Review article
Monoclonal antibodies in development in multiple sclerosis
Anticuerpos monoclonales en desarrollo en esclerosis múltiple
J. Sastre-Garriga, X. Montalban
Corresponding author
Unitat de Neuroimmunologia Clínica, Centre d’Esclerosi Múltiple de Catalunya (CEM-Cat), Hospital Vall d’Hebron, Barcelona, Spain
Read
3841
Timeswas read the article
925
Total PDF
2916
Total HTML
Share statistics
array:25 [ "pii" => "S2173580811000393" "issn" => "21735808" "doi" => "10.1016/j.nrleng.2010.06.001" "estado" => "S300" "fechaPublicacion" => "2011-11-01" "aid" => "204" "copyright" => "Sociedad Española de Neurología" "copyrightAnyo" => "2010" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "ssu" "cita" => "Neurologia. 2011;26:556-62" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1986 "formatos" => array:3 [ "EPUB" => 57 "HTML" => 1505 "PDF" => 424 ] ] "Traduccion" => array:1 [ "es" => array:20 [ "pii" => "S0213485311001010" "issn" => "02134853" "doi" => "10.1016/j.nrl.2011.02.006" "estado" => "S300" "fechaPublicacion" => "2011-11-01" "aid" => "204" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "ssu" "cita" => "Neurologia. 2011;26:556-62" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 10586 "formatos" => array:3 [ "EPUB" => 74 "HTML" => 9283 "PDF" => 1229 ] ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Revisión</span>" "titulo" => "Anticuerpos monoclonales en desarrollo en esclerosis múltiple" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "556" "paginaFinal" => "562" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Monoclonal antibodies in the development of multiple sclerosis" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Sastre-Garriga, X. Montalban" "autores" => array:2 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Sastre-Garriga" ] 1 => array:2 [ "nombre" => "X." "apellidos" => "Montalban" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173580811000393" "doi" => "10.1016/j.nrleng.2010.06.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580811000393?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485311001010?idApp=UINPBA00004N" "url" => "/02134853/0000002600000009/v1_201305151126/S0213485311001010/v1_201305151126/es/main.assets" ] ] "itemSiguiente" => array:20 [ "pii" => "S2173580811000435" "issn" => "21735808" "doi" => "10.1016/j.nrleng.2011.04.001" "estado" => "S300" "fechaPublicacion" => "2011-11-01" "aid" => "238" "copyright" => "Sociedad Española de Neurología" "documento" => "simple-article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "cor" "cita" => "Neurologia. 2011;26:563-4" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1953 "formatos" => array:3 [ "EPUB" => 41 "HTML" => 1478 "PDF" => 434 ] ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>" "titulo" => "III cranial nerve palsy and brainstem disfunction following retrobulbar anaesthesia" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "563" "paginaFinal" => "564" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Paresia de III par craneal y afectación troncoencefálica por difusión intradural de anestesia retrobulbar" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M.A. Aranda Calleja, A. Martínez Pueyo, S. Bellido Cuellar, P. García Ruiz" "autores" => array:4 [ 0 => array:2 [ "nombre" => "M.A." "apellidos" => "Aranda Calleja" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Martínez Pueyo" ] 2 => array:2 [ "nombre" => "S." "apellidos" => "Bellido Cuellar" ] 3 => array:2 [ "nombre" => "P." "apellidos" => "García Ruiz" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0213485311002258" "doi" => "10.1016/j.nrl.2011.04.013" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485311002258?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580811000435?idApp=UINPBA00004N" "url" => "/21735808/0000002600000009/v1_201305151311/S2173580811000435/v1_201305151311/en/main.assets" ] "itemAnterior" => array:20 [ "pii" => "S2173580811000423" "issn" => "21735808" "doi" => "10.1016/j.nrleng.2011.03.004" "estado" => "S300" "fechaPublicacion" => "2011-11-01" "aid" => "225" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "ssu" "cita" => "Neurologia. 2011;26:548-55" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2882 "formatos" => array:3 [ "EPUB" => 59 "HTML" => 2382 "PDF" => 441 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "FEEN report on epilepsy in Spain" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "548" "paginaFinal" => "555" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "FEEN: Informe sociosanitario FEEN sobre la epilepsia en España" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 749 "Ancho" => 1488 "Tamanyo" => 69777 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Social-working status of drug-resistant patients.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. García-Ramos, A. García Pastor, J. Masjuan, C. Sánchez, A. Gil" "autores" => array:5 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "García-Ramos" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "García Pastor" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Masjuan" ] 3 => array:2 [ "nombre" => "C." "apellidos" => "Sánchez" ] 4 => array:2 [ "nombre" => "A." "apellidos" => "Gil" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0213485311001629" "doi" => "10.1016/j.nrl.2011.04.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485311001629?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580811000423?idApp=UINPBA00004N" "url" => "/21735808/0000002600000009/v1_201305151311/S2173580811000423/v1_201305151311/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Monoclonal antibodies in development in multiple sclerosis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "556" "paginaFinal" => "562" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J. Sastre-Garriga, X. Montalban" "autores" => array:2 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Sastre-Garriga" ] 1 => array:4 [ "nombre" => "X." "apellidos" => "Montalban" "email" => array:1 [ 0 => "xavier.montalban@unic-em.