A TfR-Binding Cystine-Dense Peptide Promotes Blood–Brain Barrier Penetration of Bioactive Molecules
This week we profile a recent publication in Journal of Molecular Biology from
Dr. Zachary Crook in the laboratory of Dr. James Olson (pictured) at Fred Hutch.
Can you provide a brief overview of your lab’s current research focus?
Our lab focuses on both pediatric brain cancer research and novel protein therapeutics modalities with the aim of discovering effective therapeutics for difficult diseases. Much of the recent protein therapeutic work has centered on hyperstable miniproteins, particularly cystine-dense peptides (CDPs). They are enticing because they combine many of the strengths of small molecule drugs (manufacturability, stability, low immunogenicity) with the utility of antibodies (high affinity and specificity), while also demonstrating interesting biodistribution properties that can be leveraged, such as tumor or cartilage accumulation.
What is the significance of the findings in this publication?
Central nervous system (CNS) diseases, including many brain cancers, are particularly hard to treat because the blood-brain barrier confines most drugs to the blood and away from neurons. Some natural transporters exist, like the transferrin receptor (TfR). It is well known that TfR binding entities can be used as vehicles for CNS drug delivery, but most of them pose challenges for drug development. For example, adding a 150 kilodalton anti-TfR antibody can increase the mass of a drug by 300-fold, so even if it increases brain delivery by 10 fold, you may still be left with an immense amount of drug to administer to achieve your desired effect. We identified a series of TfR-binding CDPs that can deliver a model drug, in this case the neuropeptide neurotensin, to a mouse’s brain while only adding 6 kilodaltons to its mass. The CDP itself is easy to make to high purity, amenable to chemical conjugations, and stable in plasma. We believe this CDP or its derivatives could be used as a safe and efficacious CNS drug delivery vehicle for disorders like brain cancer where potent drugs exist that kill the cells in a dish, but simply do not reach the tumor in appreciable quantities.
What are the next steps for this research?
One ongoing project involves using the TfR binding CDP to deliver anti-inflammatory drugs to the brain to aid in recovery from radiotherapy. Many pediatric brain cancers are found deep in the brainstem where surgical resection is not possible, so high dose irradiation is commonly used. While this can kill tumors, it triggers an inflammatory response that can damage cancer cells and normal tissue alike. We want to deliver molecules to the brain that can switch the inflammatory response from a “search and destroy” mode to a “clean up and repair” mode, which could hopefully help survivors of pediatric brain cancer to avoid the brain damage that would otherwise impact their quality of life.
This work was funded by:
This work was funded by grants and fellowships from the NIH (NCI/5 R01 CA223674-02 and NIA Fellowship T32AG000057), as well as a Washington Research Foundation Innovation Fellowship through the University of Washington Institute for Protein Design.