Monoclonal Antibodies

The pioneering work of Milstein (31) initiated the development of monoclonal antibodies as a therapeutic entity. Normal immune responses of B lymphocytes are polyclonal in nature and yield a heterogeneous mixture of antibodies. In order to produce monoclonal antibodies, murine antibody-producing cells were immortalized by fusion with plasma cell tumors incapable of producing immunoglobulin but capable of supporting antibody synthesis and secretion. Subsequent cloning of the hybridomas yielded clones that are capable of producing large amounts of homogeneous murine antibody that react with a single epitope.

However, the use of murine antibodies in humans is restricted because of the immunogenic nature of the immunoglobulins. Repeated use of murine antibodies elicits an anti-immunoglobulin response known as the human antimouse antibody (HAMA) response. In addition, other limitations to the use of antibodies have been observed and have been overcome in part through the use of genetic engineering to humanize the murine antibodies (32). The redesign of murine antibodies using these techniques has resulted in the formation of antibodies that elicit a considerably reduced immune response relative to the murine antibody.

Although monoclonal antibodies have been most widely used for the diagnosis and treatment of cancer, they are also being evaluated as therapies in other areas as well. For example, abciximab (c7E3 Fab) is a chimeric human-murine monoclonal antibody Fab fragment that binds to the platelet glycoprotein IIb/ IIIa receptor and inhibits platelet aggregation. The addition of abciximab to standard aspirin and heparin therapy reduced the incidence of ischemic complications during the initial postoperative period in high-risk patients who were undergoing percutaneous coronary angioplasty or directional atherectomy. Abciximab also reduced the incidence of clinical restenosis when compared with placebo during a 6-month follow-up of these patients (33).

Monoclonal antibodies have been widely used for the diagnosis, localization, and treatment of cancer (34). Their advantages include a relative selectivity for tumor tissue coupled with a relative lack of toxicity. However, their ability to affect tumors is minimal unless aided by other mechanisms, the amount of antibody delivered to tumors is low, and the diffusion of antibody through tumors is often poor. The development of a HAMA response is also limiting. To aid in the antitumor effectiveness of monoclonal antibodies, antitumor drugs such as doxorubicin, toxins such as the ricin A chain, and radionuclides have been conjugated to the antibodies (34). In addition, unconjugated antibodies can mediate complement-dependent cytotoxicity and antibody-dependent cellular cytotoxic-ity. For example, the effect of the monoclonal antibody 17-1A, a monoclonal antibody against colorectal cancer, has been evaluated in patients with Dukes' Stage C colorectal cancer who had undergone curative surgery and were free of manifest residual tumor. After a median follow-up of 5 years, antibody treatment reduced the overall death rate by 27%. Effectiveness was most pronounced in patients who had distant metastasis as the first sign of relapse, and toxic effects were infrequent (35).

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