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Targeting growth factor receptors with fusion toxins
R J Kreitman1, D FitzGerald, I Pastan
1Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Abstract:
Recombinant toxins which bind to growth factor receptors have been prepared and used to kill cells responsible for malignant or autoimmune disease. Our strategy has been to genetically fuse ligands to different forms of Pseudomonas exotoxin which due to mutations or deletions do not bind to normal cells. The resulting recombinant chimeric toxins, in concentrations often less than 1 ng/ml, selectively kill cells expressing the appropriate growth factor receptor. The ligand may be a growth factor, such as transforming growth factor alpha (TGF alpha), interleukin 6 (IL6) or interleukin 2 (IL2), or single chain antigen binding proteins, such as the variable heavy and light regions of the monoclonal antibody anti-Tac. These chimeric toxins kill not only established cell lines but also fresh tumor cells from patients and display anti-tumor activity toward human malignant tumors in nude mice. While clinical trials are beginning with some of these agents, work continues to improve the effectiveness of recombinant chimeric toxins, and to widen the scope of disorders which might be treated by this approach.
Insights
Engineered toxins target and eliminate malignant and autoimmune disease cells. These recombinant chimeric toxins selectively kill cells expressing specific growth factor receptors, showing promise in preclinical studies.
Area of Science:
- Biotechnology
- Molecular Biology
- Immunology
Background:
- Cancer and autoimmune diseases involve specific cell populations.
- Targeted therapies aim to eliminate diseased cells while sparing healthy ones.
- Growth factor receptors are often overexpressed on malignant or activated immune cells.
Purpose of the Study:
- To develop novel recombinant chimeric toxins for targeted cell ablation.
- To investigate the selective killing of cells expressing specific growth factor receptors.
- To evaluate the therapeutic potential of these toxins against malignant and autoimmune diseases.
Main Methods:
- Genetically fusing ligands (growth factors or antibody fragments) to modified Pseudomonas exotoxin.
- Utilizing Pseudomonas exotoxin variants with mutations/deletions to prevent normal cell binding.
- Testing the efficacy of recombinant chimeric toxins on cell lines, primary tumor cells, and in vivo models.
Main Results:
- Recombinant chimeric toxins selectively killed cells expressing target growth factor receptors at low concentrations (ng/ml).
- Toxins demonstrated efficacy against established cell lines and fresh patient tumor cells.
- Significant anti-tumor activity was observed in human malignant tumors xenografted into nude mice.
Conclusions:
- Recombinant chimeric toxins represent a promising targeted therapy for malignant and autoimmune diseases.
- These agents exhibit potent and selective cell-killing activity.
- Ongoing research aims to enhance toxin effectiveness and broaden therapeutic applications, with clinical trials commencing.