Monoclonal antibodies are used in five different ways in the treatment of human conditions. First, antibodies have a variety of effector mechanisms that focus an array of immunologic agents (complement, various effector cells) on the target to which they bind. Second, antibodies can serve as targeting moieties to specifically deliver diverse killing or inhibitory molecules to a specific site. Third, antibodies can be directed at soluble protein or proteoglycan hormones or cytokines or their receptors to antagonize a particular function such as cell growth, invasion, or migration. Fourth, antibodies can be used as antigens to elicit antitumor responses against immunoglobulin-expressing tumors. Fifth, antibodies can be used to alter the pharmacologic behavior of other substances to either increase or decrease their half-life or alter their distribution (e.g., antibodies to digoxin used to treat digoxin toxicity).
Monoclonal antibody technology was developed in 1975 and has been widely applied in biological sciences since then. The first clinical trial of a monoclonal antibody was performed in 1980 and the first FDA approval of a monoclonal antibody for a cancer indication occurred in 1997. Currently 14 monoclonal antibody-based drugs are FDA-approved for therapeutic use; one monoclonal antibody, nofetumomab (NR-LU10, anti-CD56) labeled with technetium-99m is approved for use as an imaging agent in the staging of small-cell lung cancer (it will not be discussed here). Both the list of agents and their approved uses are likely to expand.
ANTIBODY STRUCTURE AND FUNCTION
Antibody structure was initially elucidated by using antibodies as probes of other antibodies. Three sets of determinants were defined. Isotypes are determinants that distinguish among the main classes of antibodies of a particular species and are defined by antibodies made in different species. Humans have five main heavy chain isotypes (M, G, A, D, E) and two light chain isotypes (κ, λ). Allotypes are small sequence differences or allelic differences between immunoglobulins of the same isotype in different individuals within a species and are defined by antibodies made in the same species. Idiotypes are antigenic determinants formed by the antigen-combining site of an antibody that distinguish each clonal B-cell product.
Antibodies are generally composed of four chains, two identical heavy chains (MW ~50,000 Daltons) and two identical light chains (MW ~22–25,000 Daltons). Each chain has a portion with limited sequence variability called the constant region and a portion with extensive sequence variability called the variable region. The heavy and light chains are linked by disulfide bonds and aligned such that the variable regions of the light and heavy chain are adjacent to each other (Figure 15-1). A specific antigen is bound by the antibody in the pocket formed by the heavy and light chains. The contact regions between the antigen and the antibody are usually defined by two or three regions of hypervariability within the variable regions. These are called complementarity-determining regions (CDRs).