Research Topics
Immunotoxin Therapy of Cancer
1.2 million Americans develop cancer each year and about 500,000 die from the disease. To improve the therapy of cancer new approaches and drugs with new mechanisms of action are needed. To accomplish this, we have employed genetic engineering to modify a potent bacterial toxin, so that it will kill cancer cells.
- Pseudomonas exotoxin A (PE) is a three-domain protein. We have produced anti-cancer agents by deleting the binding domain and other non-essential regions of PE and replacing them with the Fv or Fab portion of an antibody that directs the toxin to a target on the cancer cells. These agents are termed "recombinant immunotoxins" (RITs). They kill cells by arresting protein synthesis and inducing apoptosis, a mechanism not employed by other anti-cancer agents. Therefore, they can kill drug resistant cells.
Several different recombinant immunotoxins have been developed in our laboratory and we are now conducting clinical trials with 2 of them. Moxetumomab pasudotox (Lumoxiti) targets CD22 on B cell malignancies and has been approved by the FDA to treat drug resistant Hairy Cell Leukemia. LMB-100 targets mesothelin present on mesothelioma and many other epithelial cancers (pancreas, ovary, lung, bile duct and triple negative breast cancer). We are carrying out clinical trials in mesothelioma and pancreatic cancer.
Biography
Dr. Ira Pastan was educated at the Boston Public Latin School, Tufts College, and Tufts Medical School. He did his residency at the Yale School of Medicine (1957-1959) and came to NIH in 1959. In 1970, he founded the Laboratory of Molecular Biology in the NCI.
Major honors
Van Meter Prize, 1971
G. Burroughs Mider Lectureship, National Institutes of Health, 1973
Membership, National Academy of Sciences, 1982
American Academy of Arts and Sciences, 1997
Fellow, American Academy of Microbiology, 1997
Fellow, American Association for the Advancement of Science, 1997
International Feltrinelli Prize for Medicine, 2009
Nathan Davis Award of the AMA for Government Service, 2010
Membership, Institute of Medicine of the National Academies, 2010
AACR Team Science Award, 2014
Humbert Humphrey Award, DHHS, 2019
Selected Publications
- Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, Kreitman RJ, Miettinen MM, Steinberg SM, Fowler DH, Pastan I. Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci Transl Med. 2013;5(208):208ra147.
- Liu W, Onda M, Kim C, Xiang L, Weldon JE, Lee B, Pastan I. A recombinant immunotoxin engineered for increased stability by adding a disulfide bond has decreased immunogenicity. Protein Eng Des Sel. 2012;25(1):1-6.
- Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, Fitzgerald DJ, Lechleider R, Pastan I. Phase I trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J Clin Oncol. 2012;30(15):1822-8.
- Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci U S A. 1996;93(1):136-40.
- Chaudhary VK, Queen C, Junghans RP, Waldmann TA, FitzGerald DJ, Pastan I. A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature. 1989;339(6223):394-7.
Related Scientific Focus Areas
Biomedical Engineering and Biophysics
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Molecular Biology and Biochemistry
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This page was last updated on Friday, August 26, 2022