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Protein Toxins: Intracellular Trafficking for Targeted Therapy

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Protein Toxins: Intracellular Trafficking for Targeted Therapy Gene Therapy (2005) 12, 1360–1368 & 2005 Nature Publishing Group All rights reserved 0969-7128/05 $30.00 www.nature.com/gt REVIEW Protein toxins: intracellular trafficking for targeted therapy L Johannes1 and D Decaudin2 1Laboratoire ‘Trafic et Signalisation’, UMR144 Curie/CNRS, Institut Curie, Paris, France; and 2Service d’He´matologie Clinique, Institut Curie, Paris, France The immunotoxin approach is based on the use of tumor- roles are inverted: nontoxic receptor-binding toxin moieties targeting ligands or antibodies that are linked to the catalytic are used for the targeting of therapeutic and diagnostic (toxic) moieties of bacterial or plant protein toxins. In this compounds to cancer or immune cells. The cell biological review, we first discuss the current state of clinical develop- basis of these novel types of toxin-based therapeutics will ment of immunotoxin approaches describing the results be discussed, and we will summarize ongoing preclinical and obtained with the two toxins most frequently used: diphtheria clinical testing. and Pseudomonas toxin-derived proteins. In the second part Gene Therapy (2005) 12, 1360–1368. doi:10.1038/ of the review, a novel concept will be presented in which the sj.gt.3302557; published online 19 May 2005 Keywords: immunotoxin; Shiga toxin B-subunit; retrograde transport; immunotherapy; tumor targeting Introduction proteins, and we will indicate their limitations. In the second part of the review, a novel concept will be Management of unresectable or metastatic tumors is presented in which the roles are inverted: nontoxic based on the cytotoxic effect of radiotherapy and/or receptor-binding toxin moieties are used for the targeting chemotherapy. Numerous toxin-based therapies have of diagnostic and therapeutic compounds to cancer cells been developed in this field for their potent cell-killing or immune cells. This approach exploits many of the activity. However, because of the nonspecific effects of characteristics that receptor-binding toxin moieties have toxins on normal and tumor cells, targeting of cancer acquired throughout evolution, such as stability, capacity cells generally remains a prerequisite for such therapeu- to cross tissue barriers, and their unique intracellular tic applications. Targeting of toxins to cancer cells has distribution pathways. The cell biological basis of these used a variety of modalities, namely (1) a direct novel types of toxin-based therapeutics will be dis- interaction between the toxin and its natural receptor cussed, with a presentation of ongoing preclinical and expressed on tumor cells; (2) vectorization of the toxin by clinical testing. a natural ligand or a monoclonal antibody that specifi- cally recognizes cancer cells that express their natural receptors; and (3) gene therapy allowing cellular pene- tration of a viral vector expressing the toxin. In addition Recombinant immunotoxins to these direct cancer cell cytotoxic approaches, a few publications have reported anticancer immune activation To be used in clinical practice for cancer therapy, toxins via T-lymphocytes, natural killer cells, or dendritic cells must meet a number of stringent criteria: (1) the toxin with tumor-directed targeting by toxin compounds. must possess a very high inherent toxicity, in the low nanomolar range,1 because expression of the targeted The most developed class of targeted cytotoxic 5 treatments is constituted by immunotoxins. The immuno- receptors is usually less than 10 molecules per cell. For toxin approach is based on the use of tumor targeting example, one molecule of diphtheria toxin (DT), which is one of the two toxins most often used for cancer ligands or antibodies that are linked to the catalytic 2 moieties of bacterial or plant protein toxins. The targeted therapeutics, is sufficient to kill a cell; (2) the toxin toxin induces apoptosis by reaching the cytosol and compound, which includes the ligand of the target inactivating vital cell processes or by modifying the receptor, the toxin and, in most cases, a linker, should tumor cell surface membrane. In this review, we will preserve the main characteristics of the toxin; (3) delivery first discuss the current state of clinical development of of the toxin compound requires internalization of the immunotoxin approaches, focusing on clinical trials toxin after binding to the surface of cancer cells, as using diphtheria and Pseudomonas exotoxin (PE)-derived internalization leads to the apoptotic effect. Indeed, unlike radioisotope immunoconjugates, most toxins only kill cells once they are inside the cytosol;3 (4) the toxin Correspondence: Dr L Johannes, Laboratoire ‘Trafic et Signalisation’ UMR144 