Rituximab

drugbox-mab


source = chimeric (mouse/human)
target = CD20
CAS_number = 174722-31-7 | ATC_prefix = L01 | ATC_suffix = XC02 | ATC_supplemental = | PubChem = | DrugBank = BTD00014 | C=6416 | H=9874 | N=1688 | O=1987 | S=44 | molecular_weight = 143859.7 g/mol | bioavailability = 100% (IV) | protein_bound = | metabolism = | elimination_half-life = 30 to 400 hours (varies by dose and length of treatment) | excretion = Uncertain: may undergo phagocytosis and catabolism in RES | pregnancy_category = (no adequate human studies) | pregnancy_US = C
legal_US = Rx-only
legal_status = | routes_of_administration = intravenous infusion only (never bolus or "push")

Rituximab, sold under the trade names Rituxan,MabThera and Reditux, is a chimeric monoclonal antibody against the protein CD20. Rituximab is used in the treatment of B cell non-Hodgkin's lymphoma, B-cell leukemias, and some autoimmune disorders.

History

Rituximab was developed by IDEC Pharmaceuticals. Based on its safety and effectiveness in clinical trials, [cite journal |author=Maloney DG, Grillo-López AJ, White CA, "et al" |title=IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma |journal=Blood |volume=90 |issue=6 |pages=2188–95 |year=1997 |month=September |pmid=9310469 |doi= |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=9310469] rituximab was approved by the U.S. Food and Drug Administration in 1997 for B-cell non-Hodgkin lymphoma resistant to other chemotherapy regimens. [cite journal |author=Scott SD |title=Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin's lymphoma |journal=Cancer Pract |volume=6 |issue=3 |pages=195–7 |year=1998 |pmid=9652253 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1065-4704&date=1998&volume=6&issue=3&spage=195] Rituximab, in combination with CHOP chemotherapy, is now standard therapy in the initial treatment of diffuse large B cell lymphoma and other aggressive B-cell non-Hodgkin lymphomas. It is currently co-marketed by Biogen Idec and Genentech in the U.S. and by Roche in the European Union.

Uses

Rituximab destroys both normal and malignant B lymphocytes, and is therefore used to treat diseases which are characterized by having too many B cells, overactive B cells or dysfunctional B cells.

Neoplastic diseases

Most patients taking rituximab have a neoplastic disease such as leukemia or lymphoma.

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. [cite journal | author = Edwards J, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close D, Stevens R, Shaw T | title = Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis | journal = N Engl J Med | volume = 350 | issue = 25 | pages = 2572–81 | year = 2004 | pmid = 15201414 | doi = 10.1056/NEJMoa032534] (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 evidence for efficacy in a range of other autoimmune diseases, including idiopathic autoimmune hemolytic anemia, Pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP) [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.] [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 [http://www.communityoncology.net/journal/articles/0402107.pdf PDF] ] , Evans syndrome [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 [http://www.mayoclinicproceedings.com/pdf/7811/7811a3.pdf PDF] ] , vasculitis, multiple sclerosis, [ [http://content.nejm.org/cgi/content/short/358/7/676 NEJM - B-Cell Depletion with Rituximab in Relapsing-Remitting Multiple Sclerosis ] ] bullous skin disorders (for example pemphigus, pemphigoid), type 1 diabetes mellitus, Sjogren's syndrome, Devic's Syndrome and systemic lupus erythematosus, although there are significant concerns about PML infection in SLE patients [http://www.fda.gov/bbs/topics/NEWS/2006/NEW01532.html] .

Anti-rejection treatment for organ transplants

Rituximab is now being used in the management of Renal 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 renal 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: [see e.g. T Shaw, J Quan, and M Totoritis, " [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1766758 B cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience] ", Ann Rheum Dis. 2003 November; 62(Suppl 2): ii55–ii59.]
* The Fc portion of rituximab mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
* Rituximab has a general regulatory effect on the cell cycle.
* It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen).
* It elicits shedding of CD23.
* It downregulates the B-cell receptor.
* It induces apoptosis of CD20+ cells. The combined effect results in the elimination of B cells (including the cancerous ones) from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.

