Selective targeting and protection against toxic amyloid‐beta oligomers by PMN310, a monoclonal antibody rationally designed for greater therapeutic potency in Alzheimer’s disease

Abstract

AbstractBackgroundA large body of evidence indicates that the most pathogenic species of amyloid‐beta (Aß) in Alzheimer’s disease (AD) consists of soluble toxic oligomers (AßO) as opposed to insoluble fibrils and monomers. Clinical results to date indicate that non‐selective antibodies that bind Aß monomers, oligomers and plaque fail to provide a therapeutic benefit. Partially selective antibodies that bind AßO and plaque have shown improved success but are associated with dose‐limiting adverse events (amyloid‐related imaging abnormalities; ARIA). 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 epitope predicted by computational modeling to be exposed on toxic AßO but not monomers or fibrils. A summary of the selectivity and protective activity of PMN310 against toxic AßO in vitro and in vivo is presented.MethodThe binding selectivity of PMN310 was characterized and compared to that of other Aß‐directed antibodies 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 protective activity was tested in wild‐type mice injected intracerebroventricularly (ICV) with AßO and in the APP/L transgenic mouse model of AD.ResultIn SPR analysis, PMN310 showed selective binding to AßO over monomers and, compared to otherAß‐directed antibodies, was minimally impacted by monomer competition in binding to toxic oligomers from AD brain extract. In addition, PMN310 did not bind to Aß plaque or vascular deposits as determined by IHC suggesting a potentially reduced risk of ARIA compared to other Aß‐directed antibodies. In vitro, PMN310 inhibited AßO propagation and neuronal toxicity. In vivo, PMN310 prevented AßO‐induced loss of memory formation after ICV injection. Systemic administration to APP/L transgenic mice preserved memory and learning in the water maze task.ConclusionThe 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.