A newly developed antibody-based treatment and a protein-based vaccine for Alzheimer's disease (AD) have both been shown to reduce AD symptoms in mouse models of the disease, British and German researchers reported in the November 15, 2021, edition of Molecular Psychiatry.

Natural amyloid-beta protein molecules are soluble, flexible chains that can form fibers and plaques. In AD they may be truncated and are thought to be central to the development and progression of the disease.

However, numerous clinical trials of treatments targeting AD's characteristic amyloid-beta plaque accumulation have also had little or no success in reducing disease symptoms. And the 2021 approval the first plaque-targeting therapy, Aduhelm (aducanumab; Biogen/Eisai) by the FDA remains a highly controversial decision.

The new antibody and vaccine both target a soluble truncated amyloid-beta protein thought to be highly toxic instead.

"We identified a mouse antibody that would neutralize truncated forms of soluble amyloid-beta, but not bind to normal proteins or plaques," said study co-leader Thomas Bayer, a professor of molecular psychiatry at the University Medical Center Gottingen in Germany.

"Prior to discovering the murine antibody, we had studied the role of truncated amyloid-beta variants for many years, so had developed various antibodies and mouse models producing these truncated forms," Bayer told BioWorld Science.

A research team led by the study's first author, Preeti Bakrania, senior principal scientist at the British medical research charity LifeArc, then humanized the mouse antibody so it would not be recognized as foreign and rejected by the human immune system.

An analysis of how and where the newly humanized antibody, called TAP01_04, bound to the truncated amyloid-beta by scientists at the University of Leicester revealed that the protein had formed an unusual hairpin-shaped structure.

"Discovering such a distinct new structure of amyloid-beta allowed us to engineer this protein region to stabilize the hairpin shape and bind to the antibody in the same way," said study co-leader Mark Carr.

"We thought this engineered form of amyloid-beta could be used as a vaccine, potentially to trigger the immune system to make TAP01_04 type antibodies," explained the professor of biochemistry and chair of antibody-assisted drug discovery at the University of Leicester.

When Carr's team tested the engineered amyloid-beta protein in mice, those that received the purported vaccine were shown to produce TAP01-type antibodies.

The Gottingen group then tested both the TAP01_04 humanized antibody and the engineered amyloid-beta vaccine, called TAPAS (truncated amyloid protein antibodies), in two mouse models of AD, noted Bayer.

"We used the 5XFAD mouse model of familial AD, which is a good model for monitoring amyloid plaques and glucose metabolism changes," Bayer explained.

"We also used our own patented Tg4-42 model of sporadic AD, which is well suited for studying hippocampal neuron loss and its associated behavioural deficits. No studies have investigated the effects of therapy on neuron loss, which I believe to be most important."

Indeed, both therapeutic approaches were shown to lead to a striking reduction in amyloid-beta plaque formation, despite that not being directly targeted, and to help significantly restore neuronal function, increase brain glucose metabolism, and restore memory loss in the mice. The team did not identify any safety concerns.

"The TAP01_04 humanized antibody and the TAPAS vaccine are very different to previous antibodies or vaccines for AD, because they target a different form of the protein," said Bakrania.

"This makes them promising as a potential treatment for the disease, either as a therapeutic antibody or a vaccine, and if the treatment does prove successful, it could transform many patients' lives," she said.

"If these early results can be replicated in human clinical trials, it could be transformative, as it may be possible to treat Alzheimer's once symptoms are detected and potentially vaccinate against the disease before symptoms appear," said Carr.

Looking ahead, the researchers are currently seeking a pharmaceutical industry partner to help them move the therapeutic antibody and vaccine through clinical trials.

"A phase I clinical trial with the humanized TAPAS therapeutic antibody could potentially be initiated within 3-6 months of finding a pharmaceutical company partner," Carr told BioWorld Science.

"The time line for human clinical trials with the TAPAS vaccine is harder to predict, but safety trials would first need to be performed in primates and further optimization of the formulation is also probably required," he said.

However, "initial human clinical trials could be possible within 2 years of our finding a commercial partner with vaccine expertise." (Bakrania, P. et al. Mol Psychiatry 2021, Advanced publication).