Spotlight on anti-CD25: daclizumab in MS.
Monoclonal antibodies are a promising new class of therapeutic
agents that can be employed to target specific molecules of the immune
system or any tissue. They are currently being tested in a number of
clinical trials in autoimmune diseases such as multiple sclerosis (MS).
One of these, the humanized monoclonal anti-CD25 antibody daclizumab
(Zenapax[R]), is directed against the interleukin-2 (IL-2) receptor
alpha chain (CD25) that is involved in clonal expansion of autoreactive
T-cells by binding of its ligand IL
DACLIZUMAB; ANTI-CD25 TREATMENT; MULTIPLE SCLEROSIS; ANTIBODIES
2. Several years ago daclizumab was approved for the prevention of renal allograft rejection. Following promising observations in uveitis, daclizumab has since been tested in a number of small clinical trials in MS based on the rationale that blocking CD25 would prevent the expansion of autoreactive T-lymphocytes. Safety and efficacy data from the preliminary clinical exploration as well as findings about the mechanism of action of anti-CD25 treatment are reviewed here.
T cells (Health aspects)
Autoimmunity (Health aspects)
Multiple sclerosis (Prevention)
Multiple sclerosis (Health aspects)
Kidneys (Health aspects)
|Publication:||Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 PAREXEL MMS Europe Ltd. ISSN: 1352-8963|
|Issue:||Date: Nov, 2008 Source Volume: 15 Source Issue: 3|
Currently approved first-line therapies for the treatment of MS are largely targeting the inflammatory phase and early stages of the disease. The mechanisms of action of these agents are complex, unspecific and to a large extent not well understood. Although generally well tolerated and safe even when applied for more than 10 years, they are only partially effective. Interferon beta (IFNB) and glatiramer acetate (GA) are applied during the relapsing-remitting phase of the disease. Both treatments may be associated with mild-to-moderate side effects that are overall tolerable in the majority of patients. In July 2006, the first monoclonal antibody became available for the treatment of MS. Natalizumab (Tysabri[R]), an antibody against the adhesion molecule very late antigen 4 (VLA-4), has been approved for patients with highly active disease or those that have failed IFNB treatment.
Natalizumab appears to be more effective than IFNB and GA in reducing inflammatory brain activity and clinical relapses.1 However, by literally blocking the migration of activated T-cells through the blood-brain barrier, it can probably lead to a compromise of immunosurveillance in the brain parenchyma under as yet poorly understood conditions. In the pivotal trials, three cases of progressive multifocal leukoencephalopathy (PML) were described, an infectious demyelinating disease of the brain that in many cases proves fatal, caused by the human polyoma (JC) virus. (2,3) A comprehensive safety review in 3417 patients that had received natalizumab treatment detected no further case of PML. Conclusively, the extrapolated risk was approximately one in about 1000 cases (~ 0.1%) for a mean treatment of 17.9 months. (3)
Among several other therapies currently in clinical testing in relapsing-remitting multiple sclerosis (RRMS), (4) humanized monoclonal antibodies constitute a unique class of agents that aim at specific targets of the immune system. These include monoclonal antibodies against CD52 (alemtuzumab, Campath[R]), CD20 (rituximab, Rituxan[R]) and CD25 (daclizumab, Zenapax[R]) antigens.
The anti-CD25 monoclonal antibody emerged from the research of Thomas Waldmann at the National Cancer Institute, National Institutes of Health (NIH). It was originally developed to block the proliferation of virally transformed T-cells in adult T-cell leukaemia (ATL) induced by the human T-lymphotropic virus 1 (HTLV-1 ). (5,6) It is directed against the Tac epitope of the CD25 molecule, to which it binds without leading to complement fixation, antibody-mediated cellular cytotoxicity (ADCC) or relevant CD25 modulation. The anti-Tac antibody was then humanized. It is an IgG1 monoclonal antibody, that was approved several years ago for the prevention of renal allograft rejection, marketed under the name daclizumab. (7) Another anti-CD25 antibody that is a chimeric mouse/human molecule, basiliximab, is on the market as well for the same indication.
