ProMIS Neurosciences has announce its lead product candidate for Alzheimer's disease (AD), PMN310, compared to aducanumab showed significantly greater binding to the neurotoxic oligomer-enriched fraction of amyloid beta (Aβ) in brain extract from eight confirmed AD brains.
"We set out to design an improved antibody inspired by the initial successful clinical results of aducanumab announced in Dec 2014,” ProMIS Executive Chairman, Eugene Williams, said. “We recently reported greater selectivity of PMN310 for Aβ oligomers in direct comparison to other amyloid beta-directed antibodies, including aducanumab. ProMIS also recently announced that PMN310 shows a lack of binding to plaque in and around blood vessels in the brain, thereby supporting the potential for lower risk of brain swelling and possibility of higher dosing with PMN310."
Recent reports from the scientific literature indicate that small, low molecular weight Aβ oligomers, consisting of twelve strands of Aβ (dodecamers), four strands (tetramers) or two strands (dimers) of Aβ are the toxic oligomer form. To test the binding to these toxic oligomers by PMN310 and other Aβ-directed antibodies, ProMIS isolated the soluble low molecular weight (LMW) fraction of brain material from eight AD brains expected to contain dodecamers, tetramers and dimers. Binding by aducanumab, bapineuzumab and humanized PMN310 to the toxic oligomer fraction from these brains was assessed by surface plasmon resonance (SPR). The results showed greater binding of aducanumab to the toxic oligomer LMW fraction compared to bapineuzumab, in line with the greater therapeutic benefit of aducanumab. Importantly, PMN310 showed even greater binding (~1.5-2 fold) compared to aducanumab. The ability to selectively target LMW toxic Aβ oligomers without binding Aβ monomers (reduced efficacy) or plaque (increased risk of brain swelling, also called ARIA-E) is expected to allow for safe administration of higher effective doses and greater therapeutic potency.
SPR is a highly sensitive technique to detect binding interactions. In the SPR study outlined above, the test antibody therapeutics (bapineuzumab, aducanumab and humanized PMN310) were each immobilized on an SPR sensor chip. The AD brain extract containing the LMW toxic oligomers was then flowed over each of the chips and the amount of toxic oligomer extract bound by the test antibodies was measured.