By Dan Hurley
June 1, 2023
A vaccine targeting amyloid-beta (Abeta) oligomers to inhibit progression of Alzheimer's disease (AD) produced a strong antibody response that lasted for six months in mice without inducing any measurable inflammation, according to findings of an abstract presented in April at the AAN Annual Meeting.
Because drugs targeting Abeta plaques have been known to trigger a T-cell response that causes brain swelling and bleeding, the investigators targeted soluble Abeta oligomers (ABO). Using a mathematical model of the shape, or conformation, of ABO, they identified an epitope that they hypothesized would be inaccessible to the plaque or monomer forms of the molecule.
The researchers said the persistent antibody response that occurred without triggering T-cell inflammation was promising, although the mice were not bred to serve as a model of AD, and no effort was made to see if the vaccine had any behavioral effects.
“We reached very high titers after just one or two injections of the vaccine, and we showed that it did not bind to monomers, it did not bind to plaque, it only bound to the toxic oligomers,” said the first author Johanne Kaplan, PhD, chief development officer at ProMIS Neurosciences.
“We know it can induce an antibody response, but will it provide a benefit in slowing down or stopping the disease?” Dr. Kaplan said. “That's the next step, to see if it works in a mouse model of AD.”
Five other Abeta vaccines are in early clinical trials by other investigators, said Dr. Kaplan, who previously served as vice president of research at Genzyme, where she led the development of alemtuzumab and teriflunomide for the treatment of relapsing-remitting multiple sclerosis.
Dr. Kaplan said the Abeta vaccine is different from others under development because it it “does not contain Abeta T-cell epitopes, and so it will not stimulate T cells.” Instead, Dr. Kaplan's group conjugated its ABO-targeting antibody with a protein called KLH, which is derived from a mollusk. The antibody is therefore not recognized by the immune system of any mammal and does not provoke an inflammatory response linked to T cells.
The mice in her study received three immunizations four weeks apart. As measured by ELISA, the vaccine antibodies reacted with ABO only, not to monomers or plaque. T cells responded to stimulation with KLH but not to the ABO epitope.
Targeting an epitope of ABO that is inaccessible to the monomeric or plaque forms of the protein is “valuable” and “very important, but the devil is in the details, said Thomas M. Wisniewski, MD, director of the New York State Center for Excellence for Alzheimer's Disease at the Pearl I. Barlow Center for Memory Evaluation and Treatment at New York University.
Dr. Wisniewski, who has investigated potential Abeta vaccines for over a decade, added: “Whether the antibodies are truly specific for the oligomeric species and not the monomers or the fibrils will depend on an assessment of the actual data. It's also not clear how robust the clearing of the oligomeric species of abeta was. It will be important to see the full data published.”
Dr. Wisniewski's group is working on developing vaccines that target the oligomers of not only Abeta but also tau and other toxic oligomers associated with neurodegenerative disorders.
“If you can actually make the vaccines generic for all types of oligomeric species, that would be ideal,” he said. “In theory, this is an approach that would be disease-stopping. But generating antibodies with high affinity and getting them to the right target takes a bit of work.”
Dr. Kaplan agreed that the right vaccine could conceivably prevent or stop the progression of AD in its tracks.
“I don't think that's far-fetched,” she said. “My concern with a vaccine is whether you can reach and sustain high enough levels to keep those oligomers in check. That is something we can't know without clinical trials.”
ProMIS Neurosciences already has a monoclonal antibody, called PMN310, which uses the same epitope as in the vaccine, Dr. Kaplan said.
“PMN310 is our most advanced program,” she said. “We're getting ready to go into clinic this year with it.”
The monoclonal antibody, however, would need to be given to patients on a regular basis for years to come. “It would be great if you could have a vaccine so that you can make your own antibodies,” Dr. Kaplan said.
Disclosures: Dr. Kaplan has received compensation for serving as an employee of ProMIS Neurosciences, has stock or an ownership interest from ProMIS Neurosciences, and intellectual property interests from a discovery or technology relating to health care.
