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Overview of Antibody Drug Delivery

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Overview of Antibody Drug Delivery pharmaceutics Review Overview of Antibody Drug Delivery Sahar Awwad 1,2,* ID and Ukrit Angkawinitwong 1 1 UCL School of Pharmacy, London WC1N 1AX, UK; [email protected] 2 National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1 V9EL, UK * Correspondence: [email protected]; Tel.: +44-207-753-5802 Received: 27 March 2018; Accepted: 29 June 2018; Published: 4 July 2018 Abstract: Monoclonal antibodies (mAbs) are one of the most important classes of therapeutic proteins, which are used to treat a wide number of diseases (e.g., oncology, inflammation and autoimmune diseases). Monoclonal antibody technologies are continuing to evolve to develop medicines with increasingly improved safety profiles, with the identification of new drug targets being one key barrier for new antibody development. There are many opportunities for developing antibody formulations for better patient compliance, cost savings and lifecycle management, e.g., subcutaneous formulations. However, mAb-based medicines also have limitations that impact their clinical use; the most prominent challenges are their short pharmacokinetic properties and stability issues during manufacturing, transport and storage that can lead to aggregation and protein denaturation. The development of long acting protein formulations must maintain protein stability and be able to deliver a large enough dose over a prolonged period. Many strategies are being pursued to improve the formulation and dosage forms of antibodies to improve efficacy and to increase the range of applications for the clinical use of mAbs. Keywords: antibodies; protein; pharmacokinetics; drug delivery; stability 1. Introduction Monoclonal antibodies (mAbs) are by far the largest class of therapeutic proteins and a key driver in the biopharmaceutical growth [1]. Currently, humanized mAbs are the fastest growing group in clinical trials [2]. Most therapeutics mAbs that are available share common functions such as blocking target receptors or ligands, thus decreasing the overall activity of certain pathway. The Food and Drug Administration (FDA) approved the first mAb in 1986 (Orthoclone OKT3, muromonab-CD3) for the prevention of kidney transplant rejection [2,3] (later withdrawn) and many more antibodies and antibody derivatives (e.g., fragment antigen-binding (Fab), fragment crystallisable region (Fc)-fusion proteins, etc.) [4] have been developed since [5]. A majority of mAb therapeutics have been approved for oncology, rheumatoid and autoimmune diseases [4]. mAbs have revolutionized the treatment of ophthalmic conditions (e.g., use of anti-vascular endothelial growth factor (VEGF) medicines such as ranibizumab (Lucentis®) in the treatment of wet age-related macular degeneration, AMD) [6]. Monoclonal antibodies exhibit good safety profiles and enhanced efficacy; and have been reported to show higher success rates in progression through early clinical development [7]. Approximately 70 mAb products have been predicted to be available in market by 2020 for the treatment of various diseases [8]. Monoclonal antibodies are immunoglobulins (Ig) of which there are five classes (IgA, IgD, IgE, IgG and IgM) [9]. The most relevant for therapeutics is IgG, which has four subclasses (IgG1, IgG2, IgG3 and IgG4) [10]. IgGs are bivalent molecules with a molecular weight of ~150 kDa, which can be highly site specific with affinities ranging from nano- to picomolar. IgGs (Figure1) have two separate Pharmaceutics 2018, 10, 83; doi:10.3390/pharmaceutics10030083 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2018, 10, 83 2 of 24 Pharmaceutics 2018, 10, x FOR PEER REVIEW 2 of 24 identical heavy (H) and light (L) chains [11]. The N-terminal domain of an IgG consists of a variable (V) region(V) region with with the complementarity-determining the complementarity-determining region region (CDR) (CDR) that binds that to binds a specific to a epitopespecific onepitope antigens. on Otherantigens. domains Other withindomains the within IgG make the IgG up make the constant up the constant (C) regions. (C) Theregions. structure The structure of an IgG of is an broadly IgG is dividedbroadly intodivided the Fabinto (2/3) the Fab and (2/3) Fc regions and Fc (1/3). regions The (1/3). two identicalThe two Fabsidentical each compriseFabs each of comprise a light chain of a thatlight is chain closely that associated is closely by associated non-covalent by interactionsnon-covalent with interactions the heavy chain.with the There heavy is a solvent-accessiblechain. There is a interchainsolvent-accessible disulfide interchain (S-S) between disulfide the light(S-S) chainbetween and the heavy light chain chain ofand the heavy