Monoclonal antibodies

DEFINITION: Monoclonal antibodies (mAbs or Moabs) are antibodies that recognize only one antigen and that are mass-produced in the laboratory from a single clone of a B cell, the type of immune system cell that makes antibodies.

Cancers treated: Lymphoma, leukemia, breast cancer, head and neck cancers, cancer, lung cancer

Subclasses of this group: Murine (composed entirely of mouse sequences), chimeric (composed of approximately one-third mouse and two-thirds human sequences), humanized (composed of at least 90 percent human sequences), and human (antibodies that are fully human in composition)

Delivery routes: As a result of their molecular size and susceptibility to enzymatic digestion in the gut if administered orally, monoclonal antibodies must usually be administered by intravenous (IV) infusion.

How these drugs work:Antibodies are proteins that bind to a specific site, or epitope, on a specific target molecule. In response to infection or immunization with a foreign agent, the immune system generates many antibodies that bind to the foreign molecules. This pool of polyclonal antibodies contains a mixture of different antibody molecules, each binding to a specific epitope. Isolation of a single antibody from a polyclonal antibody pool would yield a highly specific molecular tool that can bind to a single epitope. Georges Köhler, César Milstein, and Niels Kaj Jerne invented the process of producing monoclonal antibodies in 1975 and shared the 1984 Nobel Prize in Physiology or Medicine for their discovery. Since then, monoclonal antibodies have become important in biological research and medicine.

Producing monoclonal antibodies involves fusing an individual B cell, which produces a single antibody with a single specificity but with a finite life span and a long-lived myeloma tumor cell. The B cell is taken from the spleen or lymph nodes of an animal challenged with the antigen of interest. The combination of the B cell and the myeloma cell produces a hybridoma cell, a perpetual antibody-producing factory. The hybridoma cell produces a single specific antibody and can be grown in culture indefinitely, allowing the production of large amounts of the monoclonal antibodies. Monoclonal antibodies are potentially more effective than conventional drugs in treating cancer since conventional drugs attack not only cancer cells but also normal cells. Monoclonal antibodies attach only to the specific target molecule. Since monoclonal antibodies are specific for a particular antigen, one designed to bind to ovarian cancer cells, for instance, will not bind to colorectal cancer cells.

The first monoclonal antibodies were made from mouse B cells. When administered to humans, mouse antibodies are recognized by the human immune system as foreign (because they are from a different species). They can elicit an immune response against them, causing allergic reactions. Researchers have since learned how to replace some portions of the mouse antibody sequences with human antibody sequences. Genetic engineering techniques have allowed the production of chimeric, humanized, and, more recently, fully human monoclonal antibodies.

An antibody molecule comprises two heavy polypeptide chains and two light polypeptide chains. Both heavy and light chains are composed of a region that varies from antibody to antibody, a variable region, and a constant region that is conserved. Combining human sequences for the constant region with murine sequences for portions of the variable region can decrease the amount of murine sequence. Depending on how much murine sequence is left, the result is either a chimeric (with approximately one-third murine and two-thirds human sequence) or a humanized (with at least 90 percent human sequence) monoclonal antibody. Genetically engineered mouse strains are now available that contain a large portion of human deoxyribonucleic acid (DNA) that codes for the antibody heavy and light chains, with the mouse’s own heavy and light chain genes inactivated. Using these mice to produce B cells for the construction of hybridomas allows the generation of fully human antibodies, which are likely safer and more effective than the previous generation of monoclonal antibodies.

One potential treatment for cancer involves using monoclonal antibodies that bind only to a cancer cell-specific component of interest and induce an immunological response against the target cancer cell (referred to as “naked” monoclonal antibodies). Monoclonal antibodies can also be designed to deliver another (nonspecific) agent, such as a toxin, radioisotope, or cytokine, to the cancer cell to kill it (referred to as “conjugated” monoclonal antibodies).

Some naked monoclonal antibodies bind to cancer cells and exert their action by marking the cells to help the body’s immune system destroy them. Rituxan (rituximab) and Campath (alemtuzumab) are examples of this type of monoclonal antibody. Rituximab binds to the CD20 antigen, a protein found on B cells, and is used to treat B-cell non-Hodgkin lymphoma. Alemtuzumab binds to the CD52 antigen, another protein on B and T cells, and is used to treat some patients with chronic lymphocytic leukemia.

Some naked monoclonal antibodies bind to functional parts of cancer cells or other cells that help cancer cells grow and act by interfering with the cancer cell’s ability to grow. Herceptin (trastuzumab), Erbitux (cetuximab), and Avastin (bevacizumab) are examples of this type of monoclonal antibody. Trastuzumab binds to the HER2/neu protein, a protein present in large numbers on tumor cells in some cancers that, when activated, helps these cells grow. Trastuzumab acts by inactivating these proteins. It is used to treat some breast cancers. Cetuximab binds to the epidermal growth factor receptor (EGFR) protein, which, when present in high levels on cancer cells, helps them grow. Cetuximab blocks the activation of EGFR and is used to treat advanced colorectal and head and neck cancers. Bevacizumab binds to the vascular endothelial growth factor (VEGF), a protein cancer cells produce to attract the new blood vessels they need for growth. Bevacizumab prevents VEGF from functioning and is used to treat some colorectal, lung, and breast cancers.

Some of these monoclonal antibodies have been used in cancer treatment for many years. At first, they were primarily used after other treatments had failed, but as more studies have been done, the trend is to use them earlier in cancer treatment.

Conjugated monoclonal antibodies (also called “tagged” or “loaded” monoclonal antibodies) are attached to anticancer (chemotherapy) drugs, toxins, or radioactive substances and used as vehicles to deliver these toxic agents directly to cancer cells. Radiolabeled monoclonal antibodies are attached to radioactive substances. Treatment with such agents is called radioimmunotherapy. Chemolabeled monoclonal antibodies are attached to anticancer drugs, and immunotoxins are monoclonal antibodies attached to toxins. Zevalin (ibritumomab tiuxetan) and Bexxar (tositumomab) are examples of radiolabeled monoclonal antibodies. Both bind to an antigen on cancerous B lymphocytes and are used to treat some B cell non-Hodgkin lymphomas. Mylotarg (gentuzumab ozogamicin) is an example of an immunotoxin. It contains the toxin calicheamicin attached to a monoclonal antibody that binds to the CD33, a protein antigen in most leukemia cells. It is used to treat some acute myelogenous leukemias.

Clinical trials of monoclonal antibody therapy are in progress for patients with almost every type of cancer. As more cancer-associated antigens have been identified and studied, researchers have been able to make monoclonal antibodies against more types of cancer.

Side effects: Antibodies that contain murine sequences can be recognized by the human immune system as foreign, causing systemic inflammatory effects such as fever, chills, weakness, headaches, nausea, vomiting, and diarrhea. Some monoclonal antibodies also have side effects associated with the target antigen. For example, some monoclonal antibodies can affect the bone marrow’s ability to produce blood cells, increasing the risk of bleeding or infection in some patients. Bevacizumab (Avastin), which restricts tumor blood flow by targeting VEGF proteins, may cause bleeding, high blood pressure, kidney damage, or blood clots. The antibody Cetuximab (Erbitux) targets the EGFR protein but may cause skin rashes.

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