The renaissance of antibodies

Illustration of protein deposits around nerve cells, as seen in Alzheimer's disease. Source: nobeastsofierce – stock.adobe.com

Researchers are divided on the use of antibodies in the treatment of Alzheimer's patients: Critics already considered the approaches a failure - but now, thanks to new findings, they are once again in the spotlight.

Whenever Alzheimer's research has made big headlines in recent years, it has often been due to setbacks: A series of complex drug trials have failed - and with them the hopes of many patients for an early treatment option have been dashed. Experts were all the more astonished when a drug called Lecanemab now achieved great success in the treatment of Alzheimer in a clinical trial. "The approach of treating Alzheimer via antibodies has not failed, as was often predicted in recent years," says the renowned brain researcher Prof. Christian Haass of the DZNE, "quite the opposite: they are promising, and Lecanemab has proven that."

Behind the use of antibodies is the theory of the amyloid cascade. Amyloid is a protein found in everyone's brain. But its concentration increases with age, and all Alzheimer's patients have whole clumps of amyloid in their brains, called plaques. The amyloid in turn has a whole series of subsequent effects at the molecular level; this is the cascade that gives the theory its name. But whether the plaques are a trigger of Alzheimer's or a consequence - that has been the subject of debate among scientists over the past decades. Christian Haass, who is considered a pioneer in amyloid research, has always been convinced that antibodies targeting this particular protein represent an effective approach to Alzheimer's treatments.

[Translate to Englisch:] Portrait Prof. Haass

The approach of treating Alzheimer's with antibodies has not failed, as has often been predicted in recent years.

Prof. Christian Haass

DZNE site speaker Munich

The success of lecanemab could now start a renaissance in antibody research. After 18 months, the subjects showed 27 percent less deterioration than the placebo group - that's the outwardly visible effect. At the molecular level, the drug, which is being tested by the pharmaceutical companies Eisai and Biogen, also has far-reaching effects. "It has been shown to reduce amyloid by more than 70 percent," says Christian Haass. Even in the Phase 2 study - the first, still small-scale application in humans - it was seen to have significant effects on phospho-tau as well, he says; that's another protein linked to Alzheimer. "You have to roll that off the tongue: You put an anti-amyloid agent into the brains of Alzheimer's patients, and it clears the plaques, slows cognitive decline and reduces phospho-tau at the same time." Amyloid triggers the formation of phospho-tau, Christian Haass explains - and comes back to the amyloid cascade: "If I dry up the cascade at the top - that is, at the amyloid - then nothing comes out at the bottom." So processes that lead to further memory decline can be stopped.

Despite these successes, however, many questions remain unanswered: How, for example, can patients be identified as early as possible, preferably before memory loss occurs? Are there side effects? Who will cover the horrendous costs, and how can the infusion of the antibody be organized logistically? "And unfortunately, it will also be the case that only patients with extremely mild memory loss will respond to the drug," says Christian Haass: "This means that there will still be no drug available to the many more advanced patients."

The chain of setbacks in previous trials began in 2014 with the drug gantenerumab, followed by crenezumab, solanezumab and aducanumab. The failed attempts, each involving multi-million dollar investments, brought criticism to the entire antibody research community. There was talk of "setbacks that can hardly be borne" and of "grandiose failure". Christian Haass believes that there are sufficient reasons to take a close look at all these studies: He doesn't call them failed studies at all, even though they didn't improve the subjects' cognition much, if at all. "We were able to learn something from each of these studies. And the fact that they had little effect on the patients has nothing to do with the amyloid hypothesis." That, he said, is evident simply from the fact that each of the drugs failed to work for different reasons. If, for example, so-called secretase inhibitors, which are supposed to prevent the formation of amyloid, do not even reach their target via the bloodstream, they cannot develop their effect there. The same could also apply to Roche's gantenerumab study, where it has just been announced that this antibody does not significantly reduce memory loss - but also does not sufficiently clear the plaques.

Among the neurodegenerative diseases, Alzheimer is the one that seems most predestined for the use of antibodies: the amyloid plaques - i.e. the targets for the antibodies - are deposited outside cells. This allows antibodies to recognize and attack them immediately. The principle sounds simple in theory: The brain is virtually flooded with anti-amyloid antibodies, which attach to the plaques, whereupon microglial cells - the brain's own immune cells - attack them. In most other neurodegenerative diseases from Parkinson's to frontotemporal dementia, the potential targets for antibodies form inside cells and are protected there. They therefore have to be transported out of the cell before they can actually be attacked there.