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Unitat de Neuroimmunologia Clínica, Centre d’Esclerosi Múltiple de Catalunya (CEM-Cat), Hospital Vall d’Hebron, Barcelona, Spain" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Anticuerpos monoclonales en desarrollo en esclerosis múltiple" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In recent decades, slowly but unstoppably, our therapeutic arsenal in neurology has witnessed the emergence of the first treatments that modify the clinical course of multiple sclerosis. Interferon and glatiramer acetate have recently been followed by natalizumab. It is true that the road ahead is still long, especially to improve comfort during administration and, of course, to improve the efficacy of currently available drugs. The rapid progress we are experiencing in recent years makes it difficult to keep up to date with all ongoing phase II trials, let alone all the molecules that have started preclinical phase I. It is obvious that, along with oral drugs, monoclonal antibodies have been the main focus of this rapid development. We have dedicated this article to a review of the main safety and efficacy results of some monoclonal antibodies that have passed through phase II clinical development: alemtuzumab, rituximab–ocrelizumab and daclizumab. In addition to the references cited, our search for information relied on that available from the following websites: <a href="http://www.clinicaltrials.gov/">www.clinicaltrials.gov</a>, the EMEA website and the website of the Spanish Medicine Agency. As a summary, <a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a> present the fundamental efficacy and safety data on all 3 monoclonal antibodies reviewed, as well as a brief summary of their direct or indirect modes of action.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Monoclonal antibodies in development</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Alemtuzumab</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mode of action</span><p id="par0010" class="elsevierStylePara elsevierViewall">Alemtuzumab or campath-1H is a monoclonal antibody humanized against the CD52 antigen, one of the first available humanized antibodies in fact.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Because this surface receptor is found in most cells in the immune system (T and B lymphocytes, monocytes and eosinophils), treatment with this antibody causes an intense, lasting depletion of immune system cells. It is important to note that CD52 is not yet expressed in the bone marrow progenitors, which do not suffer the effects of the antibody. It should also be stressed that this depletion is not as extreme in the lymphoid organs, which may explain the relatively low rate of infections suffered by patients treated with this antibody. It is possible that neutrophil cell populations and natural killer lymphocytes may intervene in the cell death mechanisms involved, and that the role of the complement is not as important as was previously thought.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> It is already being marketed in Spain under the name MabCampath<span class="elsevierStyleSup">®</span> for the treatment of B-cell chronic lymphocytic leukaemia in patients in whom chemotherapy treatment in combination with fludarabine is not appropriate (the data sheet can be found at: <a href="http://www.ema.europa.eu/humandocs/PDFs/EPAR/mabcampath/emea-combined-h353es.pdf">http://www.ema.europa.eu/humandocs/PDFs/EPAR/mabcampath/emea-combined-h353es.pdf</a>).<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3,4</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical evidence available on efficacy</span><p id="par0015" class="elsevierStylePara elsevierViewall">The first published clinical trials with this drug revealed that its use in stages of the disease with little inflammatory component would be a low-yield strategy. Consequently, those responsible for the phase II study design decided to include only patients in the earliest stages of the disease<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5</span></a>; this is why the CAMMS223 phase II study could only include patients with a disease duration under 4 years.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The key features of the CAMMS223 trial are: randomized 3-year phase II trial that included 334 patients with an EDSS score less than 3 and a maximum disease duration of 3 years. Patients were not blinded to the medication administered (due to the highly recognisable cytokine release syndrome, it was considered impossible to maintain patients blind as to who would receive this antibody) and received the following in a 1:1:1 ratio: (a) interferon beta-1a in subcutaneous dose of 44<span class="elsevierStyleHsp" style=""></span>μg 3 times per week (Rebif<span class="elsevierStyleSup">®</span>), and (b) alemtuzumab in 2 different doses (12<span class="elsevierStyleHsp" style=""></span>mg/day or 24<span class="elsevierStyleHsp" style=""></span>mg/day). The program for intravenous administration of alemtuzumab was the following: 5 consecutive days in the first month of the trial, and for 3 consecutive days on months 12 and 24 until completing 3 treatment cycles. The trial was stopped (due to safety reasons) when almost all patients had received doses for month 12, but only 25% had received the dose for month 24. As mentioned, both patients and neurologists were not blinded to the treatment administered; only the evaluating neurologist remained blinded to treatment allocation. Although this must be taken into account when assessing the results of this test, it is true that the two primary objectives (EDSS and the presence of outbreaks) yielded very encouraging results. In the group of alemtuzumab patients (both doses combined), the risk of sustained disability progression was reduced by 71% and the relapse rate by 74%, compared with the Rebif 44<span class="elsevierStyleSup">®</span> group. Although we have no data on the evolution of gadolinium-enhanced lesions, as no MRIs were performed after administration of gadolinium, the results of brain volume measurements were also remarkable. We observed statistically significant differences in the development of atrophy between alemtuzumab patients and Rebif 44<span class="elsevierStyleSup">®</span> patients between months 12 and 36 (to avoid the pseudo-atrophy effect occurring in the first months after initiation of anti-inflammatory therapy). The brain volume change was −0.2% in patients receiving Rebif 44<span class="elsevierStyleSup">®</span> and +0.9% in the alemtuzumab group. This last datum, together with an improvement of disability during the study in the group with alemtuzumab treatment, has led to speculation about a possible neuroprotective and even neuroregenerative effects of this monoclonal antibody.