Curie/CNRS, Institut Curie, 26 rue d’Ulm, F-75248 Paris must be able to survive proteolytic processing and the Cedex 05, France acidic environment of lysosomes. Intracellular trafficking Published online 19 May 2005 of the toxin therefore appears to be a checkpoint for the Intracellular trafficking for targeted therapy L Johannes and D Decaudin 1361 4 desired cytotoxic effect; and (5) in most, but not all, A phase I trial of a ligand fusion-protein DAB389IL-2 situations, the toxin must be delivered from its targeting was performed in 73 patients with lymphoma expressing compound to be in an active form.1 the interleukin-2 receptor (35 cutaneous T-cell lympho- There are three classes of immunotoxins: class I toxins, mas (CTCL), 17 non-Hodgkin’s lymphomas (NHL), and mainly used for hematologic malignancies, are intra- 21 Hodgkin’s disease).9 Most side effects consisted of cellular enzymes blocking cytosolic protein synthesis flu-like symptoms (fever/chills, nausea/vomiting, and either by modifying elongation factor 2 (DT and PE) myalgias/arthralgias), acute infusion-related events or ribosomal RNA (ricin, gelonin, saporin, etc), or by (hypotension, dyspnea, chest pain, and back pain), and degrading total RNA (angiogenin, ribonuclease);4 class a vascular leak syndrome (hypotension, hypoalbumine- II toxins such as the Fab fragment of the antiCD25 mia, edema). Titers of DT antibodies were 38% at monoclonal antibody fused to phospholipase C5 bind to baseline and reached 92% after two courses. Five the cell surface and trigger intracellular signaling path- complete responses and eight partial responses were ways; class III toxins are pore-forming peptides leading obtained (ORR 18%) with durations of response ranging to leaks in the plasma membrane; these include mellitin,6 between 2 and 39 months. The presence of antibody did the plant Pyrularia thionin peptide,7 and the cobra venom not preclude clinical responses. Various phase II trials cationic 63 amino-acid membrane lytic peptide toxin.8 were subsequently performed, showing an overall Various toxins have been used, but the two bacterial response rate of 30% in CTCL (10% of complete toxins most frequently exploited for cancer treatments responses),10 11% in fludarabine-refractory chronic lym- are DT and PE. Numerous targets have been used to phocytic leukemia with no complete responses,11 and accumulate immunotoxins on cancer cells, namely 24% in B-cell NHL, including 7% of complete res- cluster designation differentiation antigens, cytokine ponses.12 A phase I trial with DT/GMCSF fusion protein receptors (interleukin-2 receptor, IL-3R, IL-4R, IL-6R, (DT388GMCSF) on 31 patients with refractory or relapsed IL-7R, IL-9R, IL-13R, IL-15R, granulocyte–macrophage acute myeloid leukemia13 also revealed dose-related colony-stimulating factor receptor (GM-CSFR), granulo- toxicity such as liver injury observed in two out of eight cyte colony-stimulating factor receptor (G-CSFR), trans- cases receiving 4.5–5 mg/kg/day. Other toxicities were ferrin receptor, and urokinase receptor), and a hetero- mild, namely fever, chills, hypoxemia, and transient geneous group of cell membrane receptors (human postinfusion hypotension. After 15–60 days of treatment, leukocyte antigen-DR, immunoglobulin idiotype, IgMFc, 21 of 25 patients that could be evaluated had a significant etc).4 Clinical trials performed with DT- and PE-derived increase of antibody titers. Only three clinical responses proteins will be presented. were obtained (10%) with only one complete response. DT-derived proteins PE-derived proteins A very large number of DT fusion proteins have been As for DT, various ligands have been fused to PE, mainly developed and tested in preclinical models: (1) DT/GM- IL-4, IL-13, and EGF, and tested in various tumor cell CSF fusion protein (DT388GMCSF) for acute myeloid lines or xenografted tumors expressing the correspond- leukemia; (2) DT/IL2 fusion protein (Denileukin Difti- ing receptors. In contrast, various heterogeneous clinical tox) for lymphoid malignancies; (3) DT/IL3 for acute trials have been performed with PE-derived protein, as myeloid leukemia and glioblastoma multiforme; (4) DT/ shown in Table 1. In malignant gliomas, targeted toxin IL4 for acute myeloid leukemia; (5) DT/epidermal was directly delivered to tumors using stereotactic growth factor (EGF) for acute myeloid leukemia, catheters.14–16 In these four studies, neurological toxicity glioblastoma multiforme, and pancreatic cancers; (6) was observed with increases of intracranial pressure DT/vascular endothelial growth factor with an antian- most probably related to infusion volume, recurrent giogenic effect for the treatment of breast and pancreatic tumor, or stereotactic catheter placement; a few cases of carcinomas; (7) DT/alpha-fetoprotein for hepatoblasto- fatigue and emesis were also described. The most ma; (8)
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