Scientists from the Gladstone Institutes say they developed an antibody that blocks the inflammatory and oxidative activity of fibrin, which contributes to neurodegeneration in the brain, without compromising the protein’s clotting function. To come up with a precise and highly effective antibody, the researchers focused on targeting only a small region of the fibrin protein that is involved in activating the immune system in the brain. This way, they avoided interfering with the part of the protein responsible for clotting.
The team’s study (“Fibrin-targeting Immunotherapy Protects Against Neuroinflammation and Neurodegeneration”) appears in Nature Immunology.
“Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer’s disease (AD). However, the mechanisms that link disruption of the blood–brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions,” write the investigators.
“Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377–395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.”
“We have developed a monoclonal antibody to target a major culprit in the blood that damages the brain,” says Katerina Akassoglou, Ph.D., senior investigator who is also a professor in the department of neurology at University of California, San Francisco. “Fibrin-targeting immunotherapy could protect the brain from the toxic effects of blood leakage and may also have beneficial effects in other organs affected by inflammatory conditions with vascular damage.”
Dr. Akassoglou and her colleagues used models of neurodegeneration simulating two major brain diseases that are associated with BBB leakage, chronic inflammation, and vascular abnormalities: multiple sclerosis and AD.
The therapeutic fibrin antibody entered the brain, accumulated at fibrin-rich areas, and protected against neuroinflammation and neurodegeneration in both disease models. Molecular analysis showed that the treatment also reduced activation of biochemical pathways that contribute to inflammation and oxidative stress, a potential source of molecules that can poison cells, including neurons.
“We discovered that fibrin also contributes to brain disease through oxidative stress – an unanticipated result,” explains first author Jae Kyu Ryu, Ph.D., a staff research scientist on Dr. Akassoglou’s team. “Treatment with the antibody put a damper on this fibrin-driven oxidative mechanism, which may contribute to many different neurodegenerative diseases.”
In the mouse model of Alzheimer’s disease, animals were treated with the antibody after they had already developed accumulations of amyloid proteins in the brain, a hallmark of the disease. Compared to placebo-treated mice, the treated mice had less brain inflammation and lost fewer neurons.
Similarly, treatment with the antibody reduced activation of inflammatory cells and their accumulation at sites of inflammation in the mouse model of multiple sclerosis. In addition, it reduced the loss of nerve axons, which often degenerate in patients with multiple sclerosis.
“Our study supports that vascular damage leading to immune-driven neurodegeneration may be a common thread between diseases of different etiologies with BBB leaks,” says Dr. Akassoglou. “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.”
Using this approach, Dr. Akassoglou and her team could be in a position to achieve neuroprotection in diverse disorders without shutting down protective immune responses or blood clotting.
The next step will be to make a version of the antibody that can be used in human patients. Given that the treatment targets an immune response and a blood clotting factor, Dr. Akassoglou cautions, however, that tests monitoring the immune system and blood clotting will be important during clinical evaluation.