Depletion of Vβ5.2/5.3 T cells with a humanized antibody in patients with multiple sclerosis

Abstract

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.

Vβ14+T Cells Mediate the Vaccine-Enhanced Disease Induced by Immunization with Respiratory Syncytial Virus (RSV) G Glycoprotein but Not with Formalin-Inactivated RSV

“…It is not necessarily unexpected to see a selected expansion of a particular V␤-restricted T-cell subset upon exposure to RSV G. Pathogenic roles for specific T-cell subsets in several models of infection and in various autoimmune diseases, including a disease-causing population of V␤14 ϩ CD8 ϩ T cells in a mouse model of ulcerative colitis (36), have been described (6,11,12,32,36,37). Several of those studies describe a protective effect of selected depletion of the particular T-cell subset associated with disease without any toxicity or observable effect in normal populations (6,11).…”

“…Several of those studies describe a protective effect of selected depletion of the particular T-cell subset associated with disease without any toxicity or observable effect in normal populations (6,11). In fact, the deletion of the disease-causing T-cell subsets is an effective treatment for at least two autoimmune syndromes in humans (6,37). Thus, while studies have not described the effects of V␤14 ϩ -T-cell depletion in normal uninfected mice, these studies and the data reported here (for RSV-challenged mice primed with vac-lac or FI-RSV) would suggest that the elimination of this T-cell subset does not adversely affect the general immune status of mice.…”

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

“…Tomas Olsson and colleagues took these results forward into the clinic, targeting T cells with VB5.2 T-cell receptors. They substantially depleted T cells reactive to myelin basic protein that produced interferon (IFN)-γ (56).…”

Immunoglobulins—Basic considerations

“…Currently it is being tested in patients with early active relapsing-remitting MS in a comparative study with IFN-β [2]. Alternatively, mAbs for treatment of MS are directed to the T cell receptor such as the T cell depleting humanized anti-Vβ5.2/5.3 T cell receptor-specific mAb ATM-027 [11]. On the other hand, a high affinity chimeric human-mouse anti-CD20 mAb that was originally generated to treat non-Hodgkin B cell lymphoma has recently been considered highly promising for the treatment of autoimmune diseases that are mainly Ab-mediated such as RA and SLE [1].…”