Targeting Neuroinflammation to
Modulate Reactive Astrocytes for
Treatment of Neurodegenerative Disease
Elizabeth Evans, PhD
ChiefOperatingOfficer
SVPDiscovery&TranslationalMedicine
Unique Targets | AD & PD Drug Development Summit |
Novel Mechanisms | |
April 25, 2024 | |
New Medicines |
Disclosures
Elizabeth Evans is a full-time employee, executive officer and
shareholder at Vaccinex, Inc.
This presentation involves discussion of unapproved, experimental or investigational use of pepinemab.
Forward Looking Statements
To the extent that statements contained in this presentation are not descriptions of historical facts regarding Vaccinex, Inc. ("Vaccinex," "we," "us," or "our"), they are forward-looking statements reflecting management's current beliefs and expectations. Such statements include, but are not limited to, statements about the Company's plans, expectations and objectives with respect to the results and timing of clinical trials of pepinemab in various indications, the use and potential benefits of pepinemab in Head and Neck cancer, Huntington's and Alzheimer's disease and other indications, and other statements identified by words such as "may," "will," "appears," "expect," "planned," "anticipate," "estimate," "intend," "hypothesis," "potential," "advance," and similar expressions or their negatives (as well as other words and expressions referencing future events, conditions, or circumstances). Forward-looking statements involve substantial risks and uncertainties that could cause the outcome of the Company's research and pre-clinical development programs, clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, uncertainties inherent in the execution, cost and completion of preclinical and clinical trials, uncertainties related to regulatory approval, the risks related to the Company's dependence on its lead product candidate pepinemab, the ability to leverage its ActivMAb® platform, the impact of the COVID-19 pandemic, and other matters that could affect the Company's development plans or the commercial potential of its product candidates. Except as required by law, the Company assumes no obligation to update these forward-looking statements. For a further discussion of these and other factors that could cause future results to differ materially from any forward-looking statement, see the section titled "Risk Factors" in the Company's periodic reports filed with the Securities and Exchange Commission ("SEC") and the other risks and uncertainties described in the Company's most recent year end Annual Report on Form 10-K and subsequent filings with the SEC.
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Inflammation is a key driver of pathology in neurodegenerative disease
"Fillit said that researchers have learned through autopsies of elderly patients that beta amyloid can be present in the brain without progressing to Alzheimer's. If there's no strong immune reaction
to the buildup, there's no inflammation and no progression of disease."
(Howard Fillit, MD. Co-founder and CSO Alzheimer's Drug Discovery Foundation) - Annalee Armstrong, Oct 16, 2023 Fierce Biotech
Bellaver et al. Nat Med 2023 | The Astrocyte | Factor. | Astrocyte reactivity (Ast+) |
potentiates the | effect of | amyloid (A+) and/or p-tau217 | |
(Ptau+) on cognition (MMSE). [Courtesy of Bruna Bellaver, |
"Bellaver speculates that astrocytes
change when they sense amyloid buildup in the brain. "They get reactive and progressively lose neuroprotective functions and/or gain novel neurotoxic properties, disrupting brain homeostasis," she wrote to Alzforum. This reactivity might preclude their ability to contain tau pathology, she
speculated."
- Alzforum Series- AD/PDTM 2024, 12APR2024
3
University of Pittsburgh.] | 3 |
Astrocytes reach out to touch and interact with other brain cells
Astrocyte "arms" provide essential functional support to neurons.
• Fully cover capillaries and facilitate glucose uptake from circulation
• Cradle synapses and recycle glutamate
• Positioned to couple energy metabolism with neuronal activity
How do astrocytes sense damage and what triggers the conversion to reactive state?
4
Semaphorin/Plexin neuro-immune signaling pathway is upregulated in earlyAD
PlexinB1 is upregulated specifically in
astrocyte cluster genes
Genetic profiles were determined from post-mortem human prefrontal cortex (Brodmann area 10), given its major role in AD
affected traits, including cognition.
Mathys H et al. Nature 2019.
Single-cell transcriptomic analysis of
Alzheimer's disease
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SEMA4D IS OBSERVED TO BE UPREGULATED IN NEURONS DURING DISEASE PROGRESSION
Normal | Alzheimer's Disease | Huntington's Disease |
Sema4D
Neuron
(HUC/HUD)
Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity
Human autopsy sections of frontal lobe
Elizabeth E Evans, Vikas Mishra, Crystal Mallow, Elaine Gersz, Leslie Balch, Alan Howell, Ernest S. Smith, Terrence L. Fisher, Maurice Zauderer*
Journal of Neuroinflammation, 2022
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SEMA4D IS PROGRESSIVELY UPREGULATED WITH INCREASING PATHOLOGIC STAGE OF HD
SEMA4D in
neurons
Neuron
Density
7
Evans et al. Journal of Neuroinflammation, (2022) 19:200.
7
SEMA4D UPREGULATION is ASSOCIATED WITH NEURONAL LOSS AND ASTROCYTE ACTIVATION IN AD
Thalamus | Temporal Lobe | Frontal Cortex | ||
Human | Human | Human | ||
SEMA4D in
neurons
Neuron
Density
8
Evans et al. Journal of Neuroinflammation, (2022) 19:200.
8
ASTROCYTES TRANSFORM TO REACTIVE STATE IN PRESENCE OF SEMA4D
Normal | Early Huntington's Disease |
Astrocyte
(Glutamine Synthetase expressed in astrocyte end feet) | Astrocyte | |
Neuron | SEMA4D | Neuron MERGE |
(HuC/HuD expressed in neuronal body)
SEMA4D
Evans et al. Journal of Neuroinflammation, (2022) 19:200.
9
ASTROCYTE FUNCTION:
Astrocytes couple energy metabolism and synaptic activity
Astrocytes express | SEMA4D regulates |
receptors for SEMA4D | Metabolic Transporters |
Antibody blockade of SEMA4D
reverses loss of metabolic function
PLXNB1PLXNB2
Blue= anti-PLXN
Red= isotype control
Purified human astrocyte cultures
VX15 = pepinemab
Glucose Uptake: normalized FLU (AU)
2.4×104
2.3×104
2.2×104
2.1×104
2×104
Control
Sema4D
Sema4D + Pepi @ 24 hr
Sema4D + IgG4 @ 24 hr
ns
***
rSEMA4D
antibodies
1.9×104
0 hrs | 24hrs | 48 hrs |
Evans et al. Journal of Neuroinflammation, August 2022, 19:200. | 10 |
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Vaccinex Inc. published this content on 26 April 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 26 April 2024 15:41:53 UTC.