Traditionally, polyclonal antibodies have been used to induce passive immunity. These antibody preparations are made by extracting human or animal serum exposed to the antigens of interest. Antibody preparations produced by such means are heterogeneous. Antibody levels vary from bleed to bleed and, when the producer animal dies, so does the product source.
The mid 1970s development of hybridoma technology allowed production of large amounts of monospecific antibodies against virtually any antigen of interest.1,2 This technique fuses a mouse-derived (murine), antibody-producing lymphocyte with a transformed (cancerous) myeloma cell. A proportion of the daughter hybrid cells (hybridomas) continue to produce the murine antibody and also retain the immortal character of the parent myeloma cell. The hybridoma can be stored in a viable state for years, providing an almost inexhaustible seed supply of monoclonal antibody (MAb). The most striking attribute is that all the individual antibody molecules present in a monoclonal antibody preparation are identical (See "Antibody Structure" box on page 2).
SPECIFIC SELECTIVITY The binding of an antibody to the antigen against which it is produced is extremely specific. All human (and indeed other) cells display a range of surface antigens. Some are found on a range of cell types, while others — termed unique surface antigens (USAs) — are specific to a given cell type. Antibodies produced against unique surface antigens bind selectively to the surface of these cells. In effect these antibodies are "magic bullets" capable of selectively targeting specific cell types such as cancer cells, virally infected cells, or microbial cells at an infection site.
Antibodies generally display favorable safety profiles. Humanized antibodies (described below), in particular, are well tolerated at high doses. Furthermore, engineered antibodies can be quite versatile. Slight changes in the six to ten amino acids within the complementarity-determining region (Figure 1) can retarget the antibody, creating a new potential therapeutic. Common drug development and manufacturing approaches can be employed to bring the product to market.
ANTIBODY-MEDIATED CANCER DIAGNOSIS AND THERAPY When a cell is transformed (becomes cancerous), it usually begins high-level expression of several genes that were previously either unexpressed or expressed at extremely low levels. Some of the resultant proteins are found on the cell surface and are termed tumor surface antigens (TSAs). TSAs potentially represent unique surface antigens, and antibodies raised against specific TSAs are likely to be approved for oncological applications.
Several anti-TSA antibodies conjugated to radioactive tags have been approved for the detection and treatment of various cancers (Table 1). Conjugation of radioactive tags to anti-TSA MAbs facilitates targeted tumor destruction via the ionizing effects of radioactivity. 5