HUMANIZED ANTIBODIES IN CLINICAL APPLICATIONS
There are currently many different humanized monoclonal antibodies in development to treat a variety of conditions. The first humanized monoclonal antibody approved for clinical use, trastuzumab (Herceptin), is for the treatment of breast cancer. The Federal Drug Administration (FDA) approved this therapeutic agent in 1998. Herceptin recognizes a cell surface receptor called HER2. This receptor is part of a larger family, including HER3, HER4, and the founding member, the epidermal growth factor receptor (EGFR). These receptors control whether a cell proliferates, differentiates, or undergoes programmed suicide by signaling a variety of intracellular proteins that modulate gene expression. In breast cancer patients, when the HER2 receptor is overproduced, the breast cancer is much more resistant to chemotherapy. Excess receptor is thus a good indicator that the patient will not survive as long. Herceptin binds to the extracellular domain of HER2, preventing the receptor from being internalized. This prevents the cancer cell from dividing and induces the immune system to attack the cell (Fig. 6.10). When Herceptin is used in combination with chemotherapy to treat breast cancer, patients survive much longer. The main point to keep in mind is that Herceptin binds one specific protein; therefore, the particular breast cancer must have excess amounts of HER2 in order for the treatment to be effective.
One of the most common problems in today’s health care system is that hospital patients often acquire bacterial infections from just being in the hospital. Nosocomial infections, as they are called, are implicated in thousands of deaths and cost billions of dollars. Even worse, some infections are resistant to all or most antibiotics. The development of a humanized antibody to one of the major bacterial agents will hopefully provide another method for treating patients. Staphylococcus aureus is a bacterium that causes serious infections. Strains have been identified that are methicillin resistant, called MRSA (methicillin-resistant S. aureus), and other strains are vancomycin resistant, VRSA. These two antibiotics are the most effective available for S. aureus, so when these fail, the infection can become deadly.
Humanized monoclonal antibodies against S. aureus are being tested for their effectiveness. This monoclonal antibody binds to the ClfA protein (clumping factor A), which is found on the cell surface of S. aureus. The ClfA protein is responsible for the bacteria adhering to fibrinogen, a protein found at the surface of the host cell. When the antibody binds ClfA, the bacteria cannot adhere to the cell surface, and therefore, cannot invade and cause damage (Fig. 6.11). The humanized version of the antibody has been tested in rabbits. The rabbits were infected with S. aureus and then treated with the antibody. When two doses of the antibody were given, 100% of the rabbits had no bacteria in their blood for 96 hours. Only about two thirds of the blood cultures were negative for S. aureus when the rabbits were treated with just vancomycin. Clinical trials for the antibody began in March 2004 and are ongoing.
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