The rationale for the use of daclizumab in autoimmune diseases and in HTLV-1-associated myelopathy/tropical spastical paraparesis (HAM/TSP) was to block the proliferation of antigen-activated autoreactive T-cells, which are either specific for autoantigens or viral epitopes. (8,9) Early clinical trials in severe cases of uveitis at the National Eye Institute, NIH (10,11) and in HAM/TSP at the National Institute of Neurological Diseases and Stroke (NINDS), NIH, proved daclizumab treatment to be efficacious. (9) Furthermore, the treatment was well tolerated in both clinical settings. Following the promising results of these exploratory trials and with the same rationale, daclizumab was first tested as a treatment for RRMS patients at NINDS, NIH in 1999.
Clinical Trials with Daclizumab in MS
Results of four open-label studies of intravenous daclizumab in patients with active forms of either RRMS or secondary-progressive MS (SPMS) have suggested beneficial effects of daclizumab for both add-on and monotherapy protocols as measured by magnetic resonance imaging (MRI) and clinical outcomes. Two small baseline-to-treatment single-centre Phase II clinical trials have been conducted at NINDS, NIH12 (Bielekova B, personal communication, 2007) and another two at the University of Utah, Salt Lake City, USA (13,14) (Table 1). Very recently, results of a first randomized, double-blind, placebo-controlled, multicentre study (CHOICE) of daclizumab given subcutaneously in addition to IFNB in patients with active, relapsing forms of the disease have been presented. (15) Three of the open-label studies examined either RRMS or both RRMS and SPMS patients and used gadolinium (Gd) contrast-enhancing MRI lesions (CEL) as primary outcome (12,14) (Bielekova B, personal communication, 2007). Additional MRI and clinical parameters were studied as secondary outcomes.
The first study by Rose et al was largely observational and focused on clinical outcome in both RRMS and SPMS patients. (13) Dose regimens were comparable between the studies whereas the amount of applications differed, as did the duration of the follow-up period. In all the open-label trials, daclizumab was administered intravenously in a 2-week interval for the first two applications with monthly infusions of 1 mg/kg bodyweight thereafter. In the first study by Rose et al, daclizumab dosing was adjusted based on clinical response with a range between 0.8 and 1.9 mg/kg. The second study allowed an escalation of daclizumab up to 1.5 mg/kg, if cessation of IFN-B had led to an increase of CEL. Of note, daclizumab was administered as an add-on therapy to IFNB treatment in the first reported trial. (12) In the other two open-label Phase II studies it was added to IFNB treatment for 5.5 months and after withdrawal of IFNB continued in monotherapy for 10-22 months. The CHOICE study randomized a total of 230 RRMS patients to three different treatment protocols (daclizumab 2 mg/kg every 2 weeks [high dose], 1 mg/kg every 4 weeks [low dose] and placebo, respectively). It is the first out of the reported studies to date in which daclizumab was administered subcutaneously for a period of 24 weeks with a follow-up of 48 weeks. (15)
In all the studies patients showed incomplete responses to IFNB treatment before enrollment and still had substantial inflammatory CNS activity. In the first NIH trial 10 RRMS and SPMS patients were treated with daclizumab. They showed a 78% reduction of newly Gd-enhancing MRI lesions, a 80% reduction in the annualized relapse rate, significant improvements in the Scripps Neurological Rating scale and the 9-hole peg test, and trends towards improvement in all other clinical and MRI outcomes. (12) Improvement in clinical categories has to be analyzed with caution in such small clinical trials. However, the reduction in CNS inflammation was substantial and robust, particularly if one considers that the patient cohort showed very active disease with respect to their number of contrast-enhancing lesions. In a follow-up study at the NIH, a similar patient cohort with incomplete response to IFNB was studied. Daclizumab was initiated as an add-on therapy for 5.5 months. In cases of sufficient response to the combination therapy, IFNB was withdrawn and patients were continued on daclizumab as monotherapy. In this second trial the results of the first NIH trial were confirmed as regards reduction of inflammatory brain activity for both add-on and monotherapy with daclizumab. In addition, a significant improvement in all clinical measures was found (Expanded Disability Status Scale [EDSS], Scripps Neurological Rating scale and MS functional composite) (Bielekova B, personal communication, 2007).
Rose et al treated 19 ambulatory RRMS and SPMS patients, who had previously failed to respond to other therapies, with daclizumab for 5-25 months (mean 13.6 months). (13) Sustained clinical improvement as measured by the EDSS occurred in 10 patients and clinical stabilization occurred in 9 patients. Inflammatory MRI activity was reduced significantly and the treatment was well tolerated. One patient in the first reported trial, (12) who had responded incompletely and suffered from very active RRMS with up to 30 Gd-enhancing lesions per month, received twice the above dose (2 mg/kg body weight in 2-weekly intervals) and then showed reduction of CNS inflammation similar to the rest of the patient cohort. Up to eight times higher than standard doses have been given in ATL and were tolerated well (T. Waldmann, NIH, personal communication).
