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

Alemtuzumab

Alemtuzumab (ALEM) is a humanized monoclonal IgG1κ Ab raised against CD52. In the USA, it is marketed as Campath® (Genzyme; Bayer HealthCare Pharmaceuticals), in Europe as MabCampath® (Genzyme; Bayer Schering Pharma AG).

In 2001, ALEM was approved in the USA and Europe for the treatment of fludarabine-refractory B-cell chronic lymphocytic leukemia (CLL).[78] After having shown its superiority to chlorambucil treatment in CLL,[79] it additionally obtained FDA approval as a first-line therapy for CLL in September 2007.

Furthermore, ALEM has been tested in autoimmune diseases such as diffuse cutaneous scleroderma, Wegener’s granulo-matosis, autoimmune thrombocytopenic purpura and inflammatory arthritis,[80] and in renal allograft rejection.[81] As of November 2007, it had not been approved for these indications.

CD52 is a glycoprotein, which is attached to the outer layer of the cell membrane by a glycosylphosphatidylinositol lipid anchor. CD52 is expressed on most normal and malignant peripheral blood mononuclear cells (PBMCs) except plasma cells,[82] on thymocytes and in the male genital tract. In the genital tract, it is produced by epithelial cells and shed into the seminal plasma, from where it can be transferred to spermatozoa, thereby influencing sperm mobility and fertility.[83] Its function in immune cells is unknown.[84] CD52 is not expressed on hematopoietic stem cells, erythrocytes, thrombocytes or granulocytes.[84]

Alemtuzumab acts as an immune cell-depleting Ab. This effect is currently regarded as a main mechanism of action in MS patients.

In the early reconstitution phase, a relative increase of CD4+ CD25high T cells, possibly representing a protective Treg population, was observed in MS patients.[85] Recently, it has been reported that ALEM and another anti-CD52 Ab provided a costimulatory signal for CD4+ cells and consequently induced Tregs in vitro. Additionally, ALEM inhibited T-cell transmigration in vitro.[86] These findings are highly interesting in the context of MS since impaired Treg function was observed in MS patients[87] and T-cell transmigration over the BBB plays a crucial role in MS pathogenesis - possibly best evidenced by the therapeutic effect of the adhesion-blocking Ab NATA.[56] Accordingly, it was suggested that novel non-depleting anti-CD52 Abs may be effective immunomodulatory drugs.[86] The putative modes of ALEM action in MS are summarized in Figure 3.

Modes of therapeutic alemtuzumab action in multiple sclerosis.
B: B cell; MΦ: Macrophage; PBMC: Peripheral blood monouclear cell; T: T cell.

The complementary determining regions of ALEM were derived from the rat antihuman monoclonal IgG2b Ab Campath-1G,[88] which was developed at the University of Cambridge, Department of Pathology, Cambridge, UK and therefore termed Campath.[89] The lymphocyte-depleting series of Campath Abs was developed by immunization of a Dark Agouty rat with T cell-enriched human PBMCs and subsequent fusion of spleen cells with a rat myeloma cell line.[89] Campath-1 (later termed Campath-1M), a rat monoclonal IgM Ab, was the first one successfully used for the prophylactic treatment of human disease in 1986 by in vitro depletion of lympho-cytes from human bone marrow grafts, which prevented graft-versus-host disease.[90] However, when infused into CLL patients, Campath-1M caused only a transient decrease of tumor cells in peripheral blood. In contrast, an IgG2b isotype mediated substantial and long-lasting cell clearance, probably due to more efficient interaction of rat IgG2b with human effector mechanisms.[91] Campath-1G was therefore finally chosen for humanization, which reduced its immunogenicity. In contrast to the previous nomenclature, referring to the Ig subclass, it was then termed Campath-1H (for ‘human’).

The pharmocokinetics of ALEM, as evaluated in CLL patients, follow a two-compartment model with dose-dependent, non-linear elimination.[92] In a cohort of allogeneic stem cell transplant recipients, receiving ALEM 20 mg/day intravenously over 5 days and additionally being treated with fludarabine, melphalan and cyclosporine, ALEM showed a mean serum peak level of 13.7 μg/ml (range: 7.5-16.6 μg/ml), occurring 15 min after the final dose. The terminal half-life from 4 to 32 days after the last infusion was 8 days.[93]

In principle, it is possible to achieve plasma levels equivalent to those observed after intravenous infusion by subcutaneous injections, although a higher cumulative dose is required.[94] Less infusion-related adverse effects were observed after subcutaneous administration[95] but a higher rate of patients with anti-idiotype Abs (intravenous: zero of 30; subcutaneous: two of 32).[94]

