Rituximab

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and adults, but not recommended in elderly patients), rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion (injected slowly through an IV line).

Common side effects which often occur within two hours of the medication being given include rash, itchiness, low blood pressure, and shortness of breath. Infections are also common.

Severe side effects include reactivation of hepatitis B in those previously infected, progressive multifocal leukoencephalopathy, toxic epidermal necrolysis, and death. It is unclear if use during pregnancy is safe for the developing fetus or newborn baby, but it is not proven harmful.

Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. When it binds to this protein it triggers cell death.

Rituximab was approved for medical use in 1997. It is on the World Health Organization's List of Essential Medicines. Rituxan is co-marketed by Biogen and Genentech in the US, by Roche elsewhere except Japan, and co-marketed by Chugai Pharmaceuticals and Zenyaku Kogyo in Japan.

Medical uses
Rituximab is a chimeric monoclonal antibody targeted against CD20, a surface antigen present on B cells. It acts by depleting normal as well as pathogenic B cells while sparing plasma cells and hematopoietic stem cells, which do not express the CD20 surface antigen.

In the United States, rituximab is indicated to treat:


 * 1) non-Hodgkin lymphoma (NHL)
 * 2) chronic lymphocytic leukemia (CLL)
 * 3) rheumatoid arthritis having inadequate response to one or more TNF inhibitors
 * 4) vasculitides such as granulomatosis with polyangiitis and microscopic polyangiitis
 * 5) moderate to severe pemphigus vulgaris
 * 6) in combination with chemotherapy for children (≥ 6 months to < 18 years) with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), or mature acute B-cell leukemia (B-AL).

Blood cancers
Rituximab is used to treat cancers of the white blood system such as leukemias and lymphomas, including non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and nodular lymphocyte predominant Hodgkin's lymphoma. This also includes Waldenström's macroglobulinemia, a type of NHL. Rituximab in combination with hyaluronidase human, sold under the brand names MabThera SC and Rituxan Hycela, is used to treat follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. It is used in combination with fludarabine and cyclophosphamide to treat previously untreated and previously treated CD20-positive chronic lymphocytic leukemia.

Autoimmune diseases
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 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 the European Union, the license is slightly more restrictive: it is licensed for use in combination with methotrexate 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, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis (e.g., granulomatosis with polyangiitis), bullous skin disorders (for example, pemphigus, pemphigoid—with very encouraging results of approximately 85% rapid recovery in pemphigus, according to a 2006 study), type 1 diabetes mellitus, Sjögren syndrome, anti-NMDA receptor encephalitis and Devic's disease(Anti-AQP4 disease, MOG antibody disease), Graves' ophthalmopathy, autoimmune pancreatitis, Opsoclonus myoclonus syndrome (OMS), and IgG4-related disease. There is some evidence that it is ineffective in treating IgA-mediated autoimmune diseases.

Adverse events
Serious adverse events, which can cause death and disability, include:


 * Severe infusion reaction
 * Cardiac arrest
 * Cytokine release syndrome
 * Tumor lysis syndrome, causing acute kidney injury
 * Infections
 * Progressive multifocal leukoencephalopathy (PML) caused by JC virus reactivation
 * Hepatitis B reactivation
 * Other viral infections
 * 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.

At least one patient with rheumatoid arthritis developed PML after treatment with rituximab.

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.

A major concern with continuous rituximab treatment is the difficulty to induce a proper vaccine response. This was brought into focus during the COVID-19 pandemic, where persons with multiple sclerosis and rituximab treatment had higher risk of severe COVID-19. In persons previously treated with rituximab for multiple sclerosis, 9 of 10 patients who delayed re-dosing until B cell counts passed 40/μL developed protective levels of antibodies after vaccination with tozinameran.

