Fusion antibody was comparable to aducanumab treatment in clearing amyloid plaques in mice
Researchers at TGen, part of City of Hope, have developed a nanobody that can be engineered to bind and reduce amyloid plaques in a mouse model of Alzheimer’s disease. Nanobodies are tiny, super‑simple versions of antibodies that are about 10 times smaller than regular antibodies, which makes them unusually flexible and powerful.
Nanobodies, or single-domain antibodies, are derived from animals such as llamas, alpacas, and camels. Scientists are exploring their clinical possibilities because nanobodies are small, stable, and able to penetrate deep tissues, including those behind the blood-brain barrier that are often out of reach of conventional antibodies.
The study, published in Alzheimer’s and Dementia: Translational Research & Clinical Interventions, also confirms that anti-amyloid antibodies must include a key molecular region called Fc effector region to recruit immune cells called microglia to successfully clear the plaques.
In tests against amyloid plaques in mouse and human brain tissue, the TGen team found that their nanobody 2D10 alone could target but not eliminate the plaques in vivo. When they created a fusion antibody containing 2D10 and the Fc effector region, however, the fusion antibody potently cleared the plaques in mice.
“Nanobodies can be difficult to develop, but they offer remarkable molecular engineering versatility, and their ability to reach the brain makes them especially promising for treating central nervous system diseases,” said senior author John D. Fryer, Ph.D., professor and director of TGen’s Immunology and Microbiome Division and its Center for Accelerated Nanotherapeutics. “What we’re excited about is what we do next with it, which is not to just keep the nanobody with the Fc region on it, but to start to mix and match other ways to engage the immune system that are not Fc-region dependent.”
Alzheimer’s disease affects an estimated 7.2 million individuals in the United States and is an increasingly critical health challenge in aging populations worldwide. The disease is characterized in part by the accumulation of amyloid plaques in the brain.
The FDA recently approved three anti-amyloid monoclonal antibodies to treat plaques, but the treatment can produce serious side effects such as cerebral hemorrhage or edema in some patients. These side effects may result in part from unwanted immune cell recruitment, especially of vascular macrophages, by Fc domains on the antibodies.
The study’s first author, Zonghui Ding, Ph.D., an assistant professor in TGen’s Immunology and Microbiome Division, led the search to screen for llama nanobodies that could specifically bind to amyloid plaques in mouse and human brain tissue.
The screening led to 2D10, a nanobody without the Fc region, which could cross the blood-brain barrier and target plaques in mice. The unmodified nanobody, however failed to recruit microglia and reduce plaque burden in the animals.
The fusion antibody, however, performed as well at amyloid clearance as the FDA-approved monoclonal antibody aducanumab, the researchers found.
“There was still this lingering question of whether you truly need that Fc region to get amyloid clearance,” said Ding. “It’s a fairly simple experiment, but I think it demonstrates you need the Fc in place.”
Fryer said the scientists are “optimistic about using the amyloid nanobody to engage specific immune cells directly, for example, microglia, or to bring other immune cells into the brain that might serve beneficial functions, like certain T cell subsets.”
Tangles of abnormal tau protein in brain tissue are another hallmark of Alzheimer’s disease. “We are currently trying to find nanobodies that target tau,” Fryer said. “And then a single therapeutic that we might be able to use to attack both amyloid and tau, the two predominant pathologies in the brain, is another direction we want to pursue.”
The Translational Genomics Research Institute, Mayo Clinic Foundation, the Ben Dov Family Luminescence Foundation, the Rotary Coins for Alzheimer’s Research Trust Fund, the Cure Alzheimer’s Fund, the Arizona Department of Health Services (ADHS Grant No. CTR057001), and the National Institutes of Health (UL1 TR002377) funded this research.
By Becky Ham