ProMIS Neurosciences Inc. (PMN:TSX; ARFXF:OTCQB), a biotechnology company focused on the discovery and development of antibody therapeutics selectively targeting toxic oligomers implicated in the development of neurodegenerative diseases, announced that its lead antibody candidate for Alzheimer's disease (AD), PMN310, showed no binding to amyloid beta (Ab) plaque in AD brain samples in stark contrast to BAN2401 and aducanumab, which both displayed robust Ab plaque reactivity.
These findings extend the results ProMIS announced in January 2018, showing greater selectivity of PMN310 for Ab oligomers compared to aducanumab.
Binding of therapeutic antibodies to Ab deposits in brain tissue, in particular blood vessels, is believed to underlie the development of ARIA (amyloid-related imaging abnormalities; brain swelling and microhemorrhages) in treated AD patients.
"PMN310 was designed to selectively target soluble toxic Ab oligomers, now widely believed to be a root cause of AD," stated, ProMIS President and CEO, Elliot Goldstein, MD. "By not targeting Ab plaque, especially in and around blood vessels in the brain, we anticipate PMN310 may not be associated with the dose-limiting brain swelling seen with plaque-binding antibody therapeutics like BAN2401 and aducanumab. Confirmation of such an improved safety profile in clinical trials would allow for administration of higher doses to AD patients, thereby potentially leading to greater therapeutic potency of PMN310."
PMN310's binding profile in human AD brain tissues was directly compared to that of BAN2401 and aducanumab in a preclinical study using the technique of immunohistochemistry (IHC). Study results showed binding of BAN2401 and aducanumab to Ab plaque throughout the brain and in association with blood vessels.
"Conversely, binding of PMN310 to Ab plaque was not observed in any region of the AD brain tissues," noted the company. "BAN2401 (Esai/Biogen) and aducanumab (Biogen) appear to target both Ab plaque and soluble Ab oligomers. Recent clinical trials with both BAN2401 and aducanumab, reporting a dose-related response curve (i.e., higher doses enabling greater efficacy), support the targeting of Ab oligomers for the treatment of AD and at the same time indicate that treatment with antibodies also targeting Ab plaque is associated with dose-limiting brain swelling in a significant percentage of AD patients."
The company has shown in multiple preclinical studies that PMN310 has the advantage of selectively targeting toxic Ab oligomers, with no "off-target" binding to Ab plaque, potentially allowing for the safe administration of higher effective doses of PMN310 compared to BAN2401 or aducanumab.
"Although both BAN2401 and aducanumab have shown encouraging phase 2 clinical results, the greater selectivity and avoidance of plaque binding with PMN310 may confer significant advantages in the clinic supporting PMN310 as potential 'best in class' therapy," said Dr. Goldstein.
IHC is the process of selectively imaging antigens (e.g., proteins) in the cells of a tissue section by exploiting the principle of antibodies (such as PMN310, aducanumab, BAN2401) binding specifically to their antigen targets in biological tissues.
"In the study referred to above, IHC was used to assess binding of Ab-directed antibodies to Ab plaque in AD brain tissue," stated the company.
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