AAIC Whitepaper July 19 2017


This year’s Alzheimer’s Association International Conference (AAIC) is the largest yet with 5,600 experts from around the world representing medical institutions, academia and industry.   It is striking that the field now appears to have reached a consensus on the central role of toxic amyloid-beta oligomers (AβO) in the pathogenesis of Alzheimer’s disease (AD).  In the July 17 plenary session, Dr. Dennis Selkoe (Brigham and Women’s Hospital, Boston, MA) presenting to a packed audience, described AD as a condition initiated by a chronic imbalance between production and clearance of Aβ peptide which favors the formation of toxic oligomers (soluble aggregates of Aβ peptide monomers).  He outlined evidence showing that AβO present at high levels in AD brains are highly neurotoxic causing synaptic damage and memory impairment when injected into healthy animals. In contrast, Aβ monomers and plaque are not toxic to cultures of neurons or when injected into the brain of mice.  His data show that plaque may actually be protective by sequestering toxic oligomers.  The weight of this evidence indicates that successful therapies will need to specifically target toxic AβO as stated by Dr. Eliezer Masliah (National Institute on Aging) in his plenary lecture at the America Academy of Neurology (AAN) annual meeting earlier this year.

Similarly, Dr. Mathias Jucker (University of Tubingen, Germany), in his July 18 symposium presentation entitled “The Prion-Like Properties of Amyloid-β”, outlined evidence showing that soluble AβO (Aβ seeds) propagate like prions throughout the brain when injected into mice and can be transmitted from mouse to mouse.  Examination of human AD brains showed that different strains could be found in different AD subgroups (e.g. familial vs sporadic AD).  These findings not only support targeting of toxic AβO to get at the root cause of AD but also advocate for a precision medicine approach tailored to the patient.

ProMIS’ platform presentation of July 17 entitled “Targeting of Toxic Amyloid-Beta Oligomer Species by Monoclonal Antibody PMN310: Precision Drug Design for Alzheimer’s Disease” was in complete alignment with the most current understanding of the pathogenesis of AD and addresses the issues that were raised regarding AβO targeting and patient heterogeneity.  Specificity for toxic AβO is essential for a therapeutic antibody as binding to the much more abundant Aβ monomers is a distraction from the real target and is expected to reduce efficacy, while binding to plaque has been associated with an increased incidence of adverse brain edema (ARIA-E) and micro-hemorrhages (ARIA-H).   We described how the use of proprietary computer modeling algorithms allowed us to identify five different epitopes likely to be exposed in the context of misfolded toxic oligomers but not in monomers or plaque.  These conformational epitopes were used for immunization to generate monoclonal antibodies that underwent a screening process to select the best-performing candidates.  First, surface plasmon resonance (SPR) was used to select antibodies that showed preferential binding to conformational vs linear epitope, oligomers vs monomers and binding to native oligomers in the cerebrospinal fluid (CSF) and soluble brain homogenates from AD patients vs controls.  The lack of plaque binding was confirmed on sections of plaque-containing AD brains.  Antibodies with the desired oligomer-selective binding profile were then tested in vitro for their ability to inhibit oligomer propagation and to protect cultures of mouse neurons from oligomer toxicity.  Finally, antibodies underwent in vivo testing in an acute toxicity assay where the brains of mice were injected with toxic AβO with or without test antibody.  The ability of the antibodies to prevent the AβO-induced loss of short-term memory formation in these mice was measured seven days later in a novel object recognition assay. The brains were then collected and hippocampal homogenates analyzed to assess the benefit of antibody treatment on markers of inflammation (TNF-α) and synaptic damage (SNAP25, PSD-95).  Using this screening process, antibody candidates with the desired binding profile were identified for all five epitopes and additional in vivo assays led to the selection of PMN310 and PMN350 as lead candidates against two of the epitopes.  Our assessment of antibodies against the other three epitopes continues.

Importantly, the observed detection by ProMIS antibodies of target epitopes in CSF offers the possibility of a precision medicine approach tailored to the patient which is more likely to be successful than a “one size fits all” approach.

Expanding on the role of AβO in AD pathology, evidence was also presented by Dr. Selkoe that AβO can trigger Tau phosphorylation which precedes the conversion to a pathogenic form of Tau.  The prion-like propagation of misfolded, aggregated Tau was extensively described in symposium presentations by Drs. Marc Diamond (University of Texas Southwestern Medical Center) and Florence Clavaguera (Institute of Pathology, Basel, Switzerland).  A similar prion-like transmission of aggregated α-synuclein in Parkinson’s disease was described by Dr. Jeffrey Kordower (Rush University, Chicago).  Propagation of toxic misfolded proteins, now recognized as a general mechanism underlying several neurodegenerative diseases, is being addressed with the ProMIS approach to generate antibodies against disease-specific epitopes.  Programs are ongoing for Aβ (AD), SOD1 (ALS), TDP43 (ALS, frontotemporal dementia), Tau (AD, tauopathies) and α-synuclein (Parkinson’s disease).