Spatial PK–PD mismatch in tumor-targeting antibodies and ADCs: from lesion access to pharmacologic execution

Systemic pharmacokinetics and target expression do not show whether tumor cells have received enough antibody to produce the intended effect. Tumor-targeting antibodies must reach individual lesions, cross tumor tissue, bind accessible targets, and, for some platforms, align with intracellular or neighboring-cell processes required for action. This critical narrative review organizes evidence by where exposure and effect become discordant. We define four spatial PK–PD mismatches (1): systemic exposure without adequate lesion access (2); lesion uptake without adequate microscopic distribution; (3) target expression without sufficient in vivo engagement; and (4) engagement without spatially appropriate pharmacologic execution. Biological resistance after adequate spatial drug exposure is treated separately. We synthesize direct human distribution studies, lesion-resolved exposure–outcome studies, target-heterogeneity studies, preclinical interventions, and mechanistic models in a five-tier evidence hierarchy. Human immunoPET, fluorescence window studies, quantitative tissue imaging, and single-cell spatial pharmacobiology show substantial heterogeneity across lesions and cells, whereas lesion-level exposure–outcome evidence remains limited. Prior work has also shown that distribution effects depend on dose, affinity, antigen density, internalization, linker–payload properties, and bystander activity; the present review does not treat penetration as a universal determinant of efficacy. We therefore propose a mismatch-directed development workflow in which the suspected limiting step determines the measurement, corrective intervention, and validation endpoint. Spatial PK–PD is best viewed as a mechanism-based development framework rather than a validated routine companion diagnostic.