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AD/PD 2021 | Second generation of anti-amyloid monoclonal antibodies for Alzheimer’s disease

Marwan Sabbagh, MD, Lou Ruvo Center for Brain Health, Las Vegas, NV, discusses the role of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease as well as amyloid-targeting drugs in particular monoclonal antibodies. Prof. Sabbagh points out that numerous compounds have been developed to target various forms of amyloid β, monomeric, oligomeric, aggregates, and plaques. While some of the approaches have not been successful, the second generation of monoclonal antibodies targeting the oligomeric species of Aβ shows interesting outcomes. The four monoclonal antibodies that are currently in development are aducanumab, gantenerumab, lecanemab, and donanemab. This interview took place during the AD/PD™ 2021 conference.

Transcript (edited for clarity)

The fact is, is that we know that amyloid is an early seminal event that leads to downstream effects. It doesn’t correlate well with clinical progression, but we clearly think that the production and presence of amyloid drives other changes in the brain, synapse loss, excitotoxicity, inflammation, tau spread, et cetera. A lot of people have said, “Let’s target amyloid because it makes sense to remove,” but the first-generation… There were two approaches...

The fact is, is that we know that amyloid is an early seminal event that leads to downstream effects. It doesn’t correlate well with clinical progression, but we clearly think that the production and presence of amyloid drives other changes in the brain, synapse loss, excitotoxicity, inflammation, tau spread, et cetera. A lot of people have said, “Let’s target amyloid because it makes sense to remove,” but the first-generation… There were two approaches. One is clearance-based approaches. One is a production-based approaches. A production-based approach is secretase inhibitors, they haven’t worked. Then the first-generation monoclonal antibodies either were targeting the beginning of the amyloid, which is the monomeric or the end of the amyloid, which was the plaque, and neither of those works. The second generation of monoclonal antibodies is looking at targeting the oligomeric species of amyloid, which is a specific form of amyloid, which appears to be toxic. The four monoclonal antibodies that are in development now, aducanumab, lecanemab, donanemab, and gantenerumab, all target that species of amyloid. That’s why there’s an interest because there’s clear evidence that removal of that species seems to be removed, driving amyloid levels down and slowing a clinical progression.

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