Monoclonal antibody | |
---|---|
Type | Whole antibody |
Source | Chimeric (mouse/human) |
Target | CD20 |
Clinical data | |
Trade names | Rituxan, Mabthera, others |
Biosimilars | rituximab-abbs, [1] rituximab-pvvr, [2] rituximab-arrx, [3] Blitzima [4] Riabni, [3] Rixathon, [5] Riximyo, [6] Ruxience, [2] Truxima [1] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a607038 |
License data | |
Pregnancy category |
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Routes of administration | Intravenous |
Drug class | Monoclonal antibody |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 100% (IV) |
Elimination half-life | 30 to 400 hours (varies by dose and length of treatment) |
Excretion | Uncertain: may undergo phagocytosis and catabolism in RES |
Identifiers | |
CAS Number | |
DrugBank | |
ChemSpider |
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UNII | |
KEGG | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.224.382 |
Chemical and physical data | |
Formula | C6416H9874N1688O1987S44 |
Molar mass | 143860.04 g·mol−1 |
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Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. [16] 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. [16] [17] [18] [19] It is given by slow intravenous infusion (injected slowly through an IV line). [16]
Common side effects which often occur within two hours of the medication being given include rash, itchiness, low blood pressure, and shortness of breath.[ medical citation needed ] Infections are also common. [16]
Severe side effects include reactivation of hepatitis B in those previously infected, progressive multifocal leukoencephalopathy, toxic epidermal necrolysis, and death. [16] [20] It is unclear if use during pregnancy is safe for the developing fetus or newborn baby. [7] [16]
Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. [21] When it binds to this protein it triggers cell death. [16]
Rituximab was approved for medical use in 1997. [21] It is on the World Health Organization's List of Essential Medicines. [22] 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. [23] [24]
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. [25]
In the United States, rituximab is indicated to treat:
In the European Union, rituximab is indicated for the treatment of follicular lymphoma and diffuse large B cell non-Hodgkin's lymphoma (two types of non-Hodgkin's lymphoma, a blood cancer); [14] chronic lymphocytic leukemia (CLL, another blood cancer affecting white blood cells); [14] severe rheumatoid arthritis (an inflammatory condition of the joints); [14] two inflammatory conditions of blood vessels known as granulomatosis with polyangiitis (GPA or Wegener's granulomatosis) and microscopic polyangiitis (MPA); [14] moderate to severe pemphigus vulgaris, an autoimmune disease characterised by widespread blistering and erosion of the skin and mucous membranes (the linings of internal organs). 'Autoimmune' means that the disease is caused by the immune system (the body's natural defences) attacking the body's own cells. [14]
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. [27] [28] This also includes Waldenström's macroglobulinemia, a type of NHL. [16] Rituximab in combination with hyaluronidase human, sold under the brand names MabThera SC [11] and Rituxan Hycela, [29] is used to treat follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. [29] It is used in combination with fludarabine and cyclophosphamide to treat previously untreated and previously treated CD20-positive chronic lymphocytic leukemia. [13]
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. [30] 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. [31]
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, [32] [33] systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy and autoimmune anemias. [34] [35] 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. [34] [36]
Other autoimmune diseases that have been treated with rituximab include autoimmune hemolytic anemia, pure red cell aplasia, thrombotic thrombocytopenic purpura (TTP), [37] idiopathic thrombocytopenic purpura (ITP), [38] [39] Evans syndrome, [40] 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), [41] type 1 diabetes mellitus, Sjögren syndrome, anti-NMDA receptor encephalitis and Devic's disease(Anti-AQP4 disease, MOG antibody disease), [42] Graves' ophthalmopathy, [43] autoimmune pancreatitis, [44] Opsoclonus myoclonus syndrome (OMS), [45] and IgG4-related disease. [46] There is some evidence that it is ineffective in treating IgA-mediated autoimmune diseases. [47]
Serious adverse events, which can cause death and disability, include: [13] [16]
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. [54] 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. [55]
The following effects have been found: [56]
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. [58]
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. [59]
Based on its safety and effectiveness in clinical trials, [60] 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. [61] [62] 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. [63] In 2010, it was approved by the European Commission for maintenance treatment after initial treatment of follicular lymphoma. [64]
It is on the World Health Organization's List of Essential Medicines. [22]
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). [65]
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. [66] The combination is not indicated for the treatment of non-malignant conditions. [29] [66] The combination was approved based on clinical studies SABRINA/NCT01200758 and MabEase/NCT01649856. [29]
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). [67] 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. [67] This can cause serious problems and damage to organs, most notably the lungs and the kidneys. [67] It also can impact the sinuses and skin. [67] Rituximab was approved by the FDA to treat adults with granulomatosis with polyangiitis and microscopic polyangiitis in 2011. [67]
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. [26] [68] 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. [68] 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. [68] 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. [68]
In 2014, Genentech reclassified Rituxan as a specialty drug, a class of drugs that are only available through specialty distributors in the US. [69] Because wholesalers discounts and rebates no longer apply, hospitals would pay more. [69]
Patents on rituximab have expired in the European Union [70] [71] [72] and in the United States. [73] [74] [75] Biosimilars were approved in the United States, India, the European Union, Switzerland, Japan, and Australia. The US FDA approved rituximab-abbs (Truxima) in 2018, [1] [76] [77] rituximab-pvvr (Ruxience) in 2019, [2] and rituximab-arrx (Riabni) in 2020. [3] [78] [79] Truxima and Riabni are approximately $3600 per 500 mg, wholesale - 10% less than Rituxan. While Ruxience is 24% less than Rituxan. [80] . [81]
In July 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of marketing authorization to Reddy Holding GmbH for their rituximab biosimilar Ituxredi, for NHL, CLL, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis and pemphigus vulgaris. [82]
Tailored-dose rituximab is more cost-effective than fixed-dose. It is both more effective and less expensive. [83] [84]
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. [85]
A major concern with continuous rituximab treatment is the difficulty to induce a proper vaccine response. [86] 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. [87] 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 the Pfizer–BioNTech COVID-19 vaccine. [88]
In 2009, a patient receiving methotrexate-induced B-cell depletion for cancer treatment, experienced a transient remittal of their myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms. While initial trials using Rituximab were promising, a phase 3 trial published in 2019 did not find an association between Rituximab treatment and improvements in ME/CFS. [89] [90]
For CNS diseases, rituximab could be administered intrathecally and this possibility is under study. [91]
The efficacy and success of rituximab has led to some other anti-CD20 monoclonal antibodies being developed:
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes. Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years.
Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for non-Hodgkin's lymphoma. The drug uses the monoclonal mouse IgG1 antibody ibritumomab in conjunction with the chelator tiuxetan, to which a radioactive isotope is added. Tiuxetan is a modified version of DTPA whose carbon backbone contains an isothiocyanatobenzyl and a methyl group.
Tositumomab is a murine monoclonal antibody which targets the CD20 antigen produced in mammalian cell. It was combined with iodine-131 to produce a radiopharmaceutical for unsealed source radiotherapy, Iodine-131 Tositumomab, for the treatment of non-Hodgkins lymphoma. It is classified as a IgG2a lambda antibody.
B-lymphocyte antigen CD20 or CD20 is B lymphocyte cell-surface molecule.
Ofatumumab is a fully human monoclonal antibody to CD20, which appears to provide rapid B-cell depletion. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the European Union and other regions. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. It is sold by Novartis under license from Genmab.
Richter's transformation (RT), also known as Richter's syndrome, is the conversion of chronic lymphocytic leukemia (CLL) or its variant, small lymphocytic lymphoma (SLL), into a new and more aggressively malignant disease. CLL is the circulation of malignant B lymphocytes with or without the infiltration of these cells into lymphatic or other tissues while SLL is the infiltration of these malignant B lymphocytes into lymphatic and/or other tissues with little or no circulation of these cells in the blood. CLL along with its SLL variant are grouped together in the term CLL/SLL.
Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffeld and Jaffe in 1991.
Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody used as a treatment for cancer. It was originated by GlycArt Biotechnology AG and developed by Roche.
Milatuzumab is an anti-CD74 humanized monoclonal antibody for the treatment of multiple myeloma non-Hodgkin's lymphoma and chronic lymphocytic leukemia.
Marginal zone lymphomas, also known as marginal zone B-cell lymphomas (MZLs), are a heterogeneous group of lymphomas that derive from the malignant transformation of marginal zone B-cells. Marginal zone B cells are innate lymphoid cells that normally function by rapidly mounting IgM antibody immune responses to antigens such as those presented by infectious agents and damaged tissues. They are lymphocytes of the B-cell line that originate and mature in secondary lymphoid follicles and then move to the marginal zones of mucosa-associated lymphoid tissue (MALT), the spleen, or lymph nodes. Mucosa-associated lymphoid tissue is a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body such as the gastrointestinal tract, mouth, nasal cavity, pharynx, thyroid gland, breast, lung, salivary glands, eye, skin and the human spleen.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a slow-growing CD20 positive form of Hodgkin lymphoma, a cancer of the immune system's B cells.
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic condition in which individuals have increased blood levels of particular subtypes of monoclonal lymphocytes. This increase must persist for at least 3 months. The lymphocyte subtypes are B-cells that share certain features with the abnormal clones of lymphocytes that circulate in chronic lymphocytic leukemia/small lymphocyte lymphoma (CLL/SLL) or, less frequently, other types of B-cell malignancies. Some individuals with these circulating B-cells develop CLL/SLL or the lymphoma types indicated by their circulating monoclonal B-cells. Hence, MBL is a premalignant disorder
Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.
Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.
FCM, or FMC in the context of chemotherapy is an acronym for a chemotherapy regimen that is used in the treatment of indolent B cell non-Hodgkin's lymphomas. In combination with Rituximab, this regimen is called R-FCM or R-FMC, or FCM-R, FMC-R.
Celltrion, Inc. is a biopharmaceutical company headquartered in Incheon, South Korea. Celltrion Healthcare conducts worldwide marketing, sales, and distribution of biological medicines developed by Celltrion. Celltrion's founder, Seo Jung-jin, is the richest person in South Korea.
David G. Maloney is an oncologist and researcher at Fred Hutchinson Cancer Research Center and the University of Washington who specializes in developing targeted immunotherapies for the treatment of blood cancers.
Umbralisib, sold under the brand name Ukoniq, is an anti-cancer medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). It is taken by mouth.
Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).
Mosunetuzumab, sold under the brand name Lunsumio, is a monoclonal antibody used for the treatment of follicular lymphoma. It bispecifically binds CD20 and CD3 to engage T-cells. It was developed by Genentech.
The pharmaceutical company said Riabni will be marketed at a discount to the reference product of 23.7% below wholesale acquisition cost (WAC), or a WAC of $716.80 per 100 mg and $3584 per 500 mg single-dose vial. These costs are 15.2% less than the WAC for the biosimilar rituximab Truxima, Amgen said. The company added that Riabni's average sales price will be 16.7% below the current average for Rituxan.