Treating Multiple Sclerosis With Monoclonal Antibodies

Mathias Buttman, MD; Peter Rieckmann, MD, FRCPC

Disclosures

Expert Rev Neurother. 2008;8(3):433-455. 

In This Article

Daclizumab

Daclizumab (DAC) is a humanized monoclonal IgG1 Ab directed against the α-chain of the human high-affinity IL-2 receptor (IL-2Rα, CD25).[148] DAC is composed of complementarity-determining regions from a murine monoclonal anti-Tac Ab, variable framework regions of the Eu myeloma Ab and constant regions of human IgG1.[149,150]

In 1997, DAC was approved for renal allograft rejection in the USA. It received EU approval for this indication in 1999. In the meantime, it has been used in more than 50,000 transplant recipients worldwide, showing a favorable adverse-effect profile in this patient cohort.[151] DAC has been tested in a number of autoimmune diseases, summarized in a review by Waldmann in whose laboratory anti-Tac/DAC was developed.[152]

Interleukin-2Rα is expressed on activated but not on resting T cells, B cells, NK cells and monocytes.[149,150,153,154] Furthermore, CD25 is expressed on classical regulatory T cells (CD4+ CD25+ Foxp3+) and on negative regulatory NK cells (CD56bright IL-10-producing).[155,156]

Interleukin-2 is one of the first cytokines identified. It is an important regulator of T-cell proliferation and function. In the T-helper (Th)1/Th2 model, IL-2 and IFN-γ have long been recognized as signature cytokines secreted by Th1cells, a T-cell type responsible for a cell-mediated immune response to intra-cellular pathogens and critically involved in the pathogenesis of certain autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE) and MS. A recent, genome-wide association study in 931 MS family trios (one child and both parents affected) in comparison to controls revealed that two single nucleotide promoter polymorphisms in the IL-2Rα gene were highly significantly associated with the development of MS.[157] By contrast, Th2 cells are characterized by secretion of IL-4, IL-5 and IL-13, and regarded as key regulators of humoral immunity, involved in the pathogenesis of other autoimmune diseases, such as asthma.[158,159,160]

However, it turned out that mice lacking critical components of the Th1 axis developed autoimmune diseases, supposed to be Th1-mediated such as EAE, with normal or increased magnitude, finally leading to the identification of a novel Th cell type Th17 cells. This cell type is characterized by the production of IL-17, which is not secreted by Th1 or Th2 cells. There is now increasing evidence that Th17 cells also play a crucial role in the pathogenesis of the human disease, MS.[161] Besides a known Treg promoting function,[162] IL-2 has recently been recognized to inhibit Th17 polarization, which might explain why IL-2-deficient mice develop widespread autoimmune disease.[163] Based on these findings, IL-2 blockade by DAC in MS patients may inhibit immune cell types supposed to be beneficial, such as Tregs, and promote others supposed to have a detrimental effect, such as Th17 cells, which is in obvious contra-diction to the positive initial clinical findings. However, as outlined in the next section, other immuno-logical mechanisms may be involved in its mode of action.

Daclizumab binding to CD25 blocks IL-2 binding to this receptor subunit, thereby largely but not completely inhibiting IL-2-induced and β/γ-chain-mediated activation of JAK-1 and -3 and of the transcription factor STAT-5, which are still activated to a lower extent through the β- and γ-chains of the IL-2 receptor when the α-chain is blocked.[164,165,166]

Presently, it is not known how DAC takes its therapeutic effect in MS. One plausible explanation was recently provided by Bielekova and colleagues, demonstrating an expansion of CD56bright IL-10-producing NK cells, a negative regulatory subtype of NK cells, in DAC-treated MS patients (Figure 5).[167] In support of this interpretation, NK cells have been demonstrated to play a protective role in the pathogenesis of myelin oligodendrocyte glycoprotein (MOG)35-55-induced EAE in B6 mice.[168]

Modes of therapeutic daclizumab action in multiple sclerosis.
NK: Natural killer.

