Antibody–Drug Conjugates in Contemporary Oncology: A Clinical Perspective on Dose Optimization, Sequencing, and Combination Strategies

Antibody–drug conjugates (ADCs) have matured from a technically challenging concept into an established therapeutic platform across hematologic and solid malignancies. By linking a monoclonal antibody to a potent cytotoxic payload, ADCs seek to increase tumor-directed drug delivery while limiting systemic exposure; however, clinical performance depends on much more than target expression. Target accessibility, antigen density and heterogeneity, internalization, intracellular trafficking, linker stability, payload properties, drug-to-antibody ratio, bystander effect, tumor penetration, and host-tissue handling jointly shape efficacy and toxicity. This review provides a clinician-oriented assessment of the contemporary ADC landscape and the principal biologic and pharmacologic determinants of benefit. We discuss signature toxicities, including interstitial lung disease and ocular injury, and summarize evolving mechanisms of resistance and biomarker development. Particular emphasis is placed on three translational problems that are becoming increasingly important as ADCs move into earlier lines and overlapping disease settings: dose optimization beyond the maximum tolerated dose, sequencing across targets and payload classes, and biologically rational combination strategies. We also present a conceptual Sequential Tumor Attack Model as a hypothesis-generating framework for tumor-access priming, ADC-mediated cytotoxic injury, and immune amplification, while explicitly recognizing that the complete model has not been clinically validated. The future impact of ADCs will depend not only on next-generation constructs, but also on rigorous evidence for how these agents should be dosed, ordered, and combined in practice.