translational research new therapies for ms dennis bourdette m d and arthur a vandenbark ph d
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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.

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translational research new therapies for ms dennis bourdette m d and arthur a vandenbark ph d

TRANSLATIONAL RESEARCHNew Therapies for MSDennis Bourdette, M.D. and Arthur A. Vandenbark, Ph.D.

TCR peptide therapy

Recombinant TCR ligand (RTL) therapy

slide5
Therapeutic Vaccination of MS Patient

Stimulus:

100

TCR BV5S2 Peptide

Myelin Basic Protein

EDSS

7

6

10

5

4

LDA Frequency x 10-6

EDSS

3

1

2

1

0.1

0

65

13

26

39

52

0

Weeks on Therapy

slide6
TCR Peptide VaccinationPilot 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

P < 0.001

Strong Response: > 8 cells/million

Moderate Response: 2 - 8 cells/million

0020963B

slide8
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
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
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

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
T cell activation

Responsive T Cell

Inflammatory factors

β2 domain of MHC II contains key binding site for CD4 protein

recombinant t cell receptor ligand
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-β linker

α-β linker

effect of rtl on t cell activation
PRO-inflammatory cytokines are NOT released, causing a local reduction of T cell response in inflamed area

P-α linker

Antigenic Peptide

RTL

ANTI-Inflammatory cytokines (IL-10) released:

  • Suppress neighboring inflammatory cells
  • Protect lesions from further attack (bystander suppression)

a

1

b

1

Portion of MHC II molecule; without lower a2 and b2chains

β-α linker

X

CD4 no longer binds, since it lacks the b2 domain of the MHC II. Thus, activation is altered

b2

a2

Effect of RTL on T Cell activation
slide17
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
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 aspects1
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
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