Antibody-mediated suppression of Vbeta5.2/5.3(+) T cells in multiple sclerosis: results from an MRI-monitored phase II clinical trial.
The objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM-027 in a baseline versus treatment magnetic resonance imaging-monitored study. Expansion of Vbeta5.2/5.3(+) T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM-027 depleted these cells in peripheral blood and, in parallel, T-cell MBP reactivity and IFN-gamma expression were reduced. We studied 59 patients with relapsing-remitting MS (47 on ATM-027 and 12 on placebo) stratified for HLA-DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T-cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow-up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM-027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run-in, active lesions were found in 78.7% (37/47) of patients treated with ATM-027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm(3) at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon-gamma messenger RNA, and decreased T-cell reactivity to several myelin antigens were found in ATM-027 treated patients. In conclusion, consistent suppression of Vbeta 5.2/5.3(+) T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.
Killestein
Joep
J
Department of Neurology, VU Medical Center, Amsterdam, The Netherlands.
Olsson
Tomas
T
Wallström
Erik
E
Svenningsson
Anders
A
Khademi
Mohsen
M
Blumhardt
Lance D
LD
Fagius
Jan
J
Hillert
Jan
J
Landtblom
Anne-Marie
AM
Edenius
Charlotte
C
Arfors
Leopold
L
Barkhof
Frederik
F
Polman
Chris H
CH
D000328:Adult; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015802:HLA-DR2 Antigen / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007165:Immunosuppression Therapy / Q000379:methods; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger / Q000032:analysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D011994:Recombinant Proteins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*
D001324:Autoantigens; D016207:Cytokines; D015802:HLA-DR2 Antigen; D007074:Immunoglobulin G; C571326:MOG protein, human; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins; C113248:T cell receptor peptide Vbeta5.2