This project involves basic and clinical approaches to the treatment of acute myelogenous leukemia (AML) using monoclonal antibodies cytotoxic to myeloid leukemia cells. Using two monoclonal antibodies (PM-81 and AML-2-23) already prepared by the Principal investigator, as well as others which we propose to develop in this study, we plan a clinical trial of autologous bone marrow transplantation in AML using monoclonal antibodies to purge bone marrow from patients in remission. The studies are designed to improve the ability to remove leukemia cells from remission bone marrow by producing and selecting appropriate antibodies that deal more effectively with the issue of antigenic heterogeneity on myeloid leukemia cells. The efficacy of immunotoxins and chemotherapeutic agents combined with monoclonal antibodies in killing leukemia cells in vitro will be examined. In addition, we will study the surface antigen expression of leukemia colony-forming cells (L-CFC) in vitro using monoclonal antibodies and complement-mediated cytotoxicity. Patients will be followed serially in order to examine whether the cell surface antigen and L-CFC data correlate with their clinical response to autologous bone marrow transplant with monoclonal antibody purging. Another aspect of this study is the development of methods to enrich and purify pluripotent progenitor cells from bone marrow to use for basic studies and in transplantation. These will employ a monoclonal antibody already prepared by the P.I. which appears to be reactive with numerous classes of progenitor cells including multi-potent hematopoietic progenitor cells. We will attempt to utilize panning and cell sorting techniques to purify progenitor cells using the AML-1-99 monoclonal antibody. We propose to continue our Phase I study of monoclonal antibody purging of remission bone marrow in patients with acute myeloid leukemia who are in second or third remission. After achieving the goal of 10 successful transplants, demonstrating that engraftment is not abrogated by treatment with monoclonal antibodies, we intend to begin a Phase II clinical trial of monoclonal antibody purging of bone marrow from patients in first remission with AML. It is important to emphasize that the funding requested is for the preclinical aspects of this program. Support for the clinical trial is expected to come from third-party carriers and/or institutional overhead. We propose a large number of extremely important preclinical studies that will significantly increase our knowledge of the cell biology of AML. In addition, these studies may lead to a superior form of therapy for patients with AML, the majority of whom are not eligible for allogeneic bone marrow transplantation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Experimental Therapeutics Subcommittee 1 (ET)
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University of Pittsburgh
Schools of Medicine
United States
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Balaian, Larisa; Zhong, Rui-kun; Ball, Edward D (2003) The inhibitory effect of anti-CD33 monoclonal antibodies on AML cell growth correlates with Syk and/or ZAP-70 expression. Exp Hematol 31:363-71
Zhong, Rui-Kun; Rassenti, Laura Z; Kipps, Thomas J et al. (2002) Sequential modulation of growth factors: a novel strategy for adoptive immunotherapy of acute myeloid leukemia. Biol Blood Marrow Transplant 8:557-68
Myers, D E; Uckun, F M; Ball, E D et al. (1988) Immunotoxins for ex vivo marrow purging in autologous bone marrow transplantation for acute nonlymphocytic leukemia. Transplantation 46:240-5