Rituximab

Rituximab, sold under the brand name Rituxan among others, is a medication used to treat certain autoimmune diseases and types of cancer.[3] It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers.[3][4][5][6] It is given by slow injection into a vein.[3]

Rituximab
Monoclonal antibody
TypeWhole antibody
SourceChimeric (mouse/human)
TargetCD20
Clinical data
Trade namesRituxan, MabThera, Truxima, others[1]
Other namesrituximab-abbs, rituximab-pvvr
AHFS/Drugs.comMonograph
MedlinePlusa607038
License data
Pregnancy
category
  • AU: C [2]
  • US: N (Not classified yet) [2]
    Routes of
    administration    		Intravenous infusion
    Drug classMonoclonal antibody
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability100% (IV)
    Elimination half-life30 to 400 hours (varies by dose and length of treatment)
    ExcretionUncertain: may undergo phagocytosis and catabolism in RES
    Identifiers
    CAS Number
    DrugBank
    ChemSpider
    • none
    UNII
    KEGG
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.224.382
    Chemical and physical data
    FormulaC6416H9874N1688O1987S44
    Molar mass143859.7 g/mol g·mol−1
     NY (what is this?)  (verify)

    Common side effects, which often occur within two hours of the medication being given, include rash, itchiness, low blood pressure, and shortness of breath.[3] Other severe side effects include reactivation of hepatitis B in those previously infected, progressive multifocal leukoencephalopathy, and toxic epidermal necrolysis.[3][7] It is unclear if use during pregnancy is safe for the baby.[3][2]

    Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells.[8] When it binds to this protein it triggers cell death.[3]

    Rituximab was approved for medical use in 1997.[8] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[9] The wholesale price in the developing world as of 2014 was US$148–496 per 100 mg.[10] In the United Kingdom, the NHS paid approximately £182 per 100 mg in 2015.[11] In the United States, the average price paid was approximately $705 per 100 mg in 2014.[12] The typical treatment for rheumatoid arthritis (1,000 mg IV dose, 2 weeks apart) in the United States would have been $14,100 a month in 2014.[12] The patent expired in 2016, and a number of biosimilars have been launched.[13]

    Medical uses

    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.

    Rituximab is used in combination with fludarabine and cyclophosphamide to treat previously untreated and previously treated CD20-positive chronic lymphocytic leukemia.[14] Rituximab is used in combination with methotrexate to treat moderately-to severely-active rheumatoid arthritis with inadequate response to one or more TNF antagonist therapies.[14] Rituximab is used in combination with glucocorticoids to treat both granulomatosis with polyangiitis and microscopic polyangiitis.[14]

    Rituximab in combination with hyaluronidase human, sold as brand name "Rituxan Hycela", is used to treat follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.[15]

    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 lymphocyte predominant subtype, of Hodgkin's Lymphoma.[16] This also includes Waldenström's macroglobulinemia a type of NHL.[3]

    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.[17] 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.[18]

    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,[19] systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy and autoimmune anemias.[20] 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.[20][21]

    Other autoimmune diseases that have been treated with rituximab include autoimmune hemolytic anemia, pure red cell aplasia, thrombotic thrombocytopenic purpura (TTP),[22] idiopathic thrombocytopenic purpura (ITP),[23][24] Evans syndrome,[25] 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),[26] type 1 diabetes mellitus, Sjögren syndrome, anti-NMDA receptor encephalitis and Devic's disease,[27] Graves' ophthalmopathy,[28] autoimmune pancreatitis,[29] Opsoclonus myoclonus syndrome (OMS),[30] and IgG4-related disease.[31] There is some evidence that it is ineffective in treating IgA-mediated autoimmune diseases.[32]

    Organ transplants

    Rituximab is 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.

    Adverse events

    Serious adverse events, which can cause death and disability, include:[14][3]

    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.[36]

    At least one patient with rheumatoid arthritis developed PML after treatment with rituximab.[37]

    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.[38]

    Mechanisms of action
    Rituximab mechanisms of action; the three major independent mechanisms are (1) antibody dependent cellular cytotoxicity (ADCC), (2) complement mediated cytotoxicity (CMC), and (3) apoptosis; subset panel illustrates a schematic view of CD20 structure and rituximab.[39]
    Rituximab binding to CD20. The CD20 proteins are sticking out of the cell membrane, and rituximab, the Y-shaped antibody, is binding to the CD20 proteins.

    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.[40][41]

    The following effects have been found:[42]

    • 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.

    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.[43]

    History

    Rituximab was developed by researcher Nabil Hanna and coworkers at IDEC Pharmaceuticals under the name IDEC-C2B8. The U.S. patent for the drug was issued in 1998 and expired in 2015.[44]

    Based on its safety and effectiveness in clinical trials,[45] 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.[46] 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.[47] In 2010, it was approved by the European Commission for maintenance treatment after initial treatment of follicular lymphoma.[48]

    Rituximab is currently co-marketed by Biogen and Genentech in the U.S., by Hoffmann-La Roche in Canada and the European Union, Chugai Pharmaceuticals, Zenyaku Kogyo in Japan and AryoGen in Iran.

    It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[9]

    In 2014 Genentech reclassified rituxan as a specialty drug, a class of drugs that are only available through specialty distributors in the US.[49] Because wholesalers discounts and rebates no longer apply, hospitals would pay more.[49]

    Originally available for intravenous injection (e.g. over 2.5 hrs), in 2016 it gained EU approval in a formulation for subcutaneous injection for CLL.[50]

    Patents on the drug in expired in Europe in February 2013 and in the US in September 2016.[51] By November 2018, several biosimilars had been approved in the US, India, the European Union, Switzerland, Japan and Australia.[52][51][53]

    Research

    Chronic fatigue syndrome

    Rituximab did not improve symptoms in patients with chronic fatigue syndrome in a trial published in 2019.[54][55] 22% of participants had serious events.[54] This potential use was investigated after improvements in chronic fatigue syndrome was seen in two cancer patients treated with rituximab.[56]

    Intrathecal

    For CNS diseases, rituximab could be administered intrathecally and this possibility is under study.[57]

    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.[58]
    • Third-generation anti-CD20s such as obinutuzumab have a glycoengineered Fc fragment (Fc)[59] with enhanced binding to Fc gamma receptors, which increase ADCC (antibody-dependent cellular cytotoxicity).[60] 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.[61]

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