FDA’s Decision to Approve New Treatment for Alzheimer’s Disease

Up-and-Coming Immunotherapies Target Aβ and Tau

While aducanumab, donanemab, and lecanemab are FDA-approved or inching closer to approval, the next generation of immunotherapies is moving through the ranks. At AAIC, scientists presented preclinical data on both passive and active immunotherapies targeting specific forms of Aβ, and even a combination vaccine against both Aβ and tau.
  • A combo vaccine revs anti-Aβ and anti-tau antibodies.
  • An active vaccine stokes immune response against pyroglutamate Aβ.
  • PRX012, an anti-Aβ antibody, rallies microglia to clear pyroglutamated Aβ.
The latter one is a vaccine that takes aim at the top two offending proteins in AD. Robin Barbour of Prothena, South San Francisco, debuted an active dual vaccine against both proteins. Essentially, the researchers crafted three versions of the antigen used in this vaccine. Each consisted of the N-terminal 28 residues of Aβ, fused to one of three microtubule binding regions of tau. They injected mice, guinea pigs, and monkeys with the fusion proteins, along with an adjuvant. In all animals, all three constructs triggered antibody responses against both the Aβ and tau epitopes included in the vaccine. What’s more, the antibodies latched onto Aβ and tau deposits in postmortem brain tissue from people with AD.
The vaccines triggered no cytotoxic T cell responses in any of the animals—a desirable trait in such a vaccine given the potential for toxicity.
The anti-Aβ and anti-tau antibodies elicited by the vaccine showed signs of countering Aβ and tau toxicity. Antisera from immunized guinea pigs successfully blocked soluble Aβ aggregates from adhering to cultured neurons. They also blocked tau from binding heparin, considered a proxy for tau’s interaction with cell-surface heparin sulfate proteoglycans that allow tau oligomers to pass from cell to cell. Finally, antisera from mice immunized with the dual vaccine prompted cultured THP-1 cells—a human monocyte cell line—to gobble up synthetic Aβ42 protofibrils, raising the possibility that they could perhaps instigate microglia in the brain to do the same.
Another active vaccine also posted promising preclinical data at AAIC. Karen Zagorski of the Institute for Molecular Medicine, Huntington Beach, California, described a vaccine against Aβ with a pyroglutamate modification on its truncated N-terminus (pE3-Aβ). Sound familiar? Lilly’s donanemab takes direct aim at pE3-Aβ, which has only been found within amyloid plaques (Aug 2021 conference news). Zagorski cited donanemab’s success as part of the rationale behind developing an active vaccine against pE3-Aβ. Compared to a passive antibody treatment, a vaccine could theoretically prevent Aβ aggregation from happening in the first place, and would not need to be administered for months on end.
Zagorski’s pE3-Aβ vaccine was developed using Multi-TEP technology. This platform takes an antigen of choice— in this case, a series of three pE3-Aβ peptides—and attaches it to a string of antigenic peptides derived from infectious pathogens, such as tetanus and influenza. These peptides are designed to rally memory T helper cells that have seen the antigens before. Once activated, the pathogen-specific T cells crank out cytokines that give B cells a boost, improving their proliferation and production of antibodies. This platform has been used to develop vaccines against other neurodegenerative proteins, including tau and α-synuclein (Davtyan et al., 2019Hovakimyan et al., 2019Davtyan et al., 2017). Zagorski said that enlisting the help of memory T cells—which have recognized their cognate antigen in the past and are primed for a quick response—is particularly critical in older people, who have few remaining immunologically naïve T cells to rouse in response to a strange antigen, such as pE3-Aβ.
The Multi-TEP-P3-Aβ vaccine elicited high titers of pE3-Aβ-specific antibodies in rhesus macaques. Zagorski reported that immunized 5xFAD transgenic mice also churned out antibodies specific to pE3-Aβ, but not to unmodified Aβ42. Nevertheless, the total level of insoluble human Aβ42—including all forms of the peptide—halved in the brains of treated mice. This suggested that the pE3-Aβ-specific antibodies also instigated the clearance of unmodified forms of the peptide that co-mingle with the pyroglutamate-Aβ.
On this note of sweeping out types of Aβ that mingle together, Prothena presented preclinical data that PRX012, a fully humanized IgG1 antibody that binds Aβ at its N-terminus, clears pE3-Aβ as well. Wagner Zago and colleagues had wondered how PRX012 compared in this regard to aducanumab, which also binds the N-terminus of Aβ. They also wondered if PRX012 had cleared this toxic form of the peptide by binding to it.
To address the latter question, the researchers used an ELISA, and found that while PRX012 binds to full-length Aβ42 with high affinity, it does not bind to pE3-Aβ. Next, they used surface plasmon resonance spectroscopy to compare the binding characteristics of PRX012 to those of aducanumab. The technique gauges interactions between an immobilized ligand and its partner by detecting changes in light caused by jostling electrons on a sensor surface. They found that PRX012 bound synthetic, full-length Aβ42 fibrils with 10-fold higher avidity than did aducanumab. The scientists did not report if this aducanumab, which they produced themselves, bound pE3-Aβ, although a previous study reported that aducanumab binds to the pE3-Aβ with 31-fold lower affinity than it does to the unmodified, full-length peptide (Arndt et al., 2018). 
If PRX012 does not bind pE3-Aβ, then how can it clear it from the brain? Using immunohistochemistry, the scientists found that PRX012 glommed onto Aβ plaques within tissue sections from AD brain, including onto the dense cores where pE3-Aβ abounds. When primary mouse microglia were added to the sections along with PRX-012, the cells ate up both forms of Aβ—nearly halving Aβ42 fibrils and reducing pE3-Aβ by roughly three-quarters. PRX012 instigated the microglial mop-up of pE3-Aβ at roughly ninefold lower concentration than did aducanumab. Zago presented no comparison of PRX012 to donanemab, which specifically targets pE3-Aβ. His company aims to test PRX012 in clinical trials starting in 2022.
Notably, the amount of PRX012 needed to clear pE3-Aβ from the brain tissue sections was on par with the concentration expected in the brain following a subcutaneous injection. Compared to the intravenous infusions currently used for other immunotherapies, including aducanumab, subcutaneous injections would ease the burden of treatment because they can be administered at home.—Jessica Shugart