Optimized Amyloid-targeting Vaccine ACI-24 Shows Promise in Animal Studies
An optimized version of ACI-24, an experimental vaccine designed to induce an immune response against abnormal protein clumps that drive Alzheimer’s disease, was able to induce a powerful immune response — as intended — and generally was well-tolerated in animal studies.
Scientists at AC Immune, which is developing ACI-24, published the findings in Brain Communications, in a study titled “An Amyloid-beta (Abeta) vaccine that safely drives immunity to a key pathological species in Alzheimer’s disease: pyroglutamate Abeta.”
“Taken together, our findings demonstrate that optimized ACI-24 vaccination represents a breakthrough to provide a safe immune response,” the researchers wrote.
AC Immune intends to start clinical testing of this new ACI-24 formulation in the first half of this year, the company said in a press release, stating that the “data further support advancing optimized ACI-24 into the next stage of clinical development.”
Alzheimer’s is characterized by aggregates, or clumps, of the protein amyloid beta (Abeta) in the brain. These toxic tangles of protein are believed to drive the disease. One potential strategy for breaking up amyloid-beta aggregates, or preventing them from forming in the first place, is through vaccination — training the body’s immune system to attack and destroy the abnormal protein clumps by creating antibodies to target amyloid beta.
Antibodies are made by immune cells called B-cells. Another class of immune cell, called T-cells, do not make antibodies but play important roles in supporting the activation of B-cells that do.
Two previous attempts at an anti-Abeta vaccine have produced frustrating results. An early vaccine called AN1792, which was designed to activate both B-cells and T-cells against Abeta, was able to produce an anti-Abeta immune response and showed signs of being able to slow disease progression. However, development was terminated because the experimental vaccine also caused dangerous brain inflammation in some participants, which was attributed to an out-of-control inflammatory reaction by T-cells attacking Abeta.
A later vaccine called ACC-001 was designed only to activate B-cells, not T-cells. It was well-tolerated in clinical studies, but failed to slow decline in cognition.
ACI-24 is an experimental anti-Abeta vaccine that contains a small fragment of the amyloid-beta protein in a particular shape that is characteristic of Alzheimer’s-driving clumps. The original formulation had been tested in three small clinical trials; data showed it to be generally well-tolerated and able to induce an anti-Abeta immune response. That response was evidenced by the production of antibodies targeting amyloid beta.
The original formulation of ACI-24 was designed mainly to stimulate B-cells. To optimize its activity, here researchers modified the vaccine to make it better at activating T-cells. Put simply, this involved adding a small protein sequence similar to proteins found in common disease-causing microorganisms, like the bacteria that causes tetanus.
“This approach has the advantage to obtain T-cell help without engaging Abeta-specific T-cells, ensuring an optimal anti-Abeta antibody response without the risk of developing an unwanted inflammatory reaction,” the researchers wrote.
The scientists tested the optimized ACI-24 in animals. Initial experiments in mice showed that the experimental vaccine could stimulate the production of antibodies against amyloid beta, including pyroglutamate Abeta, called pyroGlu-Abeta, a particularly toxic form of the protein.
Further experiments in non-human primates consistently showed that ACI-24 induced a powerful antibody response targeting Abeta. Notably, the antibody response induced by ACI-24 was more potent than that of either AN1792 or ACC-100, as evidenced both by high levels of antibodies and a greater diversity of specific parts of the amyloid-beta protein targeted by the antibodies.
“These data suggest that ACI-24 likely is the best-in-class Abeta vaccine in development because of the robust polyclonal immune response, including high concentrations of antibodies against highly neurotoxic pyroGlu-Abeta variants, which are thought to be key drivers of early AD,” said Andrea Pfeifer, CEO of AC Immune.
“These neurotoxic pyroGlu-Abeta species are not strongly targeted by competing anti-Abeta vaccines,” Pfeifer said.
In the monkey studies, the vaccine was, overall, well-tolerated; the only reported side effects were reactions at the injection site that resolved on their own in time.
“Our data provide evidence, that the optimized ACI-24 can elicit a safe and potent immune response, with a preference towards pathologic [disease-driving] forms of Abeta,” the scientists concluded.
“Thanks to its strong immunogenicity against pyroGlu-Abeta, the optimized ACI-24 formulation represents a potential breakthrough in Abeta vaccination that warrants further study in the clinic,” said Michael Rafii, MD, PhD, a professor of neurology at the Keck School of Medicine who was not directly involved in this study.
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