ALAIN01—Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential

BMC Neurology, Mar 2016

Background Alemtuzumab (Lemtrada®) is a newly approved therapeutic agent for relapsing-remitting multiple sclerosis (RRMS). In previous phase II and III clinical trials, alemtuzumab has proven superior efficacy to subcutaneous interferon beta-1a concerning relapse rate and disability progression with unprecedented durability and long-lasting freedom of disease activity. The humanized monoclonal antibody targets CD52, leading to a rapid and long-lasting depletion, especially of B and T cells. Arising from hematopoietic precursor cells a fundamental reprogramming of the immune system restores tolerogenic networks effectively suppressing autoimmune inflammatory responses in the central nervous system (CNS). Despite its favourable effects alemtuzumab holds a severe risk of side effects with secondary autoimmunity being the most considerable. Markers for risk stratification and treatment response improving patient selection and therapy guidance are a big unmet need for MS patients and health care providers. Methods/design This is a mono center, single arm, explorative phase IV study including 15 patients with highly active RRMS designed for 3 years. Patients will be studied by a high-resolution analysis comprising a repertoire of various immunological assays for the detection of immune cells and their function in peripheral blood as well as the cerebrospinal fluid (CSF). These assays encompass a number of experiments investigating immune cell subset composition, activation status, cytokine secretion, migratory capacity, potential neuroprotective properties and cytolytic activity complemented by instrument-based diagnostics like MRI scans, evoked potentials and optical coherence tomography (OCT). Discussion Our study represents the first in-depth and longitudinal functional analysis of key immunological parameters in the periphery and the CNS compartment underlying the fundamental effects of alemtuzumab in MS patients. By combining clinical, experimental and MRI data our study will provide a deeper understanding of alemtuzumab’s mechanisms of action (MOA) potentially identifying immune signatures associated with treatment response or the development of secondary autoimmunity. After validation in larger cohorts this might help to improve efficacy and safety of alemtuzumab therapy in RRMS patients. Trial registration NCT02419378 (clinicaltrials.gov), registered 31 March 2015.

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ALAIN01—Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential

Ruck et al. BMC Neurology ALAIN01-Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential Tobias Ruck 0 1 4 Ali Maisam Afzali 0 1 4 Karl-Friedrich Lukat 3 Maria Eveslage 2 Catharina C. Gross 1 4 Steffen Pfeuffer 1 4 Stefan Bittner 1 4 Luisa Klotz 1 4 Nico Melzer 1 4 Heinz Wiendl 1 4 Sven G. Meuth 1 4 0 Equal contributors 1 Department of Neurology, University of Münster , Albert-Schweitzer-Campus 1, 48149 Münster , Germany 2 Institute of Biostatistics and Clinical Research, University of Münster , Münster , Germany 3 Center for Clinical Studies, University of Münster , Münster , Germany 4 Department of Neurology, University of Münster , Albert-Schweitzer-Campus 1, 48149 Münster , Germany Background: Alemtuzumab (Lemtrada®) is a newly approved therapeutic agent for relapsing-remitting multiple sclerosis (RRMS). In previous phase II and III clinical trials, alemtuzumab has proven superior efficacy to subcutaneous interferon beta-1a concerning relapse rate and disability progression with unprecedented durability and long-lasting freedom of disease activity. The humanized monoclonal antibody targets CD52, leading to a rapid and long-lasting depletion, especially of B and T cells. Arising from hematopoietic precursor cells a fundamental reprogramming of the immune system restores tolerogenic networks effectively suppressing autoimmune inflammatory responses in the central nervous system (CNS). Despite its favourable effects alemtuzumab holds a severe risk of side effects with secondary autoimmunity being the most considerable. Markers for risk stratification and treatment response improving patient selection and therapy guidance are a big unmet need for MS patients and health care providers. Methods/design: This is a mono center, single arm, explorative phase IV study including 15 patients with highly active RRMS designed for 3 years. Patients will be studied by a high-resolution analysis comprising a repertoire of various immunological assays for the detection of immune cells and their function in peripheral blood as well as the cerebrospinal fluid (CSF). These assays encompass a number of experiments investigating immune cell subset composition, activation status, cytokine secretion, migratory capacity, potential neuroprotective properties and cytolytic activity complemented by instrument-based diagnostics like MRI scans, evoked potentials and optical coherence tomography (OCT). Discussion: Our study represents the first in-depth and longitudinal functional analysis of key immunological parameters in the periphery and the CNS compartment underlying the fundamental effects of alemtuzumab in MS patients. By combining clinical, experimental and MRI data our study will provide a deeper understanding of alemtuzumab's mechanisms of action (MOA) potentially identifying immune signatures associated with treatment response or the development of secondary autoimmunity. After validation in larger cohorts this might help to improve efficacy and safety of alemtuzumab therapy in RRMS patients. Trial registration: NCT02419378 (clinicaltrials.gov), registered 31 March 2015. Alemtuzumab; Multiple sclerosis; Disease-modifying therapy; Risk stratification; Mechanism of action; Secondary autoimmune disease Background Approximately 2.5 million people around the world suffer from multiple sclerosis (MS) [ 1 ], a chronic inflammatory disorder of the central nervous system (CNS). Inflammation, demyelination, and axonal degeneration are distinctive features of the pathological mechanism [ 2 ]. Its clinical course is typically characterized by initial episodes of transient neurological deficits with full or partial recovery (relapsing-remitting MS); over the time deficits may cumulate to increasing disability. With the development of new therapeutic agents treatment goals are changing from solely stabilizing to reversing the disease. Alemtuzumab is a new promising therapy for RRMS, which might be able to fulfil this aim. Alemtuzumab has been approved by the EMA (European Medicines Agency) in September 2013 and the FDA (U.S. Food and Drug Administration) in November 2014 for the treatment of RRMS under the name Lemtrada®. It is a humanized monoclonal antibody targeting CD52 primarily expressed on T- and B-lymphocytes, and to lesser extents on dendritic cells, monocytes and macrophages [ 3 ]. Alemtuzumab leads to a rapid and significant depletion of CD52 expressing cells by antibody-dependent cell-mediated and complement-dependent cytotoxicity [ 4, 5 ]; hematopoietic precursor cells are not affected. Subsequent to depletion a slow repopulation starts arising from hematopoietic precursor cells following a distinct pattern. B cells repopulate rapidly within 6 months with predominating immature B cells, prolonged CD27+ memory B cell lymphopenia and increased serum levels of BAFF (B cell activating factor) [6]. In contrast, CD4+ and CD8+ lymphocytes do not recover to (...truncated)


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Tobias Ruck, Ali Afzali, Karl-Friedrich Lukat, Maria Eveslage, Catharina Gross, Steffen Pfeuffer, Stefan Bittner, Luisa Klotz, Nico Melzer, Heinz Wiendl, Sven Meuth. ALAIN01—Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential, BMC Neurology, 2016, pp. 34, 16, DOI: 10.1186/s12883-016-0556-9