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      Antibody–Drug Conjugates for Cancer Therapy

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          Abstract

          Antibody–drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.

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          Most cited references185

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          Regulated portals of entry into the cell.

          The plasma membrane is the interface between cells and their harsh environment. Uptake of nutrients and all communication among cells and between cells and their environment occurs through this interface. 'Endocytosis' encompasses several diverse mechanisms by which cells internalize macromolecules and particles into transport vesicles derived from the plasma membrane. It controls entry into the cell and has a crucial role in development, the immune response, neurotransmission, intercellular communication, signal transduction, and cellular and organismal homeostasis. As the complexity of molecular interactions governing endocytosis are revealed, it has become increasingly clear that it is tightly coordinated and coupled with overall cell physiology and thus, must be viewed in a broader context than simple vesicular trafficking.
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            Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

            Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
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              IgG Subclasses and Allotypes: From Structure to Effector Functions

              Of the five immunoglobulin isotypes, immunoglobulin G (IgG) is most abundant in human serum. The four subclasses, IgG1, IgG2, IgG3, and IgG4, which are highly conserved, differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptors (FcγR) and C1q. As a result, the different subclasses have different effector functions, both in terms of triggering FcγR-expressing cells, resulting in phagocytosis or antibody-dependent cell-mediated cytotoxicity, and activating complement. The Fc-regions also contain a binding epitope for the neonatal Fc receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement. How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function will be the focus of the current review.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                16 October 2020
                October 2020
                : 25
                : 20
                : 4764
                Affiliations
                [1 ]Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC 3084, Australia; umbreen.hafeez@ 123456onjcri.org.au (U.H.); sagun.parakh@ 123456onjcri.org.au (S.P.); hui.gan@ 123456onjcri.org.au (H.K.G.)
                [2 ]Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, VIC 3084, Australia
                [3 ]School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
                [4 ]Department of Medicine, University of Melbourne, Melbourne, VIC 3084, Australia
                [5 ]Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC 3084, Australia
                Author notes
                [* ]Correspondence: andrew.scott@ 123456onjcri.org.au ; Tel.: +61-39496-5000
                Author information
                https://orcid.org/0000-0003-3891-2489
                Article
                molecules-25-04764
                10.3390/molecules25204764
                7587605
                33081383
                d1cc4f06-583e-4822-b6ef-d23bc85c3378
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 August 2020
                : 13 October 2020
                Categories
                Review

                antibody–drug conjugate,adc,monoclonal antibody,cytotoxic payload,linkers,cancer,molecular imaging

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