Rituximab

Rituximab
Monoclonal antibody
Type Whole antibody
Source Chimeric (mouse/human)
Target CD20
Clinical data
Trade names Rituxan, others[1]
AHFS/Drugs.com Monograph
Pregnancy
category
  • US: C (Risk not ruled out)
  • (no adequate human studies)
Routes of
administration		 intravenous infusion only (never bolus or "push")
ATC code L01XC02 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (IV)
Biological half-life 30 to 400 hours (varies by dose and length of treatment)
Excretion Uncertain: may undergo phagocytosis and catabolism in RES
Identifiers
CAS Number 174722-31-7 YesY
DrugBank DB00073 YesY
ChemSpider none
UNII 4F4X42SYQ6 YesY
KEGG D02994 YesY
ChEMBL CHEMBL1201576 N
ECHA InfoCard 100.224.382
Chemical and physical data
Formula C6416H9874N1688O1987S44
Molar mass 143859.7 g/mol
 NYesY (what is this?)  (verify)

Rituximab is a monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. Rituximab destroys B cells and is therefore used to treat diseases which are characterized by overactive, dysfunctional, or excessive numbers of B cells. This includes many lymphomas, leukemias, transplant rejection, and autoimmune disorders. Rituximab is a chimeric molecule.

The drug is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[2] It has a wholesale price of USD$159–$2,480 per vial as of 2014.[3]

Medical 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 cancers

Rituximab is used to treat cancers of the white blood system such as leukemias and lymphomas, including non-Hodgkin's lymphoma and lymphocyte predominant subtype of Hodgkin's Lymphoma.[4]

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.[5] 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 therapy. In Europe, the license 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.[6]

There is some evidence for efficacy, but not necessarily safety, in a range of other autoimmune diseases, and rituximab is widely used off-label to treat difficult cases of multiple sclerosis,[7] systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy and autoimmune anemias.[8] The most dangerous, although among the most rare, side effect is progressive multifocal leukoencephalopathy (PML) infection, which is usually fatal; however only a very small number of cases have been recorded occurring in autoimmune diseases.[8][9]

Other autoimmune diseases that have been treated with rituximab include autoimmune hemolytic anemia, pure red cell aplasia, thrombotic thrombocytopenic purpura (TTP),[10] idiopathic thrombocytopenic purpura (ITP),[11][12] Evans syndrome,[13] vasculitis (for example granulomatosis with polyangiitis, formerly Wegener's), bullous skin disorders (for example pemphigus, pemphigoid—with very encouraging results of approximately 85% rapid recovery in pemphigus, according to a 2006 study),[14] type 1 diabetes mellitus, Sjogren's syndrome, anti-NMDA receptor encephalitis and Devic's disease,[15] Graves' ophthalmopathy,[16] autoimmune pancreatitis,[17] Opsoclonus myoclonus syndrome (OMS),[18] and IgG4-related disease.[19] There is some evidence that it is ineffective in treating IgA-mediated autoimmune diseases.[20]

In October 2011, a double-blind controlled study was published in PLOS ONE which suggests that rituximab can help patients with chronic fatigue syndrome, leading to a proposed theory relating chronic fatigue syndrome to other autoimmune conditions, however more research is required to verify if such a link exists.[21] A new multi-centre double-blinded trial with 152 patients began in October 2014,[22] after a follow-up open study published in July 2015 suggested a longer acting effect when four maintenance doses were added to the dosing schedule.[23] Two-thirds of the patients responded favorably to the drug, in accordance with previous findings.[24][25][26]

Organ transplants

Rituximab is 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.

Adverse events

Serious adverse events, which can cause death and disability, include:[27]

Two patients with systemic lupus erythematosus died of progressive multifocal leukoencephalopathy (PML) after being treated with rituximab. PML is caused by activation of JC virus, a common virus in the brain which is usually latent. Reactivation of the JC virus usually results in death or severe brain damage.[30]

At least one patient with rheumatoid arthritis developed PML after treatment with rituximab.[31]

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.[32]

Mechanisms of action

Rituximab mechanisms of action; the three major independent mechanisms are (1) antibody dependent cellular cytotoxicity (ADCC), (2) complement mediated cytotoxicity (CMC), and (3) apoptosis; subset panel illustrates a schematic view of CD20 structure and rituximab.[33]
Rituximab binding to CD20. The CD20 proteins are sticking out of the cell membrane, and rituximab, the Y-shaped antibody, is binding to the CD20 proteins.

The antibody binds to 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.

