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Antibody Reduced Plaque By More Than Half in Animal Model of Alzheimer's Disease


Investigators at Eli Lilly designed a monoclonal antibody that attacks a relatively rare and especially toxic form of amyloid-beta, and found it reduced plaques by more than half in a mouse model of Alzheimer's disease.

A new monoclonal antibody has reduced plaques by more than half in a mouse model of Alzheimer's disease (AD) without causing microhemorrhages, a common side effect of the treatment. Eli Lilly, the developer of the antibody, has already humanized the antibody, and plans to begin phase I clinical trials within a year.

“We can't discuss our clinical plans, but in general we'll focus on Alzheimer's patients who have plaque buildup,” said Eli Lilly biochemist Ronald B. DeMattos, PhD, lead author of the Dec. 6, 2012, paper in Neuron that describes the new antibody. “We're eager to get started. Based on our current knowledge of the disease, we believe we'll have a beneficial outcome.”

Dr. DeMattos and his colleagues designed the antibody, known as mE8, to attack pyroglutamate amyloid-beta (pGluAβ),a relatively rare and especially toxic form of amyloid-beta (Abeta) found exclusively in plaques. (In the Neuron paper DeMattos and his colleagues refer to pGluAβ as Aβp3–42.) pGluAβ is created when glutaminyl cyclase, an enzyme elevated in AD patients,modifies the N-terminus of truncated Abeta. Found at the core of plaques, and highly resistant to degradation, pGluAβ is believed to provide the “seed” to which soluble oligomers attach to create a plaque.

“We picked this truncated form of Abeta because pyroglutamate 3–42 is only present in plaque,” Dr. DeMattos said. “We can't see it in CSF, or in the fluid around neurons, or in the blood. This appears to provide antibodies with an ideal target.”

The Lilly researchers developed two antibodies built on an immunoglobulin G “backbone.” One produced a 38 percent decrease in Abeta, while the otherproduced a 53 percent decrease and stimulated stronger phagocytosis by microglia.

This version of the mE8 antibody ignores the soluble species of Abeta and attaches to the plaque exclusively, which may be why it does not produce microhemorrhages, according to Dr. DeMattos.

“When mE8 attaches to pyroglutamate Abeta, it stays put in the plaques until microglia come and break them down through phagocytosis,” Dr. DeMattos said. “In contrast, antibodies that attach to soluble species may be carried directly to the vessel wall, where they build up and compromise the integrity of the wall, leading to microbleeds.”

DR. RONALD DEMATTOS: “We cant discuss our clinical plans, but in general well focus on Alzheimers patients who have plaque buildup. Were eager to get started. Based on our current knowledge of the disease, we believe well have a beneficial outcome.”


As knowledge about AD has grown, researchers have retained their belief that the build-up of Abetatriggers the cascade of pathology that ultimate destroys neurons and causes dementia. The first clinical trial of an immunotherapy — a vaccine known as AN 1792 developed by Elan and Wyeth—began in 1999. Although the vaccine actually lowered amyloid levels compared with controls, and slowed cognitive decline somewhat, the trial was halted because about 6 percent of the participants developed meningoencephalitis.

Monoclonal antibodies developed in the lab can be designed to attack Abetadirectly, without help from the patient's own immune system, but so far only one, bapineuzumab, has been found to lower Abeta in humans; in phase 3 trials, however, it failed to produce significant cognitive benefit or plaque reduction. Also, the tendency of monoclonal antibodies to cause microhemorrhages is considered a major problem.


Recently some researchers have concluded that antibodies would be more effective at preventing the buildup of Abeta rather than removing established plaques, but that would require administering them decades before symptoms appear, when the toxic species is just starting to aggregate.Preventionwould require reliable biomarkers that could identify people just starting down the road to AD.

The new antibody revives hopes that the insoluble plaques can be removed from the brain safely, thereby slowing and possibly reversing Alzheimer's pathology.The antibody emerges from recent insights into the N-terminus of Abeta-42.

Thomas Bayer, PhD, professor of molecular psychiatry at the Georg-August-University of Göttingenin Germany, led the team that discovered a monoclonal antibody they call 9D5, which attacked pGluAβ in a mouse model of AD, reduced the plaque load and, surprisingly, alleviated anxiety behavior. They published their results in 2010 in the Journal of Biological Chemistry.

