August 16, 2018 News by Iqra Mumal, MSc

Lemtrada Can Lower Number of B-cells Infiltrating Nervous System and Forming Clumps, Animal Study Shows

Treating mice in a model of multiple sclerosis with Lemtrada (alemtuzumab) prevented the formation of B-cell aggregates in the animals’ central nervous system and disrupted already existing ones, researchers report. The treatment also reduced disease activity when administered at the peak of disease. The study, “Anti-CD52 antibody treatment depletes B…

August 3, 2018 News by Marta Figueiredo, PhD

Blood Levels of IgG3 Antibodies May Predict Faster Shift to MS in Clinically Isolated Syndrome Patients, Study Says

Higher-than-usual levels of specific antibodies in the blood of patients with clinically isolated syndrome (CIS) may predict a faster progression to multiple sclerosis (MS), an Australian study reports. The specific antibody is known as IgG3, an immunoglobulin known to promote inflammation. The study, “Higher Serum Immunoglobulin G3 Levels May Predict…

May 1, 2018 News by Patricia Inacio, PhD

#AAN2018 — Ocrevus Lowers Immune Response to Vaccines in Relapsing MS, Phase 3 Trial Shows

Treatment with Ocrevus (ocrelizumab) is linked to a reduced immune response to vaccinations in patients with relapsing multiple sclerosis (MS), according to a Phase 3 trial. These results were recently presented at the 2018 American Academy of Neurology (AAN) Annual Meeting in Los Angeles in a presentation titled, “Effect of Ocrelizumab on Vaccine Responses in Patients With Multiple Sclerosis.” Genentech’s Ocrevus is an approved MS therapy that targets the CD20 protein located on the surface of B-cells, targeting the cells for destruction. B-cells are immune system cells involved, for example, in the production of antibodies necessary to fight off infection. At the AAN meeting, researchers reported that in MS patients, treatment with Ocrevus decreased the ability of B-cells to activate other immune cells, improving the rate of MS attacks. Penn Medicine neurologist Amit Bar-Or, MD, presented these findings, which showed that interactions between different classes of immune cells, such as B- and T-cells, promote MS attacks. Vaccination against infections is an important part of the management of patients with MS. So, in a second study (NCT02545868), researchers investigated the impact treatment with Ocrevus has on patient response to vaccines. They recruited 102 patients with relapsing MS and randomized them in two groups. In group A, 68 people received a single dose of 600 mg Ocrevus (administered into the blood); in group B, 34 patients received no disease-modifying therapy or interferon-beta. All patients were then administered vaccines for tetanus, seasonal flu, and pneumococcus. Patients in group A received the vaccines 12 weeks after they were treated with Ocrevus, while group B patients received the vaccines on day one. Researchers also tested patients’ response to a novel protein (an antigen) never "seen" by their immune system, called keyhole limpet hemocyanin (KLH) neoantigen. The vaccinations led to an immune system response in all patients, but the level of response in patients treated with Ocrevus was lower. A positive response to the tetanus vaccine at eight weeks after treatment was 23.9% in group A (Ocrevus) compared with 54.5% in group B (no treatment); the response to pneumococcus vaccination was 71.6% in group A and 100% in group B. After four weeks of treatment, the levels of antibodies against the different strains of the flu virus were lower in Ocrevus-treated patients than in the control group, ranging from 55.6% to 80.0% in the Ocrevus group compared with 75.0% to 97.0% in the controls. The immune response to the neoantigen KLH was also decreased in the Ocrevus group. "This study shows that while people with MS treated with ocrelizumab [Ocrevus] can still mount vaccine responses, it's not nearly as strong as prior to treatment," Bar-Or said in a press release. "While antibody responses were reduced in the ocrelizumab treated patients, they still responded to a certain level," he said. "This is valuable information in terms of seasonal vaccines such as the flu — it appears safe for patients taking ocrelizumab to get vaccinated and vaccination is likely to provide them with at least some protection from such infections." These findings correlate with standard guidelines that advise patients to undergo vaccinations six weeks before they start treatment with Ocrevus.

