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AD/PD 2023 | Improving the next generation of anti-amyloid antibodies: prioritizing selectivity with PMN310

Johanne Kaplan, PhD, ProMIS™ Neurosciences, Inc., Cambridge, MA, explains the importance of selectivity of amyloid beta (Aβ)-directed antibodies in Alzheimer’s disease (AD). Unlike some other Aβ-directed antibodies, PMN310 is selective for soluble toxic oligomers and does not bind to non-pathogenic forms of Aβ (e.g. monomers and plaques). Dr Kaplan explains how they investigated the selectivity of several antibodies and how this may correlate with clinical utility. A side-by-side comparison of different Aβ antibodies (PMN310, donanemab, aducanumab, lecanemab, crenezumab, solanezumab, and gantenerumab) was conducted, using surface plasmon resonance to assess binding in soluble brain extracts from patients with AD. The impact of pre-exposure to competing monomers on oligomer binding was also assessed. Various levels of binding to the oligomers were noted in the absence of competing monomers. In the presence of monomers, the non-selective antibodies could no longer bind to the toxic oligomers, aligning with the negative clinical trial outcomes seen with their use. Donanemab, aducanumab, and lecanemab were less impacted. PMN310 was the least affected by monomer competition, leading to higher levels of toxic oligomer binding. Subject to IND approval, it is hoped that PMN310 will enter clinical trials this year. This interview took place at the AD/PD™ 2023 congress in Gothenburg, Sweden.

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Transcript (edited for clarity)

The difference between PMN310 and other antibodies really resides in its selectivity for soluble toxic oligomers of amyloid beta, or Aβ for short, and not binding to other forms of Aβ that are not pathogenic like monomers and plaque. Not all Aβ antibodies are the same and Aβ is not a single entity. It exists in different forms. And what our presentation is about this year at AD/PD is the importance of selectivity of targeting just the right species of Aβ, which is the toxic oligomers not monomers and not plaque...

The difference between PMN310 and other antibodies really resides in its selectivity for soluble toxic oligomers of amyloid beta, or Aβ for short, and not binding to other forms of Aβ that are not pathogenic like monomers and plaque. Not all Aβ antibodies are the same and Aβ is not a single entity. It exists in different forms. And what our presentation is about this year at AD/PD is the importance of selectivity of targeting just the right species of Aβ, which is the toxic oligomers not monomers and not plaque. The current antibodies that have been approved, there’s a lot of hope and excitement and it’s great progress. Lecanemab, aducanumab, which have real efficacy although it is modest and unfortunately comes along with an increased risk of brain edema, ARIA-E. So there is room for improvement and what should that improvement be for the next generation of antibodies? And we believe that it is selectivity.

This was really a study to pressure test the concept of selectivity and how it might correlate with clinical outcome. So what we did is a side by side comparison of all the different Aβ antibodies that have gone through the clinic, so we know that the clinical outcome, and doing a comparison of how well they can bind a toxic oligomer enriched fraction from Alzheimer’s brains, so the real driver of disease. And we tested the binding with and without monomer competition. So basically trying to replicate in vivo, in a patient, how well can these different antibodies overcome encountering so many monomers which are very abundant first in the circulation and then again in the brain so that you have anything left to go and find and bind those toxic oligomers which are really a rare species that are present only at picomolar amounts. So we did this in vitro and what we found was really pretty clear cut. Antibodies that are monomer binders that are nonselective, they bind every form of Aβ including monomers, like solanezumab, gantenerumab, crenezumab. When they’re exposed to monomers, their binding sites become occupied and they are no longer able to bind toxic oligomers and that’s what we saw, there was zero binding to brain oligomers with these antibodies when monomers were present. Other antibodies that are better at avoiding monomers like lecanemab and aducanumab, donanemab, those antibodies did retain more binding to the toxic oligomers even when they were faced with monomer competition. And that’s been associated with the positive clinical data that we’ve seen. In the side by side, very encouraging for us, PMN310 was the least affected by monomer competition because we do believe from our data and data that’s been published on other antibodies that that it does have more selectivity so it’s better able to overcome the monomer competition and also will not be wasted on plaque, will not bind plaque which should also reduce the risk of ARIA which is caused by binding to plaque in the parenchyma and in the blood vessels.

We’ve also completed all the formal GLP toxicity studies that are required for an IND submission, investigational new drug application, with the FDA to be allowed to conduct a clinical trial and the safety profile is very good in terms of manufacturing, it’s a very well-behaved antibody with good yields. So we’re on the cusp of filing the IND and pending approval from FDA, we would then be able to enter the clinic this year. So we’re very excited about this and to see how PMN310 will perform.

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Disclosures

Dr Kaplan is an employee of ProMIS Neurosciences.