Immunotoxins are a class of pharmacologic reagents in which monoclonal antibodies are linked to potent toxins such as ricin, pokeweed antiviral protein (PAP), or saporin. We will develop and characterize a panel of immunotoxins for use in clinical bone marrow transplantation. Bone marrow transplantation has become the preferred treatment for a number of hematologic diseases, and most notably, for certain types of acute and chronic leukemias. In allogeneic bone marrow transplants, immunocompetent T cells that cause graft-versus-host disease can be purged from donor grafts by using immunotoxins prior to infusion. In autologous bone marrow transplants, contaminating leukemia cells can be removed from remission autografts prior to autologous rescue. This grant will primarily be directed towards synthesizing the most selective and potent immunotoxins against normal and leukemic lymphocytes. We will optimize pretreatment protocols for ex vivo treatment of bone marrow and investigate the ability of various chemical potentiators to improve the activity of our reagents. We will develop a panel of immunotoxins against T-lineage cells which can be used for allogeneic bone marrow transplantation and autologous bone marrow transplantation of patients with T-cell leukemias. A panel of anti-B cell immunotoxins will be developed for autologous bone marrow transplantation for B leukemias/lymphoma. A panel of antimyeloid immunotoxins will be used for autologous bone marrows transplantation of patients with myelogenous leukemia. We will also attempt to synthesize new immunotoxins for in vivo therapy. Our studies will focus on immunotoxins made from phytotoxins which represent a class of naturally occurring A chains having no reactivity with the surface of human cells but high reactivity inside the cytosol. We will test these reagents to determine their usefulness in treatment of residual disease. These studies will provide information of great clinical value leading to the development of new protocols for the University of Minnesota Bone Marrow Transplantation Program. (TT)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036725-03
Application #
3174309
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1984-01-01
Project End
1986-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Oh, Felix; Todhunter, Deborah; Taras, Elizabeth et al. (2018) Targeting EGFR and uPAR on human rhabdomyosarcoma, osteosarcoma, and ovarian adenocarcinoma with a bispecific ligand-directed toxin. Clin Pharmacol 10:113-121
Schmohl, Joerg U; Todhunter, Deborah; Taras, Elizabeth et al. (2018) Development of a Deimmunized Bispecific Immunotoxin dDT2219 against B-Cell Malignancies. Toxins (Basel) 10:
Pilbeam, Kristy; Wang, Hongbo; Taras, Elizabeth et al. (2018) Targeting pediatric sarcoma with a bispecific ligand immunotoxin targeting urokinase and epidermal growth factor receptors. Oncotarget 9:11938-11947
Borgatti, Antonella; Koopmeiners, Joseph S; Sarver, Aaron L et al. (2017) Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR. Mol Cancer Ther 16:956-965
Schmohl, Jörg U; Felices, Martin; Oh, Felix et al. (2017) Engineering of Anti-CD133 Trispecific Molecule Capable of Inducing NK Expansion and Driving Antibody-Dependent Cell-Mediated Cytotoxicity. Cancer Res Treat 49:1140-1152
Schmohl, J U; Gleason, M K; Dougherty, P R et al. (2016) Heterodimeric Bispecific Single Chain Variable Fragments (scFv) Killer Engagers (BiKEs) Enhance NK-cell Activity Against CD133+ Colorectal Cancer Cells. Target Oncol 11:353-61
Schmohl, Joerg U; Felices, Martin; Todhunter, Deborah et al. (2016) Tetraspecific scFv construct provides NK cell mediated ADCC and self-sustaining stimuli via insertion of IL-15 as a cross-linker. Oncotarget 7:73830-73844
Schmohl, Joerg U; Felices, Martin; Taras, Elizabeth et al. (2016) Enhanced ADCC and NK Cell Activation of an Anticarcinoma Bispecific Antibody by Genetic Insertion of a Modified IL-15 Cross-linker. Mol Ther 24:1312-22
Vallera, Daniel A; Felices, Martin; McElmurry, Ron et al. (2016) IL15 Trispecific Killer Engagers (TriKE) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence, In Vivo Expansion, and Enhanced Function. Clin Cancer Res 22:3440-50
Schmohl, Joerg U; Todhunter, Deborah; Oh, Seung et al. (2015) Mutagenic Deimmunization of Diphtheria Toxin for Use in Biologic Drug Development. Toxins (Basel) 7:4067-82

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