Rituximab, sold under the brand name Rituxan among others, is a

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...

medication used to treat certain autoimmune diseases and types of

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. It is used for

non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...

chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...

(in children and adults, but not recommended in elderly patients),

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

granulomatosis with polyangiitis Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis (WG), after Nazi German physician Friedrich Wegener, is a rare, long-term, systemic disorder that involves the formation of granulomas and vasculitis, inflammatio ...

idiopathic thrombocytopenic purpura Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is an Autoimmunity, autoimmune primary disorder of hemostasis characterized by a low platelet count in the absence of other cause ...

pemphigus vulgaris Pemphigus vulgaris is a rare chronic blistering skin disease and the most common form of pemphigus. Pemphigus was derived from the Greek word ''pemphix'', meaning blister. It is classified as a type II hypersensitivity reaction in which antibody, ...

myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...

and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion (injected slowly through an IV line). The most common side effects with intravenous infusions are reactions related to the infusion (such as fever, chills and shivering) while most common serious side effects are infusion reactions, infections and heart-related problems. Similar side effects are seen when it is injected under the skin, with the exception of reactions around the injections site (pain, swelling and rash), which occur more frequently with the skin injections. Severe side effects include reactivation of

hepatitis B Hepatitis B is an infectious disease caused by the '' hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...

in those previously infected, progressive multifocal leukoencephalopathy,

toxic epidermal necrolysis Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and f ...

, and death. It is unclear if use during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

is safe for the developing fetus or newborn baby. Rituximab is a chimeric

against the protein

CD20 B-lymphocyte antigen CD20 or CD20 is B lymphocyte cell-surface molecule. It is a 33-37 kDa non-glycosylated protein. CD20 is expressed on the surface of B-cells from the pre-B phase, the expression is lost in terminally differentiated plasm ...

, which is primarily found on the surface of immune system

B cells B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

. 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 Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of the treatment of neurological diseases to patients worldwide. Biogen ope ...

and

Genentech Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It operates as an independent subsidiary of holding company Roche. Genentech Research and Early Development operates as an independent cent ...

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 A surface, as the term is most generally used, is the outermost or uppermost layer of a physical object or space. It is the portion or region of the object that can first be perceived by an observer using the senses of sight and touch, and is ...

antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

present on

B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

s. It acts by depleting normal as well as pathogenic B cells while sparing

plasma cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...

s and

hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the ...

s, which do not express the CD20 surface antigen. In the United States, rituximab is indicated to treat: #

having inadequate response to one or more TNF inhibitors # vasculitides such as

and microscopic polyangiitis # moderate to severe

# 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 Burkitt's lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa ...

(BL), Burkitt-like lymphoma (BLL), or mature acute B-cell leukemia (B-AL). 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); chronic lymphocytic leukemia (CLL, another blood cancer affecting white blood cells); severe rheumatoid arthritis (an inflammatory condition of the joints); two inflammatory conditions of blood vessels known as granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA); 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.

Blood cancers

Rituximab is used to treat cancers of the white blood system such as

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

s and

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...

s, including non-Hodgkin's lymphoma,

, and nodular lymphocyte predominant Hodgkin's lymphoma. This also includes Waldenström's macroglobulinemia, a type of non-Hodgkin lymphoma. 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

treatment in three randomised controlled trials and is now licensed for use in

refractory In materials science, a refractory (or refractory material) is a material that is resistant to decomposition by heat or chemical attack and that retains its strength and rigidity at high temperatures. They are inorganic, non-metallic compound ...

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 Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...

, in a range of other autoimmune diseases, and rituximab is widely used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...

to treat difficult cases of

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...

chronic inflammatory demyelinating polyneuropathy Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is sometimes calle ...

and autoimmune

anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

s. The most dangerous, although among the most rare, side effect is progressive multifocal leukoencephalopathy 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 Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in thrombi, blood clots forming in small blood vessels throughout the body. This results in a thrombocytopenia, low platelet count, hemolytic anemia, low red blood cells d ...

