Muromonab-CD3

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Muromonab-CD3

Definition

Muromonab-CD3 is a mouse-derived (murine) monoclonal antibody that specifically binds to the CD3 (T3) protein found on the surface of T cells. It is a protein known to be necessary for activation (immune responses) of T cells. Muromonab-CD3 is marketed in the United States under the Orthoklone OKT3 brand name.

Purpose

Muromonab-CD3 is believed to have two effects when it binds to the CD3 protein on the surface of T cells. In the short term the T cells are activated and begin to excrete cytokines—small proteins that boost immune function. In the long term, function of the T cells is eliminated because access to the CD3 protein is blocked and binding by the antibody encourages removal of the cell from the bloodstream by the immune system.

When using muromonab-CD3 to treat cancer, doctors are seeking the short-term effect by boosting the activity of T cells against tumor antigens. In this setting muromonab-CD3 is not administered directly to the patient. Rather, it is used to stimulate white blood cells (lymphocytes) that have been removed from the patient, treated outside the body, then reinfused (infused back into the patient). In the test tube the binding of the antibody to the CD3 protein stimulates the T cells so they can begin the cell-mediated destruction of the tumor cells upon reentry into the patient's bloodstream. Often, the T cells used for this treatment are either preselected to be specific against the proteins found on the tumor surface (tumor antigens) or are genetically engineered before reinfusion to express the desired tumor-antigen specific receptors. This is often followed by stimulation of T-cell division using interleukin-2.

As of spring 2001 clinical trials using this stimulated lymphocyte treatment were ongoing for astrocytoma , oligodendroglioma , nonmetastatic kidney cancer , metastatic melanoma , Kaposi's sarcoma (a twin study), and advanced epithelial ovarian cancer .

Description

In late 1986 Muromonab-CD3 was the first monoclonal antibody approved for use by the FDA as an immunosuppressive drug in kidney transplantation. The use of this drug in transplantation is based on the long-term effect of antibody binding, blocking cellular interaction with the CD3 protein known to be necessary to activate T cells involved in the rejection of transplanted tissue. As of mid-2001 it had not been approved for use as a cancer therapy. However, there were at least five active clinical trials to test its ability to activate lymphocytes outside the body in preparation for reinfusion.

A second use of the muromonab-CD3 antibody to treat cancer required the development of a humanized monoclonal antibody called hOKT3, using the same binding sites as muromonab-CD3. This treatment involves direct administration of the antibody to the patient. The humanized antibody retains the murine sequences at the antibody's two binding sites, but has human sequences in the other areas of the antibody molecule. This allows the monoclonal antibody to be directly administered to the patient without the immune reaction against the mouse antibodies seen when muromonab-CD3 is used. hOKT3 was used in a clinical trial of 24 patients against a wide variety of cancers. Although testing the antibody's function as a therapy was not the main goal of the study, three patients with cancers of the peritoneum cavity (lower abdomen) did see a clinical improvement.

Recommended dosage

To treat cancer, muromonab-CD3 is not administered directly to the patient. However, a similar humanized antibody, hOKT3, has been given to patients during a clinical trial. The most effective dosage in the trial was three doses of 800 micrograms every two weeks in a 10-minute infusion, but further study is necessary to confirm this finding.

Precautions

As the two uses of muromonab-CD3 are still in the clinical trial stage, the exact precautions for this drug (or the humanized version, hOKT3) are not yet known. However, for monoclonal antibody treatment in general, preexisting heart conditions and arrhythmias can make taking this drug more dangerous. Vaccination during the treatment session is also not recommended, given the T-cell depletion that occurs during treatment.

Side effects

During clinical trials the majority of side effects occurred during the first administration of activated T cells or humanized antibody. These side effects included flu-like symptoms, headache, dizziness, and shortness of breath. The humanized antibody also caused edema (collection of fluid) in all three patients that exhibited a clinical benefit from the treatment.

Interactions

Still in the early clinical trial stages in 2001, muromonab-CD3 had not been studied to determine interactions with other drugs.

Michelle Johnson, M.S., J.D.

KEY TERMS

Antibody

—A protective protein made by the immune system in response to an antigen; also called an immunoglobulin.

Cytokine

—A protein produced by cells of the immune system that help boost immune function.

hOKT3

—A humanized version of the muromonab-CD3 antibody.

Humanization

—Fusing the constant and variable framework region of one or more human immunoglobulins with the binding region of an animal immunoglobulin; done to reduce human reaction against the fusion antibody.