Monoclonal Antibodies

Fig. 1 - Mouse Cholera Antibody

Monoclonal antibodies are showing enormous potential as biological tools in the diagnosis and treatment of human disease.

Monoclonal antibodies (MAbs) are immunoglobulin proteins made to target potentially any molecule capable of instigating the production of antibodies. Such molecules are known as antigens. The antigen of concern is injected into mice, where white blood cells known as B cells produce antibodies against it (see figure 1).

The antibody -producing B cells are then hybridised with myeloma tumour cells to form ‘hybridoma’ cells, which multiply quickly, producing clones of themselves and, in turn, vast amounts of antibodies. The term ‘monoclonal’ is derived from the fact that they are produced from one type of cell- the hybridoma cell. This revolutionary procedure was developed by Kohler and Milstein, who were awarded a Nobel Prize for their work in 1984.

Because antibodies are specific for their target antigen only, MAbs have the potential to be more efficient than other drugs, which may also attack normal body cells. As a result, side effects of therapy such as nausea or allergic reactions are reduced.

Monoclonal Antibodies in Human Therapy

Monoclonal antibodies have several uses; the most obvious one being to fight the specific antigen they were produced from. One such example is Mylotarg, a drug derived from a MAb which binds to CD33, a cell-surface molecule expressed by the cancerous cells in acute myelogenous leukemia . Other MAbs approved by the FDA attack tumor cells in lymphomas and some breast cancers, while some target receptor cells on the cancerous white blood cells in chronic lymphocytic leukemia.

The immune system can also be suppressed using monoclonal antibodies; one example is Muromonab-CD3, which binds to the CD3 molecule on the surface of T cells. This acts to prevent the acute rejection of organs after transplant operations.

Despite the moderate success of these and other monoclonal treatments, progress in human therapy has been relatively slow because the human immune system naturally rejects antibodies that have originated in mice. As a result, the antibodies are usually comparatively short lived and have limited success rates. Additional drawbacks can include side effects such as vomiting and fever.

Newer therapies are consequently employing genetically engineered antibodies that combine the antigen binding properties of the mouse antibody with genetic material from human antibodies. This technique aims to reduce rejection to a manageable level. Examples of FDA approved human or chimeric MAbs include Synagis, Herceptin and Remicade,used in the treatment of breast cancer, leukaemia and rheumatoid arthritis respectively.

Monoclonals as Diagnostic Tools

The specificity of MAbs for the antigen that stimulates their production also makes them useful in the detection of these antigens in the body. This has been utilised in the identification of ABO blood groups in human serum and in the diagnosis of pregnancy-related hormones such as HCG in pregnancy testing kits.

Other diagnostic tests include the detection of drug levels, infectious diseases such as AIDS (using the ELISA test), tumour antigens and specific hormones in the human body. While many of these tests employ the use of immunoassay procedures, which quantify the formation of antigen antibody complex (Ag-Ab complex), others involve the attachment of MAbs to radioactive atoms in a process known as radioimmunodetection. In some situations fluorescent molecules or metal atoms such as copper and gold (see figure 2) may also be coupled to the antibody to assist in imaging the target.

Ethical Issues associated with MAbs

The use of mice to produce MAbs has been controversial because of the painful and debilitating effects of the procedure. In order to achieve an enhanced inflammatory immune response in the mouse, for instance, substances called adjuvants are used. These release the antigen into the mouse over a long period of time, which often results in painful lesions at the site of injection. Freund's Complete Adjuvant (FCA) has actually been banned in the Netherlands and the United Kingdom.

This, and the fact that when the required immune response has been achieved, the mouse’s spleen is removed to provide a source of antibody producing cells, has resulted in some European countries legislating to limit MAb production in mice. Alternatives being investigated include the use of tissue culture and DNA technology to produce the antibodies in vitro.

The Future of Monoclonal Antibodies

With anti-rejection technology improving continually, monoclonal antibodies may soon be extended to the therapeutic treatment of diseases outside the traditional areas of oncology, autoimmune and inflammatory disorders, such as infectious diseases and opthamology. With sales exceeding 32 billion dollars in 2008, MAbs are set to become an important sector of the pharmaceutical industry.

References

Kimball, J., 2010, `"Monoclonal Antibodies," Kimball’s Biology Pages, jkimball.ma.ultranet, accessed 23/2/2010

Lynette A. Hart, 1996, "Monoclonal antibodies," Mouse in Science,ucdavis.edu, accessed 23/2/2010

"Uses of Monoclonal Antibodies," Molecular-Plant-Biotechnology.info, accessed 25/2/2010

Washington, D.C.: Biotechnology Industry Organization, 1989, "Monoclonal Antibody Technology - The Basics," accessexcellence.org, accessed 25/2/2010