From Dual Targeting to Clinical Validation: A Translational Framework for Bispecific Antibody-Drug Conjugates.

Bispecific antibody-drug conjugates (bsADCs) are being developed to address limitations of conventional ADCs, including heterogeneous antigen expression, insufficient tumor-normal discrimination, and suboptimal intracellular trafficking. This review evaluates bsADCs from a preclinical-to-clinical translational perspective and defines the evidence needed to justify the added complexity of bispecific design. A structured search of PubMed/MEDLINE, Embase, Web of Science, Scopus, clinical-trial registries, and major oncology conference proceedings was conducted through 29 July 2026. Dual-antigen bsADCs were classified as coverage-oriented, co-expression-dependent, trafficking-assisted, or multifunctional, while biparatopic ADCs were considered mechanistically related comparators. Dual recognition can broaden tumor coverage, enhance avidity-dependent selectivity, improve intracellular trafficking, or add biological functions. These effects depend on target-pair biology, molecular format, valency, epitope geometry, arm affinity, linker-payload properties, drug-to-antibody ratio, pharmacokinetics, normal-tissue exposure, manufacturability, and biomarker feasibility. Clinically, izalontamab brengitecan supports the feasibility of selected architectures, whereas MEDI4276 and TQB2102 illustrate how complete molecular design shapes therapeutic index. We propose an integrated translational framework and functional design parsimony, defined as selecting the least complex ADC architecture capable of achieving the intended biological and translational objective. Bispecificity should be used only when it provides a demonstrable advantage over a simpler ADC design.