Molecular imaging supports the development of multispecific cancer antibodies

Multispecific antibodies are engineered antibody derivatives that can bind to two or more distinct epitopes or antigens. Unlike mixtures of monospecific antibodies, the binding properties of multispecific antibodies enable two specific molecules to be physically linked, a characteristic with important applications in cancer therapy. The field of multispecific antibodies is highly dynamic and expanding rapidly; to date, 15 multispecific antibodies have been approved for clinical use, of which 11 were approved for oncological indications, and more than 100 new antibodies are currently in clinical development. Nevertheless, substantial challenges limit the applications of multispecific antibodies in cancer therapy, particularly inefficient targeting of solid tumours and substantial adverse effects. Both PET and single photon emission CT imaging can reveal the biodistribution and complex pharmacology of radiolabelled multispecific antibodies. This Review summarizes the insights obtained from preclinical and clinical molecular imaging studies of multispecific antibodies, focusing on their structural properties, such as molecular weight, shape, target specificity, affinity and avidity. The opportunities associated with use of molecular imaging studies to support the clinical development of multispecific antibody therapies are also highlighted. Multispecific antibody constructs that bind several distinct targets can connect cells and/or simultaneously target multiple molecules. Here, Lub-de Hooge et al. discuss the varied contributions of molecular imaging to multispecific antibody design, drug development and optimization, including evaluations of antibody biodistribution and pharmacological complexity. Key points The use of multispecific antibodies in cancer treatment is expanding rapidly: 11 agents have been approved to date and many others are undergoing clinical development. The design of multispecific antibodies with optimal pharmacological properties has resulted in a wide variety of molecule formats. PET and single photon emission CT imaging are powerful non-invasive tools for studying the biodistribution of radiolabelled antibodies, including their uptake in tumour and healthy tissues, pharmacokinetics and target expression. Preclinical and clinical molecular imaging studies of multispecific antibodies underscore key structural properties that affect their biodistribution, including target affinity and avidity, molecular weight and structure. Biological