Rituximab 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 changed 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.[34][35]

The following effects have been found:[36]

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.[37]

History

Rituximab was developed by researcher Nabil Hanna and coworkers at IDEC Pharmaceuticals under the name IDEC-C2B8.[38] The U.S. patent for the drug was issued in 1998 and expired in 2015.[39]

Based on its safety and effectiveness in clinical trials,[40] rituximab was approved by the U.S. Food and Drug Administration in 1997 to treat B-cell non-Hodgkin lymphomas resistant to other chemotherapy regimens.[41] 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.[42] In 2010 it was approved by the European Commission for maintenance treatment after initial treatment of follicular lymphoma.[43]

Rituximab is currently co-marketed by Biogen Idec and Genentech in the U.S., by Hoffmann–La Roche in Canada and the European Union, Chugai Pharmaceuticals, Zenyaku Kogyo in Japan and AryoGen in Iran.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[44]

Originally available for intravenous injection (e.g. over 2.5 hrs), in 2016 it gained EU approval in a formulation for subcutaneous injection for CLL.[45]

Specialty drug

In 2014 Genentech reclassified Avastin, Herceptin and Rituxan as specialty drugs which are only available through specialty pharmacies from October 2014.[46] Because discounts no longer apply, hospitals will pay more. "Specialty drugs usually fall under the FDA’s Risk Evaluation and Mitigation Strategy (REMS) program, established for compounds like the testosterone drug AndroGel that may have unusual side effects; or for drugs that are unusually expensive."[46]

Other anti-CD20 monoclonals

The efficacy and success of Rituximab has led to some other anti-CD20 monoclonal antibodies being developed:

