The Making of a Monoclonal Antibody

In cancer treatment today, three letters have infiltrated the oncology dialect: "mab," as in rituximab (Rituxan), tositumomab (Bexxar), or Ibritumomab tiuxetan (Zevalin). This suffix is reserved formonoclonal antibodies - agents that have become a growing component of the oncologist's arsenal.



Currently, eight monoclonal antibodies, or MAbs, are approved by the FDA to treat cancer. And many more are being tested in phase II and III clinical trials for a variety of tumor types.



To understand how these drugs work, one must take a careful look at the human immune system. The immune system comprises a diverse collection of specialized cell types that circulate through the bloodstream and lymphatic system, and monitors the body for bacterial, viral, fungal, and parasitic invaders. The "innate" immune response provides the first line of defense, and includes cells such as granulocytes, macrophages, and dendritic cells, which are always ready to recognize and attack foreign particles in the body. For persistent or recurrent infections, the sophisticated "adaptive" immune response comes into play.



Dendritic cells (DCs) form the bridge between the innate immune response and the antibodies of the adaptive immune response. When DCs digest a pathogen, they save and display foreign proteins found on the surface of the pathogen - known as antigens - for the lymphocytes of the adaptive immune system to recognize. When a B lymphocyte (also called a B cell) recognizes an antigen displayed by a DC as foreign, it changes into a plasma cell that secretes antibodies - small proteins that recognize and bind to the antigen, either interfering with the invader's ability to attack the cells of the body or marking them for destruction by other immune cells.



Cancer cells exhibit many of the behaviors of foreign pathogens, such as invading and damaging healthy tissue. However, explains Dr. Robert Kreitman of NCI's CCR, "In general, the immune system recognizes cancer cells as self and does not attack them as foreign antigens." This is because they carry many of the same surface proteins as normal cells, which mark them as part of the body. The development of MAbs circumvented this obstacle.



To create an MAb, researchers first identify a protein that is overexpressed on the surface of cancer cells and that the cells depend on to survive or grow. Rituximab (Rituxan), for example, is used to treat blood cancers that overexpress the protein CD20. The more important the protein is to the ...