I cover science and tech news for Sparrho and work with Sparrho Heroes to curate, translate and disseminate scientific research to the wider public.
Antibodies are an important new alternative to anti-inflammatory drugs curbing the progress of MS.
In 10 seconds? Monoclonal antibodies - stopping rogue immune cells from causing damage - are great promise in treating MS. There are already highly efficient drugs based on them and new ones are being developed.
Mono what? And why are they great? Monoclonal antibodies – meaning carbon copies of single antibodies, which are the body’s quick reaction force taking on attackers. A ‘clone army’ of specific antibodies can be very effective on selected disease-causing targets, such as B-cells.
Why are B-cells important here? Because we are getting closer to the source of the disease with them. Earlier research and therapies focused on another group, T-cells, but targetting them is like dealing with the footsoldiers instead of the criminal masterminds - which are a group of misbehaving B-cells.
So, what's the role of antibodies and why do we need cloned ones? Y-shaped antibodies' job is identify and neutralise intruders, such as viruses or bacteria. They locate and attach themselves to specific attackers. So, tailor-made, cloned antibodies can efficiently to deplete specific ‘faulty’ B-cells or prevent them from entering the brain and cause damage.
And what’s the tangible change for patients? In contrast with earlier therapies, antibody therapy leaves the patient’s immune system mostly intact. Thanks to one such antibody, people with the worst kind of MS – primary-progressive – finally have a drug that slows down the disease. Patients with relapsing MS experience less frequent episodes.
Amazing, but are there any drawbacks? Well, currently antibody-based medication means having to use a drip feed. This often causes infections. Also, these B-cell therapies seem to be ineffective for some people, which means more research is needed. Stay tuned for more drugs with names ending with ‘mab’ – meaning monoclonal antibodies!
How monoclonal antibodies are made?
Also known as mAbs, they are created in labs by immunising mice to launch the process of creating antibodies.
Spleen cells are then harvested from the animals through an operation.
These are fused with a type of white blood cell and multiplied.
The cell mixture is diluted and clones are grown from single ‘parent’ cells.
The advantage of this technology is that the cloned antibodies can be created in unlimited quantities.
Abstract: B cells play a vital function in multiple sclerosis (MS) pathogenesis through an array of effector functions. All currently approved MS disease-modifying therapies alter the frequency, phenotype, or homing of B cells in one way or another. The importance of this mechanism of action has been reinforced with the successful development and clinical testing of B-cell-depleting monoclonal antibodies that target the CD20 surface antigen. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was approved by the Food and Drug Administration (FDA) in March 2017 after pivotal trials showed dramatic reductions in inflammatory disease activity in relapsing MS as well as lessening of disability progression in primary progressive MS. These and other clinical studies place B cells at the center of the inflammatory cascade in MS and provide a launching point for development of therapies that target selective pathogenic B-cell populations.
Pub.: 24 Jan '18, Pinned: 21 Feb '18
Abstract: Monoclonal antibodies that target CD20 expressing B cells represent an important new treatment option for patients with multiple sclerosis (MS). B cell depleting therapy is highly effective against relapsing forms of the disease, and is also the first treatment approach proven to protect against disability worsening in primary progressive MS. Moreover, evolving clinical experience with B cell therapy, combined with a more sophisticated understanding of humoral immunity in preclinical models and in patients with MS, have led to major progress in deciphering the immune pathogenesis of MS. Here, we review the nuanced roles of B cells in MS autoimmunity, the clinical data supporting use of ocrelizumab and other anti-CD20 therapies in the treatment of MS, as well as safety and practical considerations for prescribing. Lastly, we summarize remaining unanswered questions regarding the proper role of anti-CD20 therapy in MS, its limitations, and the future landscape of B cell based approaches to treatment. This article is protected by copyright. All rights reserved.
