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Advances and Limitations of Antibody Drug Conjugates for Cancer

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Advances and Limitations of Antibody Drug Conjugates for Cancer biomedicines Review Advances and Limitations of Antibody Drug Conjugates for Cancer Candice Maria Mckertish and Veysel Kayser * Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; [email protected] * Correspondence: [email protected]; Tel.: +61-2-9351-3391 Abstract: The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful devel- opment of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation. Keywords: antibody drug conjugates; drug resistance; linkers; payloads; therapeutic index; target specific; ADC clearance; protein aggregation Citation: Mckertish, C.M.; Kayser, V. Advances and Limitations of Antibody Drug Conjugates for 1. Introduction Cancer. Biomedicines 2021, 9, 872. Conventional cancer therapy often entails a low therapeutic window and non-specificity https://doi.org/10.3390/ of chemotherapeutic agents that consequently affects normal cells with high mitotic rates biomedicines9080872 and provokes an array of adverse effects, and in some cases leads to drug resistance [1]. Monoclonal antibodies (mAbs) have evidently demonstrated great therapeutical potential Academic Editors: Chiara Brignole for the treatment of a multitude of ailments, particularly for cancer [2]. Prior to the develop- and Fabio Pastorino ment of ADCs, mAbs attracted interest attributable to its target specificity, wide therapeutic Received: 4 July 2021 index, and its affiliation with fewer side effects, in particular for cancer [3], compared to Accepted: 20 July 2021 conventional therapy, which incorporates chemotherapy, radiation therapy and surgery [4]. Published: 23 July 2021 As an improvement, ADCs provide a synergistic effect upon the conjugation of a mAb to a cytotoxic drug, compared to the mAb used alone [4,5]. Publisher’s Note: MDPI stays neutral Conjugation is an approach that enables the attachment of highly toxic drugs to a with regard to jurisdictional claims in tumor specific mAb chemically, in order to construct an ADC. An ADC is comprised of a published maps and institutional affil- mAb, a linker and a cytotoxic payload [1,6], illustrated in Figure1. The linker conjugates iations. the payload to the mAb, which binds to the target that is over expressed on the tumor cell, and the payload potentiates the therapeutic action [1]. ADC payloads should exert stability in storage and in the blood stream as well as have non-immunogenic effects. The main characteristics of ADC include a good internalization rate, low immunogenicity, high Copyright: © 2021 by the authors. binding specificity and affinity, a potent payload, and a stable linker [7]. 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 (https:// creativecommons.org/licenses/by/ 4.0/). Biomedicines 2021, 9, 872. https://doi.org/10.3390/biomedicines9080872 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 25 Biomedicines 2021, 9, 872 2 of 25 FigureFigure 1. 1. BasicBasic structure structure of of an an ADC: ADC: An An ADC ADC is is compri comprisedsed of of the the monoclonal monoclonal antibody antibody (red), (red), linker linker (green)(green) and and payload. payload. The The payload payload can can be be conjugated conjugated to to different different parts parts of of the the mAb mAb and and is is commonly commonly attachedattached via via cysteine cysteine (brown) (brown) or or lysine lysine residues residues (blue). (blue). Generally, Generally, more more than than one one payload payload can can be be attached.attached. An An IgG IgG antibody antibody structure structure consists consists of of two two Fab Fab fragments. fragments. Each Each fragment fragment consists consists of of one one heavyheavy chain chain and and one one light light chain chain and and the the Fc Fc fragment. fragment. AmongstAmongst emerging emerging antibody-based antibody-based therapies, therapies, ADCs ADCs have have demonstrated demonstrated superior superior ef- fectseffects over over standard standard chemotherapeutics chemotherapeutics for for canc cancerer [8]. [8]. Amidst Amidst the the growing growing enthusiasm enthusiasm for for ADCs,ADCs, their their design design and and development development entail entail many many challenges, challenges, including including