Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease, which leads to dysfunction or death of neurons in brain regions that control memory, cognition and language.
Despite the commonality of Alzheimer’s and other neurodegenerative diseases, there has been little clinical translation of biological therapies with potential to affect underlying molecular mechanisms of the disease to actually improve the lives of patients.
Currently, one of the biggest hurdles for biological therapies is that they are unable to penetrate the blood-brain barrier.
A promising strategy under development by a team of researchers led by Albert M. Mattocks Professor of Pharmaceutical Sciences and Chemical Engineering, Peter Tessier, and Assistant Professor of Emergency and Pharmacology, Colin Greineder, recently received $3.8 million in funding from the National Institutes of Health (NIH) to address this challenge.
“Large-molecule therapeutics, such as monoclonal antibodies, hold great potential for improving treatment of Alzheimer’s, Parkinson’s and related neurodegenerative diseases, but they poorly penetrate the intact blood-brain barrier,” Tessier said. “Improving the brain delivery of these therapeutics is perhaps the most important challenge to solve in developing effective treatments for these devastating disorders.”
The research will involve developing and optimizing bifunctional antibodies, which target one molecule at the blood-brain barrier for transport into the brain and a second molecule in the brain to mediate neuroprotective function. These multifunctional antibodies achieve high and sustained antibody levels in the brain, and also mediate neuroprotective function to prevent Alzheimer’s disease-like pathology in animal models.
The bifunctional antibodies and insights gained in this work are expected to accelerate the development of therapeutics for treating Alzheimer’s disease and other neurodegenerative disorders.
Nearly all prior efforts have focused on the transferrin receptor, which is involved in iron transport, as the prototypical target despite delivery and safety challenges. Rather than focusing on this receptor, Tessier, Greineder and colleagues have developed a bispecific antibody shuttle that engages CD98hc, a protein involved in transporting amino acids throughout the body, including across the blood-brain barrier. This work has been published online as a pre-print.
The goals of this work are to optimize brain delivery of a second-generation antibody shuttle and assess the efficacy of multiple neuroprotective antibody shuttles in mouse models of AD, testing efficacy in three modes of treatment, beginning at early, intermediate and late stages AD progression.
“Our CD98hc antibody shuttles have demonstrated unexpected benefits over transferrin receptor antibody shuttles, including more specific brain targeting and longer brain retention,” Tessier said. “We are excited to test the ability of our CD98hc antibody shuttles to deliver neuroprotective antibodies to the brain and prevent disease-like phenotypes in mouse models of Alzheimer’s.”
The Tessier Lab aims to develop best-in-class therapeutic antibodies and apply them to address multiple key biomedical challenges. The group’s interdisciplinary research program uses experimental (directed evolution) and computational (machine learning) approaches for generating new fundamental insights into therapeutic antibody structure and function, stability and other therapeutic properties.
The Greineder Lab aims to develop innovative, targeted pharmacologic therapies and improve therapeutic development through analysis of therapeutic dosing, drug concentration at the intended site of action, potential for off-target toxicity, and strategies for translation of these measurements to large animal studies and early phase clinical trials. The lab tackles these issues from the very start of each new project, striving to create novel therapies and improve the translational potential of ongoing projects.
NIH’s mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life and reduce illness and disability.
NIH funded research has led to breakthroughs and new treatments, helping people live longer, healthier lives, while building a research foundation that drives discovery in health and health care.