(TTP),

(ITP), Evans syndrome, vasculitis (e.g.,

), bullous skin disorders (for example,

pemphigus Pemphigus ( or ) is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes. The name is derived from the Greek root ''pemphix'', meaning "blister". In pemphigus, autoantibody, autoantibodies form against de ...

, pemphigoid—with very encouraging results of approximately 85% rapid recovery in pemphigus, according to a 2006 study), type 1

diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...

, 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 Cardiac arrest (also known as sudden cardiac arrest CA is when the heart suddenly and unexpectedly stops beating. When the heart stops beating, blood cannot properly Circulatory system, circulate around the body and the blood flow to the ...

* Cytokine release syndrome * Tumor lysis syndrome, causing acute kidney injury * Infections ** Progressive multifocal leukoencephalopathy caused by JC virus reactivation **

Hepatitis B Hepatitis B is an infectious disease caused by the '' hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...

reactivation ** Other viral infections * Immune toxicity, with depletion of B cells in 70% to 80% of

patients * Pulmonary toxicity *

Bowel obstruction Bowel obstruction, also known as intestinal obstruction, is a mechanical or Ileus, functional obstruction of the Gastrointestinal tract#Lower gastrointestinal tract, intestines which prevents the normal movement of the products of digestion. Ei ...

and perforation A concern with continuous rituximab treatment is the difficulty to induce a proper vaccine response. This was brought into focus during the

COVID-19 pandemic The COVID-19 pandemic (also known as the coronavirus pandemic and COVID pandemic), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began with an disease outbreak, outbreak of COVID-19 in Wuhan, China, in December ...

, where persons with

and rituximab treatment had higher risk of severe COVID-19. In persons previously treated with rituximab for multiple sclerosis, nine of ten 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.

Mechanisms of action

The antibody binds to the cell surface protein

. CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated

s. 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 The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

. * 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 Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

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 cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...

s. Rituximab binds to

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s 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 trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s, rituximab was approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) in 1997 to treat B-cell

s resistant to other

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

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 authorized by the

European Commission The European Commission (EC) is the primary Executive (government), executive arm of the European Union (EU). It operates as a cabinet government, with a number of European Commissioner, members of the Commission (directorial system, informall ...

for maintenance treatment after initial treatment of follicular lymphoma. It is on the World Health Organization's List of Essential Medicines. 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.

Society and culture

Legal status

Rituximab was approved for medical use in the United States in November 1997.

Biosimilars

Biosimilar A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved ...

s are approved in the United States, India, the European Union, Switzerland, Japan, and Australia. The US FDA approved rituximab-abbs (Truxima) in 2018, rituximab-pvvr (Ruxience) in 2019, and rituximab-arrx (Riabni) in 2020. In July 2024, the Committee for Medicinal Products for Human Use of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

recommended marketing authorization for the rituximab biosimilar Ituxredi produced by Dr. Reddy's Laboratories / Holding GmbH. Ituxredi is intended for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis and pemphigus vulgaris. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Ituxredi was authorized for medical use in the European Union in September 2024. A Rituximab biosimilar was approved in India in 2007.

Economics

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. Patents on rituximab have expired in the European Union and in the United States.

s were approved in the United States, India, the European Union, Switzerland, Japan, and Australia. The US FDA approved rituximab-abbs (Truxima) in 2018, rituximab-pvvr (Ruxience) in 2019, and rituximab-arrx (Riabni) in 2020. Truxima and Riabni are approximately $3600 per 500 mg, wholesale - 10% less than Rituxan, while Ruxience is 24% less than Rituxan. The Indian biosimilar ''ituxredi'' retails for about 1/6 the price.

Tailored-dosing

Tailored-dose rituximab is more cost-effective than fixed-dose. It is both more effective and less expensive.

Research

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.

Myalgic encephalomyelitis/chronic fatigue syndrome

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.

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.

References

External links

* {{Authority control Drugs developed by Genentech Drugs developed by Hoffmann-La Roche Monoclonal antibodies for tumors Orphan drugs Specialty drugs World Health Organization essential medicines Wikipedia medicine articles ready to translate