Antibody target selection

The discovery of monoclonal antibodies and combining them with polymeric prodrugs is the newest approach to overcome the lack of selectivity for disposition in target tissue (23). Recently the selectivity of antibody-targeted polymeric anthracycline antibiotics to T lymphocytes was accomplished (25). In addition decreased immunogenicity of proteinaceous conjugates with IgG and human transferrin has been reported (26). 

Selected adhesion molecules represent yet another antibody target. Adhesion molecules, such as LFA-1 (leukocyte function-associated antigen-1) and ICAM-1 (intercellular adhesion molecule 1), play central roles in promoting migration of inflammatory cells to the sites of damage. Such activities underlie many of the symptoms of conditions such as rheumatoid arthritis. Inhibition of adhesion molecule function by administration of antibodies raised against them may, therefore, demonstrate therapeutic potential in some instances. 

Figure 10.3. Schematic representation of monoclonal antibody production using immortalized hybrid cells that secrete antibodies selective for the target antigen. The mortal, immune B cells Isolated from mice immunized with a target antigen are fused with myeloma, immortal B cells that express defective antibodies. The selecting of antigen-specific, immortal hybrid cells (hybridomas) results in identification of unique clones of cells that express antibodies with high specificity and affinity (monoclonal antibodies). These cells are cloned and expanded for large-scale monoclonal antibody preparations.

While anchoring targeting molecules such as antibodies or other ligands on the liposome surface provides target selectivity in vitro and in vivo, the cost and reproducibility of these constructs with suf-hcient purity and in sufficient quantity for pharmaceutical application continue to be barriers to their development. The lipopep-tide approach (i.e., attaching an acylated... 

MFE23 (Fv) TNF-a MFE23 contains Fv amino-acid sequences of antibody binding domain Binds to carcinoembryonic antigen (CEA) expressed on many cancer cells TNF-a Tumoricidal activity and associated inflammatory responses The F, domain of MFE23 antibody fragment increases the target selectivity of TNF in mice [107,108]... 

Endo, N. et al. (1987) Target-selective cytotoxicity of methotrexate conjugated with monoclonal anti-MM46 antibody, Cancer Immunol. Immunother. 25, 1-6. 

Guillemard, V Saragovi, H. U. Taxane-antibody conjugates afford potent c3do-toxicity, enhanced solubility and tumor target selectivity. Cancer Res., 2001, 61 694-699. 

However, therapeutic antibodies to selectively expressed, genomics-or proteomics-provided targets, such as antigens in tumors, enter clinical trials for many cancer forms very rapidly. One makes humanized or human antibodies, by different methods, which either carry something or act on their own. These are safe. They are often efficacious. But they are difficult to administer you have to inject them. They work in small indications, and they are perfect for small companies. The first Biotech company to make money in San Diego, IDEC Pharmaceuticals, did just this quite successfully, well enough later to buy Biogen and move to Boston in 2003. 

Regarding apparent nonselectivity, although a number of laboratories made the attempt, it proved difficult to find satisfactory antibodies to selectively label each subtype with certainty. They often proved satisfactory in purified membranes or cell clones only to fail in native tissues, labeling many cell types when they were expected to target only a subpopulation. In some cases, this may have involved a lack of antibody selectivity because of high conservation of sequence among G protein-coupled receptors (GPCRs). 

Goals for antibody targets are related to improvement of affinity, production of antibodies with new binding selectivities, and the design of catalytically active... 

In 1975, Kohler and MUstein (3) presented a method for preparing murine cell cultures that would produce antibodies targeted against a specific antigen. Producing mouse antibodies to selected antigens is very easy to do, and murine antibodies have been shown to have chnical utility, although all murine antibodies have been associated with the formation of human anti-murine antibodies (HAMA). 

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