Daclizumab

Definition

Daclizumab is a humanized monoclonal antibody of the IgG1 type produced by recombinant DNA technology that binds to a specific interleukin-2 (IL-2) receptor known as CD25 or Tac. This receptor is expressed on the surface of cancerous lymphocytes in a number of blood malignancies. Daclizumab has also been known as dacliximab and is marketed in the United States under the Zenapax brand name.

Purpose

When used against cancer, this drug is intended to stop the growth of blood cell (hematologic) cancers that express the CD25 protein on the surface of the cancerous cells. Some representative cancers include adult T-cell leukemia/lymphoma (ATL), hairy cell leukemia (HCL), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic lymphoma (CLL), Hodgkin's disease , non-Hodgkin's lymphoma (NHL), and other peripheral T-cell or lymphoid leukemias or lymphomas.

Based on the antibody's known ability to block IL-2 binding experimentally, this drug would be expected to work most effectively at the times that the cancerous cells require IL-2 for growth. Generally, this is in the early stages of the disease. However, limited clinical evidence and some experimental evidence support an as of yet uncharacterized alternative method of action that may work during the later, IL-2 independent stages of the cancers.

Description

Daclizumab is a genetically engineered monoclonal antibody that was approved by the FDA in late 1997 as an immunosuppressive drug for use in kidney transplantation. The use of this drug in transplantation is based on the known interaction of activated lymphocytes with IL-2 during the rejection of transplanted tissue. It has not yet been approved for use as a cancer therapy. As of mid-2001 there were at least three active clinical trials to test the ability of daclizumab to treat hematologic cancers. The drug has also been used experimentally to treat IL-2-mediated autoimmune diseases such as uveitis and tropical spastic paraparesis.

Monoclonal antibodies are proteins of the immune system that bind specifically to a particular antigen. Daclizumab was constructed to bind specifically to the alpha subunit of the IL-2 high affinity receptor, a protein also known as CD25 or Tac. By binding to the IL-2 receptor, it is theorized that daclizumab will block the action of IL-2 on the cell, whether it be uncontrolled growth or an uncontrolled immune reaction.

Fusion antibodies related to daclizumab have been developed and are being studied in clinical trials. One fusion antibody links the antibody with radioactive yttrium (Y 90), effectively bringing radiation therapy directly to the cancer cells. Another called LMB-2 fuses the antibody binding site with a bacterial exotoxin that is toxic to the cancer cells. This drug is the first recombinant immunotoxin to induce major responses in cancer during a clinical trial.

Most of the daclizumab sequence is derived from human sequences, while about 10% are from mouse sequences. The human sequences were derived from the constant domains of human IgG1 (called "constant" because it is essentially the same for all IgG antibodies) and the variable framework regions of a human antibody against an antigen seen on the surface of myeloma cells. These areas do not bind to the IL-2 receptor. Using human sequences in this part of the antibody helps to reduce patient immune response to the antibody itself and is called humanization. The actual binding site of daclizumab to the IL-2 receptor is from a mouse anti-Tac antibody.

Recommended dosage

Clinical trials are currently ongoing to determine the most effective dosage and treatment cycles for daclizumab against hematologic cancers.

Precautions

Daclizumab therapy on an outpatient basis requires regular visits to the doctor to check progress. Laboratory tests are needed to make sure daclizumab is working properly and not overly compromising immune function. Because of the possible suppression of the immune system by this drug it is important to maintain good dental hygiene and see a dentist regularly. Also, because the drug would cross the placenta and the effects on an unborn child is unknown, effective contraception is necessary for women of childbearing age while receiving this medicine.

Side effects

Some uncommon side effects of daclizumab needing medical attention include chest pain; coughing; dizziness; fever ; nausea; rapid heart rate; red, tender, oozing skin; shortness of breath; swelling of the feet or lower legs; trembling or shaking of the hands or feet; vomiting; weakness and, rarely, frequent urination.

Some also uncommon and less serious side effects include constipation; diarrhea ; headache; heartburn; joint pain; muscle pain; slow wound healing and trouble in sleeping.

Interactions

The following medications have been administered in clinical trials with daclizumab with no increase in adverse reactions: cyclosporine , mycophenolate mofetil , ganciclovir, acyclovir, azathioprine , and corticosteroids . Daclizumab has also been used by small numbers of patients without reaction with other immune suppressive drugs such as tacrolimus , muromonab-CD3 , antithymocyte globulin, and antilymphocyte globulin.

See Also Monoclonal antibodies

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.

Exotoxin

—A protein produced by a bacteria that is both toxic and produced an immune response by the host.

IgG

—Immunoglobulin type gamma, the most common type found in the blood and tissue fluids.

Interleukin-2

—A cytokine responsible for the activation of B and T-cells of the immune system that induces growth and maturation.

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.

Monoclonal

—Genetically engineered antibodies specific for one antigen.