Review proposes modular biomarker framework for antibody–drug conjugates

As approved antibody–drug conjugates (ADCs) expand across oncology indications, biomarker development remains dominated by semi-quantitative immunohistochemistry. A review in Nature Reviews Clinical Oncology outlines a modular framework intended to improve patient selection, therapeutic sequencing and identification of resistance mechanisms. The supplied preview presents a conceptual framework rather than new patient-level outcome data.

The framework considers antigen abundance and accessibility, intracellular trafficking, linker cleavage and tumour susceptibility to the payload, within the tumour microenvironment. The authors argue that target expression alone cannot predict response. Quantitative, spatial and functional assays could capture these determinants more precisely, but require prospective validation. Payload susceptibility and cross-resistance are highlighted as emerging considerations for sequencing, particularly among ADCs sharing topoisomerase I inhibitor payloads.

The review also calls for toxicity biomarkers to be developed alongside efficacy biomarkers to support dose selection and treatment decisions. Proposed applications include trial cohort expansion, rational combinations and regulatory thresholds. These strategies are not established clinical selection tools: prospective evaluation within ADC trials and harmonized development across tumour types and geographical regions are needed before broad adoption.