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      Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation

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          Abstract

          Therapeutic antibody technology heavily dominates the biologics market and continues to present as a significant industrial interest in developing novel and improved antibody treatment strategies. Many noteworthy advancements in the last decades have propelled the success of antibody development; however, there are still opportunities for improvement. In considering such interest to develop antibody therapies, this review summarizes the array of challenges and considerations faced in the design, manufacture, and formulation of therapeutic antibodies, such as stability, bioavailability and immunological engagement. We discuss the advancement of technologies that address these challenges, highlighting key antibody engineered formats that have been adapted. Furthermore, we examine the implication of novel formulation technologies such as nanocarrier delivery systems for the potential to formulate for pulmonary delivery. Finally, we comprehensively discuss developments in computational approaches for the strategic design of antibodies with modulated functions.

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          Protein structure-based drug design: from docking to molecular dynamics.

          Amedeo Caflisch, Paweł Śledź (2018)
          Recent years have witnessed rapid developments of computer-aided drug design methods, which have reached accuracy that allows their routine practical applications in drug discovery campaigns. Protein structure-based methods are useful for the prediction of binding modes of small molecules and their relative affinity. The high-throughput docking of up to 106 small molecules followed by scoring based on implicit-solvent force field can robustly identify micromolar binders using a rigid protein target. Molecular dynamics with explicit solvent is a low-throughput technique for the characterization of flexible binding sites and accurate evaluation of binding pathways, kinetics, and thermodynamics. In this review we highlight recent advancements in applications of ligand docking tools and molecular dynamics simulations to ligand identification and optimization.
          Article 0 comments Cited 134 times – based on 0 reviews     Review now
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            Industrial production of recombinant therapeutics in Escherichia coli and its recent advancements.

            Chung-Jr. Huang, Henry Lin, Xiaoming Yang (2012)
            Nearly 30% of currently approved recombinant therapeutic proteins are produced in Escherichia coli. Due to its well-characterized genetics, rapid growth and high-yield production, E. coli has been a preferred choice and a workhorse for expression of non-glycosylated proteins in the biotech industry. There is a wealth of knowledge and comprehensive tools for E. coli systems, such as expression vectors, production strains, protein folding and fermentation technologies, that are well tailored for industrial applications. Advancement of the systems continues to meet the current industry needs, which are best illustrated by the recent drug approval of E. coli produced antibody fragments and Fc-fusion proteins by the FDA. Even more, recent progress in expression of complex proteins such as full-length aglycosylated antibodies, novel strain engineering, bacterial N-glycosylation and cell-free systems further suggests that complex proteins and humanized glycoproteins may be produced in E. coli in large quantities. This review summarizes the current technology used for commercial production of recombinant therapeutics in E. coli and recent advances that can potentially expand the use of this system toward more sophisticated protein therapeutics.
            Article 0 comments Cited 116 times – based on 0 reviews     Review now
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              Nanotechnology for protein delivery: Overview and perspectives.

              Mikyung Yu, Jun Wu, Jinjun Shi … (2016)
              Protein-based therapeutics have made a significant impact in the treatment of a variety of important human diseases. However, given their intrinsically vulnerable structure and susceptibility to enzymatic degradation, many therapeutic proteins such as enzymes, growth factors, hormones, and cytokines suffer from poor physicochemical/biological stability and immunogenicity that may limit their potential benefits, and in some cases limit their utility. Furthermore, when protein therapeutics are developed for intracellular targets, their internalization and biological activity may be limited by inefficient membrane permeability and/or endosomal escape. Development of effective protein delivery strategies is therefore essential to further enhance therapeutic outcomes to enable widespread medical applications. This review discusses the advantages and limitations of marketed and developmental-stage protein delivery strategies, and provides a focused overview of recent advances in nanotechnology platforms for the systemic delivery of therapeutic proteins. In addition, we also highlight nanoparticle-mediated non-invasive administration approaches (e.g., oral, nasal, pulmonary, and transdermal routes) for protein delivery.
              Article 0 comments Cited 103 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Antibodies (Basel)
                Journal ID (iso-abbrev): Antibodies (Basel)
                Journal ID (publisher-id): antibodies
                Title: Antibodies
                Publisher: MDPI
                ISSN (Electronic): 2073-4468
                Publication date (Electronic): 03 June 2019
                Publication date Collection: June 2019
                Volume: 8
                Issue: 2
                Electronic Location Identifier: 36
                Affiliations
                School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney 2006, Australia; vsif0221@ 123456uni.sydney.edu.au (V.S.); ecru7298@ 123456uni.sydney.edu.au (E.C.); barbaros.eroglu@ 123456sydney.edu.au (B.E.)
                Author notes
                [* ]Correspondence: veysel.kayser@ 123456sydney.edu.au ; Tel.: +61-2-9351-3391
                Author information
                https://orcid.org/0000-0003-3750-9962
                https://orcid.org/0000-0003-1310-9534
                Article
                Publisher ID: antibodies-08-00036
                DOI: 10.3390/antib8020036
                PMC ID: 6640721
                PubMed ID: 31544842
                SO-VID: ba8f89d7-09eb-42f0-b067-ac00f39762e7
                Copyright © © 2019 by the authors.
                License:

                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
                Date received : 16 April 2019
                Date accepted : 31 May 2019
                Categories
                Subject: Review

                Keywords: therapeutic antibody,stability,aggregation,manufacture challenges,formulation
                Data availability:
                Keywords: therapeutic antibody, stability, aggregation, manufacture challenges, formulation

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