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. PowerPoint PPT Presentation


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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.

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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


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

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


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

TCR Peptide VaccinationPilot Trials: Composite Phase I and II Studies

Clinical Responses

Responders Improved StableWorse

Strong310

Moderate062

Non-Responders1613

P < 0.001

Strong Response:> 8 cells/million

Moderate Response: 2 - 8 cells/million

0020963B


Fraction of active mri scans tcr responders vs non responders

Fraction of Active MRI Scans:TCR Responders vs. Non-Responders


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

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


Treatment of relapsing eae with rtls

Treatment of Relapsing EAE with RTLs


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

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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