Clinical Applications of Immunotoxins (Current Topics in Microbiology and Immunology, 234)

1 2 D. FITZGERALDI, I. PASTAN , and J. ROBERTUS Introduction . . . . . . . . . . . . . I 2 Toxin Structure-Function Properties 2 2. 1 Functions. . . . . . . . . . . . . . . . . . . . . . . . 2 2. 2 Binding. . . . . . . . . . . . . . . . . . . . . . . . . 3 3 Intracellular Processing - Cleavage and Reduction . . . . . . 4 3. 1 Cytosolic Activity . . . . . . . . . . . . . . . . 5 4 Immunotoxin Design and Testing. 6 5 Conclusion. . 8 References. . . . . 8 1 Introduction While various treatment approaches for cancer include reversal of the transformed phenotype, stimulation of immune responses, inhibition of metastatic spread and deprivation of key nutrients, the goal of immunotoxin treatment is the direct killing of malignant cells. Because they are enzymatic proteins that act catalytically to kill cells, bacterial and plant toxins are often employed as the cell-killing component of immunotoxins. Here we provide background information into the structure-func­ tion relationships of toxins and discuss how they can be combined with cell-binding antibodies or other ligands to generate immunotoxins. Bacterial and plant toxins (e. g. , diphtheria toxin, Pseudomonas exotoxin and ricin) are among the most toxic substances known. However, because they bind to cell surface receptors that are present on most normal cells, unmodified toxins are generally useless as anti-cancer agents. To convert toxins into more selective agents, their binding domains are either eliminated or disabled and replaceq with cell­ binding antibodies that are tumor-selective. Front Matter....Pages i-ix Introduction....Pages 1-11 The Emerging Role of Ricin A-Chain Immunotoxins in Leukemia and Lymphoma....Pages 13-33 Clinical Trials with Blocked Ricin Immunotoxins....Pages 35-56 Saporin Immunotoxins....Pages 57-61 Diphtheria Toxin Fusion Proteins....Pages 63-81 Clinical Trials with Pseudomonas Exotoxin Immunotoxins....Pages 83-96 Immunotoxins for Brain Tumor Therapy....Pages 97-114 Conclusions....Pages 115-120 Back Matter....Pages 121-124 While over twenty clinical trials of targeted toxins have been conducted since 1980, a volume dedicated to a complete review of the efficacy, toxicity, and pharmacology of these agents in the clinical setting has not been published. This book fulfills the need for a reference source for review of previous results and methods of analogs for scientists designing these molecules and clinicians testing these agents on patients.