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Special Issue "Immunotoxins"

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A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (28 February 2011)

Special Issue Editors

Guest Editor
Prof. Dr. John H. Sampson (Website)

Duke University Medical Center, Durham, N.C. 27710, USA
Fax: +1 919 684 9045
Guest Editor
Prof. Dr. Andrea Bolognesi

Department of Experimental Pathology, University of Bologna, Via San Giacomo, 14, I-40126 Bologna, Italy
Fax: +39 051 2094746

Special Issue Information

Dear Colleagues,

In recent years, bacterial and plant toxins have been leveraged for the elimination of unwanted cells by linkage to specific antibody carriers to form immunotoxins. These potent and specific cytotoxic agents provide a promising approach to human therapy. In this special issue, we will discuss their basic biology, some of the limitations of their use as therapeutic agents, and special considerations regarding their delivery.

Prof. Dr. John H. Sampson
Prof. Dr. Andrea Bolognesi
Guest Editors

Keywords

  • immunotoxins
  • drug targeting
  • drug delivery
  • antibody
  • bacterial toxins
  • plant toxins
  • recombinant chimeric proteins
  • immunotherapy
  • tumor therapy

Published Papers (7 papers)

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Research

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Open AccessArticle A Comparison of the Anti-Tumor Effects of a Chimeric versus Murine Anti-CD19 Immunotoxins on Human B Cell Lymphoma and Pre-B Acute Lymphoblastic Leukemia Cell Lines
Toxins 2011, 3(4), 409-419; doi:10.3390/toxins3040409
Received: 3 March 2011 / Revised: 30 March 2011 / Accepted: 30 March 2011 / Published: 6 April 2011
Cited by 3 | PDF Full-text (469 KB) | HTML Full-text | XML Full-text
Abstract
Precursor B cell acute lymphoblastic leukemia (pre-B ALL) affects five to six thousand adults and almost three thousand children every year. Approximately 25% of the children and 60% of the adults die from their disease, highlighting the need for new therapies that [...] Read more.
Precursor B cell acute lymphoblastic leukemia (pre-B ALL) affects five to six thousand adults and almost three thousand children every year. Approximately 25% of the children and 60% of the adults die from their disease, highlighting the need for new therapies that complement rather than overlap chemotherapy and bone marrow transplantation. Immunotherapy is a class of therapies where toxicities and mechanisms of action do not overlap with those of chemotherapy. Because CD19 is a B cell- restricted membrane antigen that is expressed on the majority of pre-B tumor cells, a CD19-based immunotherapy is being developed for ALL. In this study, the anti-tumor activities of immunotoxins (ITs) constructed by conjugating a murine monoclonal antibody (MAb), HD37, or its chimeric (c) construct to recombinant ricin toxin A chain (rRTA) were compared both in vitro using human pre-B ALL and Burkitt’s lymphoma cell lines and in vivo using a disseminated human pre-B ALL tumor cell xenograft model. The murine and chimeric HD37 IT constructs were equally cytotoxic to pre-B ALL and Burkitt’s lymphoma cells in vitro and their use in vivo resulted in equivalent increases in survival of SCID mice with human pre-B ALL tumors when compared with control mice. Full article
(This article belongs to the Special Issue Immunotoxins)

