Annals of Neurology
Volume 51, Issue 4, 2002. Pages: 467-474
Joep Killestein, MD 1, Tomas Olsson, MD, PhD 4, Erik Wallström, MD, PhD 4, Anders Svenningsson, MD, PhD 4, Mohsen Khademi, MD, PhD 4, Lance D. Blumhardt, MD, FRCP 9, Jan Fagius, MD, PhD 5, Jan Hillert, MD, PhD 6, Anne-Marie Landtblom, MD, PhD 7, Charlotte Edenius, MD, PhD 8, Leopold Årfors, MD, PhD 8, Frederik Barkhof, MD, PhD 2 3, Chris H. Polman, MD, PhD 1
(1)Department of Neurology, VU Medical Center, Amsterdam, The Netherlands
(2)MS-MRI Center, VU Medical Center, Amsterdam, The Netherlands
(3)Image Analysis Center (IAC), VU Medical Center, Amsterdam, The Netherlands
(4)Karolinska Hospital, Stockholm
(5)Akademiska Hospital, Uppsala
(6)Huddinge University Hospital, Huddinge
(7)University Hospital, Linköping
(8)AstraZeneca AB, AstraZeneca R & D Södertälje
(9)Queens Medical Center, Nottingham, UK
Funded by: AstraZeneca R & D Södertälje, Södertälje, Sweden
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 Vb5.2/5.3+ 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-g 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 mm3 at baseline, with a reduction of 10% during treatment.
Decreased numbers of cells expressing interferon-g messenger RNA, and decreased T-cell reactivity to several myelin antigens were found in ATM-027 treated patients. In conclusion, consistent suppression of Vb 5.2/5.3+ T cells was achieved.
However, the effect size on magnetic resonance imaging was considerably
less than the targeted 60%.
Copyright © 2002 Wiley-Liss, Inc.