Dana C. Matthews

Targeted Hematopoietic Irradiation Using Radiolabeled Monoclonal Antibodies

The goal of our research is to improve the outcome for patients undergoing hematopoietic stem cell transplantation (HSCT) for acute leukemia by using monoclonal antibodies to deliver radioisotopes to the bone marrow, spleen, and lymph nodes. We have hypothesized that the delivery of targeted radiation to tissues where leukemia cells reside, while relatively sparing normal organs, may improve survival by taking advantage of the radiation sensitivity of acute leukemia while avoiding excess toxicity.

We selected the CD45 antigen as a target for radiolabeled antibody because it is expressed by normal white blood cells and their precursors as well as by the majority of acute leukemias. Anti-CD45 antibody labeled with Iodine-131 (I-131) thus binds to the majority of cells in the marrow, spleen and lymph nodes whether patients are in remission or relapse. In clinical studies of patients with acute myeloid or lymphoid leukemia, most (>85%) have had favorable biodistribution of I-131-labeled BC8 (anti-CD45) antibody, with two to four times more radiation delivered to bone marrow as compared to the normal organ receiving the highest dose, the liver. Our initial clinical studies have added I-131-anti-CD45 antibody to conventional HSCT preparative regimens. A Phase I study in patients with advanced acute leukemia or yelodysplastic syndrome demonstrated that an average estimated radiation dose of 24 Gy to marrow and 50 Gy to spleen could be delivered by I-131-BC8 antibody at the maximum tolerated dose of radiation to liver, 10 Gy, when combined with cyclophosphamide (CY) and 12 Gy TBI. Phase II studies of this combined preparative regimen are underway for patients with advanced AMLand ALL. In an ongoing Phase II study in patients with AML in first remission, average estimated radiation doses of 10 Gy to marrow and 28 Gy to spleen (at the dose of 5.25 Gy to liver) have been well tolerated when combined with busulfan and CY, and the relapse rate has been encouragingly low to date. For older patients with advanced AML, we are conducting a Phase I study to determine the maximum tolerated dose of radiation which can be delivered by I-131-BC8 antibody when combined with the recently developed, non-myeloablative regimen of 2 Gy TBI and fludarabine followed by cyclosporine and mycophenolate mofetil. We hope that the targeted hematopoietic irradiation will adequately debulk the leukemia to the extent that the Graft-versus-Leukemia effect from engrafted donor cells may control disease.

In the laboratory, we are continuing pre-clinical studies in murine models to improve the therapeutic ratio of radiation delivered to target as compared to non-target tissues. These studies include the use of a pretargeting method using streptavidin-labeled anti-CD45 antibody followed by an isotope-biotin conjugate, and the use of alternative isotopes. Secondly, we are using radiolabeled antibody alone or with low doses of TBI to ablate the host immune system in order to facilitate the engraftment of donor cells from mice which are either matched or mismatched to host mice. These studies should optimize our ability to deliver maximum doses of radiation to leukemic cells with the least possible toxicity.

Academic Experience:
Alpha Omega Alpha, University of Washington School of Medicine
Fellow, Leukemia Society of America
Special Fellow, Leukemia Society of America
Elected to Pediatric Hematology/Oncology Subboard, American Board of Pediatrics, effective 1/2005

Business Experience:
Member, Board of Trustees, Washington State Chapter of Leukemia Society of America.

I am developing clinical research in pediatric thrombosis.

I am director of the Pediatric Hemophilia Program at Children's Hospital and Regional Medical Center