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

Authors

Sitong Lai, Shanshan Li

Published in

Frontiers in oncology. Volume 16. Pages 1952445. Epub Sep 22, 2026.

Abstract

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.

PMID:
42840679
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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