Cynthia A. Lemere, PhD, associate professor of neurology at Brigham and Women's Hospital and Harvard Medical School, followed up with a paper in the February 2012 issue of Neurodegenerative Diseases showing that passive immunization with an anti-pyroglutamate 3 monoclonal antibody developed in collaboration with Probiodrug AG, a German biopharmaceutical company, reduced plaque and lowered gliosis in the hippocampus and cerebellum of a mouse model of AD. She and her colleagues also found no signs of microhemorrhage. The antibody, however, recognizes both soluble and insoluble forms of the pyroglutamate Abeta.

“We weren't expecting that a monoclonal antibody specific for pyroglutamate 3 Abeta would lower other forms of Abeta,” Dr. Lemere said. “Our explanation is that once microglia are activated at the site of a pyroglutamate Abeta-containing plaque, and the phagocytosis mechanism goes into action, they may start to clear plaques even if the plaques contain Abeta with other N-termini.”

In addition to clearing pyroglutamate Abeta, which is less abundant than general Abeta in the mouse model, the antibody also may have cleared general Abeta and thereby halted the creation of new plaques.

“Removing a seed for deposition (pyroglutamate Abeta) may have helped to prevent subsequent deposition of multiple forms of Abeta,” Dr. Lemere said. She will present her group's most recent results in March at the 11th International Conference on Alzheimer's and Parkinson's Diseases in Florence, Italy.

Veteran AD researcher Dennis Selkoe, MD, hailed these developments, which conjure the possibility of removing plaques and, in the process, significantly reducing the brain's amyloid burden.

“I think the Neuron paper reintroduces us to the importance of removing plaques,” said Dr. Selkoe, the Vincent and Stella Coates professor of neurologic diseases at Harvard Medical School and Brigham and Women's Hospital. “By getting rid of plaques you're also lowering levels of oligomers and even monomers. Dr. DeMattos is going after a species that constitutes less than 1 percent of plaque, but he's excited because it results in the removal of a lot of plaque. That's the beauty of this study. You can target a rare player and clear out lots of other Abeta species at the same time because the microglia clear everything around it. They don't know any better.”


In a commentary published in the same issue of Neuron, David Holtzman, MD, the Andrew B. and Gretchen P. Jones professor and chairman of neurology at Washington University School of Medicine, wrote he envisions combining the antibody devised by Eli Lilly biochemist Ronald B. DeMattos, PhD, and his colleagues, which attacks only plaque, with other therapies, such as other antibodies that attack soluble amyloid-beta (Abeta). Beta secretase inhibitors or gamma secretase modulators that curb the cleavage of amyloid precursor protein — the source of the toxic species — might also be added to the mix.

“Such combinations might have the benefit of preventing new Aβ plaque formation and decreasing Aβ toxicity, while an antibody like mE8 could remove pre-existing plaques, a potential reservoir for toxic Aβ species,” Dr. Holtzman wrote in the commentary, which he co-authored with Jee Hoon Roh, MD, PhD, also of the Charles F. and Joanne Knight Alzheimer's Disease Research Center at Washington University School of Medicine.

Starting treatment earlier also would help, Dr. Holtzman told Neurology Today.“We know the amyloid-beta cascade of damage begins before symptoms develop, and current trials target people already well into the clinical phase of disease,” he said. “If you start in the presymptomatic period when amyloid is building up but people are still symptom free, that's when these types of therapies have a much better chance of being effective.”

Dr. DeMattos also contends combination therapies may help, but only after effective individual therapies are developed.“At Lilly we are quite interested in combination therapies, especially if we could leverage our expertise to have an antibody such as solanezumab, which binds soluble Abeta, combined with something that binds to plaque, and maybe we could even add a BACE inhibitor, which we now have in a phase 2 trial,” he said. “But for now we need to focus on individual therapies and doing what we can to get these medications to patients as soon as possible.”

—Tom Valeo


• DeMattos R, Lu J, Hutton ML, et al. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice. Neuron 2012;76: 908–920.
    • Roh JH, Holtzman DM. Stealth attack: Plaque-specific antibody allows for efficient Aβ removal without side effects. Neuron 2012;76: 859–861.
      • Wirths O, Erck C, Bayer TA, et al. Identification of lowmolecular weight pyroglutamate Aβoligomers in Alzheimerdisease: A novel tool for therapy and diagnosis. J Biol Chemistry 2010;285:41517–41524.
        • Frost JL, Liu B, Lemere CA.Passive immunization againstpyroglutamate-3 amyloid-β reduces plaque burden in Alzheimer-like transgenic mice: A pilot study. Neurodegener Dis 2012;10(1–4):265–270.
          Neurology Today archive onimmunotherapy in Alzheimer's disease:
            • For more about the research of Jee Hoon Roh, MD, PhD: