Transcript TCR Peptide Therapy

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:
TCR BV5S2 Peptide
Myelin Basic Protein
EDSS
7
6
10
5
4
3
1
2
1
0.1
0
0
13
26
39
Weeks on Therapy
52
65
EDSS
LDA Frequency x 10-6
100
TCR Peptide Vaccination
Pilot Trials: Composite Phase I and II Studies
Clinical Responses
Responders
Improved
Stable
Worse
Strong
3
1
0
Moderate
0
6
2
Non-Responders
1
6
13
Strong Response:
Moderate Response:
> 8 cells/million
2 - 8 cells/million
P < 0.001
0020963B
Fraction of Active MRI Scans:
TCR Responders vs. Non-Responders
70%
60%
50%
TCR Responder
40%
30%
TCR NonResponders
20%
10%
0%
Baseline
16 wks
20 wks
24 wks
Conclusions: 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 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
T cell activation
Responsive
ResponsiveTTCell
Cell
T Cell
Receptor
T Cell Activation
Myelin Basic Protein
(MBP) peptide
CD4
1
1
2
2
Inflammatory
Inflammatory
Factors
factors
MHC II
β2 domain of MHC II
contains key binding
site for CD4 protein
Recombinant T Cell Receptor Ligand
1. Safe and effective in animal models of MS.
2. Specific target = fewer side effects
3. Platform to treat other inflammatory diseases (e.g. arthritis)
4. Attractive manufacturing and commercial properties
p-a linker
linker
P-β
Interchangeable
Peptide
1
b-a linker
linker
α-β
1
Effect of RTL on T Cell
activation
PRO-inflammatory cytokines are NOT
released, causing a local reduction of T
cell response in inflamed area
T Cell
Receptor
Antigenic
Peptide
P-α linker
RTL
1
Portion of MHC II
molecule; without
lower 2 and 2
chains
ANTI-Inflammatory cytokines (IL-10) released:
 Suppress neighboring inflammatory cells
 Protect lesions from further attack
(bystander suppression)
1
β- linker
2
X 2
CD4 no longer binds, since it lacks the
2 domain of the MHC II. Thus,
activation is altered
Treatment of Relapsing EAE with RTLs
Control
6
RTL401 3d i.v.
RTL401 8d.i.v.
4
RTL401 s.c.
2
Days Post Immunization
46
44
42
40
38
36
34
32
30
28
26
24
22
20
18
16
14
12
0
10
Mean Disease Score
RTL401 4d.i.v.
Mean EAE Score
6
5
4
VG312(100ug)
VG312(33ug)
VG311 or 303
vehicle (Tris, pH 8.5)
3
2
1
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Days after initiation of treatment
Treatment
Incidence
Onset
VG312(100ug)
VG312(33ug)
VG311 or 303(100ug)
Vehicle
11/11
9/9
8/8
17/17
9.6 ± 1.4
9.6 ± 2.5
9.9 ± 0.6
10.2 ± 1.6
#
Mean Score at start of treatment Mean Score at end of treatment *
2.3 ± 0.5
2.6 ± 0.5
2.9 ± 0.5
1.8 ± 0.3
a = Significant difference between vehicle and experimental group (p
0.4 ± 0.1a
0.2 ± 0.4a
3.4 ± 0.5
3.8 ± 0.4
CDI
10.8 ± 2a
15.1 ± 3.7a
55.6 ± 17.4
55 ± 4
< .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)
Conclusions: 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 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 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