By David N. Leff
At the Mayo Clinic in Rochester, Minn., 102 patients donated blood - not for transfusions, but for medical research. These donors all have one thing in common - immune-system B cells operating in overdrive. B cells generate the antibodies, or immunoglobulins (Igs), that intercept alien antigens threatening the body with infections, cancers or autoimmune diseases.
One such autoimmune affliction is multiple sclerosis (MS), in which immune cells attack the brain and spinal cord cells that coat the axons of neurons with myelin. This protein sheath protects neuronal axons much as insulation shields wires and cables. Axons carry nervous system messages throughout the body. When rogue autoimmune cells destroy their myelin coat - as in MS - paralysis ensues.
This incurable disease afflicts over a million victims in the world, a fourth to a third of them in the U.S. It comes on insidiously, and worsens slowly, waxing and waning by fits and starts. "Most of the therapies that exist for MS," observed Mayo Clinic neuroscientist Arthur Warrington, "try to treat the inflammatory damage to oligodendrocytes, the nervous system's cells that produce myelin around the axons."
Mayo's 102 donors have abnormal antibodies, produced in great quantity by B cells out of control. This is due to a number of blood dyscrasias, ranging from certain lymphomas and myelomas to two less life-threatening entities - Waldenstrvm's macroglobulinemia and the even more benign MGUS - "macroglobulinemia of uncertain significance." But all these disorders pour out IgM, by far the weightiest of the immune system's 10 immunoglobulins.
Warrington is lead author of a paper in today's Proceedings of the National Academy of Sciences (PNAS), dated June 6, 2000. Its title: "Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis." Its senior author is neuroscientist Moses Rodriguez, who in the 1980s pioneered the concept of siccing immune-system monoclonal antibodies on rogue autoimmune cells that destroy myelin.
A 'First' In Preclinical Myelin Repair
"Our overall finding in PNAS," Warrington told BioWorld Today, "was that in a mouse model of multiple sclerosis we've identified two human monoclonal antibodies - natural reagents - from humans. And that mice treated with these reagents demonstrated more remyelination repair in the spinal cord than animals that got either a control polyclonal antibody or control saline. This is the first time," he added, "that a modified human antibody has been shown to be effective in an animal model of demyelination in the central nervous system."
Most MS research relies traditionally on a disease called experimental allergic encephalitis (EAE), which for the most part models the inflammatory hallmarks of MS. To get below these EAE symptoms to underlying causes, the Mayo co-authors infected their mice with a toxic virus that demyelinates the animals' axons and brings on the characteristic MS paralysis. This pathogen is Theiler's murine encephalomyelitis virus (TMEV), which the team inoculated intracerebrally.
"In this virus system," Warrington pointed out, "the TMEV virus gets into the nervous system's white matter - the glial cells - where it kills the defective oligodendrocytes. EAE has not been that predictive in modeling therapy in clinical trials of MS patients. So another model was necessary, as EAE probably doesn't present all the different facets of MS that other models, such as TMEV, may. There are different autoimmune components in MS," he went on. "However, many people in the field feel that there is some underlying pathogen, which sets this process in motion. The question has always been: Does the pathogen of autoimmunity remain in the body, or is it cleared? Are there low levels of virus?
"What we think is interesting about the Theiler's model," he continued, "is that there is a low level of virus in these MS-model animals, even up to a year after the experiment. And that's one reason we chose this model, that if one can promote remyelination repair in the face of this low level of virus infection, then if the same thing is true of MS in humans, then this might be a better alternative than merely controlling inflammation."
Warrington said, "The take-home message for the in vivo experiments is that these animals have more remyelination repair in their spinal cord than did controls. Yet we have not demonstrated a clinical change in their MS scores. The mice remain paralyzed. They're sick. And even though they show histologic repair under the microscope, we've not been able to identify a functional change. Maybe, we think, we're not treating them at the right time. The animals get progressively sicker over the course of 12 months or so. We've tended to treat them late, what we call the chronic stage, merely because the damage to the nervous system presents a larger target.
"What we're doing now is treating the mice earlier on, when they don't have a significant clinical deficit, to see if we can just stabilize them. I think for most MS patients," Warrington observed, "stabilization would be a very positive benefit."
Goal: Stop, Not Slow, MS Course
Mayo has an issued core patent on its human monoclonal technology, which is licensed to Acorda Therapeutics, of Hawthorne, N.Y. The clinic and the company organized an electronic news conference Monday afternoon to introduce their PNAS findings to the media. Ron Cohen, president and CEO of Acorda, told BioWorld Today, "The thrust of the press conference is that this is a paper on a novel piece of science, a novel antibody that stimulates remyelination. And as such it is a potential therapy for demyelinating diseases - say, MS.
"Until now," Cohen pointed out, "all of the therapies for MS have tended to slow down the course of the immune attacks, and in general improve the long-term progression of the disease. But until now there has never been a therapy that actually repairs the damage that has already occurred."
To which Warrington added: "We want to be sure that people don't describe this as a cure or a therapy. It's not. We're years from that. We think that for us it's important to get this out there, and for Acorda to try and get enough funding to go to the nexnext step - testing in small clinical trials."