Immunotoxins are hybrid proteins consisting of cell selective peptide ligands linked covalently to polypeptide toxins. Information on the three- dimensional atomic structure of both ligands including cytokines and antibody fragments and toxins including ricin toxin, diphtheria toxin, Pseudomonas exotoxin and type I ribosome-inactivating proteins can be used to better design both chemical conjugates and genetically engineered fusion proteins. In addition, the binding of ligands to their receptors and their pathways of internalization should be compared with binding, internalization pathways and mechanisms of translocation of the peptide toxins. Such comparisons can be used to choose the optimal combination of ligand domains and toxin domains for maximal efficacy. Limited knowledge is available on the in vivo and clinical pharamacology of immunotoxins. Evaluation of different animal models both for toxicities, efficacy and pharmacodynamics including tumor penetration is needed so that information from preclinical studies can be used to predict clinical pharmacologic barriers and solutions. Review of the activity of immunotoxins in different disease states and stages may define particular types of diseases or stages of diseases most likely to benefit from immunotoxin therapy. To achieve these objectives, investigators from a variety of disciplines must be assembled including protein crystallographers, protein NMR structural biologists, molecular biologists, cell biologists, protein chemists, pharmacologists, clinicians, and statisticians. Three days of meetings are planned with the first day devoted to structure-function aspects of the molecules and new immunotoxin designs. The second day is devoted to preclinical pharmacology. The third day will be a detailed review of the clinical trials with immunotoxins. Both sessions and workshops will be devoted to delineating experiments to address eight specific aims: (l) Determine the internalization pathways for different toxins, (2) Determine how toxins translocate to the cytosol, (3) Define the therapeutic index of immunotoxins or immunotoxins combined with other modalities in animal models of human malignancy, autoimmune disorders and vascular diseases, 4) Develop in vitro and animal models of immunotoxin toxicities including vascular leak syndrome, (5) Measure immunotoxin penetration into tumors and clarify the pharmacologic barriers to in vivo tumor cell saturation, (6) Specific methods to tolerize animals and patients to immunotoxins,(7) Characterize mechanisms of cell resistance to immunotoxins, (8) Report clinical conditions which have the highest clinical response rates for individual immunotoxins.
| Frankel, A E; FitzGerald, D; Siegall, C et al. (1996) Advances in immunotoxin biology and therapy: a summary of the Fourth International Symposium on Immunotoxins. Cancer Res 56:926-32 |
