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Abstract Details

Protection against toxic amyloid-beta oligomers by PMN310, a monoclonal antibody rationally designed for greater therapeutic potency in Alzheimer’s disease
Aging, Dementia, Cognitive, and Behavioral Neurology
P1 - Poster Session 1 (8:00 AM-9:00 AM)
7-006

Advances in the understanding of Alzheimer’s disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic AßO.  Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety.  Monoclonal antibody PMN310 was raised against a conformational Aß epitope predicted by computational modeling to be exposed on toxic AßO but not monomers or fibrils.

Evaluate the protective activity of PMN310 against toxic amyloid-beta oligomers (AßO) in vitro and in vivo

The binding selectivity of PMN310 was characterized by surface plasmon resonance (SPR) and immunohistochemistry (IHC).  Its ability to neutralize the propagation and toxicity of AßO was assessed in vitro in a thioflavin-T propagation assay and in cultures of primary rodent neurons, respectively.  In vivo protection was tested in wild-type mice injected intracerebroventricularly (ICV) with AßO and in the APP/L transgenic mouse model of AD. 

In SPR analysis, PMN310 showed little or no interaction with Aß monomers and, compared to other Aß-directed antibodies, was among the least impacted by excess monomer competition in binding to synthetic oligomers or naturally occurring toxic oligomers in AD brain extract.  PMN310 additionally avoided interaction with plaque and vascular deposits as determined by IHC.  In vitro, PMN310 inhibited AßO propagation and neuronal toxicity. In vivo, PMN310 prevented AßO-induced loss of memory formation after ICV injection, and systemic administration to APP/L transgenic mice preserved memory and learning in the water maze task.

The antibody PMN310 was shown to selectively bind toxic AßO and protect against their pathogenic activity in vitro.  In two rodent models of AD, PMN310 protected memory function, suggesting that PMN310 may offer a new therapeutic option for the treatment or prevention of AD.

Authors/Disclosures
Johanne M. Kaplan, PhD (ProMIS Neurosciences)
PRESENTER
Dr. Kaplan has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Kaplan has stock in ProMIS Neurosciences. Dr. Kaplan has received intellectual property interests from a discovery or technology relating to health care.
Ebrima Gibbs, Bsc,BMLSc,MSc (University of British Columbia) Dr. Gibbs has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Promis Neuroscinces.
Judith Silverman Judith Silverman has received personal compensation for serving as an employee of Bill & Melinda Gates Foundation.
Beibei Zhao Beibei Zhao has received intellectual property interests from a discovery or technology relating to health care.
Juliane Ashleigh Coutts, Other (UBC) Ms. Coutts has nothing to disclose.
Xubiao Peng No disclosure on file
Steven S. Plotkin Steven S. Plotkin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ProMIS Neurosciences. Steven S. Plotkin has stock in ProMIS Neurosciences. The institution of Steven S. Plotkin has received research support from Canadian Institutes of Health Research. The institution of Steven S. Plotkin has received research support from Digital Technology Supercluster. Steven S. Plotkin has received intellectual property interests from a discovery or technology relating to health care.
Neil R. Cashman, MD (University of British Columbia) Dr. Cashman has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Cashman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mitsubishi-Tanabe. Dr. Cashman has stock in ProMIS Neurosciences. The institution of Dr. Cashman has received research support from ProMIS Neurosciences. Dr. Cashman has received intellectual property interests from a discovery or technology relating to health care. Dr. Cashman has a non-compensated relationship as a BoD memeber with ALS Society of BC that is relevant to AAN interests or activities.