Remarkably, treatment effects were not observed immediately after initiation of treatment, but rather with a delay of 4-6 weeks.12 Likewise, cessation of daclizumab was not followed by an immediate rebound of inflammatory activity, but rather with a delay of up to 3 months or more.
Subcutaneous administration of daclizumab in the CHOICE study resulted in a significant 72% decrease of new Gd-CEL at Week 24 in the high-dose arm. In the low-dose group there was a non-significant reduction by 25% compared with placebo.
Safety and Tolerability
Long-term safety of daclizumab administration in MS patients remains unclear. In cases of renal allograft rejection it is only administered in the acute phase after transplantation and is not used in long-term immunotherapy. However, while the reported open-label trials in MS are limited by the small number of patients, a relatively short treatment follow-up and the absence of a control group, antiCD25 has been given for up to over 4 years in uveitis and was very well tolerated. (10,11) In the MS trials daclizumab was also generally safe over treatment periods of 5.5-27.5 months (12,13,14) (Bielekova B, personal communication, 2007).
Important information regarding comparison with placebo comes from the CHOICE study. Preliminary safety data revealed that the infection rate was similar across all groups. Urinary tract infections were observed more frequently in the high-dose arm (17% versus 13% under placebo). (15) Of note, the rate of cutaneous events was higher among the daclizumab-treated patients. Other side effects include single cases of transient elevations of bilirubin, liver transaminases and autoantibodies, transient photosensitivity-like rashes, mouth ulcers, transient headache and constipation, iron deficiency, breast tenderness and in one case exacerbation of ongoing depressiveness. Two cases of generalized lymphadenopathy have been reported. In one case lymph node biopsy revealed unspecific reactive changes. After the cessation of the study drug lymphadenopathy receded in both cases.
No serious adverse events were observed in any of the reported studies. In the context of MS, it is important to note that, to the best of our knowledge, PML has not been reported in daclizumab treatment so far.
A sensitive assay for the detection of anti-daclizumab antibodies developed by T Waldmann has shown that there is, if at all, very little antiglobulin response to antibody treatment and does not appear to have impact on the biological function of daclizumab.
Mechanistic Aspects of Anti-CD25 Therapy in MS
Daclizumab was originally tested with the rationale to inhibit clonal proliferation of autoreactive CD4+ T-cells in MS by blocking binding of IL-2 to its receptor. Immunological testing to document the mechanism of action of daclizumab in MS included proliferative assays to mitogen, viral recall antigen and autoantigens, flow cytometry studies of surface markers on a variety of immune cells including CD4+, CD8+ T-cells, natural killer (NK) cells and the production of cytokines. (16) Both, ex vivo testing of isolated cells from patients on daclizumab treatment, as well as in vitro studies were performed. Moreover, delayed type hypersensitivity responses to common pathogens and vaccines by in vivo skin testing were examined. The CD25 molecule is blocked close to 100% by daclizumab before the next monthly dose is administered. Staining with an antibody that binds to an epitope other than Tac shows that CD25 is still expressed at the surface of lymphocytes. Modulation of the receptor appears to be limited. Due to the modest reduction in CD4+ and CD8+ T-cell counts, there seems to be no significant elimination of T-cells.
The most striking observation has been the consistent and significant expansion of a specific subset of NK cells expressing the NK cell marker CD56 at high levels ([CD56.sup.bright] NK cells). (16) A potential role of [CD56.sup.bright] NK cells in the effects of anti-CD25 treatment is supported by the fact that the increase of [CD56.sup.bright] NK cells correlates significantly with the reduction of Gd-enhancing MRI lesions. Besides their well-known antiviral and antitumour properties [CD56.sup.bright] NK cells have immunoregulatory activity. Mechanistic studies during daclizumab treatment demonstrated that freshly isolated [CD56.sup.bright] NK cells can lyse activated autologous T-cells ex vivo via unknown receptor-ligand interactions. (16) In conclusion, our data indicate that the expansion of [CD56.sup.bright] NK cells follows functional blocking of IL-2 consumption by activated T-cells, on which the high affinity receptor complex (a/[beta]/[gamma] IL-2R; CD25, CD122, CD132) is blocked, whereas the intermediate affinity IL-2R complex on NK cells (ff/y IL-2R) is not affected. (16)
Of note, long-term daclizumab treatment seems to lead to a modest reduction of circulating CD4+CD25+Foxp3+ regulatory T-cells (Treg) and lower Foxp3 expression. This reduction appears to be associated with a differential effect on inflammatory activity depending on the tissue. Whereas CNS inflammation is clearly reduced, an increased susceptibility to newly emerging inflammatory activity is observed in the skin which may in part be due to a reduction of skin-homing Tregs (Oh U, unpublished data).
