Depletion of Vbeta5.2/5.3 T cells with a humanized antibody in patients with multiple sclerosis.
A potentially pathogenic expansion of T cells expressing T cell receptor (TCR) Vbeta5.2/5.3 has been demonstrated in patients with multiple sclerosis (MS). A humanized antibody (ATM-027) directed against these T cells has been developed to further investigate the role of this subpopulation of T cells in MS. The pharmacokinetics/dynamics and safety of ATM-027 (0.3-300 mg intravenously over 30 min) were investigated in 14 patients with MS. The effect of treatment on cytokine expression and autoreactivity to peptides of myelin basic protein (MBP) was also studied. ATM-027 was well tolerated and raised no safety concerns. Clearance of the antibody was low and elimination half-life was approximately 3 weeks. The majority of the target Vbeta5.2/5.3 expressing T cells were depleted for at least 18 months. The small remaining fraction of target cells showed a marked decrease in their TCR expression, which was recovered within 8 months. The numbers of peripheral blood mononuclear cells (PBMCs) with spontaneous expression of IFN-gamma was decreased at 72 h and 8 weeks after treatment, whilst no clear effects on TNF-alpha, IL-4, IL-10, TGF-beta expression were observed. There was also a significant decrease in the number of PBMCs producing IFN-gamma in response to MBP peptide 80-102. We conclude that long-term depletion of T cells expressing defined Vbeta subgroups in MS patients is feasible using selective immunotherapy. The selective depletion of Vbeta5.2/5.3 expressing T cells in this study resulted in a decrease in potentially disease promoting anti-MBP reactivity and pro-inflammatory cytokine production.
Olsson
Tomas
T
Neuroimmunology Unit, Centre for Molecular Medicine L8:04, Karolinska Hospital, S-171 76 Stockholm, Sweden. tomas.olsson@cmm.ki.se
Edenius
C
C
Ferm
M
M
Samuelson
P
P
Torrång
A
A
Wallström
E
E
Khademi
M
M
Andersson
M
M
Arfors
L
L
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001324:Autoantigens / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D018655:Lymphocyte Count; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy*; D009185:Myelin Proteins / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis*; D013601:T-Lymphocytes / Q000737:chemistry* / Q000166:cytology
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D009185:Myelin Proteins; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; C113248:T cell receptor peptide Vbeta5.2; D007371:Interferon-gamma