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

References in periodicals archive ?
The radioiodination yield for the four mAbs was typically 70-80%, and the amounts of free iodine in the purified mAbs was less than 0.3%.
The anecdote recounted here, telling how Mabs's mother would knock a book out of her young daughter's hand, condemning reading as a waste of time, has a personal resonance.
To address the issue, Florida State University scientists sought to develop a monoclonal antibody (mAb)-based horse-specific enzyme-linked immunosorbent assay (Elisa).
These MAbs were classified into two distinct groups: MAbs specific for C.
Heat Melt deflection Density (g/ flow index temperature Rockwell [cm.sup.3]) (g/10 min) ([degrees]C) hardness ABS1 1.40 45.0 86.0 109.0 ABS2 1.40 33.6 89.3 111.7 MABS 1.11 11.5 88.0 116.0 HIPS 1.04 6.4 79.0 82.3 TABLE 2.
Mabs Noor, 31, lives in Newport and is a business mentor for Venture Wales and a freelance consultant for the growth and low growth business sector.
But MABS boss Michael Culloty warns if you start January with a debt diet, you won't still be paying for this Christmas next year.
MABS selected a research team from the University of Granada to support the method, and a high-level internal management group and outside consultants came together to form a strategic management team.
For instance, a MAb that reduced illness and death in passively immunized mice against viruses of the H 1, H2, and H5 subtypes has been described (34,35).
Based on methyl methacrylate, acrylonitrile, butadiene, and styrene (MABS), Terlux is a specialty product in BASF's range of styrenic plastics.
Sanders' proposal of March 21, 1989, set forth that the design labor was 65 percent of that used to design the SKM and included a variety of MABs. Sanders planned from the beginning of contract performance to add the feature of IA9 to do the confidence testing without using MABs.
The partnership brings together BTI's capabilities in novel antibody discovery and Roche's expertise in developing monoclonal antibody (mAbs)[1] therapeutics, opening up the possibility of improved treatment for cancer, a leading cause of death worldwide[2].