We will continue ongoing studies on the development of immunotoxins (ITs) for in vitro and in vivo use. We will concentrate on the use of ricin A chain linked to intact or Fab fragments of cell-reactive antibodies. Two B cell tumor models will be used; the human Daudi cells and the murine BCL1 tumor. Several linkages between antibody and A chain will be compared for efficacy and in vivo stability. Fab-A immunotoxins and the intact antibody-A-ITs will be studied in vivo for their rate of clearance, biodistribution, homing to target cells, damage to normal tissue and uptake by cells of the reticuloendothelial system. In addition, we will use the """"""""piggyback"""""""" approach of cell-reactive A-IT and anti-antibody linked to ricin B chain (B-IT) or an anti-A chain linked to ricin B chain in an attempt to further potentiate the killing by the A-ITs. We will also study the in vitro properties of these B-ITs and compare the piggyback approach with univalent vs divalent antibodies for their ability to delete tumor cells and not damage normal marrow CFU. Clonogenic (Daudi) and adoptive transfer assays (BCL1) will be used as a readout system. The effect of lysosomotropic agents on the piggyback system (tumor cells and bone marrow) will also be studied. Finally, the long-term goal will be to clone and express ricin A and B chains entirely by recombinant DNA technology and eventually to prepare ITs in the same manner. We will mutagenize the A and B chain genes to obtain molecules with more favorable biological properties such as reduced antigenecity, loss of galactose-binding sites on the B chain, and lack of oligosaccharides. The insights gained from this proposal should be applicable to immunotoxins constructed with any type of monoclonal antibody, even though our own studies will be carried out in two defined tumor model systems.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA028149-08
Application #
3482110
Study Section
Experimental Immunology Study Section (EI)
Project Start
1981-04-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
8
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Overall Medical
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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
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
Vitetta, E S; Tucker, T F; Racila, E et al. (1997) Tumor dormancy and cell signaling. V. Regrowth of the BCL1 tumor after dormancy is established. Blood 89:4425-36

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