Multiple sclerosis (MS) is a chronic autoimmune disease impacting the brain, spinal cord, and optic nerves, collectively known as the central nervous system. In MS, the body’s immune system mistakenly attacks myelin, the protective sheath surrounding nerve fibers, leading to inflammation and damage. This damage disrupts the communication between the brain and the rest of the body, causing a range of symptoms. B cell depletion therapy represents a significant treatment approach for managing the progression and symptoms of MS.
The Role of B Cells in Multiple Sclerosis
B cells, a type of white blood cell, play an active part in the development and progression of multiple sclerosis. While their primary function is to produce antibodies, in MS, they contribute to the autoimmune attack on the central nervous system. These cells can present antigens, which are molecules that trigger an immune response, to other immune cells like T cells, thereby initiating or sustaining inflammatory processes. This interaction helps to direct the immune system’s attack against myelin and nerve fibers.
B cells also produce various signaling proteins called cytokines, which promote inflammation and contribute to tissue damage within the brain and spinal cord. Some of these cytokines can directly harm oligodendrocytes, the cells responsible for producing myelin, or indirectly enhance the activity of other damaging immune cells.
Furthermore, B cells mature into plasma cells, which secrete antibodies that can directly target components of the myelin sheath or neuronal structures. These autoantibodies contribute to demyelination and neuronal injury, driving the pathology observed in MS.
The presence of B cells and their products within the central nervous system, particularly in MS lesions and cerebrospinal fluid, supports their involvement. Targeting these cells offers a way to reduce inflammation and slow disease activity by disrupting these harmful processes.
Mechanism of B Cell Depletion
B cell depletion therapies for multiple sclerosis primarily function by targeting a specific protein called CD20, found on the surface of certain B cells. These therapies involve engineered proteins, known as monoclonal antibodies, that are designed to bind precisely to the CD20 marker. Once the monoclonal antibody attaches to CD20, it marks the B cell for destruction by the body’s own immune system.
The elimination of these targeted B cells occurs through several biological pathways. One common mechanism is antibody-dependent cellular cytotoxicity (ADCC), where immune cells such as natural killer cells recognize the antibody-coated B cells and then destroy them. Another pathway is complement-dependent cytotoxicity (CDC), where proteins of the complement system, a part of the immune system, bind to the antibody-coated B cells and create pores in their membranes, leading to cell lysis.
By removing these CD20-expressing B cells from circulation, the therapy aims to reduce the number of immune cells that contribute to inflammation and damage in the central nervous system. This reduction in B cell numbers subsequently decreases their capacity to present antigens, produce pro-inflammatory cytokines, and secrete harmful autoantibodies. The therapy specifically targets mature B cells and pre-B cells, while sparing plasma cells and B cell precursors, which allows for the maintenance of some antibody production and the eventual repopulation of B cells.
Approved B Cell Depletion Therapies
Ocrelizumab, marketed as Ocrevus, is a humanized monoclonal antibody that selectively targets CD20-expressing B cells. It is approved for both relapsing-remitting MS (RRMS) and primary progressive MS (PPMS), making it a notable option for a broader range of MS types. Ocrelizumab is administered as an intravenous infusion, typically given twice a year after an initial loading dose.
Ofatumumab, known by the brand name Kesimpta, is another fully human monoclonal antibody that also targets the CD20 protein on B cells. This therapy is approved for the treatment of relapsing forms of MS, which include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. A key difference in administration is that ofatumumab is given as a subcutaneous injection, which patients can often administer themselves at home on a monthly basis following an initial weekly dosing schedule.
Rituximab, sold under various brand names like Rituxan, is a chimeric (mouse-human) monoclonal antibody that similarly targets CD20. Although rituximab is not specifically approved by regulatory bodies for MS, it is widely used off-label for various forms of the disease, including relapsing-remitting and progressive MS, particularly in some regions or clinical settings. Like ocrelizumab, rituximab is generally administered as an intravenous infusion, with dosing schedules varying based on clinical practice and individual patient needs, often given every six months or annually.
Receiving and Managing Therapy
Ocrelizumab and rituximab are typically given as intravenous infusions in a clinic or hospital setting. These infusions usually take several hours, and patients are monitored for any immediate reactions during and after the administration. Ofatumumab, in contrast, is administered as a subcutaneous injection, allowing for self-administration at home after proper training.
Patients undergoing B cell depletion therapy may experience common side effects. Infusion-related reactions, such as itching, rash, fever, or headache, can occur, particularly with intravenous infusions, and are often managed with pre-medications like antihistamines and corticosteroids. A more significant concern is an increased risk of infections, as B cells play a role in the immune response; upper respiratory tract infections, urinary tract infections, and herpes virus infections are among those more frequently observed. Patients are advised to report any signs of infection promptly.
Ongoing monitoring is an important part of managing B cell depletion therapy. Regular blood tests are conducted to assess lymphocyte counts, particularly B cell levels, and to monitor for any changes in liver or kidney function. Before starting therapy, and periodically during treatment, patients may undergo screening for certain infections, such as hepatitis B or progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection. Patients should discuss any new or worsening symptoms with their healthcare provider to ensure proper management and to address any potential complications.