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.
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.
