Immune Promotion of Remyelination
Fresh animal or human oligodendrocytes were placed in culture. The remyelinating-promoting antibody rHIgM22 was overlaid on the surface of these myelinating cells. The antibody bound to the surface of all types of oligodendrocytes, indicating that the fats (lipids) reacting to the antibody were present on myelin-producing cells from multiple species, including human. This important finding indicates how the antibody RHIgM22 induced new myelin formation.
In these experiments, mice infected with Theiler's virus, which induces a disease almost identical to human multiple sclerosis, were put in a mouse MRI scan to determine whether the antibody rHIgM22 crosses the blood-brain barrier. The antibody was labeled with a molecule called biotin and then injected by vein into these mice. The antibody was chased with another molecule called streptavidin that was bound to very small iron beads that can be seen by MRI. The streptavidin molecules bind very tightly to the biotin, showing where the antibody is in the brain. The animal on the left was injected with the rHIgM22 antibody, with small red spots corresponding to the location of the antibody in the brain. In contrast, the animal on the right was injected with a control antibody sHIgM39 that doesn't induce remyelination and doesn't bind to oligodendrocytes. No red spots are seen in the brain because the antibody went into the brain but didn't find any oligodendrocytes to bind to, thus it was eliminated from circulation. These were crucial results presented to the Food and Drug Administration indicating that the antibody rHIgM22 crossed the blood-brain barrier.
This image is an explanation of how the lab conceptualizes rHIgM22 working in the brain and spinal cord to induce remyelination. The antibody, shown in pink, has five arms and 10 binding sites because rHIgM22 is a large IgM molecule. The antigens (proteins and lipids) that rHIgm22 binds to are shown in blue and are on the outside of the membrane of the oligodendrocyte (shown in hatched black and white). We believe the antibody in pink binds to the blue antigens and brings those molecules closer together by cross-linking the molecules. As a result of this process, other molecules (shown in green, red and light blue) on the inside of the cell surface are activated and send signals (arrows) into the nucleus of the cell and tell the cell to either make more oligodendrocytes or make more myelin.
Our lab is studying antibodies in an effort to discover new drugs that could promote remyelination in patients with multiple sclerosis.
We have identified a series of human monoclonal antibodies that bind to the surface of oligodendrocytes (Figure 1).
These antibodies trigger new myelin formation (remyelination) both in vivo and in vitro (Figure 2).
Antibodies have been shown to promote remyelination and functional improvement in three experimental models of multiple sclerosis: viral, autoimmune and toxic. Two monoclonal antibodies have been cloned and the sequence expressed in vectors so that large amounts of antibody can be readily made.
MRI studies show that these antibodies cross the blood-brain barrier (Figure 3) and target the multiple sclerosis lesion. These antibodies are expressed at a specific time in glial cell development and bind specifically to myelin.
One of these antibodies, rHIgM22, has been approved by the U.S. Food and Drug Administration to enter clinical trials. Acorda Therapeutics is the company responsible for carrying out the clinical trial. A phase I clinical trial has been completed in 72 patients with multiple sclerosis without side effects.
In addition, the antibody was shown to cross the blood-brain barrier in all of the 19 patients tested. The antibody was found to have a long half-life in the blood of patients, lasting for three to four days.
The first trial was done on patients with multiple sclerosis who have fixed neurological deficits. A second trial is recruiting patients who have an acute attack of multiple sclerosis (exacerbation) to determine if the drug is safe in the midst of an acute attack.
If the drug is found to be safe in both static patients and patients with acute attacks, then phase II and possibly phase III could begin to look at efficacy of the drug — whether the drug promotes remyelination.
Antibody under development
Our lab has a second antibody in the laboratory that is still under development and has not yet reached clinical utility.
This antibody, named rHIgM12, binds to neurons rather than to oligodendrocytes. The antibody has shown improvement in function in animals during the progressive phase of demyelination, a unique finding. We think this is because the antibody is targeting neurons and axons, which are the cause of progression in multiple sclerosis. In addition, we have published findings that the antibody prolongs life in two experimental models of amyotrophic lateral sclerosis.
This antibody could have utility in many diseases in the nervous system that are the result of neuronal or axonal dysfunction. Experiments are planned to test this antibody in models of spinal cord injury, stroke and hypoxic injury in the brain.