Review

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Open AccessReview Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components
Toxins 2011, 3(7), 848-883; doi:10.3390/toxins3070848
Received: 18 May 2011 / Revised: 2 July 2011 / Accepted: 6 July 2011 / Published: 14 July 2011
Cited by 31 | PDF Full-text (2024 KB) | HTML Full-text | XML Full-text
Abstract
Immunotoxins and antibody-drug conjugates are protein-based drugs combining a target-specific binding domain with a cytotoxic domain. Such compounds are potentially therapeutic against diseases including cancer, and several clinical trials have shown encouraging results. Although the targeted elimination of malignant cells is an [...] Read more.
Immunotoxins and antibody-drug conjugates are protein-based drugs combining a target-specific binding domain with a cytotoxic domain. Such compounds are potentially therapeutic against diseases including cancer, and several clinical trials have shown encouraging results. Although the targeted elimination of malignant cells is an elegant concept, there are numerous practical challenges that limit conjugates’ therapeutic use, including inefficient cellular uptake, low cytotoxicity, and off-target effects. During the preparation of immunoconjugates by chemical synthesis, the choice of the hinge component joining the two building blocks is of paramount importance: the conjugate must remain stable in vivo but must afford efficient release of the toxic moiety when the target is reached. Vast efforts have been made, and the present article reviews strategies employed in developing immunoconjugates, focusing on the evolution of chemical linkers. Full article
(This article belongs to the Special Issue Immunotoxins)
Open AccessReview Immunotoxins and Other Conjugates Containing Saporin-S6 for Cancer Therapy
Toxins 2011, 3(6), 697-720; doi:10.3390/toxins3060697
Received: 18 April 2011 / Revised: 27 May 2011 / Accepted: 3 June 2011 / Published: 22 June 2011
Cited by 22 | PDF Full-text (282 KB) | HTML Full-text | XML Full-text
Abstract
Ribosome-inactivating proteins (RIPs) are a family of plant toxins that permanently damage ribosomes and possibly other cellular substrates, thus causing cell death. RIPs are mostly divided in two types: Type 1 RIPs that are single-chain enzymatic proteins, and type 2 RIPs that [...] Read more.
Ribosome-inactivating proteins (RIPs) are a family of plant toxins that permanently damage ribosomes and possibly other cellular substrates, thus causing cell death. RIPs are mostly divided in two types: Type 1 RIPs that are single-chain enzymatic proteins, and type 2 RIPs that consist of an active A chain (similar to a type 1 RIP) linked to a B chain with lectin properties. RIP-containing conjugates have been used in many experimental strategies against cancer cells, often showing great efficacy in clinical trials. Saporin-S6, a type 1 RIP extracted from Saponaria officinalis L. seeds, has been extensively utilized to construct anti-cancer conjugates because of its high enzymatic activity, stability and resistance to conjugation procedures, resulting in the efficient killing of target cells. This review summarizes saporin-S6-containing conjugates and their application in cancer therapy, considering in-vitro and in-vivo studies both in animal models and in clinical trials. The review is structured on the basis of the targeting of hematological versus solid tumors and on the antigen recognized on the cell surface. Full article
(This article belongs to the Special Issue Immunotoxins)
Open AccessReview Use of Ribosome-Inactivating Proteins from Sambucus for the Construction of Immunotoxins and Conjugates for Cancer Therapy
Toxins 2011, 3(5), 420-441; doi:10.3390/toxins3050420
Received: 28 February 2011 / Revised: 2 April 2011 / Accepted: 25 April 2011 / Published: 29 April 2011
Cited by 28 | PDF Full-text (552 KB) | HTML Full-text | XML Full-text
Abstract
The type 2 ribosome-inactivating proteins (RIPs) isolated from some species belonging to the Sambucus genus, have the characteristic that although being even more active than ricin inhibiting protein synthesis in cell-free extracts, they lack the high toxicity of ricin and related type [...] Read more.
The type 2 ribosome-inactivating proteins (RIPs) isolated from some species belonging to the Sambucus genus, have the characteristic that although being even more active than ricin inhibiting protein synthesis in cell-free extracts, they lack the high toxicity of ricin and related type 2 RIPs to intact cells and animals. This is due to the fact that after internalization, they follow a different intracellular pathway that does not allow them to reach the cytosolic ribosomes. The lack of toxicity of type 2 RIPs from Sambucus make them good candidates as toxic moieties in the construction of immunotoxins and conjugates directed against specific targets. Up to now they have been conjugated with either transferrin or anti-CD105 to target either transferrin receptor- or endoglin-overexpressing cells, respectively. Full article
