Selective memory

New Alzheimer’s disease candidate selectively targets toxic AβO

Jim Cirigliano
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TORONTO & CAMBRIDGE, Mass.—The development-stage biotech company ProMIS Neurosciences has announced a new lead product for development in Alzheimer’s disease. The lead candidate, designated PMN330, is a monoclonal antibody that directly and selectively targets the forms of amyloid-beta oligomers (AβO) in the brain that are associated with neurotoxicity and disease progression.
“AβO does not accumulate like amyloid plaque, but rather is soluble and spreads—or propagates—around the brain, and kills neurons,” says Dr. Elliot Goldstein, president and CEO of ProMIS Neurosciences. “PMN330 has been shown in laboratory studies to stop the propagation and the neurotoxicity of oligomers.”
According to Goldstein, amyloid beta exists in the brain in three forms: monomers, oligomers and fibrils, all of which form plaque. Most other monoclonal antibodies bind multiple forms of amyloid beta. An antibody binding to abundant, harmless monomer forms of amyloid beta in the brain reduces that antibody’s efficacy, whereas binding to plaque can lead to dose-limiting side effects, such as triggering brain edema (swelling).
Goldstein cites aducanumab—a drug candidate being developed by Biogen Inc.—as the first monoclonal antibody in the clinic not to bind monomers, which he believes is likely the reason it was the first to achieve a statistically significant benefit on cognition in a relatively large and well-controlled trial. Aducanumab is currently in Phase 3 clinical trials sponsored by Biogen.
“Aducanumab, however, binds plaque, contributing to the observed dose-limiting side effect of brain edema,” says Goldstein. “PMN330 and our other lead candidates differ from other clinical candidates targeting amyloid beta in their very high selectivity for binding only the toxic oligomer form.”
“PMN330 is more selective than aducanumab, in that it binds only the oligomer and is therefore expected to achieve greater efficacy and safety,” he adds. “Similar to our other lead product candidates, PMN310 and PMN350, PMN330 directly and selectively targets the form of amyloid beta that is toxic to neurons and drives disease progression.”
“PMN330 is our newest candidate headed into preclinical development to support filing of an investigational new drug (IND) application, mainly manufacturing scale up and formal toxicology studies,” Goldstein tells DDNews. “PMN310 and PMN350 are at a similar stage of development, heading into IND-enabling work. PMN310 is our most advanced candidate, with initiation of clinical trials planned for 2019.”
All three of these lead products represent the fruits of ProMIS Neurosciences’ proprietary target discovery engine, which combines two complementary computational analytic platforms—called ProMIS and Collective Coordinates—to identify novel antibody therapeutic targets and companion diagnostics for Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). The platforms work in combination to efficiently predict disease specific epitopes on the molecular surface of misfolded proteins. An epitope is the portion of a protein that is available to the immune system, and represents the target for an antibody.
“The epitope must be defined very precisely—both the sequence of amino acids as well as the conformation, or shape,” explains Goldstein. “Our science team combines the disciplines of neurobiology, physics and computational modeling to identify epitopes that are only presented on toxic oligomer forms.”
The ProMIS platform is covered by issued U.S. patents, and Collective Coordinates is patent-pending. In addition to its computational discovery platforms, ProMIS also has developed two proprietary technologies intended to specifically identify extremely low levels of misfolded proteins in a biological sample.
ProMIS owns a portfolio of therapeutic and diagnostic patents relating to misfolded protein SOD1 in ALS, and currently has a preclinical monoclonal antibody therapeutic against this target.
“ProMIS’ unique discovery technology allows for the very rapid and effective development of antibodies that bind only the toxic form of proteins that cause neurodegenerative diseases,” says Goldstein. “In addition to Alzheimer’s disease, we are now applying this approach to other toxic proteins associated with neurodegenerative disorders, such as alpha synuclein for Parkinson’s disease and TDP43 for ALS.”

Jim Cirigliano

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