Humanized PMN310 Shows Significantly
Greater Binding to The Toxic Oligomer Fraction of Alzheimer's
Disease Brain Extract Compared to Aducanumab
TORONTO and CAMBRIDGE, MA, Jan. 23,
2018 /PRNewswire/ - ProMIS Neurosciences, Inc., a
biotechnology company focused on the discovery and development of
precision treatments for neurodegenerative diseases, today
announced further results of its previously announced and ongoing
preclinical program for Alzheimer's disease (AD). ProMIS is pleased
to announce that its lead product candidate for AD, PMN310,
compared to aducanumab (Biogen) showed significantly greater
binding to the neurotoxic oligomer-enriched fraction of amyloid
beta (Aβ) in brain extract from eight confirmed AD brains.
Commenting on these results, ProMIS Executive Chairman,
Eugene Williams, stated: "We set out
to design an improved antibody inspired by the initial successful
clinical results of aducanumab announced in Dec 2014. 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."
Williams continued, "We are pleased to announce further results
supportive of a best in class profile for our lead AD program. In
comparison to aducanumab, humanized PMN310 showed significantly
greater binding to brain material from AD patients containing toxic
Aβ oligomers, the root cause of disease. Affinity maturation of
PMN310 is ongoing and may result in an even greater advantage with
PMN310; we look forward to sharing these results in the coming
months."
Recent reports from the scientific literature1-5
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.
Additional information can be found in the latest company slide
presentation at www.promisneurosciences.com
References
- Shankar, GM et al (2008) Amyloid-β protein dimers isolated
directly from Alzheimer's brains impair synaptic plasticity and
memory. Nat Med 14: 837-842
- Jin, M et al (2011) Soluble amyloid β-protein dimers isolated
from Alzheimer cortex directly induce Tau hyperphosphorylation and
neuritic degeneration. PNAS 108: 5819-5834
- Cleary, JP et al (2005) Natural oligomers of the amyloid-β
protein specifically disrupt cognitive function. Nature
Neuroscience 8: 79-84
- Yang, T et al (2017) Large soluble oligomers of amyloid
β-protein from Alzheimer brain are far less neuroactive than the
smaller oligomers to which they dissociate. J Neurosc 37:
152-163
- Lesne, SE et al (2013) Brain amyloid-β oligomers in ageing and
Alzheimer's disease. Brain 136: 1383-1398.
About ProMIS Neurosciences, Inc.
ProMIS Neurosciences is a development stage biotechnology
company focused on discovering and developing precision medicine
therapeutics to treat neurodegenerative diseases, in particular
Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS).
The Company's proprietary target discovery engine is based on the
use of two complementary techniques. The Company applies its
thermodynamic, computational discovery platform—ProMIS™ and
Collective Coordinates — to predict novel targets known as Disease
Specific Epitopes (DSEs) on the molecular surface of misfolded
proteins. Using this unique precision medicine approach, the
Company is developing novel antibody therapeutics and specific
companion diagnostics for AD and ALS. ProMIS is headquartered in
Toronto, Ontario, with offices in
Cambridge, Massachusetts. ProMIS
is listed on the Toronto Stock Exchange under the symbol PMN.TO,
and on the OTCQB Venture Market under the symbol ARFXF.
For further information please consult the Company's website
at: www.promisneurosciences.com
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SOURCE ProMIS Neurosciences Inc.