Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibodyCD20, which is primarily found on the surface of B cells. Rituximab is used in the treatment of many lymphomas, leukemias, and some autoimmune disorders.

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 (under the trade name Rituximab) and the European Union and by Chugai Pharmaceuticals in Japan.

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 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 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]

• 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 lymphoma patients
• Pulmonary toxicity^[17]

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.

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