Immunotoxins - Biotech, Pharma and Life Science Channel

00:24 EDT 5th July 2015 | BioPortfolio

Immunotoxins are proteins that contain a toxin along with an antibody or growth factor that binds specifically to target cells. Nearly all protein toxins work by enzymatically inhibiting protein synthesis. For the immunotoxin to work, it must bind to and be internalized by the target cells, and the enzymatic fragment of the toxin must translocate to the cytosol. Once in the cytosol, 1 molecule is capable of killing a cell, making immunotoxins some of the most potent killing agents

Immunotoxin therapy is a promising molecular cancer treatment strategy. Its main advantage is seletive cytotoxicity towards tumor cells and minimal toxicity in normal tissues. At present ten immunotoxins are in phase II or higher stages of clinical development and eight projects in early clinical evaluation. At present, only 1 agent, which contains human interleukin-2 and truncated diphtheria toxin, is approved for use in cutaneous T-cell lymphoma. Another, containing an anti-CD22 Fv and truncated Pseudomonas exotoxin, has induced complete remissions in a high proportion of cases of hairy-cell leukemia. Refinement of existing immunotoxins and development of new immunotoxins are underway to improve the treatment of cancer.

Hematologic malignancies are optimal for treating with immunotoxins, since malignant cells are often intravascular and accessible to intravenously administered drug, and since patients often lack sufficient immunity to make antibodies against the toxin. Targeting solid tumors with immunotoxins is much more difficult than targeting hematologic tumors. The challenges associated with the development of many immunotoxins for cancer therapy include immunogenicity, unwanted toxicity, difficulty in production, limited half-life, and resistance.

In the past 3 to 4 decades, a wide variety of immunotoxins have been tested against a wide variety of malignancies in cell culture, in animal models, and in patients. The most useful of these agents appear to be the relatively small recombinant fusion toxins that contain either growth factor or Fv fragments as ligands. The most sensitive diseases appear to be hematologic malignancies. Future development will need to address combinations of immunotoxins with other anticancer therapies in order to overcome problems of tumor penetration, toxicity, and immunogenicity.

Source; Kreitman