Kelly M. Schwinghamer
Non-Invasive Brain Delivery, Clearance, and Efficacy of Therapeutic Antibodies in Mice
The blood-brain barrier (BBB) presents a formidable obstacle to the delivery of therapeutic agents to the brain. It is estimated that only 2% of current drugs can enter the brain from the systemic circulation. This renders the brain nearly inaccessible to large molecule therapeutics, such as neurotrophic factors, enzymes, and monoclonal antibodies (mAbs). An alternative for delivery of large molecules to the brain is drilling a hole into the skull to bypass the BBB. Thus, there is an urgent need to develop non-invasive methods to deliver drugs to the brain. The high binding specificity and affinity of mAbs make them attractive and promising drug candidates for treating a variety of brain diseases, such as Parkinson’s and Alzheimer’s disease (AD), as well as brain tumors. However, the need for non-invasive delivery of mAbs limits their use in the brain. To facilitate non-invasive transport of molecules across the BBB, the Siahaan group has designed synthetic small peptide modulators (e.g., ADTC5, HAV6) that temporarily and reversibly increase the porosity of the BBB by disrupting or modulating the “Velcro” molecules between cells of the BBB. These modulators allow mAbs to penetrate between cells of the BBB and enter the brain tissue. This project is aimed at studying the efficiency of the modulators (i.e., ADTC5 peptide) to deliver mAbs into the brains of mice. The mAb distribution and clearance from the brain and other organs over time will be evaluated to see the efficiency of our modulator to enhance delivery of mAb to the brain. Finally, the therapeutic efficacy of an mAb for AD treatment will be evaluated with the brain delivery enhancement of the mAb using ADTC5 modulator peptide compared to that of the mAb alone. The effect of mAb in the brain will be evaluated by examining the cognitive performance and brain microstructure of mice treated with mAb+ADTC5 compared to those of mAb alone, ADTC5 alone, or vehicle-treated mice as controls. It is expected that mice treated with mAb+ADTC5 will improve cognitive performance and reduce brain pathology compared to those treated with controls. The results from these studies will provide a proof-of-concept that our method can be used to improve treatments of brain diseases.
I am very honored to be a part of this prestigious fellowship. The funding provided by the PhRMA Foundation has supported my research efforts to enhance the delivery of antibodies to the brain.