Bispecific antibody-drug conjugates in cancer: therapeutic-window determinants, tumour-immune interactions, and clinical translation
Abstract
Antibody-drug conjugates (ADCs) have established targeted payload delivery as an important anticancer strategy, but their efficacy remains constrained by antigen heterogeneity, incomplete internalisation, resistance and dose-limiting toxicity. Bispecific antibody-drug conjugates (BsADCs) add a second antigen- or epitope-binding specificity with the aim of broadening tumour coverage or altering receptor trafficking. The field crossed a major translational threshold in 2026, when izalontamab brengitecan (iza-bren; BL-B01D1), an EGFR×HER3 BsADC, received its first regulatory approvals in China for previously treated recurrent or metastatic nasopharyngeal carcinoma and oesophageal squamous cell carcinoma, while phase III studies also showed survival benefit in triple-negative breast cancer. These developments shift the central question from whether bispecificity can produce antitumour activity to when it can generate a clinically meaningful therapeutic window. This review evaluates BsADC development through six linked determinants: target-pair biology and co-expression, binding geometry and avidity, internalisation and lysosomal trafficking, linker-payload chemistry and drug-to-antibody ratio, intratumoural distribution and bystander activity, and biomarker-guided dosing and patient selection. We further examine how payload-mediated immunogenic cell death, Fc/Fcγ receptor-dependent uptake, suppressive tumour-immune niches and checkpoint-based combinations may modify activity beyond target recognition. Clinical programmes illustrate divergent outcomes: iza-bren provides regulatory validation of the modality, whereas experience with MEDI4276, zanidatamab zovodotin and REGN5093-M114 shows that enhanced binding or internalisation does not guarantee sustainable development. Importantly, much of the mechanistic and combination evidence for immune activation still derives from monospecific ADCs; immune benefit should therefore not be attributed to bispecificity itself without direct evidence. Future progress should integrate human pharmacokinetic/pharmacodynamic data, target-pair and immune-contexture biomarkers, dose-exposure-toxicity relationships and comparative value over optimized monospecific ADCs.