Guiding the development of multispecific antibody-based cancer immunotherapies with 89Zr-immuno-PET imaging

Antibody-based checkpoint inhibitors improved the treatment of patients with several tumor types. Several antibodies targeting immune checkpoints have been approved for the treatment of patients with cancers. However, not all patients benefit from these medicines. Therefore, many novel immunotherapeutics are being developed. Among them are multispecific antibodies that can bind to multiple targets simultaneously, enabling innovative mechanisms. Multispecific antibodies come in diverse formats, each with unique and hard-to-predict pharmacokinetic and -dynamic behavior. Therefore, insights into their biodistribution, including tumor and healthy tissue uptake, PK, and target expression, could guide development decisions early during drug development.
The research in this thesis aims to guide the drug development of antibody-based cancer immunotherapies by utilizing zirconium-89 (89Zr) positron emission tomography (PET, 89Zr-immuno-PET) molecular imaging, focusing on multispecific antibodies.
We have determined the biodistribution of several radiolabeled antibodies with PET molecular imaging. We have identified various factors, including structural properties and biological factors, that determine the biodistribution of these multispecific antibodies. The structural properties were the multispecific antibodies’ target affinity and avidity, molecular size, and structure. The key biological factors were target expression in tumor tissues, off-tumor and immune target engagement, antibody internalization, tracer dose, and target saturation.