Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis

Abstract

Alemtuzumab is a humanized monoclonal antibody directed against CD52 to deplete circulating T and B lymphocytes; lymphocyte depletion is followed by a distinctive pattern of T- and B-cell repopulation, changing the balance of the immune system. This review reports the efficacy and safety findings of the phase 2 CAMMS223 trial and the phase 3 CARE-MS I and II trials investigating alemtuzumab for the treatment of active relapsing-remitting MS. Alemtuzumab, administered intravenously, was shown to improve relapse rate versus subcutaneous interferon beta-1a in patients who were treatment-naive (CAMMS223 and CARE-MS I) or had relapsed on prior therapy (CARE-MS II), and to reduce sustained accumulation of disability (CAMMS223 and CARE-MS II). Important adverse events were infusion-associated reactions, serious infections and autoimmune events. A safety monitoring program allowed for early detection and management of autoimmune events. Recommendations for the monitoring of adverse events are made. Alemtuzumab's mechanism of action, pharmacodynamics and opportunities for future research are discussed.

Keywords: Alemtuzumab; CD52; monoclonal antibody; multiple sclerosis.

Figure 1.

Trial design of CARE-MS I and CARE-MS II. In CARE-MS II, randomization into a third treatment arm (alemtuzumab 24 mg) was discontinued early and deemed exploratory for statistical purposes. CARE-MS: Comparison of Alemtuzumab and Rebif^® Efficacy in Multiple Sclerosis IFNβ-1a: interferon beta-1a; IV: intravenous; SC: subcutaneous.

Figure 2.

Mechanism of action of alemtuzumab. (a) Cellular targets of alemtuzumab during the complex immunopathogenesis underlying MS. APC: antigen-presenting cell; B: B cell; BBB: blood-brain barrier; BDNF: brain-derived neurotrophic factor; CNS: central nervous system; DC: dendritic cell; IFN-γ: interferon-γ; IL: interleukin; PC: plasma cell; T: T cell; Th: T-helper cell; Treg: regulatory T-cell; TGF-β: transforming growth factor-β; TNF-α; tumor necrosis factor-α. Adapted with permission from Linker RA, Kieseier BC and Gold R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci 2008; 29: 558–565, Copyright Elsevier 2008. (b) Suggested phases of alemtuzumab actions. The humanized monoclonal antibody alemtuzumab recognizes the CD52 antigen whose function is elusive on both T and B lymphocytes. By both complement-mediated and antibody-dependent cytotoxic macrophage-mediated mechanisms these cells are destroyed. Recovery of T and B cell populations occurs with different kinetics, B cells returning much earlier in peripheral blood. The repopulating T cell population is enriched in T regulatory cells that silence or diminish the impact of pathogenic autoreactive T cells.