Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial.
OBJECTIVE
To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human myelin basic protein, in patients with multiple sclerosis (MS).


METHODS
The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding.


METHODS
The trial was conducted at 4 academic institutions within North America. Patients Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years.


METHODS
BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg).


METHODS
The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium-enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses.


RESULTS
BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-gamma-producing, myelin-reactive CD4+ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone.


CONCLUSIONS
In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI.
Bar-Or
Amit
A
Montreal Neurological Institute, Montreal, Quebec, Canada.
Vollmer
Timothy
T
Antel
Jack
J
Arnold
Douglas L
DL
Bodner
Caroline Anita
CA
Campagnolo
Denise
D
Gianettoni
Jill
J
Jalili
Farzaneh
F
Kachuck
Norman
N
Lapierre
Yves
Y
Niino
Masaaki
M
Oger
Joel
J
Price
Mary
M
Rhodes
Susan
S
Robinson
William H
WH
Shi
Fu-Dong
FD
Utz
Paul J
PJ
Valone
Frank
F
Weiner
Leslie
L
Steinman
Lawrence
L
Garren
Hideki
H
D000328:Adult; D000069059:Atorvastatin; D004185:Disability Evaluation; D004311:Double-Blind Method; D023381:Endpoint Determination; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007108:Immune Tolerance / Q000276:immunology*; D007114:Immunization; D007273:Injections, Intramuscular; D018655:Lymphocyte Count; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000517:prevention & control*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000517:prevention & control; D004676:Myelin Basic Protein / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D011758:Pyrroles / Q000627:therapeutic use; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000009:adverse effects / Q000627:therapeutic use*
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004676:Myelin Basic Protein; D011758:Pyrroles; D019444:Vaccines, DNA; D000069059:Atorvastatin