Abstract

Second generation immunotoxins (ITs) containing Fab' or IgG antibody linked via hindered disulfide bonds to deglycosylated ricin A chain (IT-A) are showing promising results in Phase I clinical trials in patients with B cell lymphoma. For these ITs to work optimally in the treatment of minimal disease, their immunogenicity and toxicity must be decreased and potency increased.
The aim of this proposal will be to 1) increase the potency of IT-As by adding intracellular routing sequences and/or lipids to the A chain and using bispecific ITs which recruit effector cells as well as deliver A chain, 2) define the immunodominant T cell epitopes on the A chain in order to delete or mutate them to render the A chain less immunogenic, and 3) generate and test ricin A chain mutants in our in vitro vascular leak model to determine whether toxicity and enzymatic activities of the A chain can be mapped to different portions of the molecule. If this should be the case, we will attempt to delete the toxicity by mutagenesis. Based on this information, new third generation ITs will be designed and tested in vitro and in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA028149-14
Application #
2087705
Study Section
Experimental Immunology Study Section (EI)
Project Start
1981-04-01
Project End
1998-01-31
Budget Start
1994-04-01
Budget End
1995-01-31
Support Year
14
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390

  Publications

Schindler, J; Sausville, E; Messmann, R et al. (2001) The toxicity of deglycosylated ricin A chain-containing immunotoxins in patients with non-Hodgkin's lymphoma is exacerbated by prior radiotherapy: a retrospective analysis of patients in five clinical trials. Clin Cancer Res 7:255-8
Wei, B R; Ghetie, M A; Vitetta, E S (2000) The combined use of an immunotoxin and a radioimmunoconjugate to treat disseminated human B-cell lymphoma in immunodeficient mice. Clin Cancer Res 6:631-42
Schnell, R; Vitetta, E; Schindler, J et al. (2000) Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin. Leukemia 14:129-35
Baluna, R; Vitetta, E S (1999) An in vivo model to study immunotoxin-induced vascular leak in human tissue. J Immunother 22:41-7
Schnell, R; Vitetta, E; Schindler, J et al. (1998) Clinical trials with an anti-CD25 ricin A-chain experimental and immunotoxin (RFT5-SMPT-dgA) in Hodgkin's lymphoma. Leuk Lymphoma 30:525-37
Marches, R; Scheuermann, R H; Uhr, J W (1998) Cancer dormancy: role of cyclin-dependent kinase inhibitors in induction of cell cycle arrest mediated via membrane IgM. Cancer Res 58:691-7
Clinchy, B; Vitetta, E S (1998) The use of an anti-CD3 immunotoxin to prevent the development of lymphoproliferative disease in SCID/PBL mice. J Immunol Methods 218:141-53
Engert, A; Sausville, E A; Vitetta, E (1998) The emerging role of ricin A-chain immunotoxins in leukemia and lymphoma. Curr Top Microbiol Immunol 234:13-33
Ghetie, M A; Podar, E M; Ilgen, A et al. (1997) Homodimerization of tumor-reactive monoclonal antibodies markedly increases their ability to induce growth arrest or apoptosis of tumor cells. Proc Natl Acad Sci U S A 94:7509-14
Senderowicz, A M; Vitetta, E; Headlee, D et al. (1997) Complete sustained response of a refractory, post-transplantation, large B-cell lymphoma to an anti-CD22 immunotoxin. Ann Intern Med 126:882-5

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