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TRANSLATIONAL RESEARCH New Therapies for MS Dennis Bourdette, M.D. and Arthur A. Vandenbark, Ph.D.

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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  1. TRANSLATIONAL RESEARCHNew Therapies for MSDennis Bourdette, M.D. and Arthur A. Vandenbark, Ph.D. TCR peptide therapy Recombinant TCR ligand (RTL) therapy

  2. 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

  3. 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

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

  5. Conclusions: TCR Peptide Therapy • Safe and well tolerated • May induce missing regulatory T cell population in MS patients • Peptide cocktails more effective

  6. 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.

  7. 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

  8. 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

  9. T cell activation Responsive T Cell Inflammatory factors β2 domain of MHC II contains key binding site for CD4 protein

  10. 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

  11. 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

  12. Treatment of Relapsing EAE with RTLs

  13. 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

  14. 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

  15. 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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