Cancer Immunotherapy seeks to use the immune system to treat or cure cancer. This field may be broadly divided into active T cell immunization against unique tumor antigens, or passive administration of antibodies specific for cell surface tumor antigens. Of these two, administration of genetically humanized monoclonal antibodies has made more of a significant impact on clinical oncology. All of the antibodies used to treat cancer patients are of the gamma 1 isotype (lgG1). This standard is largely based on historical data that needs to be reexamined. This proposal will explore the possibility that superior antibodies for cancer therapeutics are possible by engaging effector cells of the allergic immune system. This hypothesis will be tested by construction of three humanized antibodies specific for two different tumor antigens. The antibodies will further be reshaped by changing their constant region and making them epsilon antibodies (IgE). By doing this, the antibodies will be able to engage mast cells, eosinophils and basophils; all potent effector cells of the allergic immune system. Monoclonal antibodies to CD20 and two glycosylated forms of MUC1 will be humanized. The former is a validated target in the treatment of non-Hodgkin's lymphomas and the latter a novel target in the treatment of breast, pancreatic and prostate cancer and multiple myeloma. Once constructed, the antibodies will be evaluated for their ability to mediate tumor lysis in vitro using mast cells and eosinophils as effector cells. To more rigorously evaluate the clinical utility of these novel agents, their ability to eradicate tumors in mice will be assessed. Significant differences exist between the human and mouse allergic immune system that may underestimate the real value of these agents in humans. Fortunately, a genetically altered mouse exists that has had the endogenous mouse receptor for IgE deleted and replaced by the human receptor. The tumor specific, humanized IgE antibodies will be tested for their ability to treat implanted tumors in these transgenic mice.
| Teo, Pearline Zhaoying; Utz, Paul J; Mollick, Joseph A (2012) Using the allergic immune system to target cancer: activity of IgE antibodies specific for human CD20 and MUC1. Cancer Immunol Immunother 61:2295-309 |
