Genetically engineered monoclonal antibodies for direct anti-neoplastic treatment and cancer cell specific delivery of chemotherapeutic agents

Classical therapeutic modalities such as surgery, radiation, and chemothera py not only fail to cure the great majority of malignant tumors, but their employment often leads to severe and debilitating side effects. The severe cancer related morbidity is also in direct correlation with the use of x-ra diation and chemotherapy, making them less than ideal forms of therapy. The development of hybridoma technology and the advances in monoclonal antibod y (MoAB) production have revitalized the initial concept of Ehrlich concern ing the existence of cancer cell-targeted, specific "magic bullets". Entire ly new approaches to cancer therapy that are neoplastic cell-directed, and specifically lethal to malignant cells and less toxic to normal tissues are being observed and developed, adhering to the old prayer: "Destroy the dis eased tissues, preserve the normal." Immunotherapy as a fourth modality of cancer therapy has already been developed and proven to be quite effective. Strategies for the employment of antibodies for anti-cancer immunotherapy include: 1) Immune reaction directed destruction of cancer cells; 2) Interf erence with the growth and differentiation of malignant cells; 3) Antigen e pitope directed transport of anti-cancer agents to malignant cells; 4) Anti -idiotype vaccines; and 5) Development of engineered (humanized) mouse mono clonals for anti-cancer therapy. In addition, a variety of different agents (e.g. toxins, radionuclides, chemotherapeutic drugs) have been conjugated to mouse and human MoABs for selective delivery to cancer cells. Preclinica l observations in athymic, nude mice using xenografted human cancers and mo use, antihuman MoABs were more than impressive and have lead to the develop ment of clinical trials. Phase I studies established the safety of employin g immunoconjugates in humans, but the in vivo therapeutic results were less impressive. The clinical use of mouse MoABs in humans is limited due to the development of a foreign anti-globulin immune response by the human host. Genetically engineered chimeric human-mouse MoABs have been developed by replacing the mouse Fc region with the human constant region. Moreover, the framework reg ions of variable domains of rodent immunoglobulins were also experimentally replaced by their human equivalents. These antibodies can also be designed to have specificities and effector functions determined by researchers, wh ich may not appear in nature. The development of antibodies with two bindin g ends (bispecific antibodies) provided a great improvement in targeting ca ncer cells. The existing inadequacies of MoABs in immunotherapy may also be improved by increasing their efficiency with chemical coupling to various agents such as bacterial or plant toxins, radionuclides or cytotoxic drugs. The astonishing immunophenotypic (IP) heterogeneity of neoplastically tran sformed cells, the different cytotoxic activity associated with the moiety linked to given MoABs, and mostly the impressive genetic modulation capabil ities of cancer cells still remain as yet unsolved difficulties in the pres ent immunotherapy of human cancer. In writing this review article, one of our main goals is to encourage furth er clinical research with the use of genetically engineered rodent MoABs an d various immunoconjugates in the treatment of human cancer, as well as the combination of such immunotherapy with the three conventional modalities o f therapy. Finally, we propose that MoAB-based immunotherapy be accepted as a conventional form of therapy and employed not only in terminal cancer pa tients but also, for instance, during and following surgical resection.