Rituximab
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Rituximab, sold under the trade names Rituxan® and MabThera®, is a chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders.
History
Rituximab was developed by IDEC Pharmaceuticals and initially approved by the FDA in 1997 for lymphoma that was refractory to other chemotherapy regimens. The original approval followed the availability of the McLaughlin et al[1] study data. It now is standard therapy in the initial treatment of aggressive lymphomas (e.g. diffuse large B cell lymphoma) in combination with CHOP chemotherapy. It is currently co-marketed by Biogen Idec and Genentech in the U.S. market and Roche in the EU.
Uses
Rituximab depletes B cells, and therefore is 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.[2] (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 TNF-alpha therapies.) There is evidence for efficacy in a range of other autoimmune diseases, including idiopathic autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (ITP)[3][4], Evans syndrome[5], vasculitis, bullous skin disorders, 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[3].
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. It does not shed, modulate or internalise. Although the function of CD20 is relatively unknown it has been indicated that CD20 could 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:[6]
- The Fc portion mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
- It 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.
Binder et al further described the part of the CD20 molecule that 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.[7]
Adverse events
Serious adverse events, which can cause death and disability, include:[8]
- Severe infusion reactions
- 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[9]
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%-905% human) B-cell agonist.
- ofatumumab (HuMax-CD20) a fully-human B-cell agonist.[10]
- Third-generation anti-CD20s have a glycoengineered Fc fragment (Fc)[11] with enhanced binding to Fc gamma receptors, which increase ADCC (antibody dependent cellular cytotoxicity).[12] Modifications in the variable regions (variable regions)[13] can enhance apoptosis.
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
- ↑ McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825-33. PMID 9704735.
- ↑ 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. PMID 15201414.
- ↑ 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 PDF
- ↑ 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
- ↑ 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.
- ↑ Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M. (2006). "The epitope recognized by rituximab". Blood. 108: 1975–1978. PMID 16705086.
- ↑ "Genentech: Products - Product Information - Immunology - Rituxan RA Full Prescribing Information". Retrieved 2007-12-03.
- ↑ 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. PMID 12826649.
- ↑ "Genmab.com / HuMax-CD20 (ofatumumab)". Retrieved 2007-12-03.
- ↑ "Fc-structure". Retrieved 2007-12-03.
- ↑ "Monoclonal antibodies targeting cancer: 'magic bullets' or just the trigger?". Retrieved 2007-12-03.
- ↑ "monoclonal domains". Retrieved 2007-12-03.
External links
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