was higher in high grade dysplasia (94%) than in low grade dysplasia (22%). In adenocarcinoma, c-met expression was significantly related with lymph node metastasis. CONCLUSIONS: c-erbB-2 would be involved in the development of relatively early stage gastric carcinogenesis. c-erbB-2 is related with histologic type and c-met with lymph node metastasis in gastric carcinomas. Although meaning for the experession of these proteins in gastric carcinomas would be different, these proteins may play as important oncogenes in gastric carcinogenesis.
Subject(s)
Aged , Female , Humans , Male , Middle Aged , Adenocarcinoma/metabolism , Adenoma/metabolism , Antibodies, Monoclonal , Disease Progression , Immunohistochemistry , Lymphatic Metastasis , Proto-Oncogene Proteins c-met/immunology , Receptor, ErbB-2/immunology , Stomach Neoplasms/metabolism , Biomarkers, TumorABSTRACT
OBJECTIVES: To develop and verify a standardized protocol for HER2 immunohistochemical assays on invasive ductal carcinoma of the breast in Thailand. MATERIAL AND METHOD: A two-phase study approach was employed. In the Phase One, after verifying the proposed protocol that adopted the HercepTest procedure using readily available primary antibodies, CB11 and A0485, Lab 1 performed the HER2 immunohistochemical staining for 137 cases of invasive ductal carcinoma twice with two types of the antibody. Nine pathologists from 8 centers independently examined and scored all the 2 x 137 stained slides that were blinded for antibody type. Interobserver reliability was calculated using pair-wise kappa. Following discussion of the results, the Phase Two study was planned. Lab 2 and Lab 3 independently performed the HER2 staining according to the protocol for 60 invasive breast carcinoma cases. The same group of pathologists scored 2 x 60 stained slides that were masked for laboratories. Interobserver reliability and interlaboratory agreement from each pathologist were calculated using kappa statistics. Three interpreted categories--namely negative, equivocal and positive tests were used in the analyses. RESULTS: Phase One study showed interobserver agreement between pairs varied from kappa 0.75 (95%CI, 0.68-0.82) to 0.06 (95%CI, 0-0.14) while Phase Two study obtained pair-wise kappa scores ranged from 0.84 (95%CI, 0. 80-0.89) to 0. 65 (95%CI, 0.59-0.71). Interlaboratory kappa for each pathologist was 0.67 (95%CI, 0.61-0.73). CONCLUSION: The standardization of HER2 immunohistochemical assay was achieved through this two-phase study model. It had added benefits of improving pathologists' expertise and verifying the HER2 testing protocol to be used in Thailand.