Rituximab (RTX) is a human/mouse chimeric monoclonal IgG1κ Ab raised against human CD20, which was derived from the murine monoclonal anti-CD20 Ab 2B8. In the USA, RTX is marketed by Genentech and Biogen Idec. In the rest of the world except Japan, it is marketed by Roche. In the USA, Canada and Japan, it is marketed as Rituxan® while in the rest of the world it carries the name MabThera®.
In 1997, RTX was approved by the FDA and in 1998 by the European authorities for treatment of relapsed or refractory low-grade or follicular CD20+ B-cell non-Hodgkin lymphoma. Since then it has become a key element of B-cell lymphoma therapy. More than 300,000 patients worldwide have been treated either with RTX alone or in combination with chemotherapy schemes, such as the cyclophosphamide, doxorubicin, vincristine and prednisone scheme.
In March 2006, RTX obtained FDA approval for treatment of refractory rheumatoid arthritis (RA).[108,109] In uncontrolled trials, it has been tested in a number of other auto-immune diseases where B cells are thought to play an important pathogenic role, including immune thrombocytopenia and systemic lupus erythematosus (SLE). Of special note, RTX has also been studied in neuromyelitis optica (Devic’s syndrome), a demyelinating disease of the spinal cord and optic nerves, where humoral immunity is thought to significantly contribute to the pathogenesis of the disease.[111,112,113]
CD20 is expressed by pre-B cells, mature Ab-producing B cells and malignant B cells, but not by plasma cells or by stem cells.[114,115] CD20 is a nonglycosylated transmembrane phosphoprotein, probably acting as a calcium channel and functionally involved in the regulation of cell cycle and differentiation.[116,117] CD20 is not shed from the cell surface. There is no known natural ligand of CD20.
Rituximab acts as a B cell-depleting Ab, and several mechanisms seem to contribute to this effect (Figure 4). High correlation between a FcγRIIIA gene polymorphism, that had been shown to alter receptor function[120,121] and to influence the clinical treatment response to RTX in lymphoma patients, and the grade of B-cell depletion in a cohort of SLE patients suggested that Ab-dependent cell-mediated cytotoxicity (ADCC), possibly mediated by FcγRIIIA-carrying cytolytic natural killer (NK) cells, may play an important role for the B cell-depleting effect of RTX in humans in vivo. Correspondingly, RTX efficiently induced ADCC of B cells in the presence of effector cells in vitro.
Furthermore, complement-dependent cytotoxicity (CDC) may be important for the B cell-depleting effect of RTX in vivo, as demonstrated in C1q knockout mice, inoculated with a human CD20-expressing murine lymphoma cell line and subsequently treated with RTX.In vitro, RTX is an efficient inducer of CDC.[106,125,126,127] However, a crucial role of CDC in RTX-mediated B-cell depletion in humans remains controversial. For example, expression of complement inhibitors on tumor cells did not correlate with clinical outcome after RTX treatment in patients with follicular non-Hodgkin lymphoma.
In addition to the Fc-dependent effects mentioned above, there is evidence that CD20 cross-linking by RTX may induce intracellular signaling events resulting in growth arrest and apoptosis of B cells.[129,130,131,132,133] RTX-induced signaling was reported to involve an increase of cytosolic Ca2+ levels.[132,133]
The main treatment scheme for non-Hodgkin lymphoma is intravenous RTX 375 mg/m2 weekly for 4 consecutive weeks, which may be extended to 6- or 8-weekly cycles for this indication. In RA, RTX was tested at a fixed dose of 1000 mg on days 1 and 15. This dosing scheme was also chosen for the HERMES and the OLYMPUS MS trials, which are discussed later.
In two independent studies investigating RTX pharmocokinetics in different cohorts of RA patients treated by two doses of intravenous 1000 mg RTX 2 weeks apart, RTX had a mean terminal half-life after the second infusion of 19.7 days and 19.1 days, respectively.[135,136] The mean clearance was 276 and 242 ml/day, and the mean volume of distribution was 2.98 and 4.28 l, respectively. The area under the time-concentration curve was 190 mg/h/ml for women and 122 mg/h/ml for men in one study, and 228 mg/h/ml in the other study. Baseline B cell counts did not influence RTX pharmacokinetics in RA patients.
In a cohort of methotrexate-pretreated RA patients, 16% of whom had a baseline B cell level below the lower limit of normal, RTX induced rapid and complete B-cell depletion in all patients. B-cell recovery started from week 16, with onset and rate of recovery showing high interindividual variability. A total of ten of 121 patients showed prolonged B-cell depletion of 20% or less lower limit of normal after 2 years.
