Alzheimer Disease Vaccination Program Initiated by ProMIS Neurosciences

Author(s):

The vaccine could be given therapeutically to individuals living with a diagnosis of AD to inhibit further disease progression.

Neil Cashman, MD

ProMIS Neurosciences announced the initiation of a program to construct and test a multivalent peptide vaccine for Alzheimer disease (AD) after early in vivo preclinical data demonstrated neuronal protection and improvement in cognitive deficits.¹

The critical first steps in the development of the vaccine, called PMN 310, will be carried out by the University of Saskatchewan’s Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), a global leader in vaccine research and development. There, they will start with the generation of multivalent vaccine constructs based on the ProMIS peptides linked to a carrier protein and formulated with an adjuvant to maximize induction of a protective antibody response to amyloid-beta toxic oligomers (ABOs).

“Again demonstrating the versatility of ProMIS’ proprietary discovery platform, we’re now advancing our program to develop a safe and effective vaccine to induce a specific immune response against toxic ABOs, a root cause of AD,” Neil Cashman, MD, chief executive officer, ProMIS, said in a statement.

The company identified 6 different peptide epitopes selectively exposed on toxic ABOs in a proof-of-concept study. Researchers also identified an ABO-subclass epitope defined by differential solvent orientation of the lysine 28 side chain in a constrained loop of serine-asparagine-lysine (cSNK), which is rarely displayed in molecular dynamics simulations of monomer and fibril ensembles. The acute peripheral infusion of a murine immunoglobin G1 (IgG1) anti-ABOcSNK in 2 AD mouse models showed a reduction of soluble brain AB aggregates by 20–30%.²

Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-AβOcSNK IgG1 response without epitope spreading to Aβ monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. The data indicated that the oligomer subtype AβOcSNK participates in synaptotoxicity and propagation of Aβ aggregation in vitro and in vivo.

“These encouraging initial results clearly support the development of a multivalent vaccine for AD prevention, uniquely positioning ProMIS as offering a 3-pronged approach to combat AD: detect with blood-based biomarkers, treat with PMN 310, and prevent with a vaccine,” Cashman added.

The company also noted that a vaccine capable of inducing an effective antibody response against ABOs could be administered prophylactically to at-risk individuals to prevent development of symptomatic disease. The hope for the vaccine is to also be given therapeutically to individuals living with a diagnosis of AD to inhibit further disease progression.

There are no current programs ongoing with PMN 310 nor did the company disclose when, or if, a trial with human subjects would begin.

Targeting amyloid-beta deposition in the brain as an underlying cause of AD has been well documented. Biogen’s aducanumab is currently under review by the FDA and if approved, will represent the first disease-modifying therapy for AD. James Kupiec, MD, chief medical officer of ProMIS, commented on how aducanumab will help slingshot the innovation needed to drive the next generation of therapies. Click here to read his comments.

REFERENCES

1. ProMIS Neurosciences to develop multivalent vaccine for Alzheimer’s disease. News release. Toronto and Cambridge, Mass: September 22, 2020. Accessed September 28, 2020. https://www.globenewswire.com/news-release/2020/09/22/2097050/0/en/ProMIS-Neurosciences-to-develop-multivalent-vaccine-for-Alzheimer-s-disease.html

2. Silverman JM, Gibbs E, Peng X, et al. A rational structured epitope defines a distinct subclass of toxic amyloid-beta oligomers. NIH. Published April 16, 2018. doi: 10.1021/acscemneuro.7b00469.