Rituximab
Encyclopedia
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....

, which is primarily found on the surface of B cells. Rituximab is used in the treatment of many lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

s, leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...

s, transplant rejection
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...

 and some autoimmune disorders.

History

Rituximab was developed by IDEC Pharmaceuticals
Biogen Idec
Biogen Idec, Inc. is a biotechnology company specializing in drugs for neurological disorders, autoimmune disorders and cancer. The company was formed in 2003 by the merger of Cambridge, Massachusetts-based Biogen Inc. and San Diego, California-based IDEC Pharmaceuticals...

 (formed in 1986 by Ivor Royston
Ivor Royston
Ivor Royston, M.D., is an oncologist, researcher, scientist, entrepreneur and venture capitalist, recognized for his efforts to develop treatments for multiple disease targets and to fund biotechnology companies with promising science, technology or medicines....

 and Howard Birndorf
Howard Birndorf
Howard Civian Birndorf is a biotechnology entrepreneur and one of the founders of the biotech industry in San Diego, California. Along with former University of California professor and current venture capitalist Ivor Royston, Birndorf founded San Diego's first biotech in 1978, the monoclonal...

) under the name IDEC-C2B8.

Based on its safety and effectiveness in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s, rituximab was approved by the U.S. Food and Drug Administration in 1997 to treat B-cell non-Hodgkin lymphoma
Non-Hodgkin lymphoma
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....

s resistant to other chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 regimens. Rituximab, in combination with CHOP
CHOP
CHOP is the acronym for a chemotherapy regimen used in the treatment of non-Hodgkin lymphoma. CHOP consists of:* Cyclophosphamide, an alkylating agent which damages DNA by binding to it and causing cross-links...

 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
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....

 for maintenance treatment after initial treatment of follicular lymphoma
Follicular lymphoma
Follicular lymphoma is the most common of the indolent non-Hodgkin's lymphomas, and the second most common form of non-Hodgkin's lymphomas overall. It is defined as a lymphoma of follicle center B-cells , which has at least a partially follicular pattern...

.

Rituximab is currently co-marketed by Biogen Idec
Biogen Idec
Biogen Idec, Inc. is a biotechnology company specializing in drugs for neurological disorders, autoimmune disorders and cancer. The company was formed in 2003 by the merger of Cambridge, Massachusetts-based Biogen Inc. and San Diego, California-based IDEC Pharmaceuticals...

 and Genentech
Genentech
Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...

 in the U.S., by Hoffmann–La Roche in Canada and the European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...

, and by Chugai Pharmaceuticals and Zenyaku Kogyo in Japan.

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.

Hematological neoplastic diseases

Rituximab used to treat hematological neoplasms
Hematological malignancy
Hematological malignancies are the types of cancer that affect blood, bone marrow, and lymph nodes. As the three are intimately connected through the immune system, a disease affecting one of the three will often affect the others as well: although lymphoma is technically a disease of the lymph...

 such as leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...

s and lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

s.The use of rituximab in Hodgkin's lymphoma, including the lymphocyte predominant subtype has been reviewed recently.

In multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...

, 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.

Autoimmune diseases

Rituximab has been shown to be an effective rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

 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
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. 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 licence 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
Pharmacovigilance
Pharmacovigilance is the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short term side effects of medicines...

, in a range of other autoimmune diseases, and rituximab is widely used off-label to treat difficult cases of multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

, systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...

 and autoimmune anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...

s. There are significant concerns about progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...

 (PML) infection in SLE patients and other conditions.

Other autoimmune diseases that have been treated with rituximab include autoimmune hemolytic anemia
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia occurs when antibodies directed against the person's own red blood cells cause the RBCs to burst , leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases...

, pure red cell aplasia, idiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura is the condition of having an abnormally low platelet count of no known cause . As most incidents of ITP appear to be related to the production of antibodies against platelets, immune thrombocytopenic purpura or immune thrombocytopenia are terms also used to...

 (ITP), Evans syndrome
Evans syndrome
Evans syndrome is an autoimmune disease in which an individual's antibodies attack their own red blood cells and platelets. Both of these events may occur simultaneously or one follow on from the other....

, vasculitis (for example Wegener's Granulomatosis
Wegener's granulomatosis
Wegener's granulomatosis , more recently granulomatosis with polyangiitis , is an incurable form of vasculitis that affects the nose, lungs, kidneys and other organs. Due to its end-organ damage, it is life-threatening and requires long-term immunosuppression...

), bullous skin disorders (for example pemphigus
Pemphigus
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes.In pemphigus, autoantibodies form against desmoglein. Desmoglein forms the "glue" that attaches adjacent epidermal cells via attachment points called desmosomes...

, pemphigoid
Pemphigoid
Pemphigoid is a group of uncommon and rare autoimmune blistering skin diseases. As its name indicates, pemphigoid is similar to pemphigus, but, unlike pemphigus, pemphigoid does not feature acantholysis....

), type 1 diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

, Sjogren's syndrome
Sjögren's syndrome
Sjögren's syndrome , also known as "Mikulicz disease" and "Sicca syndrome", is a systemic autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva....

