Denali antibody clears amyloid plaques without dangerous brain bleeds in Alzheimer's mouse model

 Great, now can your incompetent? doctor and hospital get human testing going?

Do you prefer your doctor and hospital incompetence NOT KNOWING? OR NOT DOING?

Denali antibody clears amyloid plaques without dangerous brain bleeds in Alzheimer's mouse model

When given to mice, Denali Therapeutics' molecule was able to spread broadly throughout their brains and dismantle amyloid plaques, with MRIs showing this didn’t result in any ARIA-like leakage from blood vessels. (Artur Plawgo/iStock/Getty Images Plus)

Ever since Biogen and Eisai’s Aduhelm (aducanemab) was approved in 2021 as the first antibody to treat Alzheimer’s disease by clearing amyloid plaques from the brain, the modality has been dogged by a serious side effect: brain bleeding called amyloid-related imaging abnormalities, or ARIA. 

Now, researchers from Denali Therapeutics have debuted an antibody that can cross the blood-brain barrier and attack amyloid, but without triggering this potentially life-threatening complication.

When given to mice, the molecule was able to spread broadly throughout their brains and dismantle amyloid plaques, with MRIs showing this didn’t result in any ARIA-like leakage from blood vessels. The results were published in Science on Aug. 7.

The Bay Area biotech plans to bring an optimized form of the antibody, which targets beta amyloid (Abeta), into the clinic next year, Chief Scientific Officer Joe Lewcock, Ph.D., told Fierce Biotech.

“The molecule is currently undergoing the standard IND-enabling studies,” Lewcock said. “Once we get to the clinic, there's potential to learn from the lessons that the Abetas that have come before us have provided in terms of how to efficiently get towards a proof of concept.”

First-generation Abeta drugs, like the now-discontinued aducanemab, Eli Lilly’s Kisunla (donanemab) and Biogen and Eisai’s Leqembi (lecanemab), have proven controversial due to ARIA safety concerns that may not outweigh the approach’s benefits. These drugs don’t target the brain but are instead given systemically through the blood, so only a small fraction of the given antibody actually reaches the brain.

One hypothesis for ARIA’s cause is that the antibodies bunch up around amyloid within blood vessels, rather than reaching the plaques that occur within the actual brain tissue, triggering an immune response that damages the vessel and causes bleeding.

To circumvent this, Denali designed its antibody to bind to transferrin receptors (TfR) on the outside of the blood-brain barrier. TfRs are meant to ship iron, a vital nutrient, into the brain, a process that can be hijacked to smuggle other payloads across the barrier as well.

“This is a superb innovation,” said Matthew Schrag, M.D., Ph.D., a neuroscientist at Vanderbilt University Medical Center who was not involved with the research. “Controlling the delivery of drugs of any sort to the brain, getting them effectively into the compartment that you want to get them into, is a major accomplishment.”

Not content to stop there, Denali also tried to tamp down a potential immune reaction by removing one of the antibody’s effector sites. This is the part of the antibody that, once the molecule has bound to Abeta, actually recruits the brain’s waste disposal system to clear the plaques.

“What we've shown in the paper is that if you remove effector function entirely, you lose the ability to clear plaques as effectively,” Lewcock explained. “We essentially removed effector function from one side of the molecule,” which made the antibody safer but still as effective, he said.