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      The effects of Antibody Engineering CH and CL in Trastuzumab and Pertuzumab recombinant models: Impact on antibody production and antigen-binding

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          Abstract

          Current therapeutic antibodies such as Trastuzumab, are typically of the blood circulatory IgG1 class (Cκ/ CHγ1). Due to the binding to Her2 also present on normal cell surfaces, side effects such as cardiac failure can sometimes be associated with such targeted therapy. Using antibody isotype swapping, it may be possible to reduce systemic circulation through increased tissue localization, thereby minimising unwanted side effects. However, the effects of such modifications have yet to be fully characterized, particularly with regards to their biophysical properties in antigen binding. To do this, we produced all light and heavy chain human isotypes/subtypes recombinant versions of Trastuzumab and Pertuzumab, and studied them with respect to recombinant production and Her2 binding. Our findings show that while the light chain constant region changes have no major effects on production or Her2 binding, some heavy chain isotypes, in particularly, IgM and IgD isotypes, can modulate antigen binding. This study thus provides the groundwork for such isotype modifications to be performed in the future to yield therapeutics of higher efficacy and efficiency.

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          Therapeutic antibodies for human diseases at the dawn of the twenty-first century.

          Antibodies are highly specific, naturally evolved molecules that recognize and eliminate pathogenic and disease antigens. The past 30 years of antibody research have hinted at the promise of new versatile therapeutic agents to fight cancer, autoimmune diseases and infection. Technology development and the testing of new generations of antibody reagents have altered our view of how they might be used for prophylactic and therapeutic purposes. The therapeutic antibodies of today are genetically engineered molecules that are designed to ensure high specificity and functionality. Some antibodies are loaded with toxic modules, whereas others are designed to function naturally, depending on the therapeutic application. In this review, we discuss various aspects of antibodies that are relevant to their use as as therapeutic agents.
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            AllergoOncology: the role of IgE-mediated allergy in cancer.

            Epidemiological studies have suggested inverse associations between allergic diseases and malignancies. As a proof of concept for the capability of immunoglobulin E (IgE) to destruct tumor cells, several experimental strategies have evolved to specifically target this antibody class towards relevant tumor antigens. It could be demonstrated that IgE antibodies specific to overexpressed tumor antigens have been superior to any other immunoglobulin class with respect to antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) reactions. In an alternative approach, IgE nonspecifically attached to tumor cells proved to be a powerful adjuvant establishing tumor-specific immune memory. Active Th2 immunity could also be achieved by applying an oral immunization regimen using mimotopes, i.e. epitope mimics of tumor antigens. The induced IgE antibodies could be cross-linked by live tumor cells leading to tumoricidic mediator release. Thus, IgE antibodies may not only act in natural tumor surveillance, but could possibly also be exploited for tumor control in active and passive immunotherapy settings. Thereby, eosinophils, mast cells and macrophages can be armed with the cytophilic IgE and become potent anti-tumor effectors, able to trace viable tumor cells in the tissues. It is strongly suggested that the evolving new field AllergoOncology will give new insights into the role of IgE-mediated allergy in malignancies, possibly opening new avenues for tumor therapy.
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              Isotype selection in antibody engineering.

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                Author and article information

                Contributors
                samuelg@bii.a-star.edu.sg
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                15 January 2018
                15 January 2018
                2018
                : 8
                : 718
                Affiliations
                [1 ]ISNI 0000 0004 0637 0221, GRID grid.185448.4, Bioinformatics Institute, , Agency for Science, Technology and Research (A*STAR), ; Singapore, Singapore
                [2 ]ISNI 0000 0004 0637 0221, GRID grid.185448.4, p53 Laboratory, , Agency for Science, Technology and Research (A*STAR), ; Singapore, Singapore
                Author information
                http://orcid.org/0000-0003-0551-3545
                http://orcid.org/0000-0001-9936-5090
                Article
                18892
                10.1038/s41598-017-18892-9
                5768722
                29335579
                d07c4905-9b90-45ae-94d2-e79798b6c538
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 June 2017
                : 19 December 2017
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