Mechanisms of action




The antibody binds to the cell surface protein 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. 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 is relatively ineffective in elimination of cells with low CD20 cell-surface levels. It 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 changes 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.
 * Preferential elimination of malignant B cells with high CD20 levels and high BCR signaling propensity, especially in chronic lymphocytic leukemia (CLL).
 * 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.
 * Rituximab also induces a release of some chronic lymphocytic leukemia cells from immune niches, which might make them more sensitive to chemotherapy used in combination with an anti-CD20 antibody.

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.

Rituximab binds to amino acids 170–173 and 182–185 on CD20, which are physically close to each other as a result of a disulfide bond between amino acids 167 and 183.

History
Rituximab was developed by IDEC Pharmaceuticals under the name IDEC-C2B8. The US patent for the drug was issued in 1998 and expired in 2015.

Based on its safety and effectiveness in clinical trials, rituximab was approved by the US Food and Drug Administration (FDA) 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.

In 2014, Genentech reclassified rituxan as a specialty drug, a class of drugs that are only available through specialty distributors in the US. Because wholesalers discounts and rebates no longer apply, hospitals would pay more.

Originally available for intravenous injection (e.g. over 2.5 hrs), in 2016, it gained EU approval in a formulation for subcutaneous injection for B-cell CLL/lymphoma (CLL).

In June 2017, the US FDA granted regular approval to the combination of rituximab and hyaluronidase human (brand name Rituxan Hycela) for adults with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. The combination is not indicated for the treatment of non-malignant conditions. The combination was approved based on clinical studies SABRINA/NCT01200758 and MabEase/NCT01649856.

In September 2019, the US FDA approved rituximab injection to treat granulomatosis with polyangiitis and microscopic polyangiitis in children two years of age and older in combination with glucocorticoids (steroid hormones). It is the first approved treatment for children with these rare vasculitis diseases, in which a person's small blood vessels become inflamed, reducing the amount of blood that can flow through them. This can cause serious problems and damage to organs, most notably the lungs and the kidneys. It also can impact the sinuses and skin. Rituximab was approved by the FDA to treat adults with granulomatosis with polyangiitis and microscopic polyangiitis in 2011.

In December 2021, the US FDA approved rituximab in combination with chemotherapy for children aged 6 months to 18 years with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia. Efficacy was evaluated in Inter-B-NHL Ritux 2010, a global multicenter, open-label, randomized 1:1 trial of participants six months in age or older with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or B-cell acute leukemia. Advanced stage was defined as stage III with elevated lactose dehydrogenase level (lactose dehydrogenase greater than twice the institutional upper limit of normal values) or stage IV B-cell non-Hodgkin's lymphoma or B-cell acute leukemia. Participants were randomized to Lymphome Malin B chemotherapy that consisted of corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide, and triple drug (methotrexate/cytarabine/corticosteroid) intrathecal therapy alone or in combination with rituximab or non-US licensed rituximab, administered as six infusions of rituximab IV at a dose of 375 mg/m2 as per the Lymphome Malin B scheme.

Economics
Patents on rituximab expired in the European Union in February 2013, and in the United States in September 2016. , several biosimilars had been approved in the US, India, the European Union, Switzerland, Japan, and Australia. The US FDA approved Truxima (rituximab-abbs) in 2018, Ruxience (rituximab-pvvr) in 2019, and Riabni (rituximab-arrx) in 2020. The Riabni is about $3600 per 500 mg, wholesale, list. Truxima is about the same price as Riabni - 10% less than Rituxan, while Ruxience is 24% less than Rituxan.

Myalgic encephalomyelitis/chronic fatigue syndrome
Rituximab did not improve symptoms in patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in a trial published in 2019. Twenty-two percent of participants had serious events. This potential use was investigated after improvements in ME/CFS was seen in two cancer patients treated with rituximab.

Intrathecal
For CNS diseases, rituximab could be administered intrathecally and this possibility is under study.

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). This strategy for enhancing a monoclonal antibody's ability to induce ADCC takes advantage of the fact that the displayed Fc glycan controls the antibody's affinity for Fc receptors.