Monoclonal antibodies

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Monoclonal antibodies

Antibody proteins that bind to a specific target molecule (antigen) at one specific site (antigenic site). In response to either infection of immunization with a foreign agent, the immune system generates many different antibodies that bind to the foreign molecules. Individual antibodies within this polyclonal antibody pool bind to specific sites on a target molecule known as epitopes. Isolation of an individual antibody within the polyclonal antibody pool would allow biochemical and biological characterization of a highly specific molecular entity targeting only a single epitope. Realization of the therapeutic potential of such specificity launched research into the development of methods to isolate and continuously generate a supply of a single lineage of antibody, a monoclonal antibody (mAb).

In 1974, W. Köhler and C. Milstein developed a process for the generation of monoclonal antibodies. In their process, fusion of an individual B cell (or B lymphocyte), which produces an antibody with a single specificity but has a finite life span, with a myeloma (B cell tumor) cell, which can be grown indefinitely in culture, results in a hybridoma cell. This hybridoma retains desirable characteristics of both parental cells, producing an antibody of a single specificity that can grow in culture indefinitely.

Generation of monoclonal antibodies through the hybridoma process worked well with B cells from rodents but not with B cells from humans. Consequently, the majority of the first monoclonal antibodies were from mice. When administered into humans as therapeutic agents in experimental tests, the human immune system recognized the mouse monoclonal antibodies as foreign agents, causing an immune response, which was sometimes severe. Although encouraging improvements in disease were sometimes seen, this response made murine (mouse) antibodies unacceptable for use in humans with a functional immune system.

Fueled by advances in molecular biology and genetic engineering in the late 1980s, efforts to engineer new generations of monoclonal antibodies with reduced human immunogenicity have come to fruition. Today there are a number of clonal antibodies approved for human therapeutic use in the United States.

Characterization of the structure of antibodies and their genes laid the foundation for antibody engineering. In most mammals, each antibody is composed of two different polypeptides, the immunoglobulin heavy chain (IgH) and the immunoglobulin light chain (IgL). Comparison of the protein sequences of either heavy of light antibody chain reveals a portion that typically varies from one antibody to the next, the variable region, and a portion that is conserved, the constant region. A heavy and a light chain are folded together in an antibody to align their respective variable and constant regions. The unique shape of the cofolded heavy- and light-chain variable domains creates the variable domain of the antibody, which fits around the shape of the target epitope and confers the binding specificity of the antibody.

Mice genetically engineered to produce fully human antibodies allow the use of established hybridoma technology to generate fully human antibodies directly, without the need for additional engineering. These transgenic mice contain a large portion of human DNA encoding the antibody heavy and light chains. Inactivation of the mouse's own heavy- and light-chain genes forces the mouse to use the human genes to make antibodies. Current versions of these mice generate a diverse polyclonal antibody response, thereby enabling the generation and recovery of optimal monoclonal antibodies using hybridoma technology.

Disease areas that currently are especially amenable to antibody-based treatments include cancer, immune dysregulation, and infection. Depending upon the disease and the biology of the target, therapeutic monoclonal antibodies can have different mechanisms of action. A therapeutic monoclonal antibody may bind and neutralize the normal function of a target. For example, a monoclonal antibody that blocks the activity of the of protein needed for the survival of a cancer cell causes the cell's death. Another therapeutic monoclonal antibody may bind and activate the normal function of a target. For example, a monoclonal antibody can bind to a protein on a cell and trigger an apoptosis signal. Finally, if a monoclonal antibody binds to a target expressed only on diseased tissue, conjugation of a toxic payload (effective agent), such as a chemotherapeutic or radioactive agent, to the monoclonal antibody can create a guided missile for specific delivery of the toxic payload to the diseased tissue, reducing harm to healthy tissue. See Antibody, Antigen, Genetic engineering, Immunology

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