April 18, 2018 News by Patricia Inacio, PhD

#AAN2018 – Ocrevus Decreases Biomarkers of MS Patients’ Nerve Cell Damage, Phase 3 Trial Shows

Genentech’s Ocrevus (ocrelizumab) reduces levels of cerebrospinal fluid biomarkers that denote nerve cell damage in multiple sclerosis patients, a Phase 3 clinical trial shows. Researchers will present the results at the American Academy of Neurology’s annual meeting in Los Angeles, April 21-27. The presentation will be titled “Interim Analysis of the…

February 26, 2018 News by Alice Melão, MSc

Oxygen Sensor Protein Can Regulate B-Cell Anti-inflammatory Response in MS, Study Shows

Oxygen sensor proteins can regulate immune B-cell activity, preventing inflammation in autoimmune disorders such as multiple sclerosis, a study reports. The research, titled “Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease,” was published in Nature Communications. An autoimmune disease is one in…

November 13, 2017 News by Patricia Silva, PhD

Sanofi and Principia Join to Develop Potential B-Cell-targeting Oral MS Treatment

Sanofi Genzyme and Principia Biopharma have entered into a license agreement to advance the clinical development of PRN2246, an oral drug candidate for the treatment of multiple sclerosis and other diseases of the central nervous system. PRN2246 is an inhibitor of the Bruton’s tyrosine kinase, an enzyme encoded by the BTK gene that plays a crucial role in B-cell development and the B-cell signaling pathway. B-cells are known to be involved in the development of autoimmune diseases that affect the nervous system, including multiple sclerosis. PRN2246 is an orally available therapy designed to easily access the central nervous system (brain and spinal cord) by crossing the blood-brain barrier, and impact the signaling of immune cells and brain cells involved in autoimmunity and inflammatory processes. The drug is designed to safely and effectively modulate B-cell function without depleting these cells. A Phase 1 clinical trial is now testing the drug's safety in healthy volunteers. Under the agreement, which is expected to close shortly, Principia will grant Sanofi an exclusive, worldwide license to develop and commercialize PRN2246. Principia, in return, will receive $40 million in upfront payments from Sanofi, and future milestone payments could reach $765 million. Principia will retain the option to co-fund the treatment's Phase 3 development in exchange for other royalties in the United States. Principia has developed a novel way to design and develop better and safer therapies based on oral small molecules. The company uses its proprietary Tailored Covalency technology to develop its drug candidates, which are, according to the company's website, safer, and more selective, potent and durable than other available treatments. The terms of this licensing agreement are still subject to customary regulatory approval.

October 24, 2017 News by Alice Melão, MSc

Two Studies Show IL-35 Protein’s Potential to Curb Inflammation in Autoimmune Diseases

An immune signaling protein called interleukin-35 has anti-inflammatory properties that scientists might harness to develop a therapy for multiple sclerosis and other autoimmune disorders, according to two studies. Researchers at the National Eye Institute of the National Institutes of Health discovered that a subunit of interleukin 35, which is also known as IL-35, significantly reduced inflammation in mouse models of eye inflammation and multiple sclerosis. Immune B-cells produce IL-35 to communicate with, and regulate the behavior of, surrounding cells. In a previous study, the research team found that the protein could inhibit inflammation in the eyes of animals with autoimmune uveitis, or inflammation of the inner layers of the eye. An autoimmune disease is one in which the immune system attacks healthy cells instead of invaders. A drawback of trying to use a synthetic version of IL-35 as a therapy is that it's difficult to produce because of its complex structure and it's unstable in a solution. Natural IL-35 is composed of two subunits, IL-12p35 and Ebi3, which bind to create the full protein. The team wondered if they could use a subunit, instead of the full protein, as an anti-inflammatory agent. Their study, “IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease,” was published in the journal Nature Communications, They demonstrated that the IL-12p35 subunit could generate anti-inflammatory effects similar to those of the full IL-35 protein. Giving IL-12p35 to mice with uveitis promoted the expansion of immune B-cells that counteract autoimmune responses, reversing the animals' eye symptoms. In the second study, researchers discovered that the subunit tempered inflammation in a mouse model of multiple sclerosis. Giving the animals IL-12p35 every other day for up to 12 days promoted immune cell proliferation that inhibited inflammation in the mice's brains and spinal cords, improving their symptoms. The research demonstrated IL-35 and its subunit's potential to treat nerve-inflammation disorders. The team published its findings in the journal Frontiers of Immunology. The article is titled “IL-12p35 inhibits neuroinflammation and ameliorates autoimmune encephalomyelitis.” The team is now looking at IL-12p35's ability to treat other degenerative eye diseases, such as diabetic retinopathy and macular degeneration.

