89Zr-immuno-PET for imaging and quantification of biopharmaceuticals targeting neurodegenerative diseases

Neurodegenerative diseases cost society over a trillion dollars annually. Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) are the two most prevalent diseases, affecting 50 million and 10 million individuals globally, respectively. Since these numbers are projected to triple by 2050, the rising prevalence and societal costs of these diseases pose significant challenges to healthcare systems, economies and the well-being of millions of people worldwide. Recent FDA approvals of three monoclonal antibody (mAb)-based passive immunotherapies targeting neurotoxic amyloid-beta aggregates – among the hallmarks of AD – sparked hope but came with a history of failed clinical trials and debates about efficacy, high costs and adverse effects. With multiple immunotherapies for a diverse range of neurodegenerative diseases being under clinical investigation, better tools are needed to guide the clinical translation of these mAb-based therapeutics. 89Zr-immuno-PET combines the high affinity and outstanding specificity of mAbs with the non-invasive quantitative imaging technique of PET. It has become a valuable tool in drug development in recent years and could become the essential de-risking strategy for central nervous disease immunotherapies. It could steer drug design and development, save costs, lower attrition rates and bring efficacy rates to more desired levels by pre-stratification of patients, assessment and optimization of target engagement and monitoring of disease response. The use of 89Zr as a PET radionuclide is an attractive option due to its availability and favorable imaging qualities and half-life (t1/2 = 78.41 h) that allows the PET imaging and quantification of mAbs with their long biological half-life. Considering these factors, it becomes evident that there is a tremendous societal and economic need to develop a reliable platform to use 89Zr-immuno-PET for imaging and quantification of biopharmaceuticals targeting neurodegenerative diseases. In this thesis, three interconnected objectives were addressed. First, the current state of 89Zr-radiochemistry for antibodies and the associated quality control measures was critically reviewed, and avenues for methodological improvements were identified to expand its applicability. Second, 89Zr-radiochemistry for brain applications was successfully established using a bifunctional anti-amyloid-beta antibody designed to exploit murine transferrin receptor 1-mediated transcytosis across the blood–brain barrier, enabling direct comparison with existing radioiodine-based approaches. Third, the potential of 89Zr-immuno-PET for neurodegenerative disease research was systematically evaluated, yielding key insights into optimal imaging time points, sensitivity thresholds, dosing strategies, and its applicability to other BBB-shuttle constructs and hallmark protein targets. Collectively, these findings provide a foundation for the rational design and clinical translation of 89Zr-immuno-PET as a versatile platform for imaging and quantification of biopharmaceuticals targeting neurodegenerative diseases.