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. ↑ Drugs.com International brand names for rituximab Page accessed April 1, 2016
  2. ↑ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  3. ↑ "Rituximab". International Drug Price Indicator Guide. Retrieved 28 November 2015.
  4. ↑ Saini KS, Azim HA Jr, Cocorocchio E, Vanazzi A, Saini ML, Raviele PR, Pruneri G, Peccatori FA (2011). "Rituximab in Hodgkin lymphoma: Is the target always a hit?". Cancer Treat Rev. 37 (5): 385–90. doi:10.1016/j.ctrv.2010.11.005. PMID 21183282.
  5. ↑ 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.
  6. ↑ Tak PP, Kalden JR (2011). "Advances in rheumatology: new targeted therapeutics". Arthritis Research & Therapy. 13 (Suppl 1): S5. doi:10.1186/1478-6354-13-S1-S5. PMC 3123966Freely accessible. PMID 21624184.
  7. ↑ NEJM - B-Cell Depletion with Rituximab in Relapsing-Remitting Multiple Sclerosis
  8. 1 2 Paul, Marla (May 20, 2009). "Popular Cancer Drug Linked to Often Fatal 'Brain Eating' Virus". Northwestern University News and Information. Retrieved 2009-05-22.
  9. ↑ "Press Announcements". Fda.gov. Retrieved 2013-04-29.
  10. ↑ Froissart A, Veyradier A, Hié M, Benhamou Y, Coppo P (August 2015). "Rituximab in autoimmune thrombotic thrombocytopenic purpura: A success story.". Eur J Intern Med. 26: 659–65. doi:10.1016/j.ejim.2015.07.021. PMID 26293834.
  11. ↑ Braendstrup P, Bjerrum OW, Nielsen OJ, et al. (April 2005). "Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura". Am. J. Hematol. 78 (4): 275–80. doi:10.1002/ajh.20276. PMID 15795920.
  12. ↑ 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
  13. ↑ 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
  14. ↑ A. Razzaque Ahmed, M.D.; Zachary Spigelman, M.D.; Lisa A. Cavacini, Ph.D.; Marshall R. Posner, M.D. (October 26, 2006). "Treatment of Pemphigus Vulgaris with Rituximab and Intravenous Immune Globulin". N Engl J Med. 355: 1772–1779. doi:10.1056/nejmoa062930.
  15. ↑ 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.
  16. ↑ "Rituximab Treatment of Patients with Severe, Corticosteroid-Resistant Thyroid-Associated Ophthalmopathy". Retrieved 2011-10-19.
  17. ↑ "Immunomodulators and Rituximab in the Management of Autoimmune Pancreatitis". Retrieved 2014-04-30.
  18. ↑ Pranzatelli, Michael R.; Tate, Elizabeth D.; Travelstead, Anna L.; Longee, Darryl (2005-01-01). "Immunologic and Clinical Responses to Rituximab in a Child With Opsoclonus-Myoclonus Syndrome". Pediatrics. 115 (1): e115–e119. doi:10.1542/peds.2004-0845. ISSN 0031-4005. PMID 15601813.
  19. ↑ Arezou Khosroshahi; Z. S. Wallace; J. L. Crowe; T. Akamizu; A. Azumi; M. N. Carruthers; S. T. Chari; E. Della-Torre; L. Frulloni; H. Goto; P. A. Hart; T. Kamisawa; S. Kawa; M. Kawano; M. H. Kim; Y. Kodama; K. Kubota; M. M. Lerch; M. Löhr; Y. Masaki; S. Matsui; T. Mimori; S. Nakamura; T. Nakazawa; H. Ohara; K. Okazaki; J.H. Ryu; T. Saeki; N. Schleinitz; A. Shimatsu; T. Shimosegawa; H. Takahashi; M. Takahira; A. Tanaka; M. Topazian; H. Umehara; G. J. Webster; T. E. Witzig; M. Yamamoto; W. Zhang; T. Chiba; John H. Stone (July 2015). "International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease". Arthritis & Rheumatology. 67 (7): 1688–1699. doi:10.1002/art.39132. PMID 25809420.
  20. ↑ He Y, Shimoda M, Ono Y, Villalobos IB, Mitra A, Konia T, Grando SA, Zone JJ, Maverakis E (2015). "Persistence of Autoreactive IgA-Secreting B Cells Despite Multiple Immunosuppressive Medications Including Rituximab". JAMA Dermatol. 151 (6): 646–50. doi:10.1001/jamadermatol.2015.59. PMID 25901938.
  21. ↑ 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: 28. doi:10.1186/1471-2377-9-28. PMC 2711959Freely accessible. PMID 19566965.
  22. ↑ http://simmaronresearch.com/2015/01/chronic-fatigue-syndrome-rituximab-fluge-mella/
  23. ↑ http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129898
  24. ↑ Drug Intervention in Chronic Fatigue Syndrome
  25. ↑ "Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study". Plos One. Retrieved 2013-04-29.
  26. ↑ "Rituximab Trial Shows Promise". Retrieved 2011-11-04.
  27. ↑ "Genentech: Products - Product Information - Immunology - Rituxan RA Full Prescribing Information". Retrieved 2007-12-03.
  28. ↑ 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.
  29. ↑ "Reports of Bowel Obstruction and Perforation with RITUXAN (rituximab)" (PDF). Roche Canada. 2006-11-10.
  30. ↑ "Rituximab (marketed as Rituxan) Information". Retrieved 15 November 2009.
  31. ↑ "Rituximab, RA and PML" (PDF). Retrieved 2008-09-14.
  32. ↑ "Chronic Hepatitis After Hepatitis E Virus Infection in a Patient With Non-Hodgkin Lymphoma Taking Rituximab" (PDF). Retrieved 2008-09-14.
  33. ↑ Seyfizadeh, Narges; Seyfizadeh, Nayer; Hasenkamp, J; Huerta-Yepez, S. "A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other affections.". Crit Rev Oncol Hematol. 97: 275–290. doi:10.1016/j.critrevonc.2015.09.001. PMID 26443686.
  34. ↑ "Scientists discover why a specific cancer drug is so effective". KurzweilAI. doi:10.1182/blood-2013-02-482570. Retrieved 2013-04-29.
  35. ↑ Rudnicka, D; Oszmiana, A; Finch, DK; Strickland, I; Schofield, DJ; Lowe, DC; Sleeman, MA; Davis, DM (Jun 6, 2013). "Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity.". Blood. 121 (23): 4694–702. doi:10.1182/blood-2013-02-482570. PMID 23613524.
  36. ↑ 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.
  37. ↑ Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M. (2006). "The epitope recognized by rituximab". Blood. 108 (6): 1975–1978. doi:10.1182/blood-2006-04-014639. PMID 16705086.
  38. ↑ "Why San Diego Has Biotech", Fikes, Bradley J. San Diego Metropolitan, April 1999. Accessed June 20, 2008.
  39. ↑ DrugBank DB00073
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ Harrison's Principles of Internal Medicine, Longo et al. McGraw Hill Medical 2011 page 931
  43. ↑ "Roche Gets EC Nod for Follicular Lymphoma Maintenance Therapy". October 29, 2010.
  44. ↑ "www.who.int" (PDF).
  45. ↑
  46. 1 2 Saporito, Bill (27 October 2014). "Hospitals Furious at Cancer-Drug Price Hikes". Time. Retrieved 26 October 2015.
  47. ↑ "Genmab.com / HuMax-CD20 (ofatumumab)". Archived from the original on 2007-09-11. Retrieved 2007-12-03.
  48. ↑ "Fc-structure". Retrieved 2007-12-03.
  49. ↑ Eccles, SA (2001). "Monoclonal antibodies targeting cancer: 'magic bullets' or just the trigger?". Breast cancer research : BCR. 3 (2): 86–90. doi:10.1186/bcr276. PMC 138676Freely accessible. PMID 11250751.
  50. ↑ Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun. 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMC 4340844Freely accessible. PMID 25578468.
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