Fab. Thechain heavy of the chains Fab. The are closelyheavy chains associated are closely through associated non-covalent through interactions non-covalent within interactions the Fc region. within The the hinge Fc region. region The links hinge the Fabsregion to links the Fc the and Fabs there to arethe(usually) Fc and there two solventare (usually) accessible two disulfidessolvent accessible between disulfides the heavy chainsbetween in the hingeheavy region.chains in There the hinge are also region. intra-molecular There are also disulfides intra-molecular within each disulfides constant within and variableeach constant region and of bothvariable the region heavy andof both light the chains. heavy These and light disulfides chains. are These not disulfides solvent-accessible. are not solvent Many- aspectsaccessible. of mAbs,Many includingaspects of epitope mAbs, specificity, including immunogenicity, epitope specificity, pharmacokinetic immunogenicity, and immune-related pharmacokinetic effector and functions,immune- arerelated active effector areas functions, of research are that active is focused areas of on research the continued that is evolutionfocused on of the antibodies continued for evolution therapeutic of useantibodie [12]. s for therapeutic use [12]. Figure 1. 1. A Aschematic schematic diagram diagram representing representing the modular the modular structure structure of a monoclonal of a monoclonal antibody antibody (mAb). (mAb).(Abbreviation: (Abbreviation: CDR: complementarity CDR: complementarity-determining-determining region; COO region;-: carboxy COO-: terminal; carboxy CH: terminal;constant CH:domain, constant heavy domain, chain, CL: heavy constant chain, domain, CL: constant light domain,chain; Fab: light fragment chain; Fab: antigen fragment-binding; antigen-binding; Fc: fragment Fc:crystallisable fragment crystallisableregion, NH3:region, amino NH3: terminal amino end, terminal S-S: disulfid end, S-S:e disulfidebond; VH: bond; variable VH: variabledomain, domain, heavy heavychain; chain;VL: variable VL: variable domain, domain, light chain) light chain) The Fab structure allows different IgG moleculesmolecules to identifyidentify different antigensantigens [[13].13]. Porter and Edelman (1972)(1972) won won the the Noble Noble Prize Prize for elucidatingfor elucidating the structure the structure of antibodies of antibodies by proteolytic by proteolytic digestion usingdigestion thiol using proteases, thiol proteases, e.g., papain. e.g. With, papain. the use With of the papain, use of Porter papain, was Porter ableto was cleave able theto cleave IgG molecule the IgG intomolecule two Fabsinto two and Fabs an Fc. and The an FabFc. The can Fab bind can to bind a specific to a specific antigen antigen while thewhile Fc the is unable Fc is unable to block to bindingblock binding to a specific to a specific antigen antigen [14,15]. [14,1 Fabs5]. have Fabs been have used been in used the determination in the determination of antibody–antigen of antibody– interactionsantigen interactions [16]. Fabs [16]. usually Fabs usually have better have tissuebetter penetrationtissue penetration than full than length full length IgGs and IgGs can and allow can interactionsallow interactions with enzyme with enzyme sites (which sites (which IgGs can IgGs find can difficult find difficult to access). to access). However, However, Fabs do Fabs display do fastdisplay off-rates fast off and-rates poor and retention poor timesretention compared times compared to IgGs on to target IgGs as on a resulttarget of as the a monovalencyresult of the ofmonovalency Fab [17]. The of Fab FDA [17]. and The the FDA European and the Medicines European AgencyMedicines (EMA) Agency have (EMA) approved have approved three Fabs three i.e., ® ® ® certolizumabFabs i.e., certolizumab pegol (Cimzia pegol®), ranibizumab (Cimzia ), (Lucentisranibizumab®) and (Lucentis abciximab) and (Reopro abciximab®). Ranibizumab (Reopro is). aRanibizumab humanized Fabis a humanized with specificity Fab with to all specificity isoforms ofto VEGFall isoforms [18], and of VEGF has demonstrated [18], and has demonstrated good signs of good signs of biological activity and acceptable safety when administered as an intravitreal injection up to 6 months in patients with neovascular AMD [19–21]. Polyclonal Fabs have also been marketed such as crotalidae polyvalent immune Fab (ovine) (CroFab®), digoxin immune Fab (DigiFab®) and Pharmaceutics 2018, 10, 83 3 of 24 biological activity and acceptable safety when administered as an intravitreal injection up to 6 months in patients with neovascular AMD [19–21]. Polyclonal Fabs have also been marketed such as crotalidae polyvalent immune Fab (ovine) (CroFab®), digoxin immune Fab (DigiFab®) and digoxin immune Fab (ovine) (Digibind®)[22].
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