, and Devic's disease
Devic's disease
Neuromyelitis optica , also known as Devic's disease or Devic's syndrome, is an autoimmune, inflammatory disorder in which a person's own immune system attacks the optic nerves and spinal cord. This produces an inflammation of the optic nerve and the spinal cord...

, and thyroid-associated ophthalmopathy.

An October 2011 study from Norway suggests that rituximab can help patients with chronic fatigue syndrome
Chronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...

. A clinical trial has been completed and a new open-label trial has begun.

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.

Mechanism

The antibody binds to CD
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...

20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....

. CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...

s. CD20 does not shed, modulate or internalise. Although the function of CD20 is unknown, it may play a role in Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.

The exact mode of action of rituximab is unclear, but the following effects have been found:
  • The Fc
    Fragment crystallizable region
    The fragment crystallizable region is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system...

     portion of rituximab mediates antibody-dependent cellular cytotoxicity
    Antibody-dependent cellular cytotoxicity
    Antibody-Dependent Cell-Mediated Cytotoxicity is a mechanism of cell-mediated immunity whereby an effector cell of the immune system actively lyses a target cell that has been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune...

     (ADCC) and complement-dependent cytotoxicity
    Complement system
    The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

     (CDC).
  • Rituximab has a general regulatory effect on the cell cycle
    Cell cycle
    The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...

    .
  • It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen).
  • It elicits shedding of CD23
    CD23
    CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin...

    .
  • It downregulates the B cell receptor.
  • It induces apoptosis
    Apoptosis
    Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

     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 cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

s.

Rituximab binds to amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s 170-173 and 182-185 on CD20, which are physically close to each other as a result of a disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

 between amino acids 167 and 183.

Adverse events

Serious adverse events, which can cause death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....

 and disability
Disability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...

, include:
  • Severe infusion reactions
  • Cardiac arrest
    Cardiac arrest
    Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...

  • Tumor lysis syndrome
    Tumor lysis syndrome
    In medicine , tumor lysis syndrome is a group of metabolic complications that can occur after treatment of cancer, usually lymphomas and leukemias, and sometimes even without treatment...

    , causing acute renal failure
    Acute renal failure
    Acute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...

  • Infections
    • Hepatitis B reactivation
    • Other viral infections
    • Progressive multifocal leukoencephalopathy
      Progressive multifocal leukoencephalopathy
      Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...

       (PML)
  • Immune toxicity, with depletion of B cells in 70% to 80% of lymphoma
    Lymphoma
    Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

     patients
  • Pulmonary
    Human lung
    The human lungs are the organs of respiration in humans. Humans have two lungs, with the left being divided into two lobes and the right into three lobes. Together, the lungs contain approximately of airways and 300 to 500 million alveoli, having a total surface area of about in...

     toxicity


A small number of patients with systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...

 have died in the context of being treated with rituximab. In some cases, reactivation of latent JC virus
JC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...

 (a common virus that can cause progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...

) occurred in the brains of these patients. There has also been at least one case of a patient with rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

 who developed PML in the context of treatment with rituximab. JC virus reactivation (resulting in PML) in an immunosuppressed person commonly results in death or severe brain damage.

Rituximab has been reported as a possible cofactor in a chronic Hepatitis E
Hepatitis E
Hepatitis E is a viral hepatitis caused by infection with a virus called hepatitis E virus . HEV is a positive-sense single-stranded RNA icosahedral virus with a 7.5 kilobase genome. HEV has a fecal-oral transmission route. It is one of five known hepatitis viruses: A, B, C, D, and E...

 infection in a person with lymphoma. Hepatitis E infection is normally an acute
Acute
Acute may refer to:* Acute accent* Acute angle* Acute * Acute * Acute toxicity...

 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
    Ocrelizumab
    Ocrelizumab is a humanized anti-CD20 monoclonal antibody. It targets mature B lymphocytes and hence is an immunosuppressive drug candidate. It is under development by Hoffmann–La Roche's subsidiary Genentech, and Biogen Idec....

    , humanized (90%-95% human) B cell-depleting agent.
  • ofatumumab
    Ofatumumab
    Ofatumumab is a human monoclonal antibody which appears to inhibit early-stage B lymphocyte activation...

     (HuMax-CD20) a fully human B cell-depleting agent.
  • Third-generation anti-CD20s have a glycoengineered Fc fragment (Fc) with enhanced binding to Fc gamma receptors, which increase ADCC (antibody-dependent cellular cytotoxicity
    Antibody-dependent cellular cytotoxicity
    Antibody-Dependent Cell-Mediated Cytotoxicity is a mechanism of cell-mediated immunity whereby an effector cell of the immune system actively lyses a target cell that has been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune...

    ). 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
Belimumab
Belimumab is a fully human monoclonal antibody that inhibits B-lymphocyte stimulator , also known as B cell activation factor of the TNF family...

  and atacicept
Atacicept
Atacicept is a recombinant fusion protein designed to inhibit B cells, thereby suppressing autoimmune disease. The designer protein combines the binding site for two cytokines that regulate maturation, function, and survival of B cells, B-lymphocyte stimulator and a proliferation-inducing ligand ,...

 are examples of such an approach.

External links

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