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Rituximab

 
Oncology Encyclopedia: Rituximab
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Key Terms: Antibody, Apoptosis, CD20, Humanization.

Definition

Rituximab is a humanized monoclonal antibody that selectively binds to CD20, a protein found on the surface of normal and malignant B cells and is used to reduce the numbers of circulating B cells in patients who have B-cell non-Hodgkin's lymphoma (NHL). Rituximab is sold as Rituxan in the United States.

Purpose

Rituximab is a monoclonal antibody used to treat NHL characterized by overgrowth of B cells, the cell involved in about 85% of NHL malignancies. Of all the B-cell cancers more than 90% express the CD20 protein on the cell surface, a requirement for the proper function of rituximab. By binding the CD20 protein on the B cell, the antibody targets it for removal from the circulation. Based on data gathered in the laboratory developers believe that rituximab triggers both cell-mediated and complement-mediated means to kill the B cells, two different methods that the immune system uses to eliminate foreign cells. Binding of the antibody may also trigger apoptosis, or programmed cell death, of the B cells.

Rituximab has been most effective against lowgrade (indolent) or follicular B-cell NHL. Low-grade (slow progression) NHL often responds well to initial treatment, but frequently relapses, making rituximab a welcome addition to the treatment options. Additionally, rituximab has been used for a second course of treatments after relapse with some success. As most patients with NHL are in stage III or IV by the time of diagnosis and treatment, experience with rituximab treatment are primarily with those stages of the disease.

As of spring 2001 clinical trials were being held testing the ability of this drug to work against several other types of cancers, including newly diagnosed NHL, intermediate- or high-grade (aggressive) NHL, AIDS-associated NHL, Waldenström's macroglobulinemia, Hodgkin's disease, hairy cell leukemia (HCL), chronic lymphocytic leukemia (CLL), multiple myeloma, mantle cell lymphoma, and large cell lymphoma.

Description

Rituximab is produced in the laboratory using genetically engineered single clones of B cells. Like all antibodies it is a Y-shaped molecule that can bind to one particular substance, the antigen for that monoclonal antibody. For rituximab that antigen is CD20, a protein found on the surface of B cells. Rituximab is a humanized antibody, meaning that the regions that bind CD20, located on the tips of the Y branches, are derived from mouse antibodies but the rest of the antibody is human sequence. The presence of the human sequences helps to reduce the immune response by the patient against the antibody itself—a problem seen when complete mouse antibodies were used for cancer therapies. The human sequences also help to ensure that the various cell-destroying mechanisms of the human immune system are properly triggered with binding of the antibody.

In 1997 Rituximab was the first unconjugated (not linked to a radioactive isotope or toxin) antibody approved for use by the FDA to treat cancer. It is specifically approved for treatment of low-grade or follicular B-cell NHL. Administration of the antibody resulted in either complete or partial responses in a little less than half of those patients.

Rituximab can be used alone or in combination with other chemotherapeutic drugs. Specifically, very good results have been seen when used in combination with the CHOP chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). When used in combination, dosages of the antibody given before beginning chemotherapy, alternating with the other drugs, then after the chemotherapy as a "mop-up" have proven effective.

There are a number of clinical trials in progress testing the ability of rituximab to work in combination with other chemotherapy drugs, treatments, and cytokines. Some substances and treatments being tested include interleukins 2 and 11, stem cell transplantation, radioimmunotherapy, vaccination, and a wide variety of other chemotherapy combinations.

Recommended Dosage

The recommended dosage for patients with low-grade or follicular NHL is 375 mg/m2 infused intravenously. The infusion is given at weekly intervals for four total dosages. Acetominophen and diphenhydramine hydrochoride are given 30-60 minutes before the infusion to help reduce side effects. If given as a retreatment the dosage is the same. Clinical trials were ongoing in 2001 to help clarify the ideal dosage and treatment schedule for this drug. Generally, decrease in symptoms occurs at an average of 55 days after the last administration of the antibody.

Precautions

Serious (even fatal) infusion reactions, especially with the first infusion, have been known with this drug. There are a number of patient conditions that can make taking this drug more dangerous. Specifically, heart problems such as arrhythmias and high blood pressure, and the medications taken to treat those conditions, can be a problem with this treatment.

Side Effects

The majority of side effects occur after or during the first infusion of the drug. Some common side effects include dizziness, feeling of swelling of tongue or throat, fever and chills, flushing of face, headache, itching, nausea and vomiting, runny nose, shortness of breath, skin rash, and unusual fatigue.

