Common side effects which often occur within two hours of the medication being given include rash, itchiness,
low blood pressure, and shortness of breath. Infections are also common.[15]
Rituximab is a
chimericmonoclonal antibody against the protein
CD20, which is primarily found on the surface of immune system
B cells.[22] When it binds to this protein it triggers cell death.[15]
Rituximab is a chimeric monoclonal antibody targeted against CD20, a
surfaceantigen present on
B cells. It acts by depleting normal as well as pathogenic B cells while sparing
plasma cells and
hematopoietic stem cells, which do not express the CD20 surface antigen.[25]
In the United States, rituximab is
indicated to treat:
in combination with chemotherapy for children (≥ 6 months to < 18 years) with previously untreated, advanced stage, CD20-positive
diffuse large B-cell lymphoma (DLBCL),
Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), or mature acute
B-cell leukemia (B-AL).[26]
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.[30] In the United States, it has been
FDA approved for use in combination with
methotrexate 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 the European Union, the license is slightly more restrictive: it is licensed for use in combination with methotrexate in patients with severe active RA who have had an inadequate response to one or more anti-TNF therapy.[31]
At least one patient with
rheumatoid arthritis developed PML after treatment with rituximab.[53]
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.[54]
A major concern with continuous rituximab treatment is the difficulty to induce a proper vaccine response.[55] This was brought into focus during the
COVID-19 pandemic, where persons with
multiple sclerosis and rituximab treatment had higher risk of severe COVID-19.[56] In persons with rituximab treatment for multiple sclerosis, 9 of 10 patients with B cell counts of 40/µL or more developed protective levels of antibodies after vaccination with
tozinameran.[57]
Mechanisms of action
The antibody binds to the cell surface protein
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. 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 is relatively ineffective in elimination of cells with low CD20 cell-surface levels.[59] It 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 changes 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.[60]
Rituximab has a general regulatory effect on the
cell cycle.
Preferential elimination of malignant B cells with high CD20 levels and high BCR signaling propensity, especially in chronic lymphocytic leukemia (CLL).[59]
It increases
MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen).
Rituximab also induces a release of some chronic lymphocytic leukemia cells from immune niches, which might make them more sensitive to chemotherapy used in combination with an anti-CD20 antibody.[62]
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.[63]
History
Rituximab was developed by
IDEC Pharmaceuticals under the name IDEC-C2B8. The U.S. patent for the drug was issued in 1998 and expired in 2015.[64]
In 2014, Genentech reclassified rituxan as a
specialty drug, a class of drugs that are only available through specialty distributors in the US.[69] Because wholesalers discounts and rebates no longer apply, hospitals would pay more.[69]
Originally available for intravenous injection (e.g. over 2.5 hrs), in 2016, it gained EU approval in a formulation for subcutaneous injection for
B-cell CLL/lymphoma (CLL).[70]
Society and culture
Economics
Patents on the drug expired in Europe in February 2013, and in the US in September 2016.[failed verification][71] By November 2018[update], several
biosimilars had been approved in the US, India, the European Union, Switzerland, Japan and Australia. The US FDA approved Truxima (rituximab-abbs) in 2018, Ruxience (rituximab-pvvr) in 2019 and Riabni (rituximab-arrx) in 2020. The Riabni is about $3600 per 500 mg, wholesale, list. Truxima is about the same price as Riabni - 10% less than Rituxan, while Ruxience is 24% less than Rituxan. [72][71][73][74][75]
Research
Chronic fatigue syndrome
Rituximab did not improve symptoms in patients with
chronic fatigue syndrome in a trial published in 2019.[76][77] Twenty-two percent of participants had serious events.[76] This potential use was investigated after improvements in
chronic fatigue syndrome was seen in two cancer patients treated with rituximab.[78]
Intrathecal
For CNS diseases, rituximab could be administered
intrathecally and this possibility is under study.[79]
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.[80]
Third-generation anti-CD20s such as
obinutuzumab have a glycoengineered
Fc fragment (Fc)[81] with enhanced binding to
Fc gamma receptors, which increase ADCC (
antibody-dependent cellular cytotoxicity).[82] This strategy for enhancing a monoclonal antibody's ability to induce ADCC takes advantage of the fact that the displayed Fc glycan controls the antibody's affinity for Fc receptors.[83]
^"MabThera EPAR". European Medicines Agency. 17 September 2018. Retrieved 8 September 2021.
^
abcdefghi"Rituximab". The American Society of Health-System Pharmacists.
Archived from the original on 27 March 2016. Retrieved 8 December 2016.
^Tandan R, Hehir MK, Waheed W, Howard DB (August 2017). "Rituximab treatment of myasthenia gravis: A systematic review". Muscle & Nerve. 56 (2): 185–196.
doi:
10.1002/mus.25597.
PMID28164324.
S2CID19504332.
^Singer O, McCune WJ (May 2017). "Update on maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis". Current Opinion in Rheumatology. 29 (3): 248–253.
doi:
10.1097/BOR.0000000000000382.
PMID28306595.
S2CID35805200.
^
abWorld Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.
hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Saini KS, Azim HA, Cocorocchio E, Vanazzi A, Saini ML, Raviele PR, et al. (August 2011). "Rituximab in Hodgkin lymphoma: is the target always a hit?". Cancer Treatment Reviews. 37 (5): 385–390.
doi:
10.1016/j.ctrv.2010.11.005.
PMID21183282.
^McGinley MP, Moss BP, Cohen JA (January 2017). "Safety of monoclonal antibodies for the treatment of multiple sclerosis". Expert Opinion on Drug Safety. 16 (1): 89–100.
doi:
10.1080/14740338.2017.1250881.
PMID27756172.
S2CID36762194.
^He D, Guo R, Zhang F, Zhang C, Dong S, Zhou H (December 2013). "Rituximab for relapsing-remitting multiple sclerosis". The Cochrane Database of Systematic Reviews (12): CD009130.
doi:
10.1002/14651858.CD009130.pub3.
PMID24310855.
^Burton C, Kaczmarski R, Jan-Mohamed R (June 2003). "Interstitial pneumonitis related to rituximab therapy". The New England Journal of Medicine. 348 (26): 2690–1, discussion 2690–1.
doi:
10.1056/NEJM200306263482619.
PMID12826649.
^Seyfizadeh N, Seyfizadeh N, Hasenkamp J, Huerta-Yepez S (January 2016). "A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other affections". Critical Reviews in Oncology/Hematology. 97: 275–290.
doi:
10.1016/j.critrevonc.2015.09.001.
PMID26443686.
^
abBorsky M, Hrabcakova V, Novotna J, Brychtova Y, Doubek M, Panovska A, et al. (December 2021). "Rituximab induces rapid blood repopulation by CLL cells mediated through their release from immune niches and complement exhaustion". Leukemia Research. 111: 106684.
doi:
10.1016/j.leukres.2021.106684.
PMID34438120.
^
ab"Biosimilars of Rituximab". Generics and Biosimilars Initiative. 14 April 2017.
Archived from the original on 31 March 2017. Retrieved 29 April 2017.
^Bonnan M, Ferrari S, Bertandeau E, Demasles S, Krim E, Miquel M, et al. (2014). "Intrathecal rituximab therapy in multiple sclerosis: review of evidence supporting the need for future trials". Current Drug Targets. 15 (13): 1205–1214.
doi:
10.2174/1389450115666141029234644.
PMID25355180.