Four presentations at AD/PD™ 2021 feature latest findings from wholly owned therapeutic and diagnostic programs targeting pathological forms of alpha-synuclein and TDP-43
First biologically active small molecule inhibitors of intracellular alpha-synuclein aggregation advancing toward in vivo proof-of-concept studies
Anti-TDP-43 therapeutic antibody candidates demonstrate dual mechanism of action against pathological TDP-43 in vivo
Alpha-synuclein and TDP-43 are hallmarks of major NDD such as Parkinson’s disease and limbic-predominant age-related TDP-43 encephalopathy (LATE), respectively, and are well-recognized co-pathologies in Alzheimer’s disease linked to accelerated cognitive decline.
Details of AC Immune’s AD/PD™ 2021 presentations
Morphomer™ TDP-43 imaging
First-in-class TDP-43 PET tracers were characterized using a newly optimized radiobinding assay, which enabled the identification of several distinct chemical series of promising Morphomers™ that bind to recombinant and brain-derived TDP-43 aggregates. Selected compounds also demonstrate direct target engagement on patient-derived brain tissue, as assessed by a positive signal in a proprietary high-resolution autoradiography assay that co-localized with pathological TDP-43. Medicinal chemistry is ongoing to further optimize the properties of hit compounds, and investigational new drug (IND)-enabling studies are expected to begin in Q3 2021.
Title: Discovery of PET tracers for TDP-43 proteinopathies
Presenter: Oral presentation by Tamara Seredenina
Data to be presented show that AC Immune’s lead anti-TDP-43 antibody, the first with reported in vivo activity, significantly reduced levels of pathological (phosphorylated or insoluble) forms of TDP-43 in the brain in a murine neurodegenerative disease model. New data also demonstrate the antibody’s dual mechanism of action, showing that it inhibits TDP-43 aggregation and promotes the uptake and clearance of pre-existing TDP-43 aggregates by microglia. The lead candidate is currently in IND-enabling studies and is expected to start preclinical toxicology studies by year end.
Title: TDP-43 antibody directed microglial clearance and inhibition of seeded aggregation mitigates neuropathology in models of TDP-43 proteinopathy
Presenter: Oral presentation by
Morphomer™ alpha-synuclein imaging
New preclinical data for ACI-12589, a next-generation alpha-synuclein PET tracer being developed as a first-in-class diagnostic imaging agent for Parkinson’s disease and other alpha-synucleinopathies, confirm that the Morphomer™-derived candidate has a desirable brain-PET ligand pharmacokinetic profile in non-human primates. ACI-12589 has previously shown excellent target engagement and signal specificity on tissue samples from patients with alpha-synucleinopathies, including Parkinson’s disease, multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). ACI-12589 is currently being evaluated in a first-in-human study.
Title: [18F]ACI-12589, a novel alpha-synuclein radiotracer as a biomarker in patients with Parkinson’s disease and other synucleinopathies
E-poster ID: P531 / #868
Presenter: E-poster presentation by
Morphomer™ alpha-synuclein small molecule aggregation inhibitor
The first biologically active small molecule inhibitors targeting intracellular alpha-synuclein aggregates have been identified using the Morphomer™ platform. Data to be presented for the first time show that these initial compounds, from several distinct chemical series, significantly decrease alpha-synuclein aggregate formation in cellular assays by interfering with the fibrillation process. Iterative medicinal chemistry optimization led to the identification of compounds with favorable CNS-penetrant pharmacokinetic properties, which will be progressed into in vivo proof-of-concept studies in models of alpha-synucleinopathies, expected to begin in Q3 2021.
Title: Generating a first in class inhibitor to treat Parkinson’s disease by targeting intracellular alpha-synuclein pathology
E-poster ID: P425 / #1195
Presenter: E-poster presentation by Nadine Aït-Bouziad
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