Pub.: 16 Dec '17, Pinned: 21 Feb '18
Abstract: B cells and T cells are two major players in the pathogenesis of multiple sclerosis (MS) and cooperate at various check points. B cells, besides serving as a source for antibody-secreting plasma cells, are efficient antigen presenting cells for processing of intact myelin antigen and subsequent activation and pro-inflammatory differentiation of T cells. This notion is supported by the immediate clinical benefit of therapeutic B cell depletion in MS, presumably abrogating development of encephalitogenic T cells. However, different B cell subsets strongly vary in their respective effect on T cell differentiation which may relate to B cell phenotype, activation status, antigen specificity and the immunological environment where a B cell encounters a naïve T cell in. In this regard, some B cells also have anti-inflammatory properties producing regulatory cytokines and facilitating development and maintenance of other immunomodulatory immune cells, such as regulatory T cells. Reciprocally, differentiated T cells influence T cell polarizing B cell properties establishing a positive feedback loop of joint pro- or anti-inflammatory B and T cell developments. Further, under the control of activated T helper cells, antigen-primed B cells can switch immunoglobulin isotype, terminally commit to the plasma cell pathway or enter the germinal center reaction to memory B Cell development. Taken together, B cells and T cells thus closely support one another to participate in the pathogenesis of MS in an inflammatory but also in a regulatory manner.
Pub.: 08 Jul '09, Pinned: 22 Feb '18
Abstract: Introduction Alemtuzumab is a monoclonal antibody that targets for the destruction CD52+ cells, particularly B and T cells. Alemtuzumab is approved in more than 50 countries around the world for the treatment of adult patients with relapsing remitting multiple sclerosis (MS). Areas covered In this review, the authors summarize biological, clinical and safety data related to the use of alemtuzumab in patients with MS. The authors then provide their expert opinion on alemtuzumab and the field as of whole before providing their perspectives for the future. Expert opinion Alemtuzumab is highly efficacious; more so than first line treatments but comparable to natalizumab. Treatment schedule makes alemtuzumab administration easy and attractive to patients. However, its safety profile makes it a choice for a very limited number of patients, in a specific disease window. As of now, a cure for MS remains elusive and there is an unmet need for a safe and highly potent agent at the level of and beyond the blood brain barrier.
Pub.: 09 Jan '18, Pinned: 21 Feb '18
Abstract: Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Whilst these anti-drug responses have been reported to be of no significance, we hypothesised that they will affect the depleting-capacity and treatment-response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population-level there was lack of influence of "ever-positive" alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and side-effects during the two year trial. This was not surprising as no one prior to first-infusion, and only 0.6% of people prior to the second-infusion had pre-infusion, neutralizing antibodies (Nabs). However, at the individual-level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, suggests that problems may occur in people requiring addition alemtuzumab-cycles. In addition, we also identified individuals, following 'post-marketing' alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Thus, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete-poorly, probably due to biological-response variation and NAbs and this may lead to treatment failure. Monitoring depletion following infusion and assessment of neutralizing response prior to re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure. This article is protected by copyright. All rights reserved.
Pub.: 17 Dec '17, Pinned: 21 Feb '18
Abstract: Natalizumab (NTZ, Tysabri®; Biogen-Idec, Cambridge, MA, USA) is a humanized anti-α4 integrin monoclonal antibody, largely used in the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS). Although the drug has shown great efficacy in clinical trials (AFFIRM and SENTINEL) and in post-marketing observational studies (TYGRIS), by reducing clinical signs as disability status progression, brain lesions and annual relapse rate, there are numerous papers concerning the associated risk of progressive multifocal leukoencephalopathy (PML). PML is a brain infection caused by John Cunningham virus (JCV) and its incidence is related to intrinsic and extrinsic risk factors, such as long-term natalizumab therapy (more than 24 infusion doses), previous pharmacological immunosuppressive treatment and JVC antibody-positive status. The identification of risk factors provides an instrument to improve treatment decisions and to obtain an accurate benefit-risk evaluation. In order to evaluate the most appropriate natalizumab-MS therapy and to obtain minor incidence of PML, an accurate description of risk factors and a biological markers identification are needed. This article review aims to list some biomarkers that have been proposed to evaluate the safety of natalizumab therapy.
Pub.: 23 Jan '18, Pinned: 21 Feb '18
Abstract: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19(+) B cells.To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS.This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19(+) B-cell count to ⩾80 cells/µL.Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively.Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.
Pub.: 17 Nov '17, Pinned: 21 Feb '18
Abstract: B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS).Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77).Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.
