ABSTRACT
Despite the production of new chemotherapeutic agents, the majority of common cancers such as those of colon, lung and breast are incurable, unless detected early and removed by surgery. Moreover, most anticancer agents are non-specifically toxic to normal cells and cannot be given at sufficient doses or for long enough periods to achieve the maximum benefit to the patient. With the use of monoclonal antibodies it is possible to target drugs, toxins and isotopes to tumors and thereby reduce toxicity and the dose required for effective therapy. In vivo studies in mice have shown promising results, where small established tumors were eradicated. Based on these preclinical studies, several clinical trials have been conducted. Isotope–antibody conjugates have been most extensively used, particularly with 131I due to ease of linking to antibodies, and very promising results have been obtained (Press, 1994). In this clinical trial, 19 patients with B-cell lymphoma were given 200-800 mCi of [131I]anti-CD20 with bone marrow rescue – 16/19 complete responses and two partial responses were obtained. However, until now, a major problem with murine monoclonal antibodies has been the production of human anti-mouse antibodies (HAMA), which, in most cases, leads to shortened half-life and diversion of the therapeutic agent to Fc receptors in sites other than the cancer. Interestingly, serum sickness did not seem to be a major problem. Thus many clinical trials have been curtailed – pending the production of newer ‘more human' reagents, as discussed in this volume. Nevertheless, the early trials and experiences have been most informative and form the basis for the next series of studies with genetically engineered antibodies, particularly, as discussed in this chapter, genetically engineered ‘magic bullets'. The relative merits of using drugs, toxins and isotopes to arm antibodies are shown in Table 1and will not be discussed here.
