Background: Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune inflammatory disorder of the central nervous system, with significant morbidity and mortality. The lymphocyte depleting, anti-CD52 monoclonal antibody alemtuzumab is a highly effective treatment option in RRMS, though associated with high rates of secondary autoimmune disorders. As alemtuzumab is now in routine clinical use, following licensing in Europe and the US, understanding the effects of repeated treatment cycles and reducing the risk of secondary autoimmunity is timely and essential. In this thesis, I explore how repeated treatment impacts the extent of lymphodepletion. I also study the role of soluble CD52, recently described as suppressive via interaction with Siglec-10, in the mechanism of secondary autoimmunity, and determine the biomarker potential of pre-treatment cytokine levels. Findings: CD4 and CD8 lymphocytes are less effectively depleted with repeated treatment cycles. Lymphocyte surface CD52 density was found by flow cytometry to be significantly lower after alemtuzumab treatment, although CD52-negative clones are not seen. In a cytolysis assay, reduced CD52 density was shown to correlate with reduced susceptibility to alemtuzumab. In addition, activated proliferating T lymphocytes, as observed after treatment, downregulated CD52 expression in a gene expression assay and shed the antigen from cell surface as demonstrated by ELISA and flow cytometry. The development of immunoassays to detect and quantify anti-idiotype antibodies to alemtuzumab is presented. The occurrence of antibodies at retreatment did not reduce lymphocyte depletion. A regulatory role for soluble CD52 was not found in suppression assays, and the proportion of antigen-activated CD52hi T cells did not vary between healthy controls and RRMS individuals. Siglec-10 was not seen on cell surface of activated T cells by flow cytometry and gene expression; thus concluding that soluble CD52 does not play a role in post-alemtuzumab induced autoimmunity. Prior to treatment, the only serum cytokine found to distinguish individuals who develop autoimmunity from those who do not was IL-21 (higher in the autoimmune cohort), however currently commercially available IL-21 immunoassays have no utility as predictive biomarker tests.

Multipel skleros (MS) är en kronisk sjukdom som drabbar det centrala nervsystemet, CNS. Sjukdomen karakteriseras av återkommande och periodvisa inflammationer som orsakar demyelinisering och påföljande skada på underliggande axon som finns i hjärna, synnerv och ryggmärg. Vid demyelinisering så försämras ledningen av elektriska impulser vilket leder till störande effekt på fysisk, mental, sensorisk och känslomässig aktivitet i kroppen. I Sverige är incidensen ca 5 fall per 100 000 invånare per år och prevalensen ca 190 fall per 100 000 invånare. Det finns därmed ca 17 500 personer som är drabbade av MS i Sverige. Kvinnor drabbas dubbelt så ofta som män av MS och de flesta som insjuknar gör det i åldrarna 20–45 år. Det finns ingen behandling som botar sjukdomen och symptomen som uppstår vid MS behandlas symptomatiskt. Patienter med MS får också immunomodulerande behandling som interferon beta, fingolimod, glatirameracetat, dimetylfumarat, teriflunomid, natalizumab och alemtuzumab för att få kontroll över den inflammatoriska aktiviteten och därmed minska risken för bestående funktionsnedsättning. Akuta skov av MS behandlas med metylprednisolon och där det ej gett effekt kan plasmaferes övervägas. Syftet med det här arbetet var att jämföra behandlingarna natalizumab och alemtuzumab vid skovvis förlöpande MS. Arbetet är ett litteraturarbete där sökningar gjordes i sökbasen PubMed med sökorden ”Alemtuzumab multiple sclerosis”, ”Natalizumab multiple sclerosis” och ”Natalizumab Alemtuzumab multiple sclerosis”. Det fanns inga kliniska studier där natalizumab och alemtuzumab jämfördes. Sex studier valdes ut, tre där alemtuzumab utvärderas och tre där natalizumab utvärderas. Resultatet visade att natalizumab var något mer effektivt avseende minskning i poäng på expanded disability status scale (EDSS) och resultat på magnetisk resonanstomografi (MRI). Alemtuzumab var däremot mer effektivt avseende sjukdomsprogression. Skovfrekvens och skovfria patienter var svårt att jämföra då definitionen på skov skiljde sig mellan studierna. Biverkningsmässigt var natalizumab mer fördelaktigt då det visade färre andel patienter med allvarliga biverkningar och inte samma typ av allvarliga biverkningar. En klinisk studie där de båda läkemedlen jämförs med varandra med samma effektmått och definition på effektmått skulle vara önskvärt.

