Our Science – Pastan Website

Ira Pastan, M.D.

Laboratory of Molecular Biology Head, Molecular Biology Section Laboratory Chief Bldg. 37, Room 5106 NCI-Bethesda Bethesda, MD 20892 Phone:   301-496-4797 Fax:   301-402-1344 E-Mail:   pastani@mail.nih.gov

Biography

Dr. Pastan is chief of the Laboratory of Molecular Biology, Center for Cancer Research. He obtained his M.D. from Tufts University, received his medical training at Yale University and research training at the NIH. He established the Laboratory of Molecular Biology in 1970.

Research

New Approaches to Cancer Treatment: Recombinant Immunotoxins
Currently, 1.2 million Americans develop cancer each year and about 500,000 die from the disease, because most cancers cannot be cured once they have metastasized. To develop a new treatment for metastatic cancer, we have used genetic engineering to modify a powerful bacterial toxin, Pseudomonas exotoxin A (PE), so that instead of killing normal cells it selectively kills cancer cells. PE is a three-domain protein composed of 613 amino acids. Anti-cancer agents are produced by deleting the binding domain of PE(aa 1-252) and replacing it with the Fv fragment of an antibody or with a growth factor that binds to cancer cells. These agents are termed 'recombinant immunotoxins'. We have made several different recombinant immunotoxins and we are currently conducting clinical trials with immunotoxin BL22 that targets CD22 on B cell leukemias and lymphomas, immunotoxin LMB2 that targets CD25 on T cell malignancies, and immunotoxin SS1P that targets mesothelin present on ovarian cancer and mesothelioma. We are also participating on a multi-center phase 2 trial in which glioblastomas expressing the EGF receptor are treated with (TGF-alpha-PE38). The most active agent is BL22; it has produced complete remissions in many patients with drug resistant Hairy Cell Leukemia. Recombinant immunotoxins are produced in E. coli because large amounts can be readily purified from this source.

An ideal immunotoxin should be very active so that only small amounts need to be given to cause tumor regressions, small in size so that it can penetrate into cancers, stable so it remains functional during the 5-10 hrs required to reach the interior of a cancer, and non-immunogenic so it can be given repeatedly. We have designed and produced recombinant immunotoxins with some of these properties. Size was decreased and anti-tumor activity increased by deleting unnecessary sequences in the toxin. Stability has been obtained by designing disulfide-linked Fv (dsFv) fragments that are connected by cysteines engineered into the Fv framework regions. These dsFv immunotoxins are up to 100-fold more stable than single-chain immunotoxins and have higher anti-tumor activity.

Efforts are currently focused on using phage display to identify new antibodies and to produce new immunotoxins directed at various solid tumors (breast, ovary, prostate, lung, colon) as well as lymphomas and leukemias. We have developed a computer-based method to identify new genes expressed in prostate and breast cancer and have identified two new target genes. We have shown that we can use DNA immunization of mice to generate new antibodies. This eliminates the need to produce and purify proteins for immunization. Antibody titers of over 1:1 million have been obtained by this procedure. The mouse spleens are used to prepare libraries of Fv-phage directly or to produce hybridomas. New genes are also being studied as targets for vaccine based therapies.

Collaborators on this research at NIH include Robert Kreitman, David FitzGerald, Raffit Hassan, Tapan Bera, Wyndham Wilson, Byungkook Lee, Thomas Waldmann, Jeffrey Schlom, Jay Berzofsky and Alan Wayne.

This page was last updated on 6/12/2008.