By Lucy Piper, medwireNews reporter
medwireNews: The binding affinity of anti-amyloid monoclonal antibody treatments to cerebral amyloid angiopathy (CAA) relative to plaque amyloid does not appear to explain amyloid-related imaging abnormality (ARIA) rates, suggests research.
The affinity with which aducanumab, donanemab, and lecanemab bind to CAA amyloid-β relative to plaque amyloid-β is “indistinguishable,” despite the differences seen in ARIA edema/effusion (ARIA-E) rates with these anti-amyloid antibodies, said Andrew Stern (Brigham and Women’s Hospital, Boston, Massachusetts, USA).
Speaking at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, Spain, he cited reported ARIA-E rates of 35.2% for aducanumab, 24.0% for donanemab, and 12.6% for lecanemab, with a 2.8-fold increased rate with aducanumab versus lecanemab.
Stern pointed out that effects on the vasculature have been proposed as a possible contributing factor because CAA burden predicts ARIA risk, there is a clinicoradiologic similarity between ARIA-E and inflammatory CAA, and assessment of fatal ARIA-E cases who have undergone postmortem have resembled vasculitis.
The researchers therefore hypothesized that “ARIA-E is due to off-target binding of anti-amyloid antibodies to CAA amyloid rather than on-target binding to amyloid plaques,” and that a greater relative binding for CAA amyloid may mirror the order of ARIA-E rates among the anti-amyloid monoclonal antibodies.
To measure the antibody preference, they used postmortem brain extracts from 18 patients (nine women) with Alzheimer’s disease (AD) and CAA who were aged an average of 74.3 years. Most were apolipoprotein Ɛ4 carriers – nine heterozygous and six homozygous – but all carriers were represented.
They took paired frozen occipital lobe gray matter and overlying meninges, “as these are a hotspot for both CAA and ARIA,” said Stern, and made aqueous extracts from homogenization tissue and centrifuging to obtain a supernatant. Using antibodies synthesized from published patent amino acid sequences, the team then measured the antibody preference for binding to meningeal amyloid-β40, which is CAA enriched, and parenchymal amyloid-β42, which is plaque enriched.
Two ratios were calculated. The first, the “MP KD ratio,” which was a measure of the affinity of the antibody’s preference to bind with CAA rather than plaque amyloid. This showed no difference among the antibodies.
Specifically, binding to CAA rather than plaques was increased a mean 1.51-fold with aducanumab, 1.63-fold with donanemab, and 1.85-fold with lecanemab, which although “numerically in the order you would expect,” according to ARIA-E rates for these treatments, did not differ significantly, said Stern.
Aducanumab’s preference for binding CAA rather than plaque amyloid-β was between 0.83- and 1.8-fold, which does not explain the 2.8-fold ARIA difference.
Stern added that opposite to “what would be expected,” homozygous apolipoprotein Ɛ4 carriers seemed to cause less antibody preference for CAA.
The second ratio was the “MP Bmax ratio,” which measured how much amyloid-β was available to bind either CAA or plaque amyloid and this showed that donanemab had slightly less amyloid-β antigen availability compared with aducanumab and lecanemab.
Stern also highlighted that the findings showed “a perfect correlation” between the amyloid-β that aducanumab and lecanemab bind to in both the parenchyma and meninges. He suggested that this means “there is no special protofibril population that is accessible to lecanemab but not to aducanumab […] they both bind to the same population of amyloid-β.” He therefore proposed that this happens at different epitopes.
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group
CTAD24; Madrid, Spain: Oct 29–Nov 1
https://www.ctad-alzheimer.com
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