Nevertheless, as denoted in the previous section, the finding that IL-2 blockade by DAC seems to be effective in MS remains astounding, given the fact that at least in mice IL-2 is critically involved in the maintenance of CD4+ CD25+ Foxp3-expressing Tregs, a cell type considered to be critically involved in the control of autoimmunity,[162] and considering that mice and humans with genetic CD25 deficiency develop auto-immune disorders.[169,170,171,172,173] However, the notion that in humans the primary function of IL-2 is to promote and sustain CD25+ Tregs was recently challenged by a study suggesting that in humans DAC primarily inhibits CD25+ effector T-cell function by down-regulating expression of the costimulatory molecule CD40 ligand.[174] Nevertheless, to some extent putative DAC efficiency in MS still appears as a positive surprise. This situation mirrors the negative surprise, when blockade of the receptor for TNF-α by the mAb lenercept in patients with RRMS turned out to worsen the disease course, which would not have been expected either.[175] The original rationale for MS therapy with DAC is outlined later.

Three formulations of DAC have been tested in humans so far: intravenously administered Zenapax® (marketed by Roche) was tested and is approved for treatment after renal transplantation; subcutaneously administered DAC-Penzberg (produced in Penz-berg, Germany) has been used in the CHOICE trial; and DAC-HYP (produced by the PDL BioPharma Inc. high-yield 600 L process and therefore termed HYP) has been tested in three Phase I studies including 71 patients, and is currently used in the SELECT trial in a cooperation between PDL BioPharma and Biogen Idec. CHOICE and SELECT will be discussed later.

All three formulations show similar biological effects concerning CD25 binding and IL-2 blockade. All DAC doses tested in the CHOICE and in the SELECT trial supersaturate CD25 receptors on PBMCs by a factor of more than ten. After intra-venous application of a single dose, all three formulations showed comparable pharmakokinetics in cynomolgus monkeys. In humans, Zenapax has a terminal half-time of 20 ± 0.6 days.[176] The three DAC formulations are manufactured differently and differ in their glycosylation pattern. Furthermore, DAC-HYP shows reduced Ab-dependent cellular cytotoxicity in vitro. Therefore, MS DAC trials performed with different formulations should be compared with caution.

Similarities between the pathogenesis of transplant rejection, where DAC had shown to be effective,[176,177,178] and MS, where until recently Th1-mediated autoimmunity along the IL-2 axis was thought to play a central pathogenic role, provided the rationale for the first clinical trial of DAC in MS patients. In their open-label Phase II NIH Pilot Study, Bielekova and colleagues studied safety and efficacy of DAC as an add-on therapy to IFN-β in six patients with RRMS and in five patients with SPMS, having previously shown incomplete clinical or MRI response to IFN-β.[179] After a baseline run-in of 3 months on IFN-β, patients additionally received DAC 1 mg/kg intra-venously (one patient received 2 mg/kg every other week from month 3.5) 2 weeks apart for the first two doses and then every 4 weeks for a total of seven infusions. DAC was well tolerated and led to a 78% reduction of new contrast-enhancing lesions on monthly MRI scans in comparison to baseline values under IFN-β monotherapy, which was the primary outcome measure. Some secondary clinical outcome measures were significantly improved (relapse rate, Scripps Neurological Rating Scale, 9-hole peg test, but not EDSS progression). DAC was generally well tolerated without serious adverse events. An increased rate of mild urinary and upper respiratory tract infections was observed.

Another open-label, baseline versus treatment pilot study, the Utah study, investigated safety and efficacy of DAC in 19 patients, most of whom were treated with DAC mono-therapy (16 of 19) for an average of 13.6 months.[180] A significant reduction of EDSS progression and MRI disease activity was observed in this patient cohort. Efficacy was maintained over 27.5 months in a second study with nine patients, where monthly clinical examinations and 3-monthly MRI investigations were performed.[181] Overall, treatment was well tolerated in both studies.

