Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
A Novel Immune Approach to Fight Neurodegeneration
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Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
Two Sides of the Same Coin
Oncology Neurodegen-eration
Immune Response is Critical, yet Opposite in these Disorders
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Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
• Genetic aberrations & environment lead to incorrect cell cycle development
• Tumor growth unchecked
• Immune system does not recognize tumor cells as foreign
– i.e. underactive cancer-targeting mechanisms
Immune Systems Role in Disease
Oncology Neurodegeneration • Genetic aberrations &
environment lead to incorrect protein production
– Limited GWAS
• Alternative disease triggers are likely
• Immune system does incorrectly recognize neurons as foreign
– i.e. overactive autoimmunity
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Autoimmunity Autoimmunity
Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
Disease Progression & Treatment
Genetic Predispositions Environmental Triggers
Pre-Diagnosis/ Early Onset
Alzheimer's, Parkinson’s, ALS,MS
ThisPhotobyUnknownAuthorislicensedunderCCBY-SA
Immune Health
Clearing Plaques Has not Worked
Path
to N
euro
dege
nera
tion
Prev
enta
tive
Mea
sure
s or
Tre
atm
ents
Wellness
Neurotransmitter Modulation
FMT
Young blood transfusion
DBS
Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
Ab-42 plaque
mAb
BBB tag
Immunology Strategies for Targeting Neurodegeneration
Glial Cells
T Cells
CNS Plaque & Tangle Inhibitors Traditionally viewed as cause of degeneration
Modulate Peripheral Immune Response
Degenerating Neuron
Pro-inflammation
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BBB
PERIPHERY
CNS
Pro-Inflammation
Pro-Inflammation Anti-Inflammation T cell Function
Plaques
Plaque Clearance
Peptides & Biologics
Target Innate CNS Immune Cells
Sm. Molecules & Abs
Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
Immunology Strategies for Targeting Neurodegeneration
Glial Cells
Degenerating Neuron
Pro-inflammation
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BBB
PERIPHERY
CNS
T Cells
Ab-42 plaque
mAb
BBB tag CNS Plaque & Tangle Inhibitors
Traditionally viewed as cause of degeneration
Target Innate CNS Immune Cells
Peptides & Biologics
Sm. Molecules & Abs
Modulate Peripheral Immune Response
Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
A DIFFERENT APPROACH: TARGET T CELLS DIRECTLY
Rebalance Immune System without Immunosuppression
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Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
Autoimmunity in Parkinson’s Disease: ⍺-Synuclein & the Adaptive Immune Response…
⍺-Syn Fragment
⍺-Syn protein
Direct & indirect neuronal death pathways induced by Tresps
BBB
Glial Cells
Regulatory T cell (Treg)
IFN-γ, IL-17, TNF-α, IL-1β, IL-6, ROS
Pro-inflammatory Factors
1. Direct Neuronal Death
2. Indirect Neuronal Death
PERIPHERY
CNS
Sulzer et. al.Nature 546, 656–661 (29 June 2017)
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VPAC2 Receptor
Abad & Tan J Mol Neurosci 2018) 66:102–113
Bhattacharya et al. Cytokine 2015; Cebrian et al. Nature Communications 2014, Filiano et al. Nature Reviews
Neuroscience 2017, Mosley et al. CSH Perspective 2012; Tan & Waschek J ASN Neuro 2011; Tan et al. Brain Beh Immunity 2015
Cytotoxic / Responder T cell (Tresp)
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IFN-γ, IL-17, TNF-α, IL-1β, IL-6, ROS
Pro-inflammatory Factors
Neuroprotection
IL-10, TGF-β, GM-CSF
Anti-inflammatory Factors
Bhattacharya et al. Cytokine 2015; Cebrian et al. Nature Communications 2014, Filiano et al. Nature Reviews
Neuroscience 2017, Mosley et al. CSH Perspective 2012; Tan & Waschek J ASN Neuro 2011; Tan et al. Brain Beh Immunity 2015
X
PERIPHERY
CNS
…Modulating Peripheral Immune System is Protective
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VPAC2 Receptor
⍺-Syn Fragment
⍺-Syn protein
BBB
Glial Cells
Shifting T cell profiles from Tresp to Treg is neuroprotective Sulzer et. al.Nature 546, 656–661 (29 June 2017)
Abad & Tan J Mol Neurosci 2018) 66:102–113
Regulatory T cell (Treg) Cytotoxic / Responder T cell (Tresp)
Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
1:2 1:1 1:0.5 1:0.250
20
40
60
80
Tresp:Treg
% In
hibi
tion
± SE
Treg Suppression of Tresp
PBSVIPLBT-3393LBT-3627
n=3
*p
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LBT-3627 Efficacy To Date Preclinical Clinical
MPTP mouse
6-OHDA rat
AAV A53T (α-syn) rat
Parkinson’s Human PBMCs
Treg Tolerance
Not tested
Neuron Protection TBD
✔
✔ Confidential Confidential
Confidential Confidential
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LBT-3627 restores immune function à Paralleled by neuron survival in multiple preclinical
Parkinson’s models
Currently working to apply this strategy to other neurodegenerative disorders
Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
Parkinson’s Immune Biomarker Study: Identify & Stratify for Interventional Trial
• Multiple panels of protein markers by cell type
• In vitro cytokine profiling • In vitro Treg function
• UPDRS exam • History & Health Qs • Standard labs • Real time collection
Flow Cytometry LC-MS
• Quantitative analysis
Custom ELISA
• Novel protein analytes
Clinical
1) Clinical diagnostic 2) Evaluation of immune function 3) I/E tool for clinical trials
ClinicalTrials.gov NCT03633513 12
Support from:
Copyright 2019, Longevity Biotech, Inc. All Rights Reserved
Longevity Biotech, Inc.
Hybridtides® & Artisan Biology℠
3025 Market Street Philadelphia, PA 19104
http://www.longevitybiotech.com
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