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Antibody Designed to Stop Inflammation Protein in Brain

Katerina Akassoglou

Katerina Akassoglou (Gladstone Institutes)

16 Oct. 2018. A synthetic antibody is shown in tests with lab mice to block the blood protein fibrin from causing inflammation and related damage to brain cells found in neurodegenerative diseases. A team from Gladstone Institutes, a medical research center affiliated with University of California in San Francisco, and other organizations reports its findings in yesterday’s issue of the journal Nature Immunology (paid subscription required).

Researchers led by Gladstone neuroscientist Katerina Akassoglou are seeking better treatments for neurological disorders linked to inflammation in the brain, such as Alzheimer’s disease and multiple sclerosis. Therapies for these diseases are complicated by the presence of the blood-brain barrier that usually prevents molecules from crossing from the blood stream into brain cells. Blood vessels in the brain form a support network for brain functions, with tightly-packed cells lining blood vessels that allow nutrients like glucose to pass through, but keeping out foreign substances, including drugs to treat neurological conditions.

In neurodegenerative diseases, such as Alzheimer’s and multiple sclerosis, the blood-brain barrier becomes weaker and more permeable, allowing larger proteins in blood, such as fibrin, to leak through. Fibrin has beneficial properties, most notably promoting coagulation to prevent bleeding. But fibrin also contains components that encourage inflammation and oxidative stress that damage nerve cells. Thus targeting fibrin in treatments to treat brain inflammation could result in excessive bleeding in the brain, an unacceptable trade-off.

Akassoglou’s lab, which studies effects of proteins in blood on brain inflammation associated with neurodegenerative disorders, designed a synthetic antibody that zeroes-in on components of fibrin causing inflammation and oxidative stress. The antibody, code-named 5B8, targets a specific epitope, or binding section of fibrin that promotes inflammation and oxidation, while leaving the rest of the protein’s chemistry intact.

In lab cultures, tests show 5B8 antibodies block production of the chemical responsible for activating oxidation and promoting inflammation. Further tests in lab mice induced with Alzheimer’s disease and multiple sclerosis show the antibodies entered and accumulated in the animals’ brains where fibrin occurs, and protected against inflammation and oxidation. In mice induced with Alzheimer’s disease, the antibody reduces inflammation in the brain and brain cell loss, even after amyloid-beta plaques formed, compared to untreated animals. Mice induced with multiple sclerosis also show less inflammation in brain cells when given 5B8, compared to untreated mice.

“Our study supports that vascular damage leading to immune-driven neurodegeneration may be a common thread between diseases of different etiologies with blood-brain barrier leaks,” says Akassoglou in a Gladstone statement. “Targeting fibrin with immunotherapy is a new approach that could be used to test the therapeutic benefits of suppressing this pathogenic mechanism in multiple disease contexts.”

Akassoglouis and co-authors are inventors on patents granted and applied for by Gladstone Institute on the technologies in this study. She is also founder of and scientific adviser to Medared Inc. in Menlo Park, California, a two year-old company developing treatments for neuroinflammatory diseases. Drug maker Lundberg A/S sponsors research in Akassoglouis’s lab and had staff represented on the team for this study.

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