Mechanisms of ADC Toxicity and Strategies to Increase ADC Tolerability

SIMPLE SUMMARY: Antibody-drug conjugates (ADC) are a rapidly expanding class of anti-cancer drugs, with twelve agents in current clinical use. Despite recent successes, many ADCs fail during clinical development due to excessive toxicities and unfavorable risk-benefit profiles. Even for those ADCs that have been approved for clinical use, a substantial fraction of treated patients require dose reduction, treatment delays, or treatment discontinuation due to intolerable ADC-associated toxicity. In this report, we review the mechanisms contributing to the clinical toxicity of ADCs, and we discuss strategies to improve ADC tolerability. ABSTRACT: Anti-cancer antibody-drug conjugates (ADCs) aim to expand the therapeutic index of traditional chemotherapy by employing the targeting specificity of monoclonal antibodies (mAbs) to increase the efficiency of the delivery of potent cytotoxic agents to malignant cells. In the past three years, the number of ADCs approved by the Food and Drug Administration (FDA) has tripled. Although several ADCs have demonstrated sufficient efficacy and safety to warrant FDA approval, the clinical use of all ADCs leads to substantial toxicity in treated patients, and many ADCs have failed during clinical development due to their unacceptable toxicity profiles. Analysis of the clinical data has demonstrated 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 commonly associated with cells and tissues 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 mechanisms contributing to ADC toxicity, we summarize common ADC treatment-related adverse events, and we discuss several approaches to mitigating ADC toxicity.