TRANSLATIONAL RESEARCHNew 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

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LD

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Weeks on Therapy

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Stimulus:TCR BV5S2 PeptideMyelin Basic ProteinEDSS

Clinical ResponsesClinical Responses

TCR Peptide VaccinationPilot Trials: Composite Phase I and II Studies

0020963B

Responders Improved Stable Worse

Strong 3 1 0

Moderate 0 6 2

Non-Responders 1 6 13P < 0.001Strong Response: > 8 cells/million

Moderate Response: 2 - 8 cells/million

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

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10%

20%

30%

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70%

Baseline 16 wks 20 wks 24 wks

TCR Responder

TCR Non-Responders

Conclusions: TCR Peptide TherapyConclusions: 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 AspectsTranslational 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

MHC II

Myelin Basic Protein (MBP) peptide

1 1

22

CD4

T Cell Receptor

Responsive T Cell

T Cell Activation

Inflammatory Factors

MHC II

Myelin Basic Protein (MBP) peptide

1 1

22

CD4

T Cell Receptor

Responsive T Cell

T Cell ActivationT Cell Activation

Inflammatory Factors

T cell activation

Inflammatory factors

Responsive T Cell

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

11

b-a linker

p-a linkerInterchangeable

Peptide

11

b-a linker

p-a linkerInterchangeable

Peptide

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

Effect of RTL on T Cell activation

T Cell Receptor

T Cell Receptor

11

β linker

P-α linkerAntigenic Peptide

22 X

Altered Activation

CD4

IL10

ANTI-inflammatoryfactors

XX

Altered Activation

CD4

IL10

ANTI-inflammatoryfactors

XXPortion 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

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610 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46

Days Post Immunization

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ore

Control

RTL401 3d i.v.

RTL401 4d.i.v.

RTL401 8d.i.v.

RTL401 s.c.

Treatment of Relapsing EAE with RTLsTreatment of Relapsing EAE with RTLs

Treatment Incidence Onset Mean Score at start of treatment Mean Score at end of treatment* CDI#

VG312(100ug) 11/11 9.6 ± 1.4 2.3 ± 0.5 0.4 ± 0.1a 10.8 ± 2a

VG312(33ug) 9/9 9.6 ± 2.5 2.6 ± 0.5 0.2 ± 0.4a 15.1 ± 3.7a

VG311 or 303(100ug) 8/8 9.9 ± 0.6 2.9 ± 0.5 3.4 ± 0.5 55.6 ± 17.4Vehicle 17/17 10.2 ± 1.6 1.8 ± 0.3 3.8 ± 0.4 55 ± 4

a = Significant difference between vehicle and experimental group (p < .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)

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VG312(100ug)

VG312(33ug)

VG311 or 303

vehicle (Tris, pH 8.5)

Days after initiation of treatment

Conclusions: RTL TherapyConclusions: 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 THERAPYTIMELINE 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 AspectsTranslational 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