Evolution of bispecific and multispecific antibodies in cancer therapy

Antibody-based cancer therapy has rapidly evolved from monoclonal antibodies to bispecific and multispecific constructs that combine distinct binding specificities and mechanisms. These agents are seeing increasing clinical adoption, with European Medicines Agency approvals in haematological malignancies and selected solid tumours such as uveal melanoma and EGFR-mutant non-small-cell lung cancer. However, they are often still discussed as a single drug class, which does not capture the complexity of current formats and mechanisms, ranging from IgG-like to fragment-based architectures and from immune-cell redirection to dual immune modulation or oncogenic pathway blockade. This Series paper provides an integrated classification framework based on mechanism and format, relating key design features to pharmacology, efficacy, and safety. It synthesizes clinical evidence and ongoing development, discusses practical strategies to mitigate hallmark toxicities, and reviews emerging resistance mechanisms and rational combination approaches. It also outlines next generation directions, including higher order multispecific constructs, conditionally active antibodies, and payload conjugated multispecific formats. To consolidate these agents as an established therapeutic modality in oncology, priority should be given to rigorous understanding of mechanisms of action and toxicity, alongside rational optimisation of construct design and dosing, supported by robust prospective translational programmes.