Rituximab binds to amino acids 170-173 and 182-185, which are physically close to each other as a result of a disulfide bond between amino acids 167 and 183. [cite journal | author = Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M. | title = The epitope recognized by rituximab | journal = Blood | volume = 108 | issue = | pages =1975–1978 | year = 2006 | pmid = 16705086 | doi = 10.1182/blood-2006-04-014639]

Adverse events

Serious adverse events, which can cause death and disability, include:cite web |url=http://www.gene.com/gene/products/information/immunological/rituxan/insert.jsp |title=Genentech: Products - Product Information - Immunology - Rituxan RA Full Prescribing Information |accessdate=2007-12-03 |format= |work=]
*Severe infusion reactions
* Cardiac arrest
*Tumor lysis syndrome, causing acute renal failure
*Infections
**Hepatitis B reactivation
**Other viral infections
**Progressive multifocal leukoencephalopathy (PML)
*Immune toxicity, with depletion of B cells in 70% to 80% of patients with non-Hodgkins lymphoma
*Pulmonary toxicity [cite journal |author=Burton C, Kaczmarski R, Jan-Mohamed R |title=Interstitial pneumonitis related to rituximab therapy |journal=N Engl J Med |volume=348 |issue=26 |pages=2690–1; discussion 2690–1 |year=2003 |pmid=12826649 |doi=10.1056/NEJM200306263482619]

Several patients with systemic lupus erythematosus have died after being treated with rituximab.cite web |url=http://www.fda.gov/cder/drug/infopage/rituximab/default.htm |title=Rituximab (marketed as Rituxan) Information |format= |work= |accessdate=2008-04-28] Rituximab triggered reactivation of latent JC virus (a common virus) in the brains of these patients. There has also been at least one case of a patient with rheumatoid arthritis who developed PML on rituximab.cite web |url=http://www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf |title=Rituximab, RA and PML |format= |work= |accessdate=2008-09-14] PML reactivation in an immunosuppressed person commonly results in death or severe brain damage.

Other anti CD20 monoclonals

The efficacy and success of Rituximab has led to a few other anti CD20 monoclonal antibodies being developed:
* ocrelizumab, humanized (90%-95% human) B-cell agonist.
* ofatumumab (HuMax-CD20) a fully-human B-cell agonist.cite web |url=http://www.genmab.com/ScienceAndResearch/ProductsinDevelopment/HuMax-CD20.aspx |title=Genmab.com / HuMax-CD20 (ofatumumab) |accessdate=2007-12-03 |format= |work=]
* Third-generation anti-CD20s have a glycoengineered Fc fragment (Fc)cite web |url=http://www.healthvalue.net/Fc-structure.html |title=Fc-structure |accessdate=2007-12-03 |format= |work=] with enhanced binding to Fc gamma receptors, which increase ADCC (antibody dependent cellular cytotoxicity).cite web |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=138676 |title=Monoclonal antibodies targeting cancer: 'magic bullets' or just the trigger? |accessdate=2007-12-03 |format= |work=] Modifications in the variable regions (variable regions)cite web |url=http://www.healthvalue.net/monoclonaldomainsengl.html |title=monoclonal domains |accessdate=2007-12-03 |format= |work=] can enhance apoptosis.
* DXL625 (CD20) is a pre-clinical stage antibody currently being developed by InNexus Biotechnology Inc. for the prospective treatment of non-Hodgkin's lymphoma.

The value of a humanized molecule in oncology has not been demonstrated to this date. Another approach to B lymphocyte diseases is to confront their agonists and the receptors of these agonists. Belimumab is an example of such an approach.

References

External links

* [http://www.mabthera.com MabThera.com] Official website for use against lymphoma
* [http://www.mabthera-ra.com MabThera for Rheumatoid Arthritis] Official website for use against rheumatoid arthritis (for non US physicians and scientific media only)
* [http://www.rituxan.com Rituxan.com] Official website (for US residents only)
* [http://www.fda.gov/cder/drug/infopage/rituximab/default.htm US Food and Drug Administration (FDA) Rituximab Information]