In a retrospective multicenter study with 40 RRMS and 15 SPMS patients, DAC was generally well tolerated and improved or stabilized the EDSS score in 60% of the patients.[182]

The CHOICE study is a recently finished, randomized, double-blind, placebo-controlled trial, testing subcutaneous DAC-Penzberg as an add-on therapy in 230 patients with active RRMS on IFN-β therapy.[183] Included patients had a confirmed diagnosis of RRMS, an EDSS score of 0-5.0 at screening, at least one relapse or MRI disease activity within the previous year and IFN-β treatment for at least 6 months before inclusion. The patients were divided into three treatment arms (1:1:1), receiving either DAC 2 mg/kg subcutaneously every 2 weeks, DAC 1 mg/kg subcutaneously every 4 weeks or placebo subcutaneously every 2 weeks, for a treatment period of 24 weeks with 48 weeks follow-up. New or enlarged Gd+ MRI lesions on monthly cranial MRI scans between weeks 8 and 24 were defined as the primary outcome measure.

During weeks 8-24 the placebo patients had a mean number of 4.8 Gd+ lesions, while patients receiving the low DAC dose showed a 25% relative reduction (mean 3.6; p = 0.501) and patients receiving the high dose demonstrated a 72% relative reduction (mean 1.3; p = 0.004) in comparison to the placebo patients. Importantly, the mean number of Gd+ lesions at baseline was significantly higher in the low-dose DAC group than in the high-dose and in the placebo group, making interpretation of the MRI data in the low-dose group difficult. Annualized relapse rates as a secondary outcome measure, adjusted for the number of relapses in the 2 years preceding study entry, were 0.71 in the placebo group, 0.46 in the 1 mg/kg group (p = 0.29) and 0.47 in the 2 mg/kg group (p = 0.33).

As of June 2007, the percentage of drug-related severe adverse events was 2.6% in the placebo group, 6.4% in the low dose and 6.7% in the high dose DAC group. The overall rate of infections was comparable in the placebo (52%) and the DAC (49%) patients. However, severe infections were more frequently observed in the DAC patients (placebo: no grade 3 or 4 infections; DAC: 5.2% of various grade 3 infections, no grade 4 infection). Furthermore, cutaneous adverse events were more frequently observed in the DAC-treated (34%) than in the placebo-treated (27%) patients. There was a slight dose-dependent effect concerning adverse reactions, with more adverse reactions observed in the high-dose group.

In summary, DAC 2 mg/kg every 2 weeks as an add-on therapy to IFN-β significantly reduced the number of new or enlarged Gd+ lesions, showed a tendency to reduce the relapse rate, and was generally safe and well tolerated over a treatment period of 24 weeks.

The SELECT trial is a randomized, placebo-controlled Phase II study designed to establish safety, efficacy and optimal dosing of DAC-HYP monotherapy in patients with RRMS over a treatment period of 1 year (SELECT Investigator Meeting, Paris, 27 September 2007). Patient recruitment is expected to start in the first half of 2008. It is planned to include 297 patients at approximately 60 sites in Europe and Australia. Patients with active (clinically or MRI) RRMS, aged 18-55 years and with an EDSS score of 0-5.0 are eligible for this trial.

According to the current version of the protocol (September 2007), the patients are randomized to one of three groups, receiving a fixed dose of DAC 150 mg or 300 mg, or placebo as three subcutaneous injections every 4 weeks for a total of 13 doses. The study is divided into three parts: treatment phase (weeks 0-24), extension phase (weeks 24-52) and follow-up phase (weeks 52-72). During the follow-up phase, no active treatment will routinely be administered. However, according to the protocol, patients experiencing a confirmed relapse may be switched to one of the approved IFN-β formulations as an add-on therapy after the treatment phase of the study has been completed.

The total number of new Gd+ lesions over five MRI brain scans at weeks 8, 12, 16, 20 and 24 (calculated as the sum of these five MRI scans) will be the primary outcome measure of the SELECT trial. Secondary endpoints will include other MRI measures, annualized relapse rate over 52 weeks and quality of life at week 24 in comparison to baseline. Based on the results of the CHOICE trial, special attention is given to cutaneous adverse reactions and infections. Originally, the last patient was planned to be included in November 2008, and the final database lock was planned for May 2010. As of November 2007, the SELECT trial was not yet recruiting owing to ongoing protocol modifications in collaboration with the European regulatory authorities.

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