Pub.: 20 Jan '15, Pinned: 22 Feb '18
Abstract: Monoclonal antibodies are a potent therapeutic approach for relapsing-remitting multiple sclerosis. This group of medications comprises diverse mechanisms of action resulting in both shared and unique adverse effects. Areas covered: The major trials and safety profiles of natalizumab, alemtuzumab, daclizumab, rituximab, and ocrelizumab are discussed. While each drug has a unique safety profile, one of the potential safety concerns for all of these drugs is infection, including for some progressive multifocal leukoencephalopathy. Other potential side effects and required monitoring for each drug are addressed. Expert opinion: The treatment of multiple sclerosis is a balance between efficacy and safety. As a group, these medications are highly effective, but not without notable safety concerns; therefore more research is needed to understand the place these medications hold in the overall treatment algorithm.
Pub.: 21 Oct '16, Pinned: 21 Feb '18
Abstract: A lack of regulatory T cell function is a critical factor in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Ligation of the complement regulatory protein CD46 facilitates the differentiation of T helper 1 (TH1) effector cells into interleukin-10 (IL-10)-secreting type 1 regulatory T cells (Tr1 cells), and this pathway is defective in MS patients. Cleavage of the ectodomain of CD46, which contains three N-glycosylation sites and multiple O-glycosylation sites, enables CD46 to activate T cells. We found that stimulation of the T cell receptor (TCR)-CD3 complex was associated with a reduction in the apparent molecular mass of CD46 in a manner that depended on O-glycosylation. CD3-stimulated changes in CD46 O-glycosylation status reduced CD46 processing and subsequent T cell signaling. During T cell activation, CD46 was recruited to the immune synapse in a manner that required its serine-, threonine-, and proline-rich (STP) region, which is rich in O-glycosylation sites. Recruitment of CD46 to the immune synapse switched T cells from producing the inflammatory cytokine interferon-γ (IFN-γ) to producing IL-10. Furthermore, CD4(+) T cells isolated from MS patients did not exhibit a CD3-stimulated reduction in the mass of CD46 and thus showed increased amounts of cell surface CD46. Together, these data suggest a possible mechanism underlying the regulatory function of CD46 on T cells. Our findings may explain why this pathway is defective in patients with MS and provide insights into MS pathogenesis that could help to design future immunotherapies.
Pub.: 27 Oct '17, Pinned: 21 Feb '18
Abstract: Natalizumab was the first monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) based on its short-term efficacy and overall tolerability. However, the incidence of treatment-associated progressive multifocal leukoencephalopathy (PML), an infection of the brain caused by the John Cunningham virus, jeopardized this efficacious treatment from the beginning. Eight years after licensing of natalizumab, long-term studies confirm the considerable and sustained efficacy of natalizumab, although the PML complication still threatens one of the most successful treatments available for RRMS. During these years, considerable progress has been made in identification of risk factors that allow more effective management of PML risk. In addition, long-term studies to define better when to start or stop treatment and to optimize treatment strategies after cessation of natalizumab are ongoing, and hopefully will improve management and will allow natalizumab to remain as a valuable therapeutic option for patients with highly active RRMS.
Pub.: 18 Apr '14, Pinned: 21 Feb '18
Abstract: Background B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. Methods In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. Results The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. Conclusions Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).
Pub.: 22 Dec '16, Pinned: 21 Feb '18
Abstract: B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-remitting multiple sclerosis.We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1:1) via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg) ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-1a (30 μg) once a week. The randomisation list was not disclosed to the study centres, monitors, project statisticians or to the project team at Roche. All groups were double blinded to group assignment, except the interferon beta-1a group who were rater masked. At week 24, patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. Our primary endpoint was the total number of gadolinium-enhancing lesions (GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00676715.218 (99%) of the 220 randomised patients received at least one dose of ocrelizumab, 204 (93%) completed 24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-to-treat population of 218 patients, at week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68-97; p<0·0001) lower in the 600 mg ocrelizumab group than in the placebo group, and 96% (89-99; p<0·0001) lower in the 2000 mg group. In exploratory analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We noted serious adverse events in two of 54 (4%; 95% CI 3·0-4·4) patients in the placebo group, one of 55 (2%; 1·3-2·3) in the 600 mg ocrelizumab group, three of 55 (5%; 4·6-6·3) in the 2000 mg group, and two of 54 (4%; 3·0-4·4) in the interferon beta-1a group.The similarly pronounced effects of B-cell depletion with both ocrelizumab doses on MRI and relapse-related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-term trials.F Hoffmann-La Roche Ltd, Biogen Idec Inc.
Pub.: 04 Nov '11, Pinned: 21 Feb '18