| Abstract: | Engineering antibodies with reduced immunogenicity and enhanced effector functions, and selecting antigen targets with the appropriate specificity, density, and/or functionality, have contributed to the recent clinical successes in using unconjugated "naked" antibody therapies of B-cell lymphoma (rituximab) and breast carcinoma (Herceptin). The non-overlapping toxicities of naked antibodies and chemotherapy, together with their potential synergy, which is based on unique and complementary mechanisms of action, have contributed to the creation of new standards of care in cancer therapy and management. Clinical trial results supporting these concepts are presented. Furthermore, the exquisite specificity of antibodies renders them ideal vehicles for selective delivery of toxic payloads such as drugs or radionuclides. Although successful in therapy of hematological cancers (Zevalin, Mylotarg), the broader application of these technologies to carcinomas still remains to be proven in clinical testing. Engineering of antibody constructs with optimal blood clearance and tumor-targeting kinetics, and selecting the radionuclide that may deliver sufficient radiation energy to kill the more radio-resistant carcinomas, are discussed. With the advent of genomics and proteomics, new membrane-associated tumor antigens are being discovered and will provide novel targets for future antibody therapy of cancer. |
