Scientists have found a way to treat Alzheimer's disease with antibodies

Researchers have found a way to treat Alzheimer's disease with antibodies with double specificity: one half of the antibody molecule deceives the checkpoint between the brain and the blood capillary, and another binds to a protein that leads to the death of brain neurons.

Scientists from the biotechnology firm Genentech know how to penetrate the brain through blood vessels. At first glance, there is no problem: the brain is supplied with oxygen and nutrients through the usual network of capillaries. But physiologists more than a hundred years ago discovered between the brain and the circulatory system the so-called blood-brain barrier. Its function is to maintain biochemical constancy in the brain: no random changes (for example, in the ionic composition or pH of the blood) should not affect the functioning of the brain; Neurotransmitters controlling other systems of organs should not enter the brain; the more the brain is closed to most large molecules, such as antibodies and bacterial toxins (not to mention the bacteria themselves). The cells of the capillary walls in the brain have extremely tight contacts and have a number of other features that protect the brain from undesirable penetration. As a result, the concentration of the same antibodies here is a thousand times less than in the bloodstream.

But for the therapy of many diseases it is important to deliver drugs to the brain. And if this drug is such large proteins as antibodies, then the effectiveness of treatment is sharply reduced. Meanwhile, many hopes are associated with artificial antibodies, including among those who deal with Alzheimer's disease. This ailment is accompanied by the formation in the neurons of amyloid masses - in other words, the "sediment" of incorrectly packed protein molecules, which destroys nerve cells. Among the proteins responsible for the formation of amyloids in Alzheimerism, β-secretase 1 is most popular, which is most often chosen as the target for therapy.

So, to break through the blood-brain barrier, the researchers created bi-directional antibodies. One part of such a molecule recognized the enzyme β-secretase, the other a transferrin protein in the walls of blood vessels. The latter is the receptor responsible for the intake of iron ions in the brain. According to the scientists, the antibodies grabbed the transferrin, which sent them to the brain: thus, the barrier between the brain and the circulatory system, so to speak, "remained in a fool."

At the same time, researchers had to simultaneously solve another problem, this time having to do with antibodies proper. The strength with which antibodies bind to their target molecule, the antigen, is called affinity. Usually the antibody is better, the higher its affinity. From a medical point of view, the most strongly binding antibodies are the most effective. But in this case, scientists had to lower the binding strength of the created antibodies with transferrin, otherwise they would tightly communicate with the carrier and get stuck on the threshold. The strategy justified itself: in experiments on mice already a day after administration of such antibodies to animals, the amount of amyloidogenic proteins in the brain dropped by 47%.

In their work, researchers went against the rules that read: antibodies should be strictly specific and have high affinity, that is, it is very strong to bind only one goal. But it is the weakly binding antibodies with multiple specificities that can help in the treatment of not only Alzheimer's disease but also cancer therapy. Cancer cells carry on their surface proteins that can be recognized by antibodies, but the same proteins produce other cells, as a result antibodies against cancer cells often kill and healthy cells. Multispecific antibodies could recognize a specific combination of surface proteins characteristic of cancer cells, and a set of such proteins would allow antibodies to bind firmly only to cancerous cells, rather than ordinary cells, on which they simply would not be retained.

Skeptics from competing firms say that because of low specificity, the antibodies invented in Genentech will not receive clinical use, since for this they will have to inject a huge number of people to them. The authors say that they will not have to: our antibodies serve much longer than in mice, and their excess, which had to be introduced to the experimental animals, is only a specificity of the "mouse" system ...

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