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Safety data</span><p id="par0020" class="elsevierStylePara elsevierViewall">The encouraging efficacy results of the CAMMS223 trial were unfortunately accompanied by the death of 2 patients in the alemtuzumab group. One patient died from cardiovascular disease; this patient had presented risk factors previously. The second patient developed autoimmune thrombocytopenic purpura (a total of 6 purpura cases were detected in trial patients), which caused a brain haemorrhage. There were other cases of autoimmune pathology, mainly autoimmune thyroid disease (49 cases in patients treated with alemtuzumab), possibly as a consequence of aberrant phenomena during the regeneration process of the immune system (believed to be related to different recovery kinetics of B and T lymphocytes [<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>]). We also detected an increased risk of infections, especially of the respiratory tract, in patients taking alemtuzumab. Furthermore, 3 patients developed recurrent episodes of herpes after the infusions. A control of the infusion reaction through premedication (corticosteroids, paracetamol and antihistamines) was revealed to be important.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical development program</span><p id="par0025" class="elsevierStylePara elsevierViewall">There are two active phase III clinical trials at the present time: CAREMS-I and CAREMS-II. The former is a 2-year study comparing an alemtuzumab dose of 12<span class="elsevierStyleHsp" style=""></span>mg/day with Rebif 44<span class="elsevierStyleSup">®</span> (ratio 2:1), with a very similar design to the CAMMS223 trial, although it allows recruitment of patients with a disease duration of up to 5 years. The CAREMS-II trial includes patients who have not responded to previous treatment with immunomodulators, with a maximum disease duration of 10 years. Both studies are underway and have completed the recruitment phase.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0030" class="elsevierStylePara elsevierViewall">Although efficacy results are very encouraging, the safety profile of this drug still needs to be secured within acceptable limits. We hope that this can be achieved through the patient control measures to prevent the occurrence of serious adverse effects, especially those related to bleeding diathesis.</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Rituximab</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mode of action</span><p id="par0035" class="elsevierStylePara elsevierViewall">Rituximab is a chimeric monoclonal antibody (rodent/human) against the CD20 antigen present mainly in B-lymphocytes from the pre-B stage until the stage of activated B-cells. These cells undergo lysis after the binding of this antibody, although it is important to emphasise that this does not happen in the earliest haematopoietic precursors nor in the plasma cells, since they do not express the antigen.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> This would allow a more rapid regeneration and would thus maintain some degree of immune defence through plasma cells. The lymphopenia induced by this drug is durable and relatively selective for B-cells. In the phase II HERMES trial, only 30.7% of patients presented normal levels of B-lymphocytes 1 year after the infusion, while there were no changes in the levels of T-lymphocytes in the blood.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> It is noteworthy that, despite this, a decrease was also observed in the levels of T-lymphocytes in cerebrospinal fluid.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Rituximab is already indicated in Spain, under the commercial name Mabthera<span class="elsevierStyleSup">®</span>, for the treatment (in some cases) of non-Hodgkin lymphoma, chronic lymphocytic leukaemia and rheumatoid arthritis (the data sheet is available from: <a href="http://www.ema.europa.eu/humandocs/PDFs/EPAR/Mabthera/emea-combined-h165es.pdf">http://www.ema.europa.eu/humandocs/PDFs/EPAR/Mabthera/emea-combined-h165es.pdf</a>).</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical evidence available on efficacy</span><p id="par0040" class="elsevierStylePara elsevierViewall">The HERMES study investigated the efficacy and safety of rituximab in 104 patients with relapsing-remitting multiple sclerosis through a 1-year phase II trial. Patients were administered 1<span class="elsevierStyleHsp" style=""></span>g of the drug on 2 occasions (day 1 and day 15) or placebo (2:1 ratio). A 91% relative reduction was observed in the primary objective (total number of gadolinium-enhanced lesions at weeks 12, 16, 20 and 24 of the study). Statistically significant differences favouring the treatment group were also observed in the proportion of patients with outbreaks (14.5% vs 34.3% in the placebo group). The OLYMPUS<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> study recruited 439 patients with primary-progressive multiple sclerosis in a phase II/III study, which was negative for its primary objective. Statistically significant differences were found to favour only the rituximab group in the accumulation of lesions in T2-weighted sequences, with no such differences being observed in the development of brain atrophy. Post hoc analysis seems to show that the drug could be useful in a subgroup of patients with higher gadolinium enhancement and younger age.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Safety data</span><p id="par0045" class="elsevierStylePara elsevierViewall">Safety results from both the HERMES and the OLYMPUS studies include the presence of infusion reactions, which occurred mainly during the first rounds of drug treatment and then decreased to levels comparable to placebo in subsequent rounds. An increased risk of infections was also observed. In addition, the HERMES study found 1 coronary syndrome and 1 malignant thyroid tumour in the rituximab group. Nevertheless, its use in other indications has reported up to 57 cases of progressive multifocal leukoencephalopathy in patients who had taken rituximab<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> (although it this figure might be higher given the non-mandatory reporting of these cases). However, it is noteworthy that many of these patients already suffered from diseases which by themselves predisposed towards the onset of progressive multifocal leukoencephalopathy. Furthermore, the patients had received other immunosuppressive therapies in the vast majority of cases, although 1 of these cases involved a patient with autoimmune haemolytic anaemia who had received only corticosteroids and rituximab.