(This article belongs to the Special Issue Immunotoxins)
Open AccessReview The Use of Convection-Enhanced Delivery with Liposomal Toxins in Neurooncology
Toxins 2011, 3(4), 369-397; doi:10.3390/toxins3040369
Received: 28 February 2011 / Revised: 25 March 2011 / Accepted: 25 March 2011 / Published: 31 March 2011
Cited by 11 | PDF Full-text (663 KB) | HTML Full-text | XML Full-text
Abstract
Liposomes have long been effective delivery vehicles for transport of toxins to peripheral cancers. The combination of convection-enhanced delivery (CED) with liposomal toxins was originally proposed to circumvent the limited delivery of intravascular liposomes to the central nervous system (CNS) due to [...] Read more.
Liposomes have long been effective delivery vehicles for transport of toxins to peripheral cancers. The combination of convection-enhanced delivery (CED) with liposomal toxins was originally proposed to circumvent the limited delivery of intravascular liposomes to the central nervous system (CNS) due to the blood-brain-barrier (BBB). CED offers markedly improved distribution of infused therapeutics within the CNS compared to direct injection or via drug eluting polymers, both of which depend on diffusion for parenchymal distribution. This review examines the basis for improved delivery of liposomal toxins via CED within the CNS, and discusses preclinical and clinical experience with these therapeutic techniques. How CED and liposomal technologies may influence future neurooncologic treatments are also considered. Full article
(This article belongs to the Special Issue Immunotoxins)
Open AccessReview Monitoring Radiographic Brain Tumor Progression
Toxins 2011, 3(3), 191-200; doi:10.3390/toxins3030191
Received: 31 January 2011 / Revised: 3 February 2011 / Accepted: 11 March 2011 / Published: 15 March 2011
Cited by 12 | PDF Full-text (190 KB) | HTML Full-text | XML Full-text
Abstract
Determining radiographic progression in primary malignant brain tumors has posed a significant challenge to the neuroncology community. Glioblastoma multiforme (GBM, WHO Grade IV) through its inherent heterogeneous enhancement, growth patterns, and irregular nature has been difficult to assess for progression. Our ability [...] Read more.
Determining radiographic progression in primary malignant brain tumors has posed a significant challenge to the neuroncology community. Glioblastoma multiforme (GBM, WHO Grade IV) through its inherent heterogeneous enhancement, growth patterns, and irregular nature has been difficult to assess for progression. Our ability to detect tumor progression radiographically remains inadequate. Despite the advanced imaging techniques, detecting tumor progression continues to be a clinical challenge. Here we review the different criteria used to detect tumor progression, and highlight the inherent challenges with detection of progression. Full article
(This article belongs to the Special Issue Immunotoxins)
Open AccessReview Imaging of Convection Enhanced Delivery of Toxins in Humans
Toxins 2011, 3(3), 201-206; doi:10.3390/toxins3030201
Received: 17 January 2011 / Revised: 14 February 2011 / Accepted: 22 February 2011 / Published: 15 March 2011
Cited by 8 | PDF Full-text (140 KB) | HTML Full-text | XML Full-text
Abstract
Drug delivery of immunotoxins to brain tumors circumventing the blood brain barrier is a significant challenge. Convection-enhanced delivery (CED) circumvents the blood brain barrier through direct intracerebral application using a hydrostatic pressure gradient to percolate therapeutic compounds throughout the interstitial spaces of [...] Read more.
Drug delivery of immunotoxins to brain tumors circumventing the blood brain barrier is a significant challenge. Convection-enhanced delivery (CED) circumvents the blood brain barrier through direct intracerebral application using a hydrostatic pressure gradient to percolate therapeutic compounds throughout the interstitial spaces of infiltrated brain and tumors. The efficacy of CED is determined through the distribution of the therapeutic agent to the targeted region. The vast majority of patients fail to receive a significant amount of coverage of the area at risk for tumor recurrence. Understanding this challenge, it is surprising that so little work has been done to monitor the delivery of therapeutic agents using this novel approach. Here we present a review of imaging in convection enhanced delivery monitoring of toxins in humans, and discuss future challenges in the field. Full article
(This article belongs to the Special Issue Immunotoxins)

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