ReviewImmune mechanisms of new therapeutic strategies in multiple sclerosis—A focus on alemtuzumab
Highlights
► Alemtuzumab is a monoclonal antibody against human CD52. ► Alemtuzumab is highly effective in reducing disease severity in RRMS. ► Alemtuzumab induces long-lasting immune cell depletion via ADCC. ► Alemtuzumab treatment is associated with overt novel autoimmunity.
Introduction
Treatment with monoclonal antibodies has gained much interest during the last decade, and until now, more than 240 antibodies are currently in clinical development [1]. Established indications comprise a broad range of diseases from neoplasias such as leukemia and non-hodgkins lymphoma to autoimmune diseases such as rheumatoid arthritis, Crohn's disease and multiple sclerosis (MS), as well as in organ transplantation [1]. Treatment with the first generation of recombinant monoclonal antibodies—generated by fusion of antibody-producing B lymphocytes with murine myeloma cells [2]—was often limited by severe immune reactions elicited by the foreign protein antigen and by rapid loss of function due to generation of neutralizing antibodies. Following generations of therapeutic monoclonal antibodies (TAb) consist of chimeric antibodies, in which only the antigen-specific, highly variable part is mouse-derived, whereas all other regions are of human origin; these antibodies are therefore called “humanized” antibodies, with different levels of biotechnological humanization [3], [4]. Monoclonal antibodies have very different modes of action, most importantly treatment strategies using TAb comprise different approaches such as depletion of distinct cell populations including immune cells or malignant cells, functional blockade of cell-based molecules such as adhesion molecules, and neutralization of circulating soluble factors such as TNFα [1], [5], [6].
Section snippets
Alemtuzumab is an FDA-approved monoclonal antibody against human CD52
The monoclonal antibody alemtuzumab (Campath-1H) is a humanized IgG1k and a typical example of a cell-depleting antibody. Its target is human CD52, which is a 12 amino acid glycosylated glycosylphosphatidylinositol (GPI)-linked surface protein [7], [8]. It is expressed on T and B lymphocytes, natural killer (NK) cells, dendritic cells, and most monocytes, but importantly not on haematopoetic precursors [9]. The natural function of CD52 in immune cells is not completely resolved; however, it has
Early findings of alemtuzumab-treatment in MS patients
Based on its immune cell-depleting effect, Campath-1H was first applied in an open series of MS patients starting in 1991; the rationale being that regeneration of the T cell repertoire following lymphocyte depletion would reduce aberrant autoimmune responses [15], [16], [17]. In 2004, the Cambridge study group presented data from 58 MS patients treated with Campath-1H between 1991 and 2002, which had been prospectively followed for 280 patient years [18]. Alemtuzumab was administered as five
The CAMMS223 trial: reduced inflammation and neuroprotection?
Based on these findings, a phase II randomized, multi-center rater-blinded clinical trial was started in 2002, enrolling 334 patients with previously untreated, early RRMS with a maximal disease duration of 3 years and a maximum EDSS score of 3.0 [13]. Patients received either annual cycles of high (24 mg per day) or low (12 mg per day) dose of alemtuzumab for 36 months, or were alternatively treated s.c. with 44 μg interferon (IFN) β 1a three times per week. Alemtuzumab impressively reduced the
Novel autoimmunity—the current obstacle in alemtuzumab treatment of MS patients
One major drawback within the portfolio of alemtuzumab treatment is the critical safety profile. Within this the most remarkable finding is the frequent occurrence of overt new autoimmunity in MS patients treated with alemtuzumab, which is completely independent from its amelioration of disease activity in MS. So far, 20%–30% of alemtuzumab-treated MS patients developed thyroid autoimmunity, mainly Graves' disease [13], [18], [22], and 3% developed idiopathic thrombocytopenic purpura (ITP),
Immune responses and infections in the context of alemtuzumab—current view
Another clinical observation arguing against the simplicistic view that the efficacy of alemtuzumab solely relies on its capacity to induce profound long-term lymphopenia is the unexpectedly low frequency of (potentially) opportunistic infections following alemtuzumab treatment. So far, only eight infections might be attributable to immunosuppression by alemtuzumab: three cases of herpes zoster, one case each of varicella zoster, spirochaetal gingivitis, measles, aphthous mouth ulceration and
Conclusion
The clinical data available so far—which now encompass an observation period of up to 60 months from the cohort of the CAMMS223 trial—impressively demonstrate the efficacy and sustainability of alemtuzumab treatment, with a reduction in relapses and in accumulation of disability by more than 70% compared to IFNβ. These phase II results indicate that this therapeutic approach might be even more efficacious than currently licensed disease-modifying therapies for RRMS. The level of efficacy is
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