Insights into the Mechanisms of the Therapeutic Efficacy of Alemtuzumab in Multiple Sclerosis

Abstract

The pathogenesis of multiple sclerosis (MS) is thought to involve peripheral activation of immune cells against central nervous system (CNS) antigens and their migration across the blood-brain barrier, leading to CNS inflammation and neurodegeneration. Alemtuzumab, a humanized anti-CD52 monoclonal antibody that rapidly depletes CD52-expressing cells from the circulation, is being investigated as a new treatment option in relapsing-remitting MS (RRMS). Clinical and radiologic results indicate robust suppression of inflammation related to the depletion of T and B lymphocytes during each treatment course of alemtuzumab. Furthermore, several lines of evidence suggest that the long-term clinical effects of alemtuzumab are attributable to qualitative changes in repopulating lymphocyte subsets potentially leading to a rebalancing of the immune system. Here, we review the contribution of data from animal models, ex vivo human studies, and clinical trials to the understanding of the mechanisms underlying the therapeutic effect of alemtuzumab in patients with RRMS.

Keywords: Alemtuzumab; Efficacy; Mechanism of action; Multiple sclerosis; Safety.

Figure 1. Immune cell depletion following alemtuzumab treatment in a human CD52-transgenic mouse model

Absolute numbers of immune cell populations remaining at 72 hours after the administration of various intravenous doses of alemtuzumab were assessed. Results shown are the mean ± SEM of individual mice (n=5) and are expressed as the percentage of cells remaining after treatment relative to the number of cells present in vehicle-treated control mice (% Control). The organs examined included the blood (A), spleen (B), inguinal lymph nodes (C), and thymus (D). The cell populations analyzed consisted of CD4⁺ T cells, CD8⁺ T cells, single-positive (SP) and double-positive (DP) thymocytes, B220⁺ B cells, NK1.1⁺ CD49b⁺ NK cells and Gr-1⁺ neutrophils. (Reprinted from Figure 4 in Hu et al. [22].)

Figure 2. Effects of alemtuzumab on median lymphocyte and leukocyte counts over 36 months in the CAMMS223 Phase II study

Alemtuzumab rapidly depleted the circulating T- and B-lymphocyte subsets studied (CD4, CD8 and CD19) after each treatment course. CD4 (A) and CD8 (B) T cells reconstituted gradually after each treatment course without reaching baseline values. Median B-cell values returned to baseline and remained within normal ranges 6 months after each treatment course (C). Circulating monocyte, eosinophil, and basophil cell counts were minimally or transiently affected after each treatment course. The mean number of circulating neutrophil cells initially increased (while remaining within normal limits), but normalized within 4 weeks (D). NR=normal range; vertical reference lines represent alemtuzumab dosing; grey, horizontal lines represent the lower limit of normal. (Data from Coles et al. [36]).

Figure 3. Proportion of CD4⁺ T cells with a regulatory phenotype

The percentage of T lymphocytes with a regulatory T-cell (Treg) phenotype was elevated following alemtuzumab treatment (12 mg; 2 annual courses of IV infusions) in treatment-naïve, relapsing-remitting MS patients (CARE-MS I; unpublished data). The proportion of Treg cells gradually returned toward baseline levels, but remained elevated at Month 12. (Data from Hartung et al. [42]).