Background: Multiple sclerosis (MS) is an autoimmune disease which attacks the central nervous systems (CNS) white substance. The damages cause MS-plaques which lead to disability in the CNS. There are currently around 20,000 people in Sweden who live with the diagnosis and every year another 1,000 people develop MS. It is twice as common for women to suffer from MS in comparison with men. Objective: The purpose of the study was to investigate the efficacy and safety of the alemtuzumab and daclizumab infusion drugs. Methods: This work is a literature study based on 6 scientific articles. Results: Based on at least one of the studied parameters, which are improvement in Expanded Disability Status Scale (EDSS), annual relapse rate and sustained accumulation of disability (IFS), showed that all four studies on alemtuzumab provided a higher therapeutic effect than IFN-β-1a. The two studies on daclizumab showed in one article in comparison with placebo a better treatment effect. The article comparing daclizumab with IFN-β-1a did not show major differences between the preparations but a reduced annual relapse rate was observed. Conclusion: The studies showed that both alemtuzumab and daclizumab yield better effect than IFN-β-1a and placebo. Treatment with alemtuzumab gave slightly better results in persistent worsening of the disease (IFS) compared with daclizumab, IFN-β- 1a and placebo. Patients who were treated with alemtuzumab had worse adverse events in comparison to the group of patients who were treated with IFN-β-1a. This shows that the safety of treatment with alemtuzumab was lower in comparison to treatment with IFN-β-1a. Most fatal outcomes were found during treatment with alemtuzumab. These aspects makes one consider whether alemtuzumab may or may not be the best treatment option. Also daclizumab had some serious side effects, but those did not occur as much as with alemtuzumab treatment. IFN-β-1a has been a safer drug to use as compared to alemtuzumab and dalclizumab. On the other hand, the mechanism of action differs between the three drugs, which means that these can be tailored more individually to MS-affected patients and a more individual-based drug treatment may be possible.

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later. Here we provide an update on the long-term efficacy and safety of alemtuzumab in RRMS, including realworld experience, and advances in our understanding of its mechanism of action. Recent data from the phase II/III extension study have demonstrated that alemtuzumab reduces relapse rates, disability worsening, and the rate of brain volume loss over the long term, with many patients achieving no evidence of disease activity. In high proportions of patients, preexisting disability remained stable or improved. Alemtuzumab is associated with a consistent safety profile over the long term, with no new safety signals emerging and the overall annual incidence of reported adverse events decreasing after the first year on treatment. Acyclovir prophylaxis reduces herpetic infections, and monitoring has been shown to mitigate the risk of autoimmune adverse events, allowing early detection and overall effective management. Data from clinical practice and ongoing observational studies are providing additional information on the real-world use of alemtuzumab. Recent evidence on the mechanism of action of alemtuzumab indicates that in addition to its previously known effects of inducing depletion and repopulation of T and B lymphocytes, it also results in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS. These effects may allow preservation of innate immunity and immunosurveillance. Together, these lines of evidence help explain the durable clinical efficacy of alemtuzumab, in the absence of continuous treatment, in patients with RRMS.

Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cell subsets. Recently, single cases of multiple sclerosis patients who developed severe exacerbation after the first alemtuzumab application, accompanied by re-appearance of peripheral B cells, were reported. Here we present a case with underlying B cell-driven multiple sclerosis that impressively improves after alemtuzumab, although peripheral B cell repopulation took place. Our detailed clinical, histopathological, imaging and immunological data suggest that alemtuzumab can act as an effective rescue treatment in highly active B cell-driven and antibody/complement-mediated multiple sclerosis type II patients.