Antibody‐mediated suppression of Vβ5.2/5.3⁺ T cells in multiple sclerosis: Results from an MRI‐monitored phase II clinical trial

Abstract

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%.

Complementarity-Determining Region 3 Spectratyping Analysis of the TCR Repertoire in Multiple Sclerosis

“…Second, an increase of the proportion of V␤5.2/5.3-positive cells in PBL and CSF cells in MS patients was detected by FACS analysis. Furthermore, selective in vitro depletion of these T cell subsets resulted in a drastic decrease in the number of MBP-reactive and IFN-␥-secreting T cells (31,32). In addition to these findings, we showed in this study that V␤5.2 spectratype expansion was equally found in DRB1*1501-positive and -negative patients (Table II).…”

New immunosuppressants with potential implication in multiple sclerosis

“…ATM-027 is a recombinant humanized IgG specifically targeting vh5.2/5.3 T cells [30]. The drug is well tolerated but the reduction of disease activity as measured by MRI Gd-enhancing lesions was not statistically significant.…”

An Update on Monoclonal Antibody Therapies in Multiple Sclerosis

“…3 Even though 1 phase 2 clinical trial did show consistent suppression of Vβ5.2/5.3 T cells, there were only minimal effects on MRI lesion reduction and contrast enhancement suppression. 100 A summary of some of the mAbs used in MS is listed in Table 1. Anti-CD154 or -CD40L Thromboembolic events 3,102 development and application of mAbs for MS has demonstrated that this disease is a heterogeneous immunopathologic process that does not uniformly respond to the same treatments.…”