Emerging Monoclonal Antibody–Drug Conjugates In Cancer Therapy: A Comprehensive Review Of Design, Mechanisms, And Clinical Advances

Abstract

Antibody–drug conjugates (ADCs) are a rapidly evolving class of anticancer therapeutics that harness the tumor-targeting precision of monoclonal antibodies to deliver highly potent cytotoxic agents directly to malignant cells. This therapeutic modality offers the dual benefit of high specificity and minimized systemic toxicity. Structurally, ADCs comprise three main elements: a monoclonal antibody, a chemical linker, and a cytotoxic payload. Advances in antibody engineering, site-specific conjugation techniques, and linker chemistry have significantly improved the pharmacological profile of ADCs. Modern ADCs demonstrate enhanced tumor penetration, improved plasma stability, and bystander killing effects in heterogenous tumor environments. Several ADCs, including trastuzumab deruxtecan, enfortumab vedotin, and sacituzumab govitecan, have received regulatory approval and shown superior outcomes in breast, bladder, and lung cancers, among others. Despite these advances, challenges such as resistance mechanisms, antigen heterogeneity, off-target toxicity, and pharmacokinetic variability persist. Current research is focused on developing bispecific ADCs, novel immune-activating payloads, and personalized treatment strategies guided by biomarker profiling. This review presents a comprehensive analysis of the design principles, biological mechanisms, clinical advancements, and future directions of ADCs in oncology, affirming their central role in next-generation precision cancer therapy.