susceptibility susceptibility to to degradationdegradation due due to to the the required required low low storage storage temperature temperature and and anomalies anomalies that that arise arise during during transport.transport. Moreover, Moreover, althoughalthough highhigh formulation formulation concentrations, concentrations, through through SC SC (subcutaneous) (subcutane- ous)or IV or (intravenous), IV (intravenous), attracted attracted interest, interest, this often this leadsoftento leads lack to of stabilitylack of stability or high aggregationor high ag- gregationpropensity propensity in formulation. in formulation. Alternatively, Alternatively, low concentration low concentration reduces bioavailabilityreduces bioavaila- and bilityability and to ability penetrate to penetrate the tissue the to exerttissue effects. to exert The effects. challenge The challenge lies in obtaining lies in obtaining the optimal the optimalconcentration concentration in formulation in formulation to enhance to enha localnce bioavailability local bioavailability and tissue and penetration tissue penetra- [9,10]. tionCurrently, [9,10]. Currently, over 100 ADCs over are100 undergoingADCs are unde clinicalrgoing trials, clinical outof trials, which out approximately of which approx- 20% imatelyof ADCs 20% have of ADCs been terminatedhave been terminated or withdrawn or withdrawn during either during phase either I or phase phase I or II, phase a few II,ADCs a few were ADCs linked were to linked dose limiting to dose toxicitieslimiting toxicities [11]. A narrow [11]. A therapeutic narrow therapeutic index results index in resultstoxicity in [ 12toxicity]. Attaining [12]. Attaining an optimal an optimal dose for dose an ADC for an is ADC important is important in limiting in limiting the dosing the dosingcycles toleratedcycles tolerated by the by patient, the patient, dose reductions, dose reductions, skipped skipped doses doses or discontinuation or discontinuation in the intherapy. the therapy. There There have been have clinical been clinical and translation and translation dosing dosing schedules, schedules, including including a fractionated a frac- dosing schedule, to address dose limiting toxicities in patients [13–17]. For example, tionated dosing® schedule, to address dose limiting toxicities in patients [13–17]. For exam- ple,Mylotarg Mylotargcaused® caused a high a high rate ofrate fatal of toxicitiesfatal toxicities related related to the dosingto the scheduledosing schedule and failed and to display any amelioration in efficacy compared to standard chemotherapy and hence was failed to display any amelioration in efficacy compared to standard chemotherapy and withdrawn from the market in 2010 [4,18]. Over recent years ADC research has entailed hence was withdrawn from the market in 2010 [4,18]. Over recent years ADC research has the optimization of current ADCs, and the design and development of various linkers that entailed the optimization of current ADCs, and the design and development of various are delineated in the following sections. linkers that are delineated in the following sections. 2. Overview of ADCs 2. Overview of ADCs The interest in ADCs has increased remarkably in recent years. As mentioned, more thanThe 100 interest ADCs arein ADCs currently has increased undergoing remarkably clinical trials in recent for cancer years. indications.As mentioned, The more ma- thanjority 100 of ADCs ADCs are have currently progressed undergoing from phase clinical I trials to phase for cancer II. Phase indications. III trials The have majority shown ofpromising ADCs have results progressed for some from ADCs; phase Mirvetuximab I to phase II. soravtansine Phase III trials (NCT02631876), have shown promising indicated resultsfor the for treatment some ADCs; of ovarian Mirvetuximab cancer, and [vic]-trastuzumabsoravtansine (NCT02631876), duocarmazine indicated (NCT03262935), for the indicated for the treatment of breast cancer, are amongst a few that have progressed to Biomedicines 2021, 9, 872 3 of 25 phase III trials. Some of the ADCs in clinical trials have employed cleavable linkers such as Valine-Citrulline (Val-Cit) due to its stability in circulation. Most of the ADCs are CD targeting, except for Tusamitamab ravtansine (SAR408701) which targets carcinoembryonic antigen-related cell adhesion
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