Discipline: Chemistry and Chemical Sciences
Subcategory: Cancer Research
Rosario Guel - University of Washington
Co-Author(s): Johnnie Orozco and Aimee Kenoyer, Fred Hutchinson Cancer Research Center, Seattle, WA
Delivering lethal doses of radiation directly to tumor without damaging surrounding tissue has been one of the biggest challenges in the administration of radionuclide-based cancer therapeutics. The opening question towards the development of novel cancer therapeutics is how to minimize the spread of radiation to normal tissue and maximize the specific targeting of radiation to a cancer cell. Technologies such as one-step Radioimmunotherapy (RIT) has become a growing approach for the treatment of cancer. RIT involves a one-step delivery of radiation directly to cancer cells using a radiolabeled monoclonal antibody recognizing CD45. While RIT has proven to target cancer cells, its success as an optimal treatment is limited due to the relatively high amounts of radiation absorbed by the body as a result of non-specific targeting. An alternative approach, known as Pre-targeted radioimmunotherapy (PRIT), has been developed to serve the same purpose to directly target cancer, but unlike RIT, PRIT provides a more efficient method to minimize the toxicity in normal tissue during administration. The goal of my project has been to create a bi-specific antibody in the use of PRIT to enhance an alternative cancer treatment to the conventional RIT. If successful, this Pre-targeted system using a bispecific antibody will deliver radiation directly to sites of disease, while eliminating high amounts of radioactive exposure to normal tissues, with an overall effect of improving therapeutic outcomes. Methods used to obtain my data were performed using a biodistribution study on a murine model. The outline for this experiment include four groups of 5 mice per group, with 2 groups as controls and 2 groups as treatment group. Control mice were injected with 280 µg of CC49-C825 (a non-binding bispecific antibody control). Therapeutic groups were injected with 280 µg of 30F11-C825, the anti- bispecifc version of CD45 18 hours prior to the administration of radiation. At 16 hours post-antibody injection, all groups of mice were then injected with 5 µg of DOTAY CA (clearing agent). Two hours later all groups of mice were given 50 µCi of 90Y-DOTAbiotin. Harvesting of tissue for biodistribution was performed at 6 hrs and 24 hrs post-radioactive injection. The overall results from my experiment show that the amounts of radiation in the different tissues of the mice at 6 hours and 24 hours. Mice treated with 30F11 bispecific antibody had great amounts of radiation in the disease target sites of the spleen and bone marrow. The control mice were used to prove that our bispecific antibody was specific for binding to CD45+ tissues. The PRIT method with our bi-specific antibody has shown specific targeting of radiation to hematopoietic target tissues, with the potential to produce a better disease outcome than conventional RIT. Our data proves that our bispecific antibody is able specifically bind to sites of disease. As a follow up to this data, therapy studies will be performed next to determine efficacy of this treatment modality and compare the amounts of toxicity in relation to prior RIT studies.
Funder Acknowledgement(s): My work was supported by the National Institutes of Health & University of Washington; (R01 CA138720, R01 CA109663, R01 CA076287, R01 CA136639).
Faculty Advisor: Johnnie Orozco,