To prevent and treat inflammatory and autoimmune disorders, cancer, rheumatoid arthritis and infectious diseases, biotech and biopharmaceutical companies are using monoclonal antibodies (MAbs) that specifically target disease organisms as well as other types of molecules found in the body such as hormones, infectious substances, toxins, and proteins on the surface of normal cells or those uniquely present of the surface of cancer cells. The  specificity of MAbs makes them promising agents for human therapy.

According to Minneapolis, MN-based Arrowhead Publishers, the revenues from sales of monoclonal antibodies (MAb) and antibody therapies accounted for over $5.1 billion last year and will continue to grow at a phenomenal rate throughout the next five years. By 2008, MAbs should account for 32 percent of all revenue in the biotech market, said the research firm. 

What are MAbs and What is Needed to Make Them?  Antibodies are very important parts of the immune system that act primarily as a defense against invasion by foreign substances called antigens.  Antibodies are produced by a type of white blood cell known as a B cell and are manufactured when the antigen enters the body. Antibodies neutralize or mark antigens for destruction with the help of other cells of the immune system by attaching, or binding, to specific parts of antigens. Only the antibodies created for a specific antigen can attach to that antigen. After the antibody is produced, it continues to circulate in the blood to attack its targeted antigen the next time the antigen invades the body.

The response of the immune system to any antigen is polyclonal, which means that the system manufactures a great range of antibodies. Even if one were to isolate a single antibody-secreting cell, and place it in culture, it would die out after a few generations because of the limited growth potential of all normal cells. This problem was solved in mice by the technique devised by Milstein and Köhler to produce MAbs.

In 1975, Argentine-born British immunologist César Milstein and German immunologist Georges Köhler discovered a technique to generate a quantity of white blood cells that uniformly produced only one type of antibody, known as monoclonal antibodies (MAbs), targeting only one specific antigen to allow scientists to tag one specific substance. In 1984, Milstein and Köhler received the Nobel Prize in physiology or medicine for their work.        

The first step in the production of MAbs is to immunize a mouse with an antigen to increase the amount of antibodies in that mouse. When the mouse begins to produce antibodies to the antigen, its spleen is removed. Antibody- producing B cells from the spleen are then fused with a myeloma, a cancerous B cell in the bone marrow that can grow indefinitely. This fusion creates a hybrid cell, called a hybridoma, that can live forever and produce an unlimited supply of the antibody secreted by the original, normal B cell. The new fused cell line is grown briefly in culture and then re-injected into another mouse's peritoneum, a membrane in the mouse near the abdomen. The fluid build up that is formed, called ascites, containing the monoclonal antibodies is then removed for research.

Mouse and “Humanized” MAbs - Since MAbs are created using mouse B cells, the main difficulty is that mouse (murine) antibodies are recognized by the human immune system as foreign proteins, and the human patient mounts an immune response against them, producing HAMA ("human anti-mouse antibodies"), causing the MAbs to be attacked and neutralized. 

Biotech and biopharmaceutical companies are currently using proprietary technology platform approaches in an attempt to reduce the problem of HAMA so that fully human monoclonal antibodies can be developed and commercialized for a variety of disease targets. For example, chimeric antibodies, where the antigen-binding parts of the mouse antibody are fused to parts of a human antibody using genetic engineering but still contain mouse protein sequences (approx. 33%) and human protein sequences (approx. 66%), and "humanized" antibodies (CDR grafted), where the amino acids responsible for making the antigen binding site are inserted into a human antibody molecule replacing its own regions. 

In addition, these companies, including Abgenix (NASDAQ: ABGX), Protein Design Labs (NASDAQ: PDLI), and Medarex (NASDAQ: MEDX), build collaborative arrangements with other pharmaceutical, biotechnology and genomics companies to produce antibody therapeutic drugs to prevent and treat inflammatory and autoimmune disorders, cancer, rheumatoid arthritis, transplant-related conditions and infectious diseases.

Major Players in the MAb Field - Freemont, CA-based Abgenix, is a biopharmaceutical company focused on fully human monoclonal antibody therapies for a variety of diseases. Abgenix uses their proprietary technology platform, including XenoMouse and XenoMax technologies, to genetically engineer multiple strains of XenoMouse mice, each of which rapidly generates a different class of high-affinity, fully human antibody to perform different therapeutic functions.

The Abgenix genetically- engineered XenoMouse mice features an immune system in which the mouse antibody genes are inactivated and functionally replaced with human antibody genes so that the mice are capable of generating human antibodies to human antigens. By introducing human antibody genes into the mouse, it is not necessary to humanize each individual antibody that the mouse generates, providing a larger pool of antigen-specific antibodies from which to choose. Unlike chimeric or humanized antibodies, XenoMouse-derived antibodies contain 100% human protein sequences so they are not expected to cause immune reactions against the antibodies in patients.

According to Abgenix, they have agreements with over 50 academic and commercial organizations to provide its technology for development of new antibody-based therapeutics. Working with partner with Immunex, a wholly owned subsidiary of Thousand Oaks, CA-based Amgen (NASDAQ: AMGN), Abgenix is developing ABX-EGF or panitumumab, which targets the epidermal growth factor receptor (EGFR), to treat non-small cell lung cancers, as well as kidney, colorectal, prostate and other cancers.

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