Mechanisms and Clinical Breakthroughs of Bispecific Antibody–Drug Conjugates (BsADCs)- Dual‑Targeting Strategies Exemplified by EGFR/HER3

Abstract

Cancer remains a major burden, with conventional and single-target ADC therapies limited by toxicity, heterogeneity, and resistance. The development of bispecific ADCs (BsADCs) is a product of the latest developments in this field, but most of these drugs are still at an early stage of design and clinical evaluation. In this review, the development process, structure, and mechanisms of action of ADCs will be outlined, and a rationale will be provided for the development of BsADCs combining bispecific targeting and targeted delivery of the cytotoxic payload. Different aspects of BsADC design such as target pairs, antibody format, internalization, linker-payload engineering, and optimal drug to antibody ratio will be discussed. Some clinical candidates like BL-B01D1 and DM005 will be analyzed in order to evaluate their efficacy and safety profile. Moreover, this review will discuss major challenges related to manufacturing difficulties, tumor penetration, on-target/off-tumor toxicity, and unpredictable interaction between different targets. BsADCs represent a new promising strategy to address tumor heterogeneity, antigen escape, and bypass signaling as well as improve targeted payload delivery. This review can serve as a theoretical background for designing and testing BsADCs.