Febrile neutropenia occurred in 7% of patients. unacceptable toxicity profiles. Analysis of the clinical data has exhibited that dose-limiting toxicities (DLTs) are often shared by different ADCs that deliver the same cytotoxic payload, independent of the antigen that is targeted and/or the type of cancer that is treated. DLTs are 2C-I HCl commonly associated with cells and tissues 2C-I HCl that do not express the targeted antigen (i.e., off-target toxicity), and often limit ADC dosage to levels below those required for optimal anti-cancer effects. In this manuscript, we review the fundamental 2C-I HCl mechanisms contributing to ADC toxicity, we summarize common ADC treatment-related adverse events, and we discuss several approaches to mitigating ADC toxicity. Keywords:antibody-drug conjugate, malignancy, ADC toxicity and tolerability, targeted therapy == 1. Introduction == Antibody-drug conjugates (ADCs) are a rapidly growing class of anti-cancer therapeutics, with more than 100 ADCs undergoing clinical investigation [1]. Currently, 12 ADCs have been approved by the United States Food and Drug Administration (FDA), including gemtuzumab ozogamicin (Mylotarg), brentuximab vedotin (Adcetris), inotuzumab ozogamicin (Besponsa), trastuzumab emtansine (Kadcyla), polatuzumab vedotin (Polivy), enfortumab vedotin (Padcev), trastuzumab deruxtecan (Enhertu), sacituzumab govitecan (Trodelvy), belantamab mafodotin (Blenrep), loncastuximab tesirine (Zynlonta), tisotumab vedotin (Tivdak), and mirvetuximab soravtansine (Elahere). ADCs are composed of a monoclonal antibody (mAb) tethered to a cytotoxic small-molecule drug (i.e., payload) through a chemical linker. Most of the ADCs that have been investigated have employed payload molecules that have shown poor efficacy and substantial toxicity when administered as unconjugated (i.e., free) brokers [2,3]. As anticipated by the pharmacokinetics and biodistribution of monoclonal antibody drugs [4,5], where high-affinity mAb binding to cell membrane proteins enables the localization of a substantial portion of mAb to the targeted cell populations, the chemical conjugation of the payload to the anti-cancer mAb increases the selectivity of the delivery of the payload to the malignancy cells, and thereby increases the therapeutic index of the payload [6]. However, despite recent successes, the clinical development of ADCs has been associated with a high failure rate, as off-site toxicity remains problematic, limiting tolerable ADC doses to levels below those required for substantial anti-cancer efficacy [7,8,9,10]. Even for the ADCs that have gained FDA approval, a significant portion of treated patients require supportive treatment to reduce the severity of ADC-associated toxicities, and many patients require dose reduction, treatment delays, or treatment discontinuation [11]. The investigation of the security profile of an ADC under development requires a Ctsk series of preclinical and clinical studies; however, prior ADC development efforts suggest that the clinical toxicity profile of ADCs primarily relates to the payload component [12]. Since a relatively small group of payload molecules (i.e., MMAE, MMAF, DM1, DM4, calicheamicin, SN38, Dxd, PBD) are employed within the vast majority of approved ADCs and ADCs under development [8,13,14,15], concern of the mechanisms associated with the known toxicities of previously developed ADCs may inform the development of new ADCs. In this manuscript, we provide an overview of the main mechanisms underlying ADC toxicity, and we provide a summary of the clinical security profile of approved ADCs. Additionally, the manuscript discusses approaches to mitigating or preventing ADC toxicities. == 2. Mechanisms of ADC Toxicity == It is approximated that only ~0.1% of the injected dose of an ADC is delivered to the targeted diseased cell populace, with the vast majority of the administered dose catabolized off-site within non-targeted healthy cells, potentially leading to unwanted toxicities [16,17]. Off-site ADC toxicity may be categorized as on-target or off-target, where on-target toxicity proceeds through ADC binding to the targeted cell surface protein on healthy cells. Each component of the ADC, including the antibody, linker, and payload, may impact the extent of the ADC-induced toxicities. In this section, several mechanisms that lead to the toxicities of ADCs are discussed (Physique 1). == Physique 1. == Mechanisms of ADC toxicity. Uptake of intact ADCs into normal cells may occur through non-specific endocytosis, or through internalization upon binding to the.