Open Access Articles- Top Results for Rituximab
Journal of Nuclear Medicine & Radiation TherapyIodine-131 Rituximab Radioimmunotherapy: Durable Control of Follicular Lymphoma
Journal of Physical Chemistry & BiophysicsAFM/TEM Complementary Structural Analysis of Surface-Functionalized Nanoparticles
Journal of Nephrology & TherapeuticsRituximab for Treatment of Focal Segmental Glomerulosclerosis in a Child: A Case Report
Journal of Nephrology & TherapeuticsRituximab for Treatment of Focal Segmental Glomerulosclerosis in a Child: A Case Report
Journal of Blood & LymphHepatitis B Reactivation in Patients with Hematological Malignancies and Stem Cell Transplantation
|intravenous infusion only (never bolus or "push")|
|Half-life||30 to 400 hours (varies by dose and length of treatment)|
|Excretion||Uncertain: may undergo phagocytosis and catabolism in RES|
|14px (what is this?)|
Rituximab (trade names Rituxan, MabThera and Zytux) is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. Rituximab destroys B cells and is therefore used to treat diseases which are characterized by excessive numbers of B cells, overactive B cells, or dysfunctional B cells. This includes many lymphomas, leukemias, transplant rejection, and autoimmune disorders.
Based on its safety and effectiveness in clinical trials, rituximab was approved by the U.S. Food and Drug Administration in 1997 to treat B-cell non-Hodgkin lymphomas resistant to other chemotherapy regimens. Rituximab, in combination with CHOP chemotherapy, is superior to CHOP alone in the treatment of diffuse large B-cell lymphoma and many other B-cell lymphomas. In 2010 it was approved by the European Commission for maintenance treatment after initial treatment of follicular lymphoma.
It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.
Rituximab destroys both normal and malignant B cells that have CD20 on their surfaces, and is therefore used to treat diseases which are characterized by having too many B cells, overactive B cells, or dysfunctional B cells.
In multiple myeloma, treatment with rituximab fails to deplete circulating CD20+ B or plasma cells, even after up to four cycles of treatment; in some patients, rituximab treatment increases the number of circulating CD20+ B cells.
Rituximab has been shown to be an effective rheumatoid arthritis treatment in three randomised controlled trials and is now licensed for use in refractory rheumatoid disease. In the United States, it has been FDA-approved for use in combination with methotrexate (MTX) for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more anti-TNF-alpha therapy. In Europe, the license is slightly more restrictive: it is licensed for use in combination with MTX in patients with severe active RA who have had an inadequate response to one or more anti-TNF therapy.
There is some evidence for efficacy, but not necessarily safety, in a range of other autoimmune diseases, and rituximab is widely used off-label to treat difficult cases of multiple sclerosis, systemic lupus erythematosus, Chronic inflammatory demyelinating polyneuropathy and autoimmune anemias. The most dangerous, although among the most rare, side effect is progressive multifocal leukoencephalopathy (PML) infection, which is usually fatal however only a very small number of cases have been recorded occurring in autoimmune diseases.
Other autoimmune diseases that have been treated with rituximab include autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis (for example granulomatosis with polyangiitis, formerly Wegener's), bullous skin disorders (for example pemphigus, pemphigoid—with very encouraging results of approximately 85% rapid recovery, in the treatment of pemphigus, according to a 2006 study), type 1 diabetes mellitus, Sjogren's syndrome, Anti-NMDA receptor encephalitis and Devic's disease, Graves' ophthalmopathy, and Autoimmune pancreatitis.
An October 2011 study from Norway suggests that rituximab can help patients with chronic fatigue syndrome, leading to a proposed theory relating Chronic fatigue Syndrome to other autoimmune conditions however more research is required to verify if such a link exists. A clinical trial has been completed and a new open-label trial has begun. Additionally a Phase III study in Norway has now been fully funded. There are also plans and campaigns running to try and set up a smaller UK trial at University College London.
Anti-rejection treatment for organ transplants
Rituximab is now being used off-label in the management of kidney transplant recipients. This drug may have some utility in transplants involving incompatible blood groups. It is also used as induction therapy in highly sensitized patients going for kidney transplantation. The use of rituximab has not been proven to be efficacious in this setting and like all depleting agents, carries with it the risk of infection.
The antibody binds to CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. CD20 does not shed, modulate or internalise. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.
Rituximab tends to stick to one side of B cells, where CD20 is, forming a cap and drawing proteins over to that side. The presence of the cap changed the effectiveness of natural killer (NK) cells in destroying these B cells. When an NK cell latched onto the cap, it had an 80% success rate at killing the cell. In contrast, when the B cell lacked this asymmetric protein cluster, it was killed only 40% of the time.
The following effects have been found:
- The Fc portion of rituximab mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
- Rituximab has a general regulatory effect on the cell cycle.
- It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen).
- It elicits shedding of CD23.
- It downregulates the B cell receptor.
- It induces apoptosis of CD20+ cells.
The combined effect results in the elimination of B cells (including the cancerous ones) from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.
- Severe infusion reaction.
- Cardiac arrest
- Cytokine release syndrome
- Tumor lysis syndrome, causing acute renal failure
- Immune toxicity, with depletion of B cells in 70% to 80% of lymphoma patients
- Pulmonary toxicity
- Bowel obstruction and perforation
Two patients with systemic lupus erythematosus died of progressive multifocal leukoencephalopathy (PML) after being treated with rituximab. PML is caused by activation of JC virus, a common virus in the brain which is usually latent. Reactivation of the JC virus usually results in death or severe brain damage.
Rituximab has been reported as a possible cofactor in a chronic Hepatitis E infection in a person with lymphoma. Hepatitis E infection is normally an acute infection, suggesting the drug in combination with lymphoma may have weakened the body's immune response to the virus.
Other anti-CD20 monoclonals
The efficacy and success of Rituximab has led to some other anti-CD20 monoclonal antibodies being developed:
- ocrelizumab, humanized (90%-95% human) B cell-depleting agent.
- ofatumumab (HuMax-CD20) a fully human B cell-depleting agent.
- Third-generation anti-CD20s such as obinutuzumab have a glycoengineered Fc fragment (Fc) with enhanced binding to Fc gamma receptors, which increase ADCC (antibody-dependent cellular cytotoxicity). Modifications in the variable regions can enhance apoptosis.
The added value of a humanized molecule in oncology, compared to the original design, has not been demonstrated to this date.
Another approach to B cell diseases is to block the interaction of B cell survival or growth factors with their receptors on B cells. The monoclonal antibody Belimumab and atacicept are examples of such an approach.
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