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical development program</span><p id="par0050" class="elsevierStylePara elsevierViewall">At the present time, clinical development in multiple sclerosis continues through a humanized anti-CD20 compound: ocrelizumab (WA21493 phase II trial), and a human anti-CD20 compound: ofatumumab (GEN414 phase I/II dose finding trial). However, the clinical development of ocrelizumab in rheumatoid arthritis and systemic lupus erythematosus has recently been stopped due to an unacceptable safety profile in these two conditions (<a href="http://www.genengnews.com/analysis-and-insight/ocrelizumab-one-size-does-not-fit-all/77899315/">http://www.genengnews.com/analysis-and-insight/ocrelizumab-one-size-does-not-fit-all/77899315/</a>).</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0055" class="elsevierStylePara elsevierViewall">The efficacy results obtained in the HERMES phase II study are highly encouraging. However, its safety profile should be defined further in patients with multiple sclerosis, especially with regard to the possibility of developing progressive multifocal leukoencephalopathy symptoms. It is also necessary to obtain more information on the actual risk of infection, which has led to the interruption of the ocrelizumab development program in some pathologies.</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Daclizumab</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mode of action</span><p id="par0060" class="elsevierStylePara elsevierViewall">Daclizumab is a humanized monoclonal antibody against the CD25 surface molecule, which is the alpha chain of the interleukin-2 receptor, a crucial proinflammatory cytokine in the process of T-cell activation. Daclizumab binds selectively to the alpha subunit of the receptor, which is a constituent part of the high- and low-affinity recipients of interleukin-2. It does not form part of the intermediate-affinity receptors (which only consist of beta and gamma subunits), which are therefore not blocked. This antibody was initially tested in multiple sclerosis under the assumption of inhibition of the processes that stimulate autoreactive T-lymphocytes (which do not have intermediate affinity receptors) and which are mediated by interleukin-2.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Nevertheless, it appears that the beneficial effect in the case of multiple sclerosis is caused by an excess of circulating interleukin-2, which in turn causes a proliferation of CD56bright cells (which act as regulatory cells). These cells do have intermediate-affinity receptors not blocked by daclizumab.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Moreover, recent works indicate that the increase in autoimmune phenomena, mainly skin problems, observed with this drug could be due to a reduction of regulatory T-cells CD4+CD25+Foxp3+.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The drug was previously marketed under the name Zenapax<span class="elsevierStyleSup">®</span>; however, its European authorisation has been cancelled at the request of the pharmaceutical laboratory itself due to commercial reasons not linked to safety alerts (available from: <a href="http://www.emea.europa.eu/humandocs/PDFs/EPAR/Zenapax/68376508en.pdf">http://www.emea.europa.eu/humandocs/PDFs/EPAR/Zenapax/68376508en.pdf</a>). Its use was approved to prevent acute rejection of kidney transplants.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical evidence available on efficacy</span><p id="par0065" class="elsevierStylePara elsevierViewall">The first open clinical trial showed a 78% reduction in the number of new gadolinium-enhanced lesions. This was an open study including only 10 patients with different forms of multiple sclerosis (relapsing-remitting and secondary-progressive), who did not respond to first-line drugs. In this study, subcutaneous daclizumab was added to interferon-beta.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> A similar trial (although most patients followed monotherapy with daclizumab this time) conducted by independent researchers obtained similar results.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Recently, the results of the CHOICE<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> study have been published. This 6-month study followed a randomized, double-blind design. It recruited 230 patients with relapsing-remitting and secondary-progressive (<10%) multiple sclerosis who had suffered an outbreak in the past year while on stable immunomodulatory therapy. Daclizumab (or placebo) was administered subcutaneously every 15 days in 2 possible doses (1<span class="elsevierStyleHsp" style=""></span>mg/kg and 2<span class="elsevierStyleHsp" style=""></span>mg/kg). The results showed a 72% reduction in the mean number of gadolinium-enhanced lesions for the high dose, without significant results being found for the low dose (1.32 in the group with 2<span class="elsevierStyleHsp" style=""></span>mg/kg vs 3.58 in the group with 1<span class="elsevierStyleHsp" style=""></span>mg/kg vs 4.75 in the group with placebo) and without statistically significant results for the clinical parameters (outbreaks, EDSS, MSFC).</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Safety data</span><p id="par0070" class="elsevierStylePara elsevierViewall">The first open trials found no significant safety issues, although Rose et al.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> did notice 4 patients with skin problems. The safety results of the CHOICE study seemed to confirm these findings and demonstrate the presence of an increased risk of infection, although no increase in the risk of opportunistic infections was found. Two patients in the treated group developed tumours (in situ breast ductal carcinoma and recurrence of pseudomyxoma peritonei).</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical development program</span><p id="par0075" class="elsevierStylePara elsevierViewall">Two studies are being conducted at present. One is a phase II study with different doses of daclizumab (150<span class="elsevierStyleHsp" style=""></span>mg and 300<span class="elsevierStyleHsp" style=""></span>mg) administered monthly (DAC HYP) in monotherapy controlled with placebo (205-MS-201), with an extension period (205-MS-202 [SELECT study]). The other is a phase III study with a single dose of daclizumab (150<span class="elsevierStyleHsp" style=""></span>mg) administered monthly (DAC HYP) with an active comparison group treated with interferon beta-1a (DECIDE study).