October 19, 2017 News by Patricia Silva, PhD

#MSParis2017 – TG Therapeutics’ Ublituximab Depletes Harmful B-cells and Lowers MRI Lesions, Trial Shows

TG Therapeutics’ ublituximab nearly eradicated a type of immune B-cell believed to be involved in multiple sclerosis, according to a Phase 2 clinical trial. The result was that none of the patients had a relapse during the first six months of the trial, which is continuing, researchers said. In addition, ublituximab reduced the brain and spinal cord lesions of the relapsing MS patients involved in the trial and prevented new ones from forming. The company will present the interim trial results in three poster presentations at the 7th Joint ECTRIMS-ACTRIMS Meeting in Paris, Oct. 25-28. Meanwhile, researchers will continue to study the effectiveness of ublituximab, a B-cell-depleting antibody, versus a placebo, for another six months. The trial is being held at several U.S. medical facilities. Participants receive two initial infusions of ublituximab or a placebo on day 1 and 15 during the first 28 days. After this initial period, those in the placebo-group are also given ublituximab and followed for 52 weeks. A key trial finding was that over the initial 24 weeks of the trial, the treatment nearly wiped out a type of B-cell known as CD20 that scientists believe is involved in the development of MS. Only 1 percent of the B-cells remained after a month. While helpful immune T-cell numbers dropped slightly after the first ublituximab infusion, they bounced back quickly. Researchers also reported a reduction in patients' magnetic resonance imaging (MRI) lesions, with no new inflammatory lesions appearing during the six months. So far, none of the trial participants has had a serious adverse event. Most of the adverse events were mild or moderate and related to the infusions. The trial also demonstrated that speeding up infusions did not increase infusion-related reactions. The speed-up results indicated that — if proven effective and safe — ublituximab will be more convenient for patients than B-cell-depleting drugs that require infusions stretching over several hours.

October 10, 2017 News by Patricia Silva, PhD

Researchers Identify Quality Control Regulatory Cells That Prevent the Production of Autoantibodies

The discovery of an immune cell quality control mission may have put scientists a step closer to understanding how autoimmune conditions such as multiple sclerosis arise. University of Alabama at Birmingham researchers identified regulatory immune cells with the quality control mission of destroying antibody-producing B-cells that mistakenly target the body's own tissue after an infection. An autoimmune disease is one in which the immune system attacks healthy tissue or organs instead of invaders. Eventually, the insight could lead researchers to new approaches for treating MS and other conditions caused by aberrant immune reactions. The Alabama researchers were studying the processes involved in the body's defense against a real threat — the influenza virus — when they discovered a population of immune cells whose action is relevant to autoimmune diseases. The study noted that T follicular regulatory cells appeared in the late stages of influenza infection. Their objective was to prevent the immune system from generating self-reactive antibodies — that is, those that attack the body's own tissue. These cells are poorly understood, the researchers explained. Their experiments, published in the journal Nature Immunology, focused on the molecular events surrounding the cells’ actions.  The team discovered that about a week after the infection, levels of an immune regulator called the IL-2 protein increased. This triggered the multiplication of common regulatory T-cells, or Tregs. When this phase of the immune reaction was fading, TFR cells started multiplying, reaching peak numbers about a month after infection. The formation of the TFR cells was therefore tightly linked to the processes controlling Treg production, researchers said, with falling levels of IL-2 allowing the new phase of the immune response. The TFR cells migrated to the lymph nodes — the headquarters of antibody-producing B-cells. Here, B-cells proliferate and change their antibody-producing genes to create new, stronger antibodies. But sometimes the gene changes, or mutations, give rise to an antibody that attacks the body, instead of invaders. Researchers discovered that TFR cells prevented B-cells, which gave rise to autoantibodies, from accumulating in the lymph nodes. Importantly, the TFR cells had no impact on the immune processes targeting the influenza virus. When researchers prevented TFR cells from forming or removed them from mice, the animals started producing autoantibodies, they explained. While this suggested that people with autoimmune diseases may have flawed TFR processes, the study did not investigate this, making the topic a possibility for future studies.

