Trastuzumab

Definition

Trastuzumab is a humanized monoclonal antibody produced by recombinant DNA technology that binds specifically to the human epidermal growth factor receptor 2 protein (also known as HER2 or neu or c-erb-2) that is found on the cell surface of some cancer tumors, most notably breast cancer. The drug is marketed in the United States under the Herceptin brand name.

Purpose

Trastuzumab is a monoclonal antibody used to treat breast cancers that overexpress the HER2 protein, which occurs in about 25-30% of breast malignancies. By binding the HER2 protein on the tumor cell, the antibody targets it for destruction by the immune system. Based on data gathered in the laboratory, developers believe that trastuzumab triggers cell-mediated means to kill the tumor cells, through the action of natural killer cells and monocytes, two types of white blood cells. As binding of the antibody also slows growth of the tumor, it is theorized that the antibody may also block the interaction of the HER2 protein with a not yet identified growth factor that triggers rapid cell divisions.

Clinical trials have also begun or are soon to begin to test the use of trastuzumab against osteosarcoma, as well as endometrial, colorectal, kidney, pancreatic, prostate, ovarian, salivary gland, lung, and bladder cancers, as all of these tumor types can overexpress the HER2 protein on their surface.

Description

Trastuzumab is a genetically engineered monoclonal antibody. In 1998 it was approved by the FDA as a method of slowing growth of breast cancer tumors that overexpress the HER2 protein on the cell surface. Overexpression or overproduction of the HER2 protein is associated with aggressive disease and increased mortality.

Trastuzumab is approved for use either alone, or in combination with paclitaxel, a drug used for chemotherapeutic treatment of breast cancer. In clinical trials treating patients having breast cancer that has spread beyond the breast (metastatic breast cancer), trastuzumab had an overall response rate of 14%, with 2% having a complete response. When used in combination with paclitaxel treatment, the antibody reduced the risk of death by 24%. Higher expression of the HER2 protein on the tumor surface correlates with an increased chance of response to the drug. Additionally, clinical trials using trastuzumab in the TCH chemotherapy regime (Taxotere, cisplatin or carboplatin, and Herceptin) appears to avoid risk of heart problems (cardiotoxicity) seen with the paclitaxel/Herceptin combination.

Other clinical trials have begun testing the use of trastuzumab with other chemotherapy drugs such as doxorubicin (an antitumor anitbiotic), cyclophosphamide (an alkylating agent that interferes with mitosis and cell division), celecoxib (an aspirin-like drug called a cyclooxygenase-2, or COX-2, inhibitor), capecitabine (an antimetabolite that interferes with DNA and RNA growth), and others. Testing the combination of the monoclonal antibody and various cytokines, such as interleukins 2 and 12, is also ongoing. Additionally, doctors are also studying the combination of the antibody with other cancer treatments such as radiation and transplantation with peripheral stem cells.

Most of the trastuzumab sequence is derived from human sequences, while about 10% are from the mouse. 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. These areas do not bind to the epidermal growth factor receptor 2. 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 trastuzumab to the receptor is from a mouse anti-HER2 antibody.

Recommended dosage

Trastuzumab is administered intravenously, at a dose of 4 mg/kg for the initial administration, and 2 mg/kg for weekly maintenance until the disease progresses. The antibody can be given for longer periods to maintain tumor shrinkage.

Precautions

Extreme caution should be exercised when using trastuzumab to treat patients with existent heart problems. Also, patients with lung problems have an increased risk of side effects. Because the drug can pass to the fetus through the placenta and is present in breast milk, the drug should be used during pregnancy and nursing only if clearly indicated.

Side effects

The most severe side effects seen with this drug are heart and lung problems, which tend to occur most often in patients with a history of heart or lung disease. The use of anthracyclines and cyclophospamide in combination with trastuzumab also appears to increase these types of side effects.

The most common side effects with trastuzumab are infusion-associated symptoms, usually consisting of fever and chills on first infusion. The symptoms are often mild to moderate in severity and are treated with acetaminophen, diphenhydramine, and/or meperidine. Other common side effects include nausea and vomiting, and pain (in some cases at tumor sites), which occur less often after the first dose. Lowered red blood cell count (anemia), lowered white blood cell count (leukopenia), diarrhea, and infection occur more often in patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone. The severity of these symptoms usually do not result in discontinuation of therapy with Herceptin.

Other less common side effects are headache, abdominal pain, back pain, flu-like symptoms, sinusitis, rhinitis, pharyngitis, fluid retention (edema), insomnia, dizziness and depression.

Interactions

There have been no formal drug interaction studies done for trastuzumab. However, in clinical trials, this drug has a decreased clearance rate (time of removal from the body) when combined with some chemotherapeutic drugs including paclitaxel.

KEY TERMS

Antibody

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

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.

IgG

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

Interleukins

Cytokines responsible for the activation of B and T cells of the immune system.

Monoclonal

Genetically engineered antibodies specific for one antigen.