The long-term goals of this program are to create monoclonal antibody based therapeutic agents for myeloid leukemia and to use studies in this model to under- stand basic principles of immunotherapy and resistance to immunotherapy in order to apply the concepts to other systems. Over the last 7 years of this R01, the investigators have constructed several new recombinant CDR grafted humanized anti-CD33 monoclonal antibodies (HuM 195) and characterized their biology, biochemistry, radiobiology, and radio- chemistry. The first alpha-emitting antibodies were characterized and have now entered human clinical trials. The interactions of HuM 195, in K cells and IL-2 were evaluated and this combination has also begun human trials. Phase II and III studies of the unmodified HuM 195 have begun internationally. Work has been completed toward understanding a new p-glycoprotein mediated """"""""immunological resistance"""""""" first described as part of this R01. This renewal is intended to build on several aspects of the prior work and proposes continued exploration of the newly discovered """"""""immunological resistance."""""""" The investigators have recently observed that MDR HL60 cells were also cross-resistant to HuM 195-based immunotoxins, radioconjugates, and complement-mediated killing. Preliminary data suggest that p-glycoprotein may mediate this resistance by increasing intracellular pH (pHi).
In Aim #1 the investigators propose to study and explain this new pHi mediated immunological resistance by conducting electrophysical studies on individual cells and on populations. The structure and function studies of the membrane attack complex will also be performed. Manipulations of pHi will be done in cells from patients with PNH, a human disease associated with excessive complement mediated lysis.
In Aim #2, the investigators will focus on understanding resistance to the immunotoxin Hum 195-gelonin and will explore how MDR cells resist targeted alpha radiations.
In Aim #3 the investigators will study methods to bypass the resistance to both toxins and isotopes in vitro, ex vivo, and in vivo. It is anticipated that these studies will result in data that can be applied quickly to human clinical problems in clinical trials and to other tumor systems as well.
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