Research

Targeted therapeutics have made significant impacts in cancer treatment, resulting in increased efficacy and reduced toxicity. However, many patients with ovarian, triple-negative breast, pancreatic, or lung cancer do not yet have reliable targeted therapeutic options. Mesothelin (MSLN) is a cell surface protein that is overexpressed in numerous cancers, including breast, ovarian, lung, liver, and pancreatic tumors. Aberrant expression of MSLN has been shown to promote tumor progression and metastasis through interaction with established tumor biomarker, CA125. Therefore, molecules that specifically bind to MSLN have potential therapeutic and diagnostic applications. However, no MSLN-targeting molecules are currently approved for routine clinical use. While antibodies that target MSLN are in development, some clinical applications may require a targeting molecule with an alternative protein fold. The Fn3 scaffold has shown great versatility for its ability to be engineered to recognize a variety of targets. Fn3 proteins that bind cell surface protein MSLN would have numerous potential clinical applications, such as through diagnostic imaging, internalization for drug delivery, and metastatic reduction by blocking MSLN-MUC16 interactions.

Protein Therapeutics to Access Drug Targets in the Central Nervous System

The blood-brain barrier (BBB) protects the Central Nervous System (CNS) from potentially harmful compounds that circulate in the blood, presenting a major obstacle to delivering drugs intended to treat disorders of the CNS like Alzheimer’s Disease, Parkinson's’ Disease, or brain tumors. In order to transport specific molecules that are needed for CNS function into the brain, there exist dedicated receptors on the BBB that facilitate active transport of native large molecules from the blood into the CNS. One strategy to circumvent the challenge of drug delivery to the CNS is to use these native receptor systems for receptor-mediated transport (RMT). In using RMT as a drug delivery strategy, non-native ligands are engineered to bind an extracellular epitope on a particular BBB receptor. In binding to this receptor, these engineered proteins exploit the receptor-mediated transport system to be taken up across the BBB by the same mechanism that the receptor’s native ligand is moved into the CNS from the blood. These engineered transport proteins can then be conjugated to therapeutic drugs to facilitate the delivery of the entire drug complex across the BBB.

Conjugation of proteins to drug-loaded polymeric structures is an attractive strategy for facilitating target-specific drug delivery for a variety of clinical needs. Polymers currently available for conjugation to proteins generally have limited chemical versatility for subsequent drug loading. Many polymers that do have chemical functionality useful for drug loading are often insoluble in water, making it difficult to synthesize functional protein-polymer conjugates for targeted drug delivery. In our work, we collaborate with the Buck Lab (Chemistry Department) and use a reactive, water-soluble azlactone-functionalized polymer, Poly(2-vinyl-4,4-dimethylazlactone) (PVDMA). In ongoing work, we are conjugating the polymers to engineered non-antibody receptor-targeting proteins, as part of the development of a modular approach to engineering protein-polymer conjugates for drug delivery applications. Our approach to protein-polymer conjugate synthesis offers a simple, tailorable strategy for preparing bioconjugates of interest for a broad range of biomedical applications.

Dr. Maren Buck, Chemistry Department at Smith College: https://www.smith.edu/academics/faculty/maren-buck