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TRANSLATIONAL RESEARCH New Therapies for MS Dennis Bourdette, M.D. and Arthur A. Vandenbark, Ph.D. TCR peptide therapy Recombinant TCR ligand (RTL) therapy. Therapeutic Vaccination of MS Patient. Stimulus:. 100. TCR BV5S2 Peptide. Myelin Basic Protein. EDSS. 7. 6. 10. 5. 4. - PowerPoint PPT Presentation
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TRANSLATIONAL RESEARCHNew Therapies for MS
Dennis Bourdette, M.D. and Arthur A. Vandenbark, Ph.D.
•TCR peptide therapy
•Recombinant TCR ligand (RTL) therapy
Therapeutic Vaccination of MS Patient
100
10
1
52
0.1
13 26 39
7
6
5
4
3
2
1
0
0 65
LD
A F
req
uen
cy x
10-6
Weeks on Therapy
ED
SS
Stimulus:TCR BV5S2 PeptideMyelin Basic ProteinEDSS
Clinical ResponsesClinical Responses
TCR Peptide VaccinationPilot Trials: Composite Phase I and II Studies
0020963B
Responders Improved Stable Worse
Strong 3 1 0
Moderate 0 6 2
Non-Responders 1 6 13P < 0.001Strong Response: > 8 cells/million
Moderate Response: 2 - 8 cells/million
Fraction of Active MRI Scans:TCR Responders vs. Non-Responders
0%
10%
20%
30%
40%
50%
60%
70%
Baseline 16 wks 20 wks 24 wks
TCR Responder
TCR Non-Responders
Conclusions: TCR Peptide TherapyConclusions: TCR Peptide Therapy
Safe and well tolerated
May induce missing regulatory T cell population in MS patients
Peptide cocktails more effective
Timeline for development of TCR peptide therapy
• 1988: Aha!!• 1989: Treatment of EAE.• 1991-94: Phase I Clinical Trial.• 1996: Phase I/II Pilot Trial Suggests Efficacy. • 2001-02: Treatment with Peptide Cocktail.• 2003: Open Label Study to Improve Assays.• 2007: Phase II/III Proof of Principle Trial• 2010?: FDA Approval.
Translational AspectsTranslational Aspects
• Patent applied for through VAMC• Rights to invention were assigned to The
Immune Response Corporation (IRC)• Two initial trials were Investigator initiated• Remaining trials were run through IRC• Basic science advances continued throughout
clinical testing through NIH and NMSS funding
RTL (Recombinant TCR Ligand) Therapy for MS
Arthur A. Vandenbark, Ph.D., Gregory G. Burrows, Ph.D., Halina Offner, Dr. Med.,
Dennis Bourdette, M.D.
Funded by NIH, NMSS, VA, Virogenomics
MHC II
Myelin Basic Protein (MBP) peptide
1 1
22
CD4
T Cell Receptor
Responsive T Cell
T Cell Activation
Inflammatory Factors
MHC II
Myelin Basic Protein (MBP) peptide
1 1
22
CD4
T Cell Receptor
Responsive T Cell
T Cell ActivationT Cell Activation
Inflammatory Factors
T cell activation
Inflammatory factors
Responsive T Cell
β2 domain of MHC II contains key binding site for CD4 protein
11
b-a linker
p-a linkerInterchangeable
Peptide
11
b-a linker
p-a linkerInterchangeable
Peptide
Recombinant T Cell Receptor Ligand
3. Platform to treat other inflammatory diseases (e.g. arthritis)
4. Attractive manufacturing and commercial properties
1. Safe and effective in animal models of MS.
2. Specific target = fewer side effects
P-β linker
α-β linker
Effect of RTL on T Cell activation
T Cell Receptor
T Cell Receptor
11
β linker
P-α linkerAntigenic Peptide
22 X
Altered Activation
CD4
IL10
ANTI-inflammatoryfactors
XX
Altered Activation
CD4
IL10
ANTI-inflammatoryfactors
XXPortion of MHC II molecule; without lower 2 and 2 chains
CD4 no longer binds, since it lacks the 2 domain of the MHC II. Thus, activation is altered
ANTI-Inflammatory cytokines (IL-10) released: Suppress neighboring inflammatory cells Protect lesions from further attack
(bystander suppression)
PRO-inflammatory cytokines are NOT released, causing a local reduction of T cell response in inflamed area
RTL
0
2
4
610 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46
Days Post Immunization
Mea
n D
iseas
e Sc
ore
Control
RTL401 3d i.v.
RTL401 4d.i.v.
RTL401 8d.i.v.
RTL401 s.c.
Treatment of Relapsing EAE with RTLsTreatment of Relapsing EAE with RTLs
Treatment Incidence Onset Mean Score at start of treatment Mean Score at end of treatment* CDI#
VG312(100ug) 11/11 9.6 ± 1.4 2.3 ± 0.5 0.4 ± 0.1a 10.8 ± 2a
VG312(33ug) 9/9 9.6 ± 2.5 2.6 ± 0.5 0.2 ± 0.4a 15.1 ± 3.7a
VG311 or 303(100ug) 8/8 9.9 ± 0.6 2.9 ± 0.5 3.4 ± 0.5 55.6 ± 17.4Vehicle 17/17 10.2 ± 1.6 1.8 ± 0.3 3.8 ± 0.4 55 ± 4
a = Significant difference between vehicle and experimental group (p < .0001; Mann-Whitney Test)
* = Significant difference between each group (H = 29.96; p < .001; Kruskal-Wallis Test)
# = Significant difference between each group (H = 31.27; p < .001; Kruskal-Wallis Test)
0
1
2
3
4
5
6
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Mea
n E
AE
Sco
re
VG312(100ug)
VG312(33ug)
VG311 or 303
vehicle (Tris, pH 8.5)
Days after initiation of treatment
Conclusions: RTL TherapyConclusions: RTL Therapy
Potent therapy in animal models for MS
Induced long-lasting, highly specific T cell tolerance to myelin peptides
Changed the cytokine profile of encephalitogenic T cells
Induced neuroprotection
TIMELINE FOR RTL THERAPYTIMELINE FOR RTL THERAPY
• 1996 – Aha!!
• 1998 – Therapeutic activity in rats
• 1999 – First patent filed
• 2002 – Therapeutic activity in DR2 transgenic mice using monomer
• 2006 – IND approved by FDA
• 2007 – Phase I Safety Trial initiated
Translational AspectsTranslational Aspects
• Patents applied for through OHSU• Rights to invention were licensed to Artielle
ImmunoTherapeutics, Inc. • Company was responsible for producing GMP
grade RTL1000, toxicity studies, FDA interactions• OHSU lab tested clinical variables for therapy to
support IND application• Basic science advances continued throughout
clinical testing through NIH, NMSS & VA funding
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