Less common side effects include black, tarry stools; blood in urine or stools; fever or chills with cough or hoarseness; lower back or side pain, or painful or difficult urination; pain at place of injection; pinpoint red spots on skin; red, itchy lining of eye; swelling of feet or lower legs; unusual bleeding or bruising; and unusual weakness.

Although they are very rare this drug does have serious side effects such as chest pain and irregular heartbeat, particularly in patients already having heart conditions. It can also cause serious effects on the blood cells such as low red blood cell count (anemia) and low white blood cell count (neutropenia). Additionally, this drug has caused low blood pressure (hypotension).

In patients with high tumor burden (a large number of circulating malignant B cells) this drug can cause a side effect called tumor lysis syndrome. Thought to be due to the release of the lysed cells' contents into the blood stream, it can cause a misbalance of urea, uric acid, phosphate, and calcium in the urine and blood. Patients at risk for this side effect must keep hydrated and can be given allopurinol (an anitgout medication) before infusion.

Interactions

There have been no formal drug interaction studies done with rituximab.

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Drug Info: Rituximab
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Brand names: Rituxan®



Rituximab Solution for injection

What is this medicine?

RITUXIMAB (ri TUX i mab) is a monoclonal antibody. This medicine changes the way the body's immune system works. It is used commonly to treat non-Hodgkin's lymphoma and other conditions. In cancer cells, this drug targets a specific protein within cancer cells and stops the cancer cells from growing. It is also used to treat rhuematoid arthritis (RA). In RA, this medicine slow the inflammatory process and help reduce joint pain and swelling. This medicine is often used with other cancer or arthritis medications.
 
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
•blood disorders
•heart disease
•history of hepatitis B
•infection (especially a virus infection such as chickenpox, cold sores, or herpes)
•irregular heartbeat
•kidney disease
•lung or breathing disease, like asthma
•lupus
•an unusual or allergic reaction to rituximab, mouse proteins, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?

This medicine is for infusion into a vein. It is administered in a hospital or clinic by a specially trained health care professional.

A special MedGuide will be given to you by the pharmacist with each prescription and refill. Be sure to read this information carefully each time.

Talk to your pediatrician regarding the use of this medicine in children. This medicine is not approved for use in children.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

•cisplatin
•medicines for blood pressure
•some other medicines for arthritis
•vaccines

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Report any side effects that you notice during your treatment right away, such as changes in your breathing, fever, chills, dizziness or lightheadedness. These effects are more common with the first dose.

Visit your prescriber or health care professional for checks on your progress. You will need to have regular blood work. Report any other side effects. The side effects of this medicine can continue after you finish your treatment. Continue your course of treatment even though you feel ill unless your doctor tells you to stop.

Call your doctor or health care professional for advice if you get a fever, chills or sore throat, or other symptoms of a cold or flu. Do not treat yourself. This drug decreases your body's ability to fight infections. Try to avoid being around people who are sick.

This medicine may increase your risk to bruise or bleed. Call your doctor or health care professional if you notice any unusual bleeding.

Be careful brushing and flossing your teeth or using a toothpick because you may get an infection or bleed more easily. If you have any dental work done, tell your dentist you are receiving this medicine.

Avoid taking products that contain aspirin, acetaminophen, ibuprofen, naproxen, or ketoprofen unless instructed by your doctor. These medicines may hide a fever.

Do not become pregnant while taking this medicine. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. Talk to your health care professional or pharmacist for more information. Do not breast-feed an infant while taking this medicine.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•low blood counts - this medicine may decrease the number of white blood cells, red blood cells and platelets. You may be at increased risk for infections and bleeding.
•signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine
•signs of decreased platelets or bleeding - bruising, pinpoint red spots on the skin, black, tarry stools, blood in the urine
•signs of decreased red blood cells - unusually weak or tired, fainting spells, lightheadedness
•breathing problems
•confused, not responsive
•chest pain
•fast, irregular heartbeat
•feeling faint or lightheaded, falls
•mouth sores
•redness, blistering, peeling or loosening of the skin, including inside the mouth
•stomach pain
•swelling of the ankles, feet, or hands
•trouble passing urine or change in the amount of urine

Side effects that usually do not require medical attention (report to your doctor or other health care professional if they continue or are bothersome):
•anxiety
•headache
•loss of appetite
•muscle aches
•nausea
•night sweats

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

This drug is given in a hospital or clinic and will not be stored at home.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

Wikipedia: Rituximab
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Rituximab?
Monoclonal antibody
Source chimeric (mouse/human)
Target CD20
Identifiers
CAS number 174722-31-7
ATC code L01XC02
PubChem  ?
DrugBank BTD00014
Chemical data
Formula C6416H9874N1688O1987S44 
Mol. mass 143859.7 g/mol
Pharmacokinetic data
Bioavailability 100% (IV)
Metabolism  ?
Half life 30 to 400 hours (varies by dose and length of treatment)
Excretion Uncertain: may undergo phagocytosis and catabolism in RES
Therapeutic considerations
Pregnancy cat.