In renal allograft recipients, a single intravenous infusion of the humanized Ab caused profound T-and B-lymphocyte depletion of more than 99% within less than 1 h, while lymph node depletion took 3-5 days.[83] In MS patients receiving a single intravenous infusion of 5-10 mg ALEM, monocyte and B-cell recovery took 3 months. B cell levels slightly rose above pretreatment levels at 27 months after infusion. In contrast to the comparatively rapid recovery of B cells and monocytes, the median recovery time to baseline levels was 61 months for CD4+ cells and 30 months for CD8+ T cells.[96]

Based on the assumption that CNS infiltration by autoreactive T lymphocytes plays a central role in the pathogenesis of MS, and lymphocyte depletion may therefore be an attractive therapeutic approach, ALEM was first administered to MS patients in an open-label pilot study starting in 1991.[97] Six patients with SPMS and superimposed relapses, and one patient with PPMS were intravenously infused 12 mg/day over 10 days, resulting in profound and sustained lymphocyte depletion. Neurological symptoms transiently increased after the first infusion for several hours. The number of Gd-enhancing lesions in serial MRI scans stayed largely reduced from month 3 to 6 while initially new Gd-enhancing lesions had occurred, indicating a possible delayed therapeutic effect.

Based on these promising results, an additional seven SPMS patients were treated with a single course of ALEM.[88] Most of them received a total dose of 100 mg over 5 days. Four of these patients and one of the first cohort additionally received an anti-CD4 Ab. It was shown that a transient increase of neurological symptoms was associated with a transient systemic release of the proinflammatory cytokines TNF-α, IFN-γ and IL-6, which could not solely be attributed to the observed increase of body temperature. Both cytokine release and transient worsening of neurological symptoms could be prevented by methylprednisolone pretreatment.

A new cohort of 29 SPMS patients with an EDSS progression of at least one point over the preceding year and at least one enhancing lesion in three monthly MRI scans was studied in a further study.[98] One ALEM-treated patient was lost to follow-up. Following a 3-month observation period with monthly MRI scans all patients were treated with ALEM 20 mg/day intravenously over 5 days. A total of 14 were randomized to additionally receive a humanized anti-CD4 Ab. These two groups were each divided into three arms to be pretreated with nothing, methylprednisolone or soluble TNF-α receptor. Patients were followed for 18 months, including clinical assessment every 3 months, as well as monthly MRI scans during the first 6 months post-treatment and from month 12 to 18.

In contrast to methylprednisolone, soluble TNF-α receptor did not prevent infusion-related transient worsening of neurological symptoms, ruling out TNF-α as causative factor for transient deterioration of neurological symptoms. Although ALEM treatment in this baseline-treatment crossover design significantly reduced the number of new Gd-enhancing MRI lesions (baseline mean 2.60; month 16-18 mean 0.75; p < 0.001) and annualized relapse rate (from 1.24 to 0.34), 15 of 28 patients experienced sustained EDSS progression during the post-treatment observation period of 18 months, correlating with a faster progression of MRI cerebral atrophy during this time than was observed in the stable patients. Again, treatment was generally associated with a transient worsening of neurological symptoms, lasting for a few hours, in patients not receiving corticosteroids. Importantly, nine of 27 (33%) of these patients, reported in a separate p-ublication, developed autoimmune hyperthyroidism.[99]

A recently reported 2-year, uncontrolled, open-label trial tested ALEM in patients with RRMS who had a disease onset within the past 5 years, a baseline EDSS score of 0-6.0 and at least two relapses within 2 years under treatment with one of the approved IFN-β preparations for at least 6 months.[100] A total of 45 patients received a 5-day course of ALEM 24 mg/day intravenously at month 0 and another course for 3 days at month 12. All patients received methylprednisolone 1 g intravenously prior to the first three doses of ALEM during both cycles. The annualized relapse rate during the 2 years following the first ALEM cycle (0.17) in comparison to the 2 years preceding the first cycle (1.6) showed a relative reduction of 94% (p < 0.0001). Of the 43 patients completing the 2-year treatment period, only one patient was reported to have a sustained increase of disability. A total of 70% of patients had stable or improved MS functional composite (MSFC) scores after 2 years. ALEM was generally well tolerated, although four cases of autoimmune thyroid disorder and one case of transient thrombocytopenia were observed.

