Therapeutic application of monoclonal antibodies

The unrivalled specificity of monoclonal antibodies, coupled to their relatively straightforward production and their continuity of supply, renders them attractive biochemical tools. Therapeu-tically, they represent by far the single largest category of biopharmaceutical substances under investigation. Several hundred such preparations are currently undergoing preclinical and clinical trials. Throughout the 1980s the focus of attention rested upon their use either as in vivo imaging (i.e. diagnostic) agents or as direct therapeutic agents. Initial studies centred mainly around cancer, but monoclonal antibody preparations are now used in a variety of other medical circumstances:

• induction of passive immunity;

• diagnostic imagining;

• therapeutically (e.g. treatment of cancer, transplantation and cardiovascular disease).

All in vivo diagnostic/therapeutic applications are dependent upon the selective interaction of a monoclonal antibody with a specific target cell type in the body (e.g. a cancer cell). Therefore, a prerequisite to application of monoclonal antibody-based products in this way is the identification of a cell surface antigen unique to the target cell type (Figure 13.3). Once identified and characterized, monoclonal antibodies may be raised against that unique surface antigen (USA or USAg).

Figure 13.3 Underlying principle/approaches taken during the development and use of antibody-mediated target cell detection/destruction. A prerequisite for adoption of this strategy is the identification and characterization of a surface antigen unique to the target cell type ('unique surface antigen', USA). Antibodies raised against the USA should selectively interact with the target cell (b). In some instances the antibody is chemically coupled to a radioactive tag (c), a drug or a toxin (d)

Figure 13.3 Underlying principle/approaches taken during the development and use of antibody-mediated target cell detection/destruction. A prerequisite for adoption of this strategy is the identification and characterization of a surface antigen unique to the target cell type ('unique surface antigen', USA). Antibodies raised against the USA should selectively interact with the target cell (b). In some instances the antibody is chemically coupled to a radioactive tag (c), a drug or a toxin (d)

The specificity of antibody-antigen binding should ensure that, once injected into the body, the antibody will selectively congregate on the surface of only the target cells. Depending upon the specific intended therapeutic/diagnostic application, antibodies employed may have nothing attached to them or may be conjugated to a radioisotope, drug or toxin (Figure 13.3). With the latter approaches, the antibody is used as a 'magic bullet', delivering a radioactive/drug load to specific cells in the body. All of these various strategies have been adopted in practice, and specific examples will be provided in subsequent sections of this chapter.

In the context of antibody-mediated cell targeting, it is also important to appreciate that binding of an antibody to a USA can, by itself, trigger a number of responses. In some instances, the antibody-antigen (Ab-USA) complex is quickly internalized. In other instances, the Ab-USA complex is shed from the cell surface, whereas in yet other cases binding induces neither response. The specific response triggered is generally only determined by direct experimentation. The induction of Ab-USA shedding renders an anti-type-specific antigen (TSA) antibody clinically useless.

By 2006, a total of 29 such antibody-based products had gained marketing approval in some world regions at least (Table 13.2). Over half of these aim to detect/treat various cancers, and cancer represents the single most significant indication for antibody-based products currently in clinical trials. The application of antibodies in the context of cancer is overviewed in the next section. A minority of the products approved/in trials are intact antibodies produced by classical hybridoma technology. The majority are engineered antibodies ('chimaeric' or 'humanized') or antibody fragments. The generation/rationale for use of such engineered products is also discussed subsequently in this chapter.

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