In an open-label, multicenter, Phase I trial with 26 RRMS patients receiving RTX 1000 mg intravenously at weeks 0 and 2, and redosing at weeks 24 and 26, RTX-induced depletion of CD19+ peripheral B cells was complete (99.8%) by week 2. It was sustained through week 48, and a mean reconstitution to 34% of baseline levels was observed at week 72, the end of the observation period. Naive B-cell (CD27-) mean reconstitution from baseline to week 72 was reported to be greater than m-emory B-cell (CD27+) mean reconstitution (51 vs 14%).
Few uncontrolled studies investigating RTX in patients with MS, mainly focusing on immunologic phenomena, have been published.[138,139,140,141] However, given the importance of B cells in the pathogenesis of MS, further investigation of RTX in MS seems of high interest. Recently, interim data from a first Phase II trial in RRMS patients became available.
The HERMES trial is a double-blind, placebo-controlled Phase II study in 104 US and Canadian RRMS patients. Patients were 18-55 years old, had a diagnosis of RRMS according to the McDonald criteria, at least one relapse during the preceding year and an EDSS score of 0-5.0 at entry. They were divided into two groups to receive either RTX as two intra-venous infusions 2 weeks apart (n = 69) or placebo (n = 35). The total mean number of Gd-enhancing MRI lesions at weeks 12, 16, 20 and 24, which was defined as the single primary endpoint, was reduced from 5.5 in the placebo group to 0.5 in the RTX group, representing a 91% relative reduction (p < 0.001). The mean reduction in T2 lesion volume from baseline to weeks 24 and 36 was greater in RTX versus placebo patients (p = 0.0077 and 0.0041, respectively). The rate of patients experiencing a relapse within 24 weeks was reduced from 34.3 to 14.5%, corresponding to a 58% reduction (p = 0.0238). At week 48, it was reduced from 40.0 to 20.3%, representing a 49% relative reduction (p = 0.037). The adjusted annualized relapse rate during 48 weeks was the same as at 24 weeks with RTX (0.37), although no longer statistically significant in c-omparison to placebo (0.72; p = 0.086). RTX patients experienced twice as many infusion-associated adverse events within 24 h after the first infusion in comparison to placebo patients (78.3 vs 40.0%) but no higher rate of infections.
A placebo-controlled Phase II/III trial in 439 patients with PPMS, the OLYMPUS trial, has finished patient recruitment. This study included patients with a definite diagnosis of PPMS according to the McDonald criteria, with an age of 18-65 years, a disease duration of at least 1 year, an EDSS score of 2.0-6.0 at baseline, a score of at least 2 (representing clinically significant disability) in the functional systems scale for the pyramidal system or gait that was due to lower extremity findings, and CSF findings typical of MS (IgG oligoclonal banding or elevated IgG index) within the previous 24 months. Patients were randomized in a 2:1 ratio to receive four courses of two doses 1000 mg RTX 2 weeks apart or placebo every 24 weeks. After this treatment period of 96 weeks, a 26-week follow-up is planned. MRI evaluations are performed at weeks -2 to 0, 6, 48, 96 and 122. In this trial, time to sustained EDSS progression was defined as the primary outcome measure. Importantly, 24.8% of patients had at least one Gd-enhancing lesion in a baseline brain MRI scan, and positive CSF findings were an inclusion criterion. Therefore, this patient cohort represents a PPMS cohort with rather high inflammatory disease activity, raising hope that RTX immune therapy may show partial efficacy.
Rituximab was generally safe in the MS trials conducted so far. However, the overall safety profile of RTX in MS patients is still to be determined in larger cohorts and after longer follow-up as two cases of PML after treatment with RTX have been reported in SLE. Nevertheless, it should be noted that in contrast to MS patients, lupus patients seem to have an inherently increased risk for the development of PML independent from RTX treatment, with more than 20 cases reported in the literature. Therefore, the two RTX-treated SLE cases are not necessarily a strong indicator for an increased PML risk in RTX-treated MS patients. However, they should be a reason for a cautious approach in ongoing and future clinical MS trials, paying special attention to this possible complication.
Rituximab may especially be a promising therapeutic approach in those patients where humoral immune mechanisms are believed to play a central role in their disease (immuno-pathological pattern II according to Lassmann, Brück and Lucchinetti). Consequently, it may be promising to select patients for RTX therapy based on their response to plasma-pheresis, which could help to identify pattern II patients. RTX may open the door to a novel era of specific therapy for certain immunopathological patient subgroups.
Expert Rev Neurother. 2008;8(3):433-455. © 2008 Future Drugs Ltd.
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