Antibody-drug Conjugates in Oncology: A Comprehensive Review of Mechanism, Efficacy, and Toxicity Management View PDF

The advent of ADCs has revolutionized the landscape of oncology therapeutics, offering targeted delivery of cytotoxic agents to malignant cells while minimizing systemic toxicity [1-5]. A comprehensive understanding of their mechanism, efficacy, and toxicity management is crucial for optimizing clinical outcomes. The current literature provides detailed insights into each of these aspects, highlighting the complexity and potential of ADCs in cancer treatment. Mechanistically, ADCs are composed of a monoclonal antibody linked to a cytotoxic payload via a chemical linker [6-10]. This design enables selective targeting of tumor-associated antigens expressed on cancer cell surfaces, thereby reducing off-target effects [11]. The mechanism of action involves the binding of the ADC to its specific antigen, internalization of the complex, and subsequent release of the cytotoxic payload within the cancer cell, leading to cell death [12-17]. The structural components— antigen specificity, linker stability, and payload potency—are critical determinants of ADC efficacy [18]. Recent advances emphasize the importance of selecting ideal target antigens that are highly expressed on tumor cells but minimally present on normal tissues to enhance selectivity and reduce toxicity [18]. Additionally, innovative strategies such as multitarget approaches, pH-dependent antibodies, and masked peptide technologies are being explored to improve efficacy and safety profiles [19].

Efficacy data from clinical trials underscore the promise of ADCs across various malignancies. For instance, in lung cancer, ADCs have demonstrated significant therapeutic potential, with evidence supporting their role in improving patient outcomes [20]. Similarly, in gynecologic cancers, ADCs like mirvetuximab soravtansine and tisotumab vedotin have received FDA approval based on clinical trial results showing meaningful responses in platinum-resistant ovarian and metastatic cervical cancers, respectively [21]. The efficacy of ADCs is further supported by their ability to deliver potent cytotoxic agents directly to tumor cells, thereby overcoming some mechanisms of resistance associated with traditional chemotherapies [20].

Despite their therapeutic benefits, ADCs are associated with a spectrum of toxicities that necessitate careful management. Toxicity profiles vary depending on the payload, target antigen, and patientspecific factors. Systematic reviews and meta-analyses reveal that ADC-related adverse effects include neurologic, hematologic, ocular, and mucosal toxicities, among others [22]. For example, neurological adverse events and hematologic toxicities are notable concerns, especially when ADCs are combined with chemotherapy. Ocular toxicities, such as keratopathy and conjunctivitis, are increasingly recognized, particularly in gynecologic oncology settings, where ADCs like those targeting folate receptors have been associated with ocular adverse events [23, 24]. Management strategies for these toxicities involve routine monitoring, prophylactic interventions, and symptomatic treatments tailored to the specific adverse event [23, 25].

Toxicity management also extends to understanding the pharmacokinetics and pharmacodynamics of ADC components. Pharmacokinetic profiles influence dosing strategies and help mitigate adverse effects, especially in patients with organ dysfunction or those receiving concomitant therapies [26]. The importance of personalized approaches is emphasized, with considerations for drugdrug interactions and organ-specific toxicities such as hepatotoxicity, which is a concern with antibody-based therapies, including ADCs [27, 28]. Liver injury, in particular, requires vigilant monitoring and management to balance therapeutic efficacy with safety [27]. The development of resistance remains a significant challenge in ADC therapy. Resistance mechanisms include antigen downregulation, payload efflux, and alterations in intracellular trafficking pathways [18]. Strategies to overcome resistance involve selecting more stable linkers, optimizing payload potency, and identifying new target antigens with higher tumor specificity [18, 19]. Future perspectives focus on integrating biomarkers to predict response and resistance, thereby enabling more personalized treatment regimens [29].

In summary, ADCs represent a potent and targeted approach in oncology, with demonstrated efficacy across multiple cancer types. Their mechanism hinges on precise antigen targeting, efficient internalization, and payload release, which collectively contribute to their therapeutic success. However, toxicity management remains a critical component, requiring ongoing research into adverse effect mitigation strategies, including prophylactic measures and personalized dosing. Advances in target selection, linker technology, and payload design continue to enhance the safety and efficacy profiles of ADCs, promising further integration into standard oncologic care. As research progresses, the combination of ADCs with other modalities and the development of predictive biomarkers are poised to refine their role in precision oncology, ultimately improving patient outcomes.