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      Challenges in Optimising the Successful Construction of Antibody Drug Conjugates in Cancer Therapy

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          Abstract

          Although considerable progress has been made in the field of cancer chemotherapy, there remains a significant unmet medical need, with a requirement to move away from traditional cytotoxics and explore novel, smarter chemotherapeutic approaches. One such example of the smart chemotherapy approach is antibody-drug conjugates (ADCs), which consist of an antibody that binds selectively to a cancer antigen linked to a cytotoxic agent. When developing an ADC, it may be necessary to produce a variety of constructs to fully assess the optimal configuration for the molecule. By testing ADCs prepared using a range of cytotoxic agents, linkers, or different antibodies, it is possible to fully assess the optimal approach for this treatment modality before advancing to the clinic. Since the development and approval of first-generation ADCs, significant improvements in development technology have occurred. Here, we consider the advances made within the field of ADCs, focusing on the development of EDO-B278 and EDO-B776, both of which have demonstrated efficacy in preclinical testing. Although some limitations remain in this field of development, the potential reduction in toxicity offered by ADCs justifies the investment in research to find workable solutions that could ultimately provide patients with superior outcomes.

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          Most cited references33

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          Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index.

          The in vitro potency of antibody-drug conjugates (ADCs) increases with the drug-to-antibody ratio (DAR); however, ADC plasma clearance also increases with DAR, reducing exposure and in vivo efficacy. Here we show that accelerated clearance arises from ADC hydrophobicity, which can be modulated through drug-linker design. We exemplify this using hydrophilic auristatin drug linkers and PEGylated ADCs that yield uniform, high-DAR ADCs with superior in vivo performance.
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            Site-Specific Antibody–Drug Conjugates: The Nexus of Bioorthogonal Chemistry, Protein Engineering, and Drug Development

            Antibody–drug conjugates (ADCs) combine the specificity of antibodies with the potency of small molecules to create targeted drugs. Despite the simplicity of this concept, generation of clinically successful ADCs has been very difficult. Over the past several decades, scientists have learned a great deal about the constraints on antibodies, linkers, and drugs as they relate to successful construction of ADCs. Once these components are in hand, most ADCs are prepared by nonspecific modification of antibody lysine or cysteine residues with drug-linker reagents, which results in heterogeneous product mixtures that cannot be further purified. With advances in the fields of bioorthogonal chemistry and protein engineering, there is growing interest in producing ADCs by site-specific conjugation to the antibody, yielding more homogeneous products that have demonstrated benefits over their heterogeneous counterparts in vivo. Here, we chronicle the development of a multitude of site-specific conjugation strategies for assembly of ADCs and provide a comprehensive account of key advances and their roots in the fields of bioorthogonal chemistry and protein engineering.
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              Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry.

              Antibody drug conjugates (ADCs) have emerged as an important pharmaceutical class of drugs designed to harness the specificity of antibodies with the potency of small molecule therapeutics. The three main components of ADCs are the antibody, the linker, and the payload; the majority of early work focused intensely on improving the functionality of these pieces. Recently, considerable attention has been focused on developing methods to control the site and number of linker/drug conjugated to the antibody, with the aim of producing more homogenous ADCs. In this article, we review popular conjugation methods and highlight recent approaches including "click" conjugation and enzymatic ligation. We discuss current linker technology, contrasting the characteristics of cleavable and non-cleavable linkers, and summarize the essential properties of ADC payload, centering on chemotherapeutics. In addition, we report on the progress in characterizing to determine physicochemical properties and on advances in purifying to obtain homogenous products. Establishing a set of selection and analytical criteria will facilitate the translation of novel ADCs and ensure the production of effective biosimilars.
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                Author and article information

                Journal
                Antibodies (Basel)
                Antibodies (Basel)
                antibodies
                Antibodies
                MDPI
                2073-4468
                13 February 2018
                March 2018
                : 7
                : 1
                : 11
                Affiliations
                [1 ]Mundipharma EDO GmbH, Basel CH-4020, Switzerland
                [2 ]Consultant, Cleveland Heights, OH 441188, USA; dan.soltis@ 123456edoncology.com
                Author notes
                [* ]Correspondence: thomas.mehrling@ 123456edoncology.com ; Tel.: +41-61-205-1470
                Article
                antibodies-07-00011
                10.3390/antib7010011
                6698866
                c66f46dc-0663-4201-acd1-bad081ac9d0d
                © 2018 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
                : 13 December 2017
                : 09 February 2018
                Categories
                Review

                antibody-drug conjugate,smart chemotherapy,targeted treatment,solid tumours,haematological malignancies

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