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Antibody–Drug Conjugates for Cancer Therapy

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Antibody–Drug Conjugates for Cancer Therapy molecules Review Antibody–Drug Conjugates for Cancer Therapy Umbreen Hafeez 1,2,3, Sagun Parakh 1,2,3 , Hui K. Gan 1,2,3,4 and Andrew M. Scott 1,3,4,5,* 1 Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC 3084, Australia; [email protected] (U.H.); [email protected] (S.P.); [email protected] (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 * Correspondence: [email protected]; Tel.: +61-39496-5000 Academic Editor: João Paulo C. Tomé Received: 14 August 2020; Accepted: 13 October 2020; Published: 16 October 2020 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. Keywords: antibody–drug conjugate; ADC; monoclonal antibody; cytotoxic payload; linkers; cancer; molecular imaging 1. Introduction Despite the range of new anti-cancer drugs in the market, there were 9.6 million deaths from cancer globally in 2018, with approximately one in six of all deaths being due to cancer [1]. A recent review concluded that most of the anti-cancer drugs that entered the market between 2009 and 2013 showed only marginal gains in terms of overall survival and that there is an urgent need to increase therapeutic efficacy [2]. Systemic therapies based on the use of monoclonal antibodies (mAbs) started to emerge after the discovery of hybridoma technology by Kohler and Milstein in 1975. In 1988, Greg Winter pioneered the technique to humanize monoclonal antibodies and thereafter, therapeutic monoclonal antibodies have been successfully developed for the treatment of various cancers. To date, approximately 30 mAbs have been approved by the US Food and Drug Administration (FDA) for the treatment of cancer. The specificity of mAbs also makes them well suited for the targeted delivery of drugs to cancer cells whilst avoiding normal tissues. Monoclonal antibody technology has been further improved over the next decades by conjugating antibodies with cytotoxic drugs [3]. Such conjugates, called antibody–drug conjugates (ADCs), are targeted agents that link a cytotoxic drug (also called as cytotoxic payload or warhead) via a linker to a monoclonal antibody which specifically recognizes a cellular surface antigen and deliver toxic payload at the tumor site, thus improving the efficacy of chemotherapy and reducing systemic exposure and toxicity [4]. More than 80 ADCs are currently under clinical development worldwide [5,6]. In this paper, we provide an overview of the biology and Molecules 2020, 25, 4764; doi:10.3390/molecules25204764 www.mdpi.com/journal/molecules Molecules 2020, 25, 4764 2 of 35 Molecules 2020, 25, 4764 2 of 33 biology and chemistry of ADCs, discuss key components of ADC design and discuss the current statuschemistry of clinically of ADCs, approved discuss key and components underdeveloped of ADC ADCs. design We and also discuss discuss the resistance current status mechanisms of clinically to ADC,approved the role and underdevelopedof molecular imaging ADCs. in Wethe alsoclinic discussal development resistance of mechanisms ADCs and give to ADC, an opinion the role on of futuremolecular perspectives. imaging in the clinical development of ADCs and give an opinion on future perspectives. 2. Design Design and Structure of Antibody–Drug Conjugates The useuse ofof ADCs ADCs has has evolved evolved over over time, time, becoming becoming increasingly increasingly widespread widespread as initial as initial problems problems were wereovercome overcome by better by targetbetter selection, target selection, accompanied acco bympanied improvements by improvements in payloads, in linker payloads, technologies linker technologiesand conjugation andtechniques conjugation (Figure techniques1). (Figure 1). Figure 1. Antibody–drug conjugate structure. Figure 1. Antibody–drug conjugate structure. 