Rituximab

Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells. Rituximab is used in the treatment of many lymphomas, leukemias, transplant rejection and some autoimmune disorders.

History
Rituximab was developed by IDEC Pharmaceuticals (formed in 1986 by Ivor Royston and Howard Birndorf) under the name IDEC-C2B8.

Based on its safety and effectiveness in clinical trials, 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. Rituximab, in combination with CHOP chemotherapy, is now a standard therapy in the initial treatment of diffuse large B-cell lymphoma and many other B-cell lymphomas. In 2010 it was approved by the European Commission for maintenance treatment after initial treatment of follicular lymphoma.

Rituximab is currently co-marketed by Biogen Idec and Genentech in the U.S., by Hoffmann–La Roche in Canada and the European Union, and by Chugai Pharmaceuticals and Zenyaku Kogyo 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 used to treat hematological neoplasms such as leukemias and lymphomas.The use of rituximab in Hodgkin's lymphoma, including the lymphocyte predominant subtype has been reviewed recently.

In multiple myeloma, treatment with rituximab fails to deplete circulating CD20+ B or plasma cells, even after up to four cycles of treatment; in some patients, rituximab treatment increases the number of circulating CD20+ B cells.

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. 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 licence 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.

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, systemic lupus erythematosus and autoimmune anemias. There are significant concerns about progressive multifocal leukoencephalopathy (PML) infection in SLE patients and other conditions.

Other autoimmune diseases that have been treated with rituximab include autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP),  Evans syndrome, vasculitis (for example Wegener's Granulomatosis), bullous skin disorders (for example pemphigus, pemphigoid), type 1 diabetes mellitus, Sjogren's syndrome, and Devic's disease, and thyroid-associated ophthalmopathy.

A new study from Norway suggests that rituximab (together with methotrexate) might help patients with chronic fatigue syndrome. A clinical trial is ongoing.

Anti-rejection treatment for organ transplants
Rituximab is now 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.

Mechanism
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.

The exact mode of action of rituximab is unclear, but the following effects have been found:
 * 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.

Adverse events
Serious adverse events, which can cause death and disability, include:
 * 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

A small number of patients with systemic lupus erythematosus have died in the context of being treated with rituximab. In some cases, reactivation of latent JC virus (a common virus that can cause progressive multifocal leukoencephalopathy) occurred in the brains of these patients. There has also been at least one case of a patient with rheumatoid arthritis who developed PML in the context of treatment with rituximab. JC virus reactivation (resulting in PML) in an immunosuppressed person commonly results in death or severe brain damage.

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.

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.
 * Third-generation anti-CD20s have a glycoengineered Fc fragment (Fc) with enhanced binding to Fc gamma receptors, which increase ADCC (antibody-dependent cellular cytotoxicity). Modifications in the variable regions 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.