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Intractable and highly active relapsing multiple sclerosis - role of alemtuzumab.

Dubey D, Cano CA, Stuve O - Neuropsychiatr Dis Treat (2015)

Bottom Line: Because of its immunomodulatory properties, it was brought into clinical development in MS.Here, we review the history of drug development of alemtuzumab.Furthermore, we outline the postulated mechanisms of action, clinical evidence, and safety of alemtuzumab for its use as a disease-modifying agent in active and highly active MS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

ABSTRACT
Alemtuzumab is a humanized recombinant monoclonal antibody that was recently approved by the US Food and Drug Administration and the European Medicines Agency for the management of relapsing forms of multiple sclerosis (MS). It has been utilized for the management of chronic lymphocytic leukemia, bone marrow and renal transplantation, or graft versus host disease. Because of its immunomodulatory properties, it was brought into clinical development in MS. One Phase II (CAMMS223) and two Phase III clinical trials (CARE-MSI and -II) have evaluated the safety and efficacy of alemtuzumab in patients with relapsing-remitting MS. Even though its efficacy profile and long-lasting effect have attracted much interest among physicians and patients, it has significant potential adverse effects that may limit its use to patients with active disease. Here, we review the history of drug development of alemtuzumab. Furthermore, we outline the postulated mechanisms of action, clinical evidence, and safety of alemtuzumab for its use as a disease-modifying agent in active and highly active MS.

No MeSH data available.


Related in: MedlinePlus

Alemtuzumab-mediated cytolysis and apoptosis of T- and B-lymphocytes.Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; MAC, membrane attack complex; FcγR, Fc-gamma receptor.
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f1-ndt-11-2405: Alemtuzumab-mediated cytolysis and apoptosis of T- and B-lymphocytes.Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; MAC, membrane attack complex; FcγR, Fc-gamma receptor.

Mentions: There are three mechanisms by which alemtuzumab mediates immune cell depletion (Figure 1): antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis.14,21 In vitro experiments showed that antibody-dependent cell-mediated cytotoxicity occurs at much lower concentrations of alemtuzumab (0.01 mg/mL) than the concentration required for complement-dependent cytotoxicity and apoptosis.22,23 The cellular CD52 epitope recognized by alemtuzumab is the C-terminal peptide and is part of the glycophosphatidylinositol anchor.15 Binding of the antibody to the epitope promotes deposition of activated complement molecules and facilitates cell-mediated killing.


Intractable and highly active relapsing multiple sclerosis - role of alemtuzumab.

Dubey D, Cano CA, Stuve O - Neuropsychiatr Dis Treat (2015)

Alemtuzumab-mediated cytolysis and apoptosis of T- and B-lymphocytes.Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; MAC, membrane attack complex; FcγR, Fc-gamma receptor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581781&req=5

f1-ndt-11-2405: Alemtuzumab-mediated cytolysis and apoptosis of T- and B-lymphocytes.Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; MAC, membrane attack complex; FcγR, Fc-gamma receptor.
Mentions: There are three mechanisms by which alemtuzumab mediates immune cell depletion (Figure 1): antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis.14,21 In vitro experiments showed that antibody-dependent cell-mediated cytotoxicity occurs at much lower concentrations of alemtuzumab (0.01 mg/mL) than the concentration required for complement-dependent cytotoxicity and apoptosis.22,23 The cellular CD52 epitope recognized by alemtuzumab is the C-terminal peptide and is part of the glycophosphatidylinositol anchor.15 Binding of the antibody to the epitope promotes deposition of activated complement molecules and facilitates cell-mediated killing.

Bottom Line: Because of its immunomodulatory properties, it was brought into clinical development in MS.Here, we review the history of drug development of alemtuzumab.Furthermore, we outline the postulated mechanisms of action, clinical evidence, and safety of alemtuzumab for its use as a disease-modifying agent in active and highly active MS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

ABSTRACT
Alemtuzumab is a humanized recombinant monoclonal antibody that was recently approved by the US Food and Drug Administration and the European Medicines Agency for the management of relapsing forms of multiple sclerosis (MS). It has been utilized for the management of chronic lymphocytic leukemia, bone marrow and renal transplantation, or graft versus host disease. Because of its immunomodulatory properties, it was brought into clinical development in MS. One Phase II (CAMMS223) and two Phase III clinical trials (CARE-MSI and -II) have evaluated the safety and efficacy of alemtuzumab in patients with relapsing-remitting MS. Even though its efficacy profile and long-lasting effect have attracted much interest among physicians and patients, it has significant potential adverse effects that may limit its use to patients with active disease. Here, we review the history of drug development of alemtuzumab. Furthermore, we outline the postulated mechanisms of action, clinical evidence, and safety of alemtuzumab for its use as a disease-modifying agent in active and highly active MS.

No MeSH data available.


Related in: MedlinePlus