Immune Promotion of Remyelination

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.