| Abstract: |
Clinical research in antibody-based cancer therapy has been driven for many years by the prospect of identifying cell-surface antigens with sufficiently restrictive tissue expression patterns to allow the specific targeting of antibody to tumor tissue. Few if any such antibodies capable of targeting rapidly and efficiently to solid tumors have been identified. The main reasons for this are based on the inherent pharmacokinetics and physiology of IgG, the immunoglobulin G molecule. Factors that may limit targeting potential include accessibility of tumor antigen, and antibody affinity, molecular size, and metabolism. Immunoglobulins have evolved to optimally protect an organism from foreign invaders rather than to act as an efficient carrier molecule for therapeutic reagents. Despite these potential limitations, our growing understanding of the biologic and physiologic principles that underlie targeted therapy has led to the development of a generation of novel reagents and the first 'positive' clinical trials. Recent strategies for therapeutic use of antibodies in colon cancer have focused on (I) unmodified mouse IgG; (2) immune globulin as carrier for targeted delivery of radioisotopes; toxins, and therapeutic molecules; (3) genetically engineered antibody constructs redesigned for specific uses; (4) humanized, nonimmunogenic IgG structures; and (5) novel antigen targets in tumors. Genetically engineered antibody constructs provide an exciting approach to address and subsequently overcome some of the problems identified for unmodified IgG. These new constructs should increase the dose fraction localized in tumors versus normal tissue and thereby improve the delivery capacity. In contrast, strategies such as immune-mediated cytotoxicity are less dependent on the quantitative difference between the antibody fraction localized in tumor and the nonlocalized fraction. Because antibodies, which direct host cytotoxic mechanisms, become activated in the tumor only when bound to antigen, one would not expect nonspecific toxic effects from nonlocalized antibody. The hypothesis that antibodies alone can destroy tumor tissue solely by directing immune cytotoxic mechanisms is just now being tested in clinical trials evaluating a new generation of humanized antibodies. |