C(US) (no adequate human studies)
Legal status

℞-only(US)
Routes intravenous infusion only (never bolus or "push")


Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells. Rituximab is used in the treatment of many lymphomas, leukemias, and some autoimmune disorders.

Contents

History

Rituximab was developed by IDEC Pharmaceuticals (formed in 1986 by biotech pioneers Ivor Royston and Howard Birndorf).[1] Based on its safety and effectiveness in clinical trials,[2] rituximab was approved by the U.S. Food and Drug Administration in 1997 for B cell non-Hodgkin lymphoma resistant to other chemotherapy regimens.[3] Rituximab, in combination with CHOP chemotherapy, is now standard therapy in the initial treatment of diffuse large B cell lymphoma and many other B cell lymphomas. It is currently co-marketed by Biogen Idec and Genentech in the U.S. and by Roche in Canada and the European Union.

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 is frequently used to treat hematological neoplasms such as leukemias and lymphomas.

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.[4] 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 therapies.

There is some evidence for efficacy, but not necessarily safety, in a range of other autoimmune diseases, and it is widely used off-label to treat difficult cases of multiple sclerosis,[5] systemic lupus erythematosus and autoimmune anemias.[6] There are significant concerns about progressive multifocal leukoencephalopathy (PML) infection in SLE patients[7] and other conditions.[6]

Other autoimmune diseases that have been treated with rituximab include idiopathic autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP)[8][9], Evans syndrome[10], vasculitis (for example Wegener's Granulomatosis), bullous skin disorders (for example pemphigus, pemphigoid), type 1 diabetes mellitus, Sjogren's syndrome, and Devic's disease.[11]

A new study from Norway suggests that rituximab (together with methotrexate) might help patients with chronic fatigue syndrome.[12] A clinical trial is ongoing. [13]

Anti-rejection treatment for organ transplants

Rituximab is now being used in the management of kidney transplant recipients. This drug is especially useful in transplants involving incompatible blood groups. It is also used as induction therapy in highly sensitized patients going for kidney transplantation.

Mechanism

The antibody binds to the cluster of differentiation 20 (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. CD20 does not shed, modulate or internalise. 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.

The exact mode of action of rituximab is unclear, but the following effects have been found:[14]

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.[15]

Adverse events

Serious adverse events, which can cause death and disability, include:[16]

A small number of patients with systemic lupus erythematosus have died in the context of being treated with rituximab.[18] In some cases, reactivation of latent JC virus (a common virus that can cause progressive multifocal leukoencephalopathy) occurred in the brains of these patients. Whether rituximab caused the reactivation is unclear. There has also been at least one case of a patient with rheumatoid arthritis who developed PML in the context of treatment with rituximab.[19] JC virus reactivation (resulting in PML) in an immunosuppressed person commonly results in death or severe brain damage.

Finally, rituximab has been implicated as causing a Hepatitis E infection to become chronic (permanent) in a patient with a lymphoma. Hepatitis E infection is normally an acute (short-term) infection, suggesting the drug may have weakened the body's immune response to the virus.[20]

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.[21]
  • Third-generation anti-CD20s have a glycoengineered Fc fragment (Fc)[22] with enhanced binding to Fc gamma receptors, which increase ADCC (antibody dependent cellular cytotoxicity).[23] Modifications in the variable regions (variable regions)[24] can enhance apoptosis.
  • DXL625 (CD20) is a pre-clinical stage antibody currently being developed by InNexus Biotechnology Inc. for the prospective treatment of some forms of lymphoma.

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 and atacicept are examples of such an approach.

