Gemtuzumab

Definition

Gemtuzumab ozogamicin is a humanized monoclonal antibody produced by recombinant DNA technology that binds specifically to CD33, a protein that is found on the cell surface of most leukemic blasts, the abnormal, cancerous cells in acute myeloid leukemia (also known as acute myelocytic leukemia, or AML). It is marketed in the United States under the brand name Mylotarg.

Purpose

Gemtuzumab is a monoclonal antibody used to treat AML that is characterized by expression of the CD33 protein on the cancerous cells, called leukemic blasts. The CD33 protein is found on the surface of the leukemic blasts of about 80% of AML patients. After the gemtuzumab antibody is produced in the laboratory, a chemical reaction is used to link it to an antitumor drug called calicheamicin. About half of the antibody succeeds in acquiring the antitumor drug.

When the antibody-calicheamicin molecule binds to the cancerous cells, both the antibody and the drug are taken into the cell. There the drug binds to the cell's genetic material (deoxyribose nucleic acid or DNA) inducing breaks in the molecule and killing it. Because the antibody carries and delivers the toxic drug to the leukemic blasts targets, gemtuzumab treatment is called antibody-targeted chemotherapy.

Gemtuzumab can also be used to induce remission (remove cancerous cells) in AML patients to prepare them for stem-cell transplantation. It is indicated for refractory AML (AML that does not readily yield to treatment). The use of antibody-targeted chemotherapy has been shown to have fewer side effects than traditional chemotherapy courses and does improve the disease-free survival time after transplantation.

Description

Gemtuzumab is a genetically engineered monoclonal antibody linked to an antitumor antibiotic. It was approved by the FDA in 2000 as a method of treating relapsed AML in older patients (over 60 years of age) that are not candidates for other cytotoxic chemotherapy. About 75% of all patients with AML experience a relapse after initial treatment. In clinical trials focusing on the treatment of older patients with relapsed AML, gemtuzumab had an overall response rate of 30%, with 16% having a complete response.

Most of the gemtuzumab sequence is derived from human sequences, while about 2% are from mice. The human sequences were derived from the constant domains of human IgG4 (called "constant" because it is essentially the same for all IgG antibodies) and the variable framework regions of a human antibody. These areas do not bind to the CD33 protein. 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 gemtuzumab to the CD33 protein is from a mouse anti-CD33 antibody. The antibiotic antitumor drug calcheamicin is linked to the antibody in a way that does not interfere with the ability of the antibody to bind CD33.

Gemtuzumab is not currently approved for use in combination with other chemotherapy drugs or treatments. However, clinical trials that combine the drug with cytarabine, fludarabine, total-body irradiation, as well as other cancer treatments, are ongoing.

Recommended dosage

Gemtuzumab is administered intravenously. In the pivotal clinical trial, the drug was given at a dose of 9 mg/m² for two doses that were fourteen days apart.

Precautions

Extreme caution should be used when using gemtuzumab to treat patients with existent liver problems. Animal studies showed that the drug can cause significant harm to the development of a fetus, so it is likely the drug should not be used during pregnancy, and women of childbearing age should avoid pregnancy while on the drug. Because of the adverse effects of calicheamicin on DNA, the drug greatly reduced fertility in animal studies for males, but not females.

Side effects

A severe side effect of gemtuzumab treatment is a depletion of various types of cells in the bone marrow, including those that make white and red blood cells, a condition known as myelosuppression. Because CD33 is expressed on a patient's normal bone marrow cells, as well as on the surface of the abnormal leukemic blasts, the treatment eliminates both normal and cancerous cells. This results in severe reduction of the circulating blood cells normally produced by the bone marrow, including red blood cells (anemia), white blood cells (neutropenia), and clotting cells (thromboccytopenia). These conditions are treated with blood transfusions. However, the population of all these cells will rebound after clearance of gemtuzumab because the precursor to cells of the bone marrow, called pluripotent hematopoietic stem cells, do not express CD33 and will restore the various cell populations.

Gemtuzumab can produce a postinfusion symptom complex of fever and chills, and less commonly, low blood pressure and labored breathing during the first 24 hours after administration. Some patients developed severe liver function abnormalities, which were generally transient and reversible. The most common side effects were fever, chills, nausea, vomiting, thrombocytopenia, neutropenia, asthenia (loss of strength or energy), diarrhea, abdominal pain, headache, and stomatitis (inflammation of the lining of the mouth).

Interactions

There have been no formal drug interaction studies done for gemtuzumab.

See Also Monoclonal antibodies

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

Antibody

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

Blasts

—A type of immature cell that lacks some of the outward characteristics of the mature cell. In AML, the cancerous cells are leukemic blasts.

Calicheamicin

—An anti-tumor drug that binds to DNA within the tumor cells, causing breaks in the strands and killing the cell.

IgG

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

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.

Myelosuppression

—Reduction in the number of the cells of the bone marrow, which leads to reduction of many other circulating blood cells that are produced by the marrow.