Currently, several antibodies are still in development for the fight against Alzheimer's disease; for two of them, the data from the clinical phase 2 study so far look promising, according to experts. Independently of this, the DZNE would like to work on a kind of two-stage therapy procedure: First, patients are administered a high dose of antibodies that significantly reduce amyloid plaques. Next, they are given a molecule designed to keep amyloid levels low. This will soon be tried on mouse models. "We need the antibodies for the initial effect, to clear the plaques as much as possible. But to keep amyloid levels down after that, gamma secretase modulators can be used." These modulators do not prevent the formation of amyloid, but interfere with it. Thus, the longer version of amyloid with 42 or 43 amino acids, which therefore quickly clumps together, is not formed - but a shorter one with 37 or 38 amino acids. According to initial findings, these shorter chains even have a protective effect.

Another approach that DZNE researchers are currently pursuing relies on mechanisms with which the body could protect itself. Microglia cells - special immune cells in the brain - can possibly be specifically activated by an antibody. The goal is for them to become active on their own to fight harmful developments and to support anti-amyloid antibodies in clearing plaques. Here, too, there are now promising approaches.

Further informations

EMA: No Recommendation for Marketing Authorization for Alzheimer's drug "Aducanumab”

Eisai drug means breakthrough in therapy against early Alzheimer's disease, interview with Prof. Frank Jessen

Research group Prof. Christian Haass

Alzheimer's

continue

Alzheimer's According to projections, there are currently around 1.6 million people living with dementia in Germany - and numbers are rising. The majority of them are affected by Alzheimer's disease. Morbus Alzheimer, the technical name of the best-known and most common dementia, is a disease that usually manifests in old age. Only rarely are affected individuals younger than 60 years old. [...]

ALS

Lewy body dementia

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis, or ALS, is a neurodegenerative disease that affects a very specific group of neurons: the neurons for motor function, also known as motor neurons. They are located in the brain and spinal cord and are responsible for controlling the muscles. The motor neurons are destroyed by the disease. This result in progressive muscle paralysis. [...]

Lewy body dementia Lewy body dementia usually occurs after the age of 65. To date, it is not really clear whether Lewy body dementia is a disease in its own right or a variant of Parkinson's with early onset dementia: Individuals with Lewy body dementia sometimes have symptoms similar to those of Alzheimer's and Parkinson's patients. Mixed forms of these three diseases are also known. Men are probably more likely than women to be affected by Lewy body dementia. [...]

Parkinson's Parkinson's disease is the second most common neurodegenerative disease – right after Alzheimer's disease. According to estimates, there are at least 200,000 people affected in Germany, with a clear upward trend. Parkinson's disease mostly occurs in older adulthood: The vast majority of those affected are at least 60 years old. However, ten percent of all Parkinson's patients develop the disease before the age of 50. [...]

Frontotemporaldementia Frontotemporal dementia (FTD) is a rare form of rapidly progressive dementia. It is estimated that, together with Alzheimer's, it accounts for the majority of all forms of dementia in individuals under the age of 65. A characteristic feature of FTD is the loss of neurons, especially in the frontal lobe and temporal lobe. Important functions are controlled in these brain areas. [...]

Huntington's Huntington's chorea, also called "Huntington's disease" or "Morbus Huntington", is an inherited disorder of the brain. It was named after the US physician George Huntington, who was the first to scientifically describe the disease in 1872. Involuntary twitching movements of the head, arms, legs and hands, but also of the trunk, up to a characteristic dance-like gait: in the Middle Ages, these symptoms had earned the disease the now-obsolete name 'St. Vitus' dance'. [...]

Childhood dementia Dementia is not just a question of age. Children and adolescents can also be affected by progressive neurodegenerative diseases of the brain. More than 250 different disorders are now known to affect the cognitive abilities of children. These conditions, collectively referred to as "childhood dementia," are among the rare diseases: Depending on the form of the disease, childhood dementia affects between 1 in 2,000 and 1 in 500,000 newborns. [...]

Ataxias The term "ataxia" is derived from the Greek word "a-taxia" meaning "a lack of order". Ataxia is the name for a number of rare disorders of the brain and spinal cord in which the interaction of various muscle groups is disturbed. As a result, the sense of balance and coordination of movements are impaired. Walking is affected, as is sitting or standing, speaking, hand movements, and the control of eye movements. The person's gait becomes unsteady and wide-based, handwriting becomes illegible, gripping and holding objects become difficult. [...]

Parkinson's

Fronto- temporal dementia

Huntington's

Childhood dementia

Ataxias

Lewy body dementia

Fronto- temporal dementia

A look at these different research approaches, which are being pursued at great expense, reveals the important role that the amyloid thesis and the antibody research based on it continue to play. After years of setbacks, the search for suitable antibodies is once again becoming a beacon of hope for Alzheimer's patients, who are still urgently awaiting a breakthrough.