References

  1. ^ "Why San Diego Has Biotech", Fikes, Bradley J. San Diego Metropolitan, April 1999. Accessed June 20, 2008.
  2. ^ Maloney DG, Grillo-López AJ, White CA, et al. (September 1997). "IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma". Blood 90 (6): 2188–95. PMID 9310469. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=9310469. 
  3. ^ Scott SD (1998). "Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin's lymphoma". Cancer Pract 6 (3): 195–7. doi:10.1046/j.1523-5394.1998.006003195.x. PMID 9652253. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1065-4704&date=1998&volume=6&issue=3&spage=195. 
  4. ^ Edwards J, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close D, Stevens R, Shaw T (2004). "Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis". N Engl J Med 350 (25): 2572–81. doi:10.1056/NEJMoa032534. PMID 15201414. 
  5. ^ NEJM - B-Cell Depletion with Rituximab in Relapsing-Remitting Multiple Sclerosis
  6. ^ a b Paul, Marla (May 20, 2009). "Popular Cancer Drug Linked to Often Fatal 'Brain Eating' Virus" (in English). Northwestern University News and Information. http://www.northwestern.edu/newscenter/stories/2009/05/bennett.html. Retrieved 2009-05-22. 
  7. ^ [1]
  8. ^ Braendstrup P, Bjerrum OW, Nielsen OJ, Jensen BA, Clausen NT, Hansen PB, Andersen I, Schmidt K, Andersen TM, Peterslund NA, Birgens HS, Plesner T, Pedersen BB, Hasselbalch HC. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura. Am J Hematol 2005;78:275-80. PMID 15795920.
  9. ^ Patel V, Mihatov N, Cooper N, Stasi R, Cunningham-Rundles S, Bussel JB,Long-term responses seen with rituximab in patients with ITP, Community Oncology Vol. 4 No. 2, February 2007:107 PDF
  10. ^ Shanafelt, Tait D, MD; Madueme, Hans L, MD; Wold, Robert C, PharmD; Tefferi, Ayalew, MD Rituximab for Immune Cytopenia in Adults: Idiopathic Thrombocytopenic Purpura, Autoimmune Hemolytic Anemia, and Evans Syndrome Mayo Clinic Proc. 2003;78:1340-1346 PDF
  11. ^ Jacob A, Weinshenker BG, Violich I, McLinskey N, Krupp L, Fox RJ, Wingerchuk DM, Boggild M, Constantinescu CS, Miller A, De Angelis T, Matiello M, Cree BA (2008). "Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients.". Arch Neurol 65 (11): 1443–1448. doi:10.1001/archneur.65.11.noc80069. PMID 18779415. http://archneur.ama-assn.org/cgi/content/full/65/11/1443. 
  12. ^ Fluge O, Mella O (July 2009). "Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series". BMC Neurology 9 (1): 28. doi:10.1186/1471-2377-9-28. PMID 19566965. http://www.biomedcentral.com/1471-2377/9/28. 
  13. ^ Drug Intervention in Chronic Fatigue Syndrome
  14. ^ see e.g. T Shaw, J Quan, and M Totoritis, "B cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience", Ann Rheum Dis. 2003 November; 62(Suppl 2): ii55–ii59.
  15. ^ Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M. (2006). "The epitope recognized by rituximab". Blood 108: 1975–1978. doi:10.1182/blood-2006-04-014639. PMID 16705086. 
  16. ^ "Genentech: Products - Product Information - Immunology - Rituxan RA Full Prescribing Information". http://www.gene.com/gene/products/information/immunological/rituxan/insert.jsp. Retrieved 2007-12-03. 
  17. ^ Burton C, Kaczmarski R, Jan-Mohamed R (2003). "Interstitial pneumonitis related to rituximab therapy". N Engl J Med 348 (26): 2690–1; discussion 2690–1. doi:10.1056/NEJM200306263482619. PMID 12826649. 
  18. ^ "Rituximab (marketed as Rituxan) Information". http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm109106.htm. Retrieved 15 November 2009. 
  19. ^ "Rituximab, RA and PML". http://www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf. Retrieved 2008-09-14. 
  20. ^ "Chronic Hepatitis After Hepatitis E Virus Infection in a Patient With Non-Hodgkin Lymphoma Taking Rituximab". http://www.annals.org/cgi/reprint/150/6/430-a.pdf. Retrieved 2008-09-14. 
  21. ^ "Genmab.com / HuMax-CD20 (ofatumumab)". http://www.genmab.com/ScienceAndResearch/ProductsinDevelopment/HuMax-CD20.aspx. Retrieved 2007-12-03. 
  22. ^ "Fc-structure". http://www.healthvalue.net/Fc-structure.html. Retrieved 2007-12-03. 
  23. ^ "Monoclonal antibodies targeting cancer: 'magic bullets' or just the trigger?". http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=138676. Retrieved 2007-12-03. 
  24. ^ "monoclonal domains". http://www.healthvalue.net/monoclonaldomainsengl.html. Retrieved 2007-12-03. 

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Oncology Encyclopedia. Gale Encyclopedia of Cancer. Copyright © 2006 by The Gale Group, Inc. All rights reserved.  Read more
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Wikipedia. This article is licensed under the Creative Commons Attribution/Share-Alike License. It uses material from the Wikipedia article "Rituximab".  Read more