Antibody-Based Therapies

It has long been known that antibodies, produced naturally by the immune system, are highly efficient at targeting and binding to proteinaceous antigens on the surface of bacteria and viruses, and it follows that they should be capable of targeting antigens on the surface of tumor cells. Prior to 1975, insufficient quantities of antibodies could be obtained to test this hypothesis, however this situation changed when Milstein and Koehler working at Cambridge University (UK) unveiled their “murine hybridoma” technology which was the first reliable method for producing monoclonal antibodies (mAbs) with unique target selectivity in almost unlimited quantities. After an introduction to antibodies and their production methods, this chapter focuses on the various ways in which mAbs have been used to develop cancer therapies. First, the use of antibodies as single agents (i.e., “naked” antibodies) is described which has produced well-known therapies such as trastuzumab (Herceptin^TM) and bevacizumab (Avastin^TM) for breast and bowel cancer, respectively. Next, antibody-drug conjugates (ADCs) are explored which consist of antibodies chemically conjugated to cell-killing entities such as small-molecule cytotoxic agents, radionuclides, or other cell-killing moieties (e.g., enzymes, cytokines, drug-filled nanoparticles, RNAi) which can be transported selectively to the tumor site while sparing healthy tissues. Finally, new types of therapies based on bispecific antibodies are described which involve the engineering of antibodies to simultaneously target two different antigens. Approved agents within each subfamily are described in detail along with information relating to their discovery, chemical structure where appropriate, mechanism of action, pharmacology, clinical activity, and mechanism-based toxicity. Prominent clinical-stage experimental agents within each subfamily are also described.