Humanized mouse monoclonal
date. In addition, some antibodies may directly activate intrinsic apoptosis pathways in tumor cells; this is the proposed mechanism for the use of anti-CD30 to treat lymphomas, currently in clinical trials. A monoclonal antibody (Herceptin) specific for the oncogene product HER2/Neu, is an approved treatment for breast cancer patients whose tumors express high levels of HER2/Neu. In addition to eliciting immune effector mechanisms, the anti-HER2/Neu antibody interferes with growth-signaling functions of the HER2/Neu molecule.
Because the anti-tumor antibodies used in the early human trials were mouse monoclonal antibodies, an immune response frequently occurred against the mouse Ig, resulting in anti-mouse Ig antibodies that caused increased clearance of the anti-tumor antibodies or blocked binding of the therapeutic agent to its target. This problem has been diminished by use of "humanized" antibodies consisting of the variable regions of a mouse monoclonal antibody specific for the tumor antigen combined with human Fc portions. One of the most difficult problems with the use of anti-tumor antibodies is the outgrowth of antigen loss variants of the tumor cells that no longer express the antigens that the antibodies recognize. One way to avoid this problem may be to use cocktails of antibodies specific for different antigens expressed on the same tumor.
Many variations on anti-tumor antibodies have been tried in attempts to improve their effectiveness. Tumor-specific antibodies may be coupled to toxic molecules, radioisotopes, and anti-tumor drugs to promote the delivery of these cytotoxic agents specifically to the tumor. Toxins such as ricin and diphtheria toxin are potent inhibitors of protein synthesis and can be effective at extremely low doses if they are carried to tumors attached to anti-tumor antibodies; such conjugates are called immunotoxins. This approach requires covalent coupling of the toxin (lacking its cell-binding component) to an anti-tumor antibody molecule without loss of toxicity or antibody specificity. The systemically injected immunotoxin is endocytosed by tumor cells, and the toxin part is delivered to its intracellular site of action. Several practical difficulties must be overcome for this technique to be successful. The specificity of the antibody must be such that it does not bind to non-tumor cells. A sufficient amount of antibody must reach the appropriate tumor target before it is cleared from the blood by Fc receptor-bearing phagocytic cells. The toxins, drugs, or radioisotopes attached to the antibody may have systemic effects as a result of circulation through normal tissues. For example, hepatotoxicity and vascular leak syndromes are common problems with immunotoxin therapy. Administration of immunotoxins may result in antibody responses against the toxins and the injected antibodies. Because of these practical difficulties, clinical trials of immunotoxins have had variable and modest success.
Anti-idiotypic antibodies have been used to treat B cell lymphomas that express surface Ig with particular idio-types. The idiotype is a highly specific tumor antigen because it is expressed only on the neoplastic clone of B cells, and it was once hoped that anti-idiotypic antibodies would be effective therapeutic reagents with absolute tumor specificity. (Anti-idiotypic antibodies are raised by immunizing animals with a patient's B cell tumor and depleting the serum of reactivity against all other human immunoglobulins.) The approach has not proved generally successful, largely because of the selective outgrowth of tumor cells with altered idiotypes that are not recognized by the anti-idiotypic antibody. In part, this result may reflect the high rate of somatic mutation in Ig genes and the fact that the surface Ig is dispensable for tumor growth.
Tumor growth is usually dependent on growth factors, which are potential targets for therapy. Antibodies that block the epidermal growth factor receptor are approved for the treatment of colorectal tumors. Tumors depend on the formation of new blood vessels that supply the tumor with oxygen and nutrients. This process, called tumor angiogenesis, is dependent on other specialized growth factors, including VEGF. Various inhibitors of these angio-genic factors can block tumor growth. Anti-VEGF antibodies are now approved for clinical use, in combination with chemotherapeutic agents, to treat some metastatic tumors, although their efficacy is modest.
Anti-tumor antibodies are also used to remove cancer cells from the bone marrow before autologous marrow transplantation. In this protocol, some of the patient's bone marrow is removed, and the patient is given doses of radiation and chemotherapy lethal enough to destroy tumor cells as well as the remaining normal marrow cells. The bone marrow cells removed from the patient are treated with antibodies or immunotoxins specific for tumor antigens in order to kill most or all tumor cells. The treated marrow, having been purged of tumor cells, is transplanted back into the patient to reconstitute the hematopoietic system destroyed by irradiation and chemotherapy.
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