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

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.

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.