</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0080" class="elsevierStylePara elsevierViewall">Ongoing monotherapy studies will help us to better understand the efficacy and safety profile of this monoclonal antibody, since at present the high-quality data obtained are mainly from the CHOICE study, with an add-on design.</p></span></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0085" class="elsevierStylePara elsevierViewall">Although there is currently a significant amount of data regarding the efficacy and safety of the three monoclonal antibodies reviewed, it is still too early to decide which position they will occupy within the therapeutic arsenal that will be available shortly for the treatment of multiple sclerosis. If the data available from phase II trials are confirmed, the efficacy parameters would appear to be higher than first-line drugs available at present. Nevertheless, it is crucial to continue accumulating short- and long-term safety data on these drugs. These data will shape the future of the 3 monoclonal antibodies under development for multiple sclerosis reviewed in this chapter. When the time comes for their clinical application, it will also be critical to develop the management and prevention algorithms required to minimise the risk of adverse effects.</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interests</span><p id="par0090" class="elsevierStylePara elsevierViewall">Jaume Sastre-Garriga has served as a consultant or advisory board member for Novartis, TEVA, Biogen, Almirall, Bayer Schering Pharma and Merck-Serono, and has participated as a speaker at events organised by Novartis, Sanofi-Aventis, Biogen, Almirall, Bayer Schering Pharma and Merck-Serono.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Xavier Montalban has served as a consultant or advisory board member for Novartis, TEVA, Biogen, Sanofi-Aventis, Almirall, Bayer Schering Pharma and Merck-Serono and has participated as a speaker at events organised by Novartis, Sanofi-Aventis, Biogen, Almirall, Bayer Schering Pharma and Merck-Serono.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:2 [ "identificador" => "xres169563" "titulo" => array:4 [ 0 => "Abstract" 1 => "Introduction" 2 => "Contents and methods" 3 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec157676" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres169564" "titulo" => array:4 [ 0 => "Resumen" 1 => "Introducción" 2 => "Desarrollo" 3 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec157677" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Monoclonal antibodies in development" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Alemtuzumab" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Mode of action" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Clinical evidence available on efficacy" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Safety data" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Clinical development program" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Conclusions" ] ] ] 1 => array:3 [ "identificador" => "sec0045" "titulo" => "Rituximab" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Mode of action" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Clinical evidence available on efficacy" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Safety data" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Clinical development program" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusions" ] ] ] 2 => array:3 [ "identificador" => "sec0075" "titulo" => "Daclizumab" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0080" "titulo" => "Mode of action" ] 1 => array:2 [ "identificador" => "sec0085" "titulo" => "Clinical evidence available on efficacy" ] 2 => array:2 [ "identificador" => "sec0090" "titulo" => "Safety data" ] 3 => array:2 [ "identificador" => "sec0095" "titulo" => "Clinical development program" ] 4 => array:2 [ "identificador" => "sec0100" "titulo" => "Conclusions" ] ] ] ] ] 6 => array:2 [ "identificador" => "sec0105" "titulo" => "Conclusions" ] 7 => array:2 [ "identificador" => "sec0110" "titulo" => "Conflict of interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2010-05-04" "fechaAceptado" => "2010-06-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec157676" "palabras" => array:6 [ 0 => "Monoclonal antibody" 1 => "Multiple sclerosis" 2 => "Alemtuzumab" 3 => "Daclizumab" 4 => "Rituximab" 5 => "Ocrelizumab" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec157677" "palabras" => array:6 [ 0 => "Anticuerpo monoclonal" 1 => "Esclerosis múltiple" 2 => "Alemtuzumab" 3 => "Daclizumab" 4 => "Rituximab" 5 => "Ocrelizumab" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The last fifteen years have seen the gradual appearance of a number of different drugs that have been shown to be effective as disease modifying therapies in multiple sclerosis. The opening and subsequent widening of the therapeutic armamentarium in multiple sclerosis will continue on a expanding course in the next few years due to the already known positive results of phase III clinical trials with orally administered molecules. Along with these, we have also seen the appearance of a group of drugs which, instead of being defined by their route of administration, are considered together as a consequence of their similar design: the monoclonal antibodies.</p> <span class="elsevierStyleSectionTitle">Contents and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The principal safety and efficacy results of three of the monoclonal antibodies that have already obtained positive results in phase II studies will be reviewed in this paper: alemtuzumab, rituximab/ocrelizumab, and daclizumab. For the preparation of this paper, information was obtained from already published articles and from the following web pages: <span class="elsevierStyleInterRef" href="http://www.clinicaltrials.gov/">www.clinicaltrials.gov</span> of the National Institute of Health of the USA, the EMA (European Medicines Agency) web page and the Spanish Medicines Agency (Agencia Española del Medicamento) web page.</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Final results from the phase III clinical trials in progress are required to produce definitive statements on the efficacy and safety of the reviewed drugs. However, and subject to confirmation of the presently available data from phase II trials, it is likely that this group of drugs is to be placed one step beyond the currently available disease-modifying therapies in terms of efficacy, but with a safety pattern which will make careful monitoring of treated patients a mandatory requirement so as to obtain adequate risk/benefit profiles.