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Contact information Recent publications Curriculum vitae Laboratory of Molecular Biology |
Biography: Dr. Kreitman received his M.D. from Ohio State University in 1985 and obtained his internal medicine residency training at Duke University from 1985 to 1988. He received his medical oncology fellowship training here at the NIH from 1988 to 1991 and has been working in the immunotoxin field since 1989. He won the Federal Technology Transfer award.Research: Recombinant toxins are proteins made in bacteria and contain two parts, one for binding selectively with certain types of cells and one which kills the cell. We are developing recombinant toxins which bind selectively to malignant hematopoietic cells, such as leukemias, lymphomas, Hodgkin's disease, and multiple myeloma. Some also bind to solid tumors such as glioblastoma and GI carcinomas. We are now conducting a Phase I clinical trial with anti-Tac(Fv)-PE38 (LMB-2), a recombinant toxin which has shown promising preclinical activity against malignant cells displaying interleukin 2 receptors.We are attempting to target mutated forms of Pseudomonas exotoxin, which inside cells translocates a smaller fragment to the cytosol and kills by inhibition of protein synthesis. Since the toxin ADP-ribosylates elongation factor 2 catalytically, one molecule is sufficient to kill a cell. The mutated toxin is fused to a binding domain, either a growth factor or a single-chain antibody, which binds selectively to cancer cells. Cells with several hundred or thousands of binding sites per cell may internalize enough so that one or several molecules reach the cytoplasm. Normal cells, which have much fewer binding sites per cell, are protected.Recombinant toxins are made by using recombinant DNA techniques to design a plasmid encoding the protein molecule, expressing the plasmid in bacteria and then purifying the protein so that it binds selectively to cancer cells. The cytotoxic activity is determined by incubating the recombinant toxins with tumor cells in tissue culture, and determining cell killing or inhibition of protein synthesis. Recombinant toxins with good cytotoxic activity are then tested in mice bearing human tumor cells, to see if the mice can be cured at safe doses. If so, the lab consults the FDA and determines which safety studies should be done to determine if it is safe to administer the drug to people. The principal investigator is a board certified medical oncologist who is able to direct clinical trials through the medicine branch for recombinant toxins developed in the lab.In addition to interleukin 2 receptor-bearing malignant cells, the lab is also targeting 1) interleukin 6-receptor bearing multiple myeloma, 2) interleukin-4 receptor-bearing lymphoma, colon cancer, glioblastoma and renal cell carcinoma, 3) CD19 and CD22-bearing leukemias and lymphomas, 4) other growth factor receptors specific for malignant cells. A major emphasis deals with basic science questions related to intracellular metabolism and transport of toxins, and recombinant antibody engineering.Recent Publications: |
Contact Information: Laboratory of Molecular Biology,NCI, NIHBuilding 37, Room 4B2737 CONVENT DR MSC 4255BETHESDA MD 20892-4255Phone: 301-496-6947Fax:301-402-1344Email: rk21n@nih.gov
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