Advances and perspectives of next-generation antitumor antibody-based modalities: Structural innovation and target-driven strategies

Abstract

Antibody-based therapies have gained significant traction in oncology, as evidenced by their prominent presence at international conferences such as American Association for Cancer Research (AACR) and American Society of Clinical Oncology (ASCO). Modalities including antibody–drug conjugates (ADCs), bispecific antibodies (BsAbs), and T-cell engagers (TCEs) are increasingly recognized as pillars of precision medicine. Driven by advances in molecular engineering, antibody formats and mechanisms of action have evolved beyond conventional antigen blockade to encompass multimodal cytotoxicity and immune modulation. ADCs now leverage optimized linkers and payloads for targeted delivery and potent tumor cell killing. BsAbs simultaneously engage tumor and immune cell targets to enhance immune activation, while TCEs enable T cells to recognize intracellular antigens presented via MHC, overcoming the limitations of extracellular targeting. Emerging design strategies are increasingly tailored to target-specific features such as expression levels, internalization capacity, and cellular subtype. Innovations include non-internalizing ADCs for low-abundance targets and biased antibody architectures that preferentially activate CD8⁺ T cells. These developments are expanding the therapeutic landscape toward greater efficacy, safety, and personalization. This review outlines the global landscape of antibody drug development, highlighting a paradigm shift toward target-driven design principles that integrate structural innovation with functional precision.