July 10, 2017 News by Patricia Silva, PhD

B-cell-secreted Toxins Kill Neurons and Myelin-Producing Cells, MS Study Reports

B-cells of patients with relapsing-remitting multiple sclerosis (RRMS) secrete substances that are toxic to both neurons and neuron-protecting myelin-forming cells, causing both kinds to die, according to a study. Despite analyses of numerous inflammatory and other factors believed to drive MS processes, researchers were unable to identify the molecules that are toxic, however. Dr. Robert Lisak of Wayne State University in Detroit, Dr. Amit Bar-Or of McGill University in Montreal and their teams are now working on identifying the factor, and learning if the process is also involved in progressive MS. Their study, “B-cells from patients with multiple sclerosis induce cell death via apoptosis in neurons in vitro,” was published in the Journal of Neuroimmunology. It demonstrated that B-cells gathered from the blood of RRMS patients killed lab-grown neurons and oligodendrocyte cells, which form myelin, a protecting coating for nerve cells. Deterioration of the myelin coating and the death of neurons are hallmarks of MS. An earlier study the team conducted indicated that B-cells from MS patients could kill oligodendrocytes. But since the experiments involved only three patients and three controls, the team scaled up their experiments to include 13 patients and an equal number of controls. Both rat and human neurons died when mixed with MS-derived B-cells. In contrast, B-cells from healthy people had little or no impact on the survival of the brain cells. Researchers also discovered that the secreted toxic molecules had no impact on other types of central nervous system cells — astrocytes and microglia. The toxins killed only neurons and myelin-producing cells. The B-cells triggered a process called apoptosis, or programmed cell death, researchers said. This is basically a suicide program. It tells a cell to die when exposed to stressful factors or toxins. The process differs from cell disintegration. Despite thoroughly screening about 40 inflammation-related substances, researchers were unable to identify any factors that caused the cells to die. The National MS Society and the Research Foundation of the MS Society of Canada funded the research, which the U.S. society highlighted in a news release. In the newest phase of the study, researchers will try to learn more about the processes underlying neuron and myelin-related cell deaths and identify the factors responsible. In addition to testing B-cells from progressive MS patients, the team will examine patients with other autoimmune conditions to see if the process is unique to MS or not. Researchers increasingly realize that B-cells are important to MS processes. This observation was underscored by U.S. regulators' approval of the B-cell depleting therapy Ocrevus (ocrelizumab) at treatment for both relapsing and primary progressive MS.

June 28, 2017 News by Patricia Silva, PhD

In Ongoing Phase 2 Trial, Ublituximab Seen to Effectively and Safely Deplete B-cells

TG Therapeutics’ investigational treatment — ublituximab (TG-1101) — led to a near total depletion of B-cells in patients with relapsing forms of multiple sclerosis (MS) taking part in an ongoing Phase 2 trial, the company recently announced. In addition, the company said that ublituximab had an infusion time as short as one hour, without excessive side…

June 22, 2017 News by Alice Melão, MSc

MS Researcher Stephen Hauser, MD, Awarded the 2017 Taubman Prize

Stephen L. Hauser, MD, director of the University of California, San Francisco (UCSF)‘s Weill Institute for Neurosciences, has been awarded the 2017 Taubman Prize for Excellence in Translational Medical Research. Recognized for scientific work that challenged the way multiple sclerosis (MS) is regarded, Hauser’s discoveries have opened new therapeutic…

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