CAMMS223 compares two different doses of ALEM with IFN-β1a 44 μg three times a week subcutaneously (Rebif®) in 334 treatment-naive patients with early RRMS who were randomized in a 1:1:1 ratio.[101] The trial is performed as an open-label, evaluator-blinded study. All patients had an onset of MS within 3 years of screening, an EDSS score of 0-3.0 at screening, two or more attacks in the previous 2 years and one or more Gd+ lesion on the screening brain MRI scan. Therefore, these patients represent a cohort with rather active disease. The ALEM-treated patients received 12 or 24 mg/day intravenously over 5 days. After 1 year, they were infused the same daily dose over 3 days. Some patients were additionally treated after 24 months. All patients received intravenous methylprednisolone for 3 days at month 0, 12 and 24.

Alemtuzumab dosing was prematurely terminated in September 2005 when three cases of idiopathic thrombocytopenic purpura (ITP), the first case resulting in a fatal hemorrhagic stroke, became known. So far, six patients (2.8%) have developed ITP. The surviving five patients showed a favorable outcome after adequate treatment, with none of them requiring splenectomy in the course of ITP or maintenance therapy.[102]

After a median of 2.2 years, antithyroid-stimulating hormone receptor Abs, which were determined every 3 months, were observed in 21.8% (47 of 216) of ALEM-treated and 1.9% (two of 103) of IFN-treated patients. A total of 11.1% of ALEM-treated patients and 1.9% of IFN-treated patients developed thyroid clinical adverse events. A total of 6.5% (14 of 216) of ALEM-treated patients and none of the IFN-treated patients developed Graves’ disease or hyperthyroidism.[103] Interestingly, autoimmune hyperthyroidism has not been reported in ALEM-treated CLL patients. These differences demonstrate that safety results in a certain study cohort should only be transferred into another cohort with a different disease entity with great caution. Infusion-related events such as fever, rigors and nausea were frequently observed in the ALEM-treated patients.[101]

In a blinded 1-year interim analysis ALEM reduced the risk for relapse by at least 75% (p = 0.00267) and the risk for sustained progression of disability by at least 60%, however the latter was not significant (p > 0.05).[104] After 2.2 years median follow-up, a prespecified 2-year interim analysis showed that ALEM-treated patients in comparison to IFN-treated patients had a 72% relative reduction in the risk for relapse when receiving the low dose (p < 0.0001) and a 87% relative reduction when receiving the high dose (p < 0.0001).[105] The relative decrease in the risk for sustained accumulation of disability was 88% in the low dose and 66% for the high dose group compared with IFN-β1a (both p < 0.01), demonstrating no dose-dependency for this parameter at the two dosages tested. The MSFC score and time to first relapse as well as MRI parameters were also greatly in favor of the ALEM-treated patients.[100]

Especially bearing in mind that the ALEM-treated patients were compared with high-dose IFN-treated patients, these clinical results look astonishing. However, the clinical data should be interpreted with some caution since, in contrast to the examining physicians, patients were not blinded to treatment. Even more importantly, the control group consisted of selected IFN-β1a nonresponders and was therefore not representative for the total group of IFN-β1a-treated patients. Consequently, we would expect that a head-to-head trial in treatment-naive patients, such as the currently conducted Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS1) trial, may reveal that ALEM is not as superior to IFN-β1a as observed in CAMMS223.

The CARE-MS1 trial is a Phase III trial comparing safety and efficacy of ALEM with IFN-β1a in treatment-naive RRMS patients. It is planned to include up to 525 patients in 60 centers, who will be randomized in a 2:1 ratio to receive either ALEM or IFN-β1a. ALEM-treated patients will receive 12 mg/day intravenously over 5 days, followed by a refresher course of 3 days (12 mg/day) after 1 year. The patients will be followed for 2 years and the ALEM-treated patients will receive an additional safety follow-up for an additional 3 years. Time to sustained EDSS progression and annualized relapse rate will be the co-primary outcome measures, evaluated by rater-blinded investigators.

Another Phase III trial will enroll treatment-experienced RRMS patients with breakthrough disease. It is termed CARE-MS2. To participate, patients must have experienced at least one relapse during a period of 1 year while under licensed disease-modifying treatment for MS with the exception of mitoxantrone or NATA. It is planned to randomize approximately 1200 patients to receive either ALEM 12 or 24 mg/day or IFN-β1a 44 μg in a 2:2:1 ratio. ALEM patients will receive a 5-day cycle at month 0 and a 3-day cycle at month 12. Time to sustained EDSS progression and annualized relapse rate over 2 years will again be the co-primary outcome measures. This trial was about to start recruitment in late 2007.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....