Developing potent therapeutics against brain cancers and neurodegenerative diseases is hampered by the difficulties for drugs to cross the Blood Brain Barrier (BBB), a formidable barrier that protects the brain from toxins and pathogens. Transferrin receptor (TfR1) naturally crosses the BBB to provide the brain with iron using a process called receptor-mediated transcytosis. One strategy to introduce therapeutic agents into the brain is to manipulate this process via ‘trojan horse’ delivery, whereby TfR1 antibodies are conjugated to drugs of interest. Hence, leveraging off the physiological process of receptor-mediated transcytosis, therapeutic cargo can be delivered across the BBB for brain cancer targeting.
Intriguingly, TfR1 is a known receptor for host cell entry by some of the deadliest infectious diseases caused by malaria and New World Hemorrhagic Arenaviruses. We identified a nanobody that blocks TfR1 engagement with malaria parasite invasion ligands and new world hemorrhagic proteins. We hypothesize that this nanobody against TfR1 could be used to ‘trojan horse’ drug cargo across the BBB, analogous to antibody delivery, with the additional benefits that nanobody drug development ensues (such as higher stability, affinity, distinct binding capacity and cheaper manufacturing).
To test the feasibility of our TfR1 nanobody, we are developing next generation nanobody technologies, including fluorescently labeled and drug conjugated nanobodies. These nanobody tools will allow us to (1) detect nanobody binding to TfR1 at the cell surface; (2) detect and quantify TfR1 transcytosis; and (3) measure drug delivery across models of the BBB. By developing next generation TfR1 targeted nanobodies, we aim to generate a scaffold for delivering drugs to the brain for treatment of a wide range of debilitating diseases.