More effective treatment of Alzheimer's

Date:
September 30, 2021
Source:
Uppsala University
Summary:
Researchers have designed new antibodies that might provide more
effective treatment methods for Alzheimer's disease. By designing
antibodies that bind even to the smaller aggregates, or clumps,
of the amyloid-beta protein, it may be possible to check the
progress of the disease.



FULL STORY ========================================================================== Researchers at Uppsala University have designed new antibodies that might provide more effective treatment methods for Alzheimer's disease. By
designing antibodies that bind even to the smaller aggregates, or clumps,
of the amyloid- beta protein, it may be possible to check the progress
of the disease.


========================================================================== Developing effective treatment methods for Alzheimer's disease has
proved difficult. The most effective, which have just been approved,
only provide marginal effects. There are several major reasons why they
are not effective, one of which is that the antibodies used do not bind
to all the types of toxic clumps that cause Alzheimer's disease.

In Alzheimer's disease, the amyloid-beta protein begins to form
clumps. This process is called aggregation, and the clumps created are
called aggregates.

The research group has previously shown that treatment with the peptide somatostatin causes the body to begin breaking down building blocks of
the aggregate. In the new study, the researchers use an antibody that
can bind to the toxic aggregates to stop them from harming cells.

The problem with the treatment methods currently tested in patient
studies is that the antibodies bind much more strongly to large clumps
and hardly at all to small clumps. The small clumps are just as toxic as
the large ones and many think that they are actually even more dangerous
since they can move more.

The purpose of the current study was to develop an antibody format that
can bind to both large and small clumps of amyloid-beta. Antibodies use
the avidity effect to bind strongly to their targets. This requires the
binding of both arms of the antibody to the same target at the same time.

The distance between the arms of the antibody is crucial for how small an aggregate the antibody can bind to strongly. If the aggregate is smaller
than the distance between the arms, they do not bind to the aggregate
strongly. If it is larger, they bind to the aggregate very strongly. In
the new article, the researchers have developed a new antibody format
with shorter distances between the arms so that they bind to smaller aggregates. The new format also has more binding sites to make the
binding extra strong.

"Thanks to the avidity effect, the new antibody format is at least 40
times stronger in binding to the clumps. The new type of antibody can
also bind to small aggregates with avidity, which we have not previously
seen any other antibody do. That is fantastic," says Greta Hultqvist,
Senior lecturer and Associate Professor in Protein drug design at Uppsala University who led the study.

The effects of the antibodies were also tested in a cell culture
experiment, which showed that the new antibody format could save cells
from death caused by amyloid-beta aggregates. Although no pre-clinical experiments were included, the team thinks their results suggest that the
new antibody design could be more effective than those trialled so far.

"The focus of the study was targeting the amyloid-beta protein in
Alzheimer's disease, but the new antibody design can be general and
applicable to other disease-causing clumps. From a long-term perspective,
we hope that the new format can open up new avenues for the generation
of future treatments, not only in Alzheimer's disease, but also other
diseases where proteins start to form aggregates, like Parkinson's
disease," says Fadi Rofo, doctoral student and first author of the study.

========================================================================== Story Source: Materials provided by Uppsala_University. Original written
by Elin Ba"ckstro"m.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Fadi Rofo, Jos Buijs, Ronny Falk, Ken Honek, Lars Lannfelt, Anna M.

Lilja, Nicole G. Metzendorf, Tobias Gustavsson, Dag Sehlin,
Linda So"derberg, Greta Hultqvist. Novel multivalent design of a
monoclonal antibody improves binding strength to soluble aggregates
of amyloid beta.

Translational Neurodegeneration, 2021; 10 (1) DOI:
10.1186/s40035-021- 00258-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210930140727.htm

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