Antibody-Drug Conjugates in Oncology: Why Potency Is No Longer the Limiting Factor

Antibody-drug conjugates (ADCs) have transitioned from experimental constructs to a clinically validated therapeutic class, with a rapidly expanding portfolio of approvals across hematologic and solid malignancies. Despite this success, the most ADC development programs continue to fail, particularly in solid tumors, underscoring a persistent gap between molecular design and clinical performance. This review argues that payload potency, long regarded as the primary determinant of ADC efficacy, is no longer the principal limitation. Instead, clinical outcomes are increasingly governed by system-level interactions among antibody distribution, linker kinetics, payload diffusibility, tumor heterogeneity, and host toxicity mechanisms. We synthesize mechanistic, pharmacologic, and clinical evidence across constraint-driven design shifts of ADC development to identify the design inflection points that have genuinely altered therapeutic indices. We further evaluate why high-drug-to-antibody ratio constructs, bystander-capable payloads, and site-specific conjugation strategies have succeeded where earlier generations failed. Finally, we outline emerging next-generation paradigms, including mutant-selective targeting, bispecific architectures, and dual-payload ADCs, that reframe ADCs as adaptable platforms rather than static cytotoxic delivery vehicles. By integrating molecular engineering with tumor biology and clinical constraints, this review proposes a design framework to guide the next decade of ADC innovation in oncology.