Abstract

Monoclonal antibodies selectively bind tumor cell differentiation antigens in vitro and in vivo. Since natural effector mechanisms often do not mediate killing of monoclonal antibody bound cells we have devised methods of linking extremely toxic proteins to the antibodies to selectively kill tumor cells. We have succeeded in developing several new approaches to apply immunotoxins in vivo. (1) Cloning toxins, then altering their structure at the gene level to decrease non target cell toxicity; (2) preparation of genetically engineered immunotoxins for clinical trials of human brain tumor patients; (3) prevention of an immune response against immunotoxin with anti-CD4 antibodies; (4) use of human cytotoxic proteins such as RNase linked to antibodies to selectively target cells; and (5) understanding the mechanism of human RNase neurotoxins; 6) Discovering that RNases block HIV infection in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002674-12
Application #
2579557
Study Section
Special Emphasis Panel (SNB)
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
1996
Total Cost
Indirect Cost

  Institution

Name
National Institute of Neurological Disorders and Stroke
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Antignani, Antonella; Youle, Richard J (2007) The cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), can deliver Bcl-XL as an extracellular fusion protein to protect cells from apoptosis and retain differentiation induction. J Biol Chem 282:11246-54
Youle, Richard J (2007) Cell biology. Cellular demolition and the rules of engagement. Science 315:776-7
Antignani, Antonella; Youle, Richard J (2005) A chimeric protein induces tumor cell apoptosis by delivering the human Bcl-2 family BH3-only protein Bad. Biochemistry 44:4074-82
Christiansen, Stephen P; Peterson, Daniel; To, Thu et al. (2002) Long-term effects of ricin-mAb 35 on extraocular muscles of rabbits: potential treatment for strabismus. Invest Ophthalmol Vis Sci 43:679-85
Ichinose, Makoto; Liu, Xiu-Huai; Hagihara, Naoshi et al. (2002) Extracellular Bad fused to toxin transport domains induces apoptosis. Cancer Res 62:1433-8
Nechushtan, A; Smith, C L; Lamensdorf, I et al. (2001) Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J Cell Biol 153:1265-76
Leonidas, D D; Boix, E; Prill, R et al. (2001) Mapping the ribonucleolytic active site of eosinophil-derived neurotoxin (EDN). High resolution crystal structures of EDN complexes with adenylic nucleotide inhibitors. J Biol Chem 276:15009-17
Liu, X H; Collier, R J; Youle, R J (2001) Inhibition of axotomy-induced neuronal apoptosis by extracellular delivery of a Bcl-XL fusion protein. J Biol Chem 276:46326-32
Richter, B W; Mir, S S; Eiben, L J et al. (2001) Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family. Mol Cell Biol 21:4292-301
Frank, S; Gaume, B; Bergmann-Leitner, E S et al. (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1:515-25

Showing the most recent 10 out of 20 publications