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle">Introducción</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Los últimos 15 años han visto aparecer de manera progresiva diferentes fármacos que se han mostrado eficaces para el tratamiento de fondo de la esclerosis múltiple. Esta inauguración y posterior ampliación del arsenal terapéutico en esclerosis múltiple seguirá un curso ascendente en los próximos años dados los resultados positivos ya conocidos de ensayos clínicos fase III con moléculas de administración oral. Junto a ellos también hemos observado la aparición de un grupo de fármacos que en lugar de definirse por su vía de administración lo hacen por su diseño: los anticuerpos monoclonales.</p> <span class="elsevierStyleSectionTitle">Desarrollo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">En este artículo se revisan los principales resultados de seguridad y eficacia de tres de los anticuerpos monoclonales que ya han obtenido resultados positivos en estudios de fase II: alemtuzumab, rituximab-ocrelizumab y daclizumab. Para la elaboración de este trabajo se ha obtenido información de artículos ya publicados y de las siguientes páginas web: <span class="elsevierStyleInterRef" href="http://www.clinicaltrials.gov/">www.clinicaltrials.gov</span> del National Institute of Health (NIH) de los EE. UU., de la EMA (Agencia Europea del Medicamento) y de la Agencia Española del Medicamento.</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Es necesario disponer de los resultados de los ensayos fase III en marcha actualmente para emitir juicios adecuados sobre estos fármacos. Sin embargo, es de esperar que, confirmándose los datos de los ensayos fase II disponibles, nos hallemos ante fármacos de eficacia superior a los actuales, pero cuya seguridad será necesario ajustar para obtener perfiles adecuados de beneficio/riesgo.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Sastre-Garriga J, Montalban X. Anticuerpos monoclonales en desarrollo en esclerosis múltiple. Neurología. 2011;26:556–62.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Gd+: gadolinium-enhanced lesions; MS: multiple sclerosis; PPMS: primary-progressive MS; RRMS: relapsing-remitting MS; sc: subcutaneous.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Safety \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Efficacy \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alemtuzumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II: autoimmune processes during the reconstitution period of the immune system (idiopathic thrombocytopenic purpura, Graves disease, etc.); risk of infections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II: 74% reduction in relapse rate and 71% reduction in risk of progression compared to interferon-beta-1a sc 44<span class="elsevierStyleHsp" style=""></span>μg; decline of disability compared with an increase in the group of interferon-beta-1a sc 44<span class="elsevierStyleHsp" style=""></span>μg at 36 months (−0.39 vs +0.38) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rituximab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II: risk of progressive multifocal leukoencephalopathy by cases in other pathologies (no cases reported in MS patients at present); risk of infections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II: in RRMS reduction vs placebo in the number of lesions Gd+ (91% reduction) and in number of patients experiencing outbreaks (14.5% vs 34.3%, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.02); negative results in PPMS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Daclizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II: infections and skin reactions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II: no differences were observed in relapse rate; 72% reduction in the mean number of Gd+ lesions \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab264700.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Main safety and efficacy features of the monoclonal antibodies reviewed in this chapter. Importantly, the difference in study design does not allow a direct comparison of the efficacy data.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Taken from Bielekova and Becker.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>" "tabla" => array:2 [ "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">BL: B-lymphocytes; CNS: central nervous system; IL: interleukin; MOA: mode of action; NK: natural killer; PML: progressive multifocal leukoencephalopathy; TL: T lymphocytes.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Direct effects \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Indirect effects \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Consequences (therapeutic and adverse effects) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Rituximab</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Depletion of BL (antigen CD20) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inhibition of macrophage function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Most relevant early therapeutic effect \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absence of presentation of antigen by BL with subsequent loss of action of TL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Possibly contributing to MOA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prolonged depletion of BL memory which may prevent renewal of plasmatic cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Possible effect on immunity mediated by antibodies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regeneration through pre-BL of bone marrow \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May contribute to the risk of PML \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Alemtuzumab</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Depletion of cells with CD52 antigen (BL and TL, macrophages, monocytes, dendrite cells and granulocytes) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stabilises HEB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Responsible for the early therapeutic effect (decreases inflammation in CNS without excessively increasing the risk of infection) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-uniform regeneration: BL at start and subsequently TL (CD25high cells and caspasa-3 positive cells) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Responsible for long-term beneficial effects, although may be the cause of autoimmune phenomena \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Daclizumab</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Inhibition of IL-2 high affinity receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Expansion of NK CD56bright cells with depletion of activated TL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Most relevant therapeutic effect \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Inhibition of TL regulator survival CD4+CD25+FoxP3+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probable related with the risk of developing autoimmune complications and skin lesions \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab264701.