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      Novel prostate cancer immunotherapy with a DNA-encoded anti-prostate-specific membrane antigen monoclonal antibody

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          Abstract

          Prostate-specific membrane antigen (PSMA) is expressed at high levels on malignant prostate cells and is likely an important therapeutic target for the treatment of prostate carcinoma. Current immunotherapy approaches to target PSMA include peptide, cell, vector or DNA-based vaccines as well as passive administration of PSMA-specific monoclonal antibodies (mAb). Conventional mAb immunotherapy has numerous logistical and practical limitations, including high production costs and a requirement for frequent dosing due to short mAb serum half-life. In this report, we describe a novel strategy of antibody-based immunotherapy against prostate carcinoma that utilizes synthetic DNA plasmids that encode a therapeutic human mAb that target PSMA. Electroporation-enhanced intramuscular injection of the DNA-encoded mAb (DMAb) plasmid into mice led to the production of functional and durable levels of the anti-PSMA antibody. The anti-PSMA produced in vivo controlled tumor growth and prolonged survival in a mouse model. This is likely mediated by antibody-dependent cellular cytotoxicity (ADCC) effect with the aid of NK cells. Further study of  this novel approach for treatment of human prostate disease and other malignant conditions is warranted.

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          Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial.

          Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3.
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            Antibody therapeutics in cancer.

            In a relatively short period of time, monoclonal antibodies have entered the mainstream of cancer therapy. Their first use was as antagonists of oncogenic receptor tyrosine kinases, but today monoclonal antibodies have emerged as long-sought vehicles for the targeted delivery of potent chemotherapeutic agents and as powerful tools to manipulate anticancer immune responses. With ever more promising results from the clinic, the future will likely see continued growth in the discovery and development of therapeutic antibodies and their derivatives.
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              A synthetic consensus anti-spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates.

              First identified in 2012, Middle East respiratory syndrome (MERS) is caused by an emerging human coronavirus, which is distinct from the severe acute respiratory syndrome coronavirus (SARS-CoV), and represents a novel member of the lineage C betacoronoviruses. Since its identification, MERS coronavirus (MERS-CoV) has been linked to more than 1372 infections manifesting with severe morbidity and, often, mortality (about 495 deaths) in the Arabian Peninsula, Europe, and, most recently, the United States. Human-to-human transmission has been documented, with nosocomial transmission appearing to be an important route of infection. The recent increase in cases of MERS in the Middle East coupled with the lack of approved antiviral therapies or vaccines to treat or prevent this infection are causes for concern. We report on the development of a synthetic DNA vaccine against MERS-CoV. An optimized DNA vaccine encoding the MERS spike protein induced potent cellular immunity and antigen-specific neutralizing antibodies in mice, macaques, and camels. Vaccinated rhesus macaques seroconverted rapidly and exhibited high levels of virus-neutralizing activity. Upon MERS viral challenge, all of the monkeys in the control-vaccinated group developed characteristic disease, including pneumonia. Vaccinated macaques were protected and failed to demonstrate any clinical or radiographic signs of pneumonia. These studies demonstrate that a consensus MERS spike protein synthetic DNA vaccine can induce protective responses against viral challenge, indicating that this strategy may have value as a possible vaccine modality against this emerging pathogen.
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                Author and article information

                Contributors
                215 898 3986 , dweiner@wistar.org
                Journal
                Cancer Immunol Immunother
                Cancer Immunol. Immunother
                Cancer Immunology, Immunotherapy
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-7004
                1432-0851
                17 August 2017
                17 August 2017
                2017
                : 66
                : 12
                : 1577-1588
                Affiliations
                [1 ]ISNI 0000 0001 1956 6678, GRID grid.251075.4, Vaccine and Immunotherapy Center, , The Wistar Institute, ; 3601 Spruce Street, Philadelphia, PA 19104 USA
                [2 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Pathology and Laboratory Medicine, Perlman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA 19104 USA
                [3 ]ISNI 0000 0001 2353 285X, GRID grid.170693.a, Department of Molecular Medicine, , University of South Florida Morsani College of Medicine, ; Tampa, FL 33612 USA
                [4 ]ISNI 0000 0004 0417 098X, GRID grid.421774.3, Inovio Pharmaceuticals, ; Plymouth Meeting, PA 19462 USA
                Article
                2042
                10.1007/s00262-017-2042-7
                5676807
                28819703
                8f104a53-1670-4582-baaa-b2ae2de205c2
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 21 September 2016
                : 12 July 2017
                Funding
                Funded by: Inovio Pharmaceuticals
                Funded by: Defense Advanced Research Projects Agency (DARPA)-Prophylactic Options to Environmental and Contagious Threats (PROTECT)
                Award ID: W31P4Q-13-1-0003
                Award Recipient :
                Funded by: Defense Advanced Research Projects Agency (DARPA)-Prophylactic Options to Environmental and Contagious Threats (PROTECT)
                Award ID: W31P4Q-13-1-0003
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2017

                Oncology & Radiotherapy
                prostate cancer,prostate-specific membrane antigen,dna-encoded monoclonal antibodies,immunotherapy,in vivo electroporation

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