The number of MS patients treated with daclizumab so far is limited, and data from controlled trials has only very recently been reported. However, antiCD25 treatment appears to be effective in patients with ongoing disease activity as regards clinical and MRI outcomes. In fact, daclizumab has only been tested in patients where the disease is still active despite treatment with IFNB. Results from these studies show clear efficacy of anti-CD25 in this group. Although generally initiated in combination regimen in the studies, daclizumab monotherapy appears to be equally efficacious. Moreover, there are no severe safety concerns arising from clinical testing so far.
Daclizumab has not yet been approved for the treatment of MS and as long-term safety and efficacy remain unclear, the use of daclizumab should clearly be restricted to controlled clinical trials. A recently launched Phase II trial (SELECT) is currently recruiting relapsing-remitting patients and is testing daclizumab as a monotherapy administered subcutaneously. The most exciting aspect of anti-CD25 treatment besides its promising efficacy is that it acts via an entirely new mechanism, i.e. the expansion of [CD56.sup.bright] NK cells. As can be extrapolated from the role of these cells in the control of virus-infected cells, tumour cells and the control of autoreactive T-cells, we anticipate that neither the reactivation of latent viruses such as herpes viruses or JC virus nor the occurrence of secondary malignancies will likely become a safety concern during anti-CD25 therapy.
Until today, treatment options for patients with disease breakthrough while on first-line therapy are clearly limited. Moreover, guidelines on how to proceed with these patients are still a matter of debate. If our predictions held, anti-CD25 treatment could add substantial benefit to current MS treatment of patients with active disease. Among other questions, future studies need to address whether anti-CD25 should be used in combination or as monotherapy.
Conflicts of Interest
R Martin together with B Bielekova, HF McFarland and T Waldmann are co-inventors on an NIH-filed patent about the use of anti-CD25 antibodies in MS.
Received: 20 December 2007
Accepted: 26 March 2008
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(16.) Bielekova B, Catalfamo M, Reichert-Scrivner S, et al. Regulatory [CD56.sup.bright] natural killer cells mediate immunomodulatory effects of IL-2Ra-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci USA 2006; 103: 5941-5946.
Sven Schippling [1,2], Roland Martin  *
 Institute of Neuroimmunology and Clinical Multiple Sclerosis Research (INiMS *), Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany;  Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
* INiMS is supported by the Gemeinnutzige Hertie Stiftung
Address for Correspondence
Dr Sven Schippling
Neurologische Klinik und Poliklinik
Universitatsklinikum Hamburg Eppendorf
Martinistr. 52, 20246 Hamburg, Germany
Phone: +49 40 42803 7868
Fax: +49 40 42803 9955
Table 1: Daclizumab trials in MS Patients Study design Treatment treated Bielekova et Phase II open- Daclizumab 10 RRMS and al. 2004 label baseline- (1 mg/kg iv) SPMS patients to-treatment added to IFNB with active therapy disease under IFNB therapy Rose et al. Open-label Daclizumab 19 RRMS and 2004 Phase I case monotherapy SPMS with series (1 mg/kg iv, active disease adjusted to 0.8-1.9 mg/kg during treatment period) Rose et al. Phase II open- Daclizumab 9 RRMS patients 2007 label baseline- (1 mg/kg iv) with active to-treatment in combination disease under with IFNB IFNB therapy followed by daclizumab monotherapy Bielekova et Phase II open- Daclizumab 15 RRMS al. submitted label baseline- (1 mg/kg iv) patients with to-treatment in combination active disease with IFNB under IFNB followed by therapy daclizumab monotherapy CHOICE trial Phase II Daclizumab 230 patients (Montalban et multicentre, (2 mg/kg, vs. with active al. 2007) double-blind, 1 mg/kg vs. relapsing MS randomized, placebo sc) under IFNB placebo- added to IFNB therapy controlled
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