2.1. Target Selection 2.1. TargetUnconjugated Selection mAbs have various mechanisms of action including target receptor neutralization, receptorUnconjugated downregulation, mAbs signalling have disruption,various mechanisms antibody dependent of action cell-mediated including cytotoxicity target receptor (ADCC), neutralization,complement-dependent receptor downregu cell-mediatedlation, cytotoxicity signalling (CDCC) disruption, and immuneantibody checkpoint dependent inhibition cell-mediated [7,8]. cytotoxicityOn the other (ADCC), hand, ADCs complement-dependent rely on target receptor ce internalizationll-mediated cytotoxicity to deliver the(CDCC) cytotoxic and payload immune to checkpointthe cancer cells.inhibition Hence, [7,8]. selecting On the an other appropriate hand, ADCs target rely antigen on target is areceptor critical stepinternalization for the success to deliver of an theantibody–drug cytotoxic payload conjugate. to the cancer cells. Hence, selecting an appropriate target antigen is a critical step forIdeally, the success the target of an antigen antibody–drug should be conjugate. abundant on the cell surface to be available for binding by theIdeally, circulating the target ADC, antigen e.g., melanoma should be cellabundant lines withon the p97 cell receptor surface expressionto be available levels for from binding 80,000 by theto 280,000 circulating receptors ADC, per e.g., cell melanoma showed sensitivity cell lines with to ADC p97 L49-vcMMAF, receptor expression while otherlevels cancer from 80,000 cell lines to with280,000 lower receptors p97 expression per cell showed were resistantsensitivity to to L49-vcMMAF ADC L49-vcMMAF, [9]. However, while other various cancer other cell ADCs lines havewith lowershown p97 effi expressioncacy over a were wide resistant range of to antigen L49-vcMMAF expression [9]. However, levels based various on other other characteriztics ADCs have shown of the efficacytarget antigen, over a includingwide range binding of anti agenffinity expression and rate levels of internalization. based on other Gemtuzumab characteriztics ozogamicin of the target has antigen,demonstrated including efficacy binding at a relatively affinity lowand expressionrate of internalization. of CD33 (5000 Gemtuzumab to 10,000 receptors ozogamicin per cell) has as demonstrated efficacy at a relatively low expression of CD33 (5000 to 10,000 receptors per cell) as Molecules 2020, 25, 4764 3 of 33 compared to trastuzumab emtansine (T-DM1) which usually requires high ErbB2 expression levels (>2 million receptors per cell) [10,11]. The high surface expression of the antigen may not lead to ADC efficacy if trafficking into the tumor cell is impaired. Inge et al. [12] showed that after antibody binding CD21 does not effectively internalize, even when expressed at very high levels, resulting in a lack of efficacy with anti-CD21-MCC-DM1 ADCs. This study also showed that CD21 forms a complex with CD19 on the surface of B cells and prevents internalization of CD19 after it is bound to anti-CD19 antibody and decreasing anti-CD19-MCC-DM1 efficacy [12]. To minimize off-target toxicity, the target antigen should have exclusive or preferential expression on cancer cells with a minimal expression on healthy tissue. Four out of nine approved ADCs—inotuzumab ozogamicin, gemtuzumab ozogamicin, brentuximab vedotin, and polatuzumab vedotin—target lineage-specific markers that include CD22, CD33, CD30 and CD79, respectively. These antigens have consistent expression across the target cell population. The target antigen should also have minimal secretion in circulation from the cancer cells, as antibodies can bind to these secreted receptors in the circulation, thus limiting the amount of antibody available for target cell binding [13]. The target antigen should internalize efficiently upon ADC binding to allow the antigen–ADC complex to be internalized via receptor-mediated endocytosis, and it should undergo appropriate intracellular trafficking and degradation, thereby allowing the cytotoxic warhead to be released [14]. Target antigens on the cell surface can have variable rates for basal and antibody induced internalization which can affect ADC efficacy [12]. For example, CD74 antigen is rapidly internalized into target cells following antibody binding. The preclinical data for anti-CD74 ADC immu-110 showed similar efficacy to other ADCs that target slower internalizing antigens with more potent cytotoxic payloads [15]. Inadequate or inefficient internalization increases the chance of toxicity from inappropriate payload delivery outside the cancer cell
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