Bispecific, trispecific antibodies, and ADCs advance cancer therapy beyond conventional monoclonals.

While monoclonal antibodies (mAbs) are a cornerstone of modern oncology, their therapeutic potential is often limited by target-dependent and independent resistance mechanisms. Conventional mAbs primarily rely on antigen binding and Fc-mediated effector functions, which can be insufficient against heterogeneous tumors or in overcoming immune evasion. There is a critical need for advanced molecular designs that can enhance tumor specificity, improve immune engagement, and deliver potent payloads more effectively, thereby expanding the therapeutic window in both hematologic and solid tumors.

This comprehensive review synthesizes the current landscape of advanced antibody formats, including bispecific antibodies (bsAbs), trispecific antibodies (tsAbs), and antibody-drug conjugates (ADCs). It examines their intricate molecular architectures, diverse mechanisms of action, and clinical performance. The review specifically analyzes how these novel designs impact efficacy, toxicity profiles, and the emergence of resistance in cancer therapy, providing a detailed overview of the evolving strategies to overcome limitations of traditional monoclonal antibodies.

Novel antibody formats significantly enhance therapeutic efficacy by leveraging complex mechanisms. BsAbs and tsAbs function as pharmacological matchmakers, simultaneously engaging tumor antigens and immune receptors to physically bridge effector cells and malignant cells, promoting immunological synapse formation. Their activity is tightly linked to valency, target geometry, and Fc configuration. ADCs exploit mAb specificity to deliver highly potent, otherwise intolerable cytotoxic payloads directly into tumor cells, thereby expanding the therapeutic window. ADC efficacy reflects a tripartite pharmacology integrating target engagement, intracellular payload release, and bystander cytotoxicity. Despite their potency, these platforms remain vulnerable to resistance, which can arise through target-dependent mechanisms like antigen downregulation and epitope masking, or target-independent processes such as altered intracellular trafficking, lysosomal dysfunction, payload efflux, and adaptive survival signaling. > A comprehensive understanding of antibody architecture, target biology, pharmacokinetic/pharmacodynamic (PK/PD) behavior, toxicity profiles, and resistance mechanisms is essential to optimize treatment selection and sequencing.