A Novel Immune Approach to Fight Neurodegeneration...• History & Health Qs • Standard labs •...

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A Novel Immune Approach to Fight Neurodegeneration

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Two Sides of the Same Coin

Oncology Neurodegen-eration

Immune Response is Critical, yet Opposite in these Disorders

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•  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


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


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


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


A DIFFERENT APPROACH: TARGET T CELLS DIRECTLY

Rebalance Immune System without Immunosuppression

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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)


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)


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


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


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:


Longevity Biotech, Inc.

Hybridtides® & Artisan Biology℠

3025 Market Street Philadelphia, PA 19104

http://www.longevitybiotech.com

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A Novel Immune Approach to Fight Neurodegeneration...• History & Health Qs • Standard labs •...

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