1. TRANSLATIONAL RESEARCH New Therapies for MS Dennis Bourdette, M.D. and Arthur A. Vandenbark, Ph.D. TCR peptide therapy Recombinant TCR ligand (RTL) therapy

5. Therapeutic Vaccination of MS Patient 100 10 1 52 0.1 132639 7 6 5 4 3 2 1 0 0 65 LDA Frequency x 10 -6 Weeks on Therapy EDSS Stimulus: TCR BV5S2 Peptide Myelin Basic Protein EDSS

6. Clinical Responses TCR Peptide Vaccination Pilot Trials: Composite Phase I and II Studies 0020963B Responders Improved StableWorse Strong310 Moderate062 Non-Responders1613 P < 0.001 Strong Response:> 8 cells/million Moderate Response: 2 - 8 cells/million

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

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

9. 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.

10. 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

11. 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

12. T cell activation Inflammatory factors Responsive T Cell β 2 domain of MHC II contains key binding site for CD4 protein

13. 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

14. Effect of RTL on T Cell activation  1  1 β  linker P-α linker Antigenic Peptide 22 22 X Portion 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

15. Treatment of Relapsing EAE with RTLs

17. 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

18. 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

19. 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