Antibodies are our body`s foot soldiers in the fight against infectious diseases. They are also widely used as targeted therapy against a range of diseases. In this research project we will study biological mechanisms to reveal how antibodies protect us on the inside of our own cells. This knowledge of antibody structure and function will be utilized to design potent and long-acting antibodies targeting dementia, such as Alzheimers disease. The goal is to gain a more comprehensive understanding of how antibodies can protect us against neuronal cellular damage. This molecular and cellular insight will then form the basis for design of novel antibody variants. In the long run, this may lead to new drug candidates for targeted treatment of dementia but also infectious diseases.
Dementia, of which Alzheimer`s disease is the most common cause, affects nearly 50 million people worldwide, with numbers expected to increase. Thus, there is an urgent need for new treatment options to combat neurodegenerative disorders. Alzheimer's disease is characterized by accumulation of extracellular beta-amyloid plaque and self-propagating intracellular aggregates of tau protein. Following disappointing clinical trials targeting beta-amyloid, attention has now shifted towards targeting of tau. This is supported by pre-clinical results demonstrating that passive transfer of anti-tau antibodies reduce spreading of intracellular tau aggregation and improves neurological function. However, the mechanism by which these antibodies offer protection is unknown. In collaboration with international partners, I have designed monoclonal antibodies that for the very first time show that this process is dependent on an intracellular receptor, TRIM21. In addition, I have unpublished data on how antibodies can be engineered for improved receptor engagement. As such, I here seek funding for a Researcher Project for Young Talents where I will fully explore this biology with the aim to take a quantum leap in our understanding of intracellular antibody-mediated immunity in the context of neurodegenerative diseases. The in-depth molecular and cellular knowledge obtained will be translated into design of antibodies with tailored mode-of-action. This will be done by combining unique biochemical and cellular assays with studies in state-of-the-art mouse models. The project bridges cutting-edge research with innovative strategies that may pave the way for establishment of new biomedical technologies to combat neurological disorders.