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Modes of action and consequences, both therapeutic and in terms of side effects, of the monoclonal antibodies reviewed.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.J. Coles" 1 => "A. Cox" 2 => "E. Le Page" 3 => "J. Jones" 4 => "S.A. Trip" 5 => "J. Deans" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00415-005-0934-5" "Revista" => array:6 [ "tituloSerie" => "J Neurol" "fecha" => "2006" "volumen" => "253" "paginaInicial" => "98" "paginaFinal" => "108" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16044212" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Hu" 1 => "M.J. Turner" 2 => "J. Shields" 3 => "M.S. Gale" 4 => "E. Hutto" 5 => "B.L. Roberts" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2567.2009.03115.x" "Revista" => array:6 [ "tituloSerie" => "Immunology" "fecha" => "2009" "volumen" => "128" "paginaInicial" => "260" "paginaFinal" => "270" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19740383" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Emerging monoclonal antibody therapies for multiple sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "B. Cree" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/01.nrl.0000204859.15501.6b" "Revista" => array:6 [ "tituloSerie" => "Neurologist" "fecha" => "2006" "volumen" => "12" "paginaInicial" => "171" "paginaFinal" => "178" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16832236" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification and development of new therapeutics for multiple sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R.A. Linker" 1 => "B.C. Kieseier" 2 => "R. Gold" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.tips.2008.07.012" "Revista" => array:6 [ "tituloSerie" => "Trends Pharmacol Sci" "fecha" => "2008" "volumen" => "29" "paginaInicial" => "558" "paginaFinal" => "565" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18804288" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.J. Coles" 1 => "M.G. Wing" 2 => "P. Molyneux" 3 => "A. Paolillo" 4 => "C.M. Davie" 5 => "G. Hale" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Neurol" "fecha" => "1999" "volumen" => "46" "paginaInicial" => "296" "paginaFinal" => "304" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10482259" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Alemtuzumab vs. interferon beta-1a in early multiple sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.J. Coles" 1 => "D.A. Compston" 2 => "K.W. Selmaj" 3 => "S.L. Lake" 4 => "S. Moran" 5 => "D.H. Margolin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa0802670" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2008" "volumen" => "359" "paginaInicial" => "1786" "paginaFinal" => "1801" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18946064" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "B-cell depletion with rituximab in relapsing-remitting multiple sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.L. Hauser" 1 => "E. Waubant" 2 => "D.L. Arnold" 3 => "T. Vollmer" 4 => "J. Antel" 5 => "R.J. Fox" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa0706383" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2008" "volumen" => "358" "paginaInicial" => "676" "paginaFinal" => "688" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18272891" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.H. Cross" 1 => "J.L. Stark" 2 => "J. Lauber" 3 => "M.J. Ramsbottom" 4 => "J.A. Lyons" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jneuroim.2006.06.029" "Revista" => array:6 [ "tituloSerie" => "J Neuroimmunol" "fecha" => "2006" "volumen" => "180" "paginaInicial" => "63" "paginaFinal" => "70" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16904756" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Hawker" 1 => "P. O’Connor" 2 => "M.S. Freedman" 3 => "P.A. Calabresi" 4 => "J. Antel" 5 => "J. Simon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ana.21867" "Revista" => array:6 [ "tituloSerie" => "Ann Neurol" "fecha" => "2009" "volumen" => "66" "paginaInicial" => "460" "paginaFinal" => "471" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19847908" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K.R. Carson" 1 => "A.M. Evens" 2 => "E.A. Richey" 3 => "T.M. Habermann" 4 => "D. Focosi" 5 => "J.F. Seymour" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2008-10-186999" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2009" "volumen" => "113" "paginaInicial" => "4834" "paginaFinal" => "4840" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19264918" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spotlight on anti-CD25: daclizumab in MS" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D.S. Schippling" 1 => "R. Martin" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Int MS J" "fecha" => "2008" "volumen" => "15" "paginaInicial" => "94" "paginaFinal" => "98" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18808743" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulatory CD56 (bright) natural killer cells mediate immunomodulatory effects of IL-2R alpha-targeted therapy (daclizumab) in multiple sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Bielekova" 1 => "M. Catalfamo" 2 => "S. Reichert-Scrivner" 3 => "A. Packer" 4 => "M. Cerna" 5 => "T.A. Waldmann" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.0601335103" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci USA" "fecha" => "2006" "volumen" => "103" "paginaInicial" => "5941" "paginaFinal" => "5946" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16585503" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulatory T cells are reduced during anti-CD25 antibody treatment of multiple sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "U. Oh" 1 => "G. Blevins" 2 => "C. Griffith" 3 => "N. Richert" 4 => "D. Maric" 5 => "C.R. Lee" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/archneurol.2009.16" "Revista" => array:6 [ "tituloSerie" => "Arch Neurol" "fecha" => "2009" "volumen" => "66" "paginaInicial" => "471" "paginaFinal" => "479" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19364932" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Bielekova" 1 => "N. Richert" 2 => "T. Howard" 3 => "G. Blevins" 4 => "S. Markovic-Plese" 5 => "J. McCartin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.0402653101" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci USA" "fecha" => "2004" "volumen" => "101" "paginaInicial" => "8705" "paginaFinal" => "8708" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15161974" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J.W. Rose" 1 => "H.E. Watt" 2 => "A.T. White" 3 => "N.G. Carlson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ana.20287" "Revista" => array:6 [ "tituloSerie" => "Ann Neurol" "fecha" => "2004" "volumen" => "56" "paginaInicial" => "864" "paginaFinal" => "867" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15499632" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Wynn" 1 => "M. Kaufman" 2 => "X. Montalban" 3 => "T. Vollmer" 4 => "J. Simon" 5 => "J. Elkins" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1474-4422(10)70033-8" "Revista" => array:6 [ "tituloSerie" => "Lancet Neurol" "fecha" => "2010" "volumen" => "9" "paginaInicial" => "381" "paginaFinal" => "390" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20163990" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Monoclonal antibodies in MS: mechanisms of action" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "B. Bielekova" 1 => "B.L. Becker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1212/WNL.0b013e3181c97ed3" "Revista" => array:7 [ "tituloSerie" => "Neurology" "fecha" => "2010" "volumen" => "74" "numero" => "Suppl. 1" "paginaInicial" => "S31" "paginaFinal" => "S40" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20038761" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735808/0000002600000009/v1_201305151311/S2173580811000393/v1_201305151311/en/main.assets" "Apartado" => array:4 [ "identificador" => "9423" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Review articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735808/0000002600000009/v1_201305151311/S2173580811000393/v1_201305151311/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580811000393?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 3 | 0 | 3 |
| 2024 October | 21 | 14 | 35 |
| 2024 September | 18 | 15 | 33 |
| 2024 August | 29 | 12 | 41 |
| 2024 July | 11 | 9 | 20 |
| 2024 June | 24 | 3 | 27 |
| 2024 May | 8 | 3 | 11 |
| 2024 April | 17 | 6 | 23 |
| 2024 March | 17 | 8 | 25 |
| 2024 February | 11 | 7 | 18 |
| 2024 January | 16 | 7 | 23 |
| 2023 December | 15 | 13 | 28 |
| 2023 November | 15 | 8 | 23 |
| 2023 October | 26 | 17 | 43 |
| 2023 September | 16 | 7 | 23 |
| 2023 August | 19 | 2 | 21 |
| 2023 July | 24 | 7 | 31 |
| 2023 June | 29 | 4 | 33 |
| 2023 May | 98 | 7 | 105 |
| 2023 April | 51 | 1 | 52 |
| 2023 March | 44 | 4 | 48 |
| 2023 February | 30 | 4 | 34 |
| 2023 January | 47 | 6 | 53 |
| 2022 December | 51 | 7 | 58 |
| 2022 November | 44 | 10 | 54 |
| 2022 October | 16 | 7 | 23 |
| 2022 September | 27 | 10 | 37 |
| 2022 August | 60 | 17 | 77 |
| 2022 July | 45 | 10 | 55 |
| 2022 June | 44 | 13 | 57 |
| 2022 May | 24 | 7 | 31 |
| 2022 April | 28 | 8 | 36 |
| 2022 March | 23 | 16 | 39 |
| 2022 February | 21 | 5 | 26 |
| 2022 January | 46 | 6 | 52 |
| 2021 December | 35 | 9 | 44 |
| 2021 November | 22 | 12 | 34 |
| 2021 October | 50 | 16 | 66 |
| 2021 September | 41 | 14 | 55 |
| 2021 August | 17 | 10 | 27 |
| 2021 July | 10 | 6 | 16 |
| 2021 June | 16 | 18 | 34 |
| 2021 May | 15 | 10 | 25 |
| 2021 April | 35 | 27 | 62 |
| 2021 March | 11 | 15 | 26 |
| 2021 February | 8 | 7 | 15 |
| 2021 January | 11 | 11 | 22 |
| 2020 December | 12 | 7 | 19 |
| 2020 November | 14 | 8 | 22 |
| 2020 October | 10 | 9 | 19 |
| 2020 September | 11 | 11 | 22 |
| 2020 August | 12 | 5 | 17 |
| 2020 July | 16 | 10 | 26 |
| 2020 June | 8 | 2 | 10 |
| 2020 May | 11 | 9 | 20 |
| 2020 April | 7 | 2 | 9 |
| 2020 March | 13 | 1 | 14 |
| 2020 February | 15 | 3 | 18 |
| 2020 January | 20 | 8 | 28 |
| 2019 December | 20 | 10 | 30 |
| 2019 November | 13 | 4 | 17 |
| 2019 October | 5 | 1 | 6 |
| 2019 September | 8 | 2 | 10 |
| 2019 August | 9 | 3 | 12 |
| 2019 July | 6 | 20 | 26 |
| 2019 June | 28 | 12 | 40 |
| 2019 May | 112 | 23 | 135 |
| 2019 April | 28 | 4 | 32 |
| 2019 March | 5 | 4 | 9 |
| 2019 February | 12 | 5 | 17 |
| 2019 January | 9 | 1 | 10 |
| 2018 December | 12 | 3 | 15 |
| 2018 November | 14 | 4 | 18 |
| 2018 October | 17 | 7 | 24 |
| 2018 September | 12 | 1 | 13 |
| 2018 August | 10 | 0 | 10 |
| 2018 July | 3 | 2 | 5 |
| 2018 June | 5 | 0 | 5 |
| 2018 May | 5 | 2 | 7 |
| 2018 April | 6 | 0 | 6 |
| 2018 March | 5 | 2 | 7 |
| 2018 February | 3 | 1 | 4 |
| 2018 January | 4 | 0 | 4 |
| 2017 December | 15 | 0 | 15 |
| 2017 November | 12 | 0 | 12 |
| 2017 October | 11 | 3 | 14 |
| 2017 September | 12 | 6 | 18 |
| 2017 August | 18 | 2 | 20 |
| 2017 July | 14 | 2 | 16 |
| 2017 June | 17 | 2 | 19 |
| 2017 May | 16 | 3 | 19 |
| 2017 April | 11 | 2 | 13 |
| 2017 March | 8 | 34 | 42 |
| 2017 February | 6 | 0 | 6 |
| 2017 January | 12 | 1 | 13 |
| 2016 December | 13 | 5 | 18 |
| 2016 November | 25 | 2 | 27 |
| 2016 October | 28 | 1 | 29 |
| 2016 September | 24 | 2 | 26 |
| 2016 August | 18 | 8 | 26 |
| 2016 July | 16 | 3 | 19 |
| 2016 June | 20 | 6 | 26 |
| 2016 May | 13 | 9 | 22 |
| 2016 April | 8 | 14 | 22 |
| 2016 March | 18 | 23 | 41 |
| 2016 February | 19 | 12 | 31 |
| 2016 January | 7 | 10 | 17 |
| 2015 December | 6 | 10 | 16 |
| 2015 November | 12 | 11 | 23 |
| 2015 October | 16 | 8 | 24 |
| 2015 September | 22 | 4 | 26 |
| 2015 August | 11 | 4 | 15 |
| 2015 July | 16 | 7 | 23 |
| 2015 June | 10 | 2 | 12 |
| 2015 May | 22 | 2 | 24 |
| 2015 April | 16 | 13 | 29 |
| 2015 March | 18 | 5 | 23 |
| 2015 February | 18 | 4 | 22 |
| 2015 January | 25 | 6 | 31 |
| 2014 December | 39 | 10 | 49 |
| 2014 November | 34 | 1 | 35 |
| 2014 October | 44 | 3 | 47 |
| 2014 September | 31 | 2 | 33 |
| 2014 August | 35 | 2 | 37 |
| 2014 July | 42 | 6 | 48 |
| 2014 June | 20 | 3 | 23 |
| 2014 May | 28 | 4 | 32 |
| 2014 April | 29 | 1 | 30 |
| 2014 March | 38 | 5 | 43 |
| 2014 February | 25 | 6 | 31 |
| 2014 January | 21 | 4 | 25 |
| 2013 December | 16 | 3 | 19 |
| 2013 November | 29 | 7 | 36 |
| 2013 October | 26 | 3 | 29 |
| 2013 September | 32 | 5 | 37 |
| 2013 August | 47 | 8 | 55 |
| 2013 July | 38 | 5 | 43 |
Show all
