Ira Pastan, M.D.
NIH Distinguished Investigator
Laboratory of Molecular Biology
Building 37, Room 5106
Bethesda, MD 20892
New Approaches to Cancer Treatment: Recombinant Immunotoxins
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. We are developing a treatment that incorporates both these principles. We employ genetic engineering to modify a potent bacterial toxin, which is designed to kill many different types of cells, to one that kills cancer cells.
Pseudomonas exotoxin A (PE) is a three-domain protein composed of 613 amino acids. We have produced anti-cancer agents by deleting the binding domain of PE (aa 1-252), and replacing it with the Fv portion of an antibody that directs the toxin to a target on cancer cells. These agents are termed "recombinant immunotoxins" (RITs). They kill cells by arresting protein synthesis, a mechanism not employed by other anti-cancer agents.
Several different recombinant immunotoxins have been developed in our laboratory and we are conducting clinical trials with 3 of them. Moxetumomab pasudotox (HA22) targets CD22 on B cell malignancies, LMB2 targets CD25 on T cell malignancies, and SS1P targets mesothelin present on mesothelioma and many other epithelial cancers (pancreas, ovary, lung, bile duct and triple negative breast cancer).
Moxetumomab pasudotox has produced complete remissions in many patients with drug-resistant Hairy Cell Leukemia (HCL) and has also shown anti-tumor activity in childhood acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is licensed to MedImmune LLC and they are sponsoring clinical trials in leukemias and lymphomas expressing CD22. Recently a phase 3 trial has opened in patients with drug-resistant Hairy Cell Leukemia.
SS1P is being evaluated in clinical trials in mesothelioma, where it is combined with chemotherapy. Recently we found that some patients with advanced drug-resistant mesothelioma had profound and prolonged remissions when SS1P was combined with cytoxan and pentostatin.
Because the toxin portion of RITs is a foreign protein, patients with solid tumors who have normal immune function usually make antibodies to the RITs and inactivate them, limiting their efficacy. To allow us to give more treatment cycles and achieve better anti-tumor activity, we have designed and produced new RITs in which the major B cell epitopes and T cell epitopes in the toxin have been identified and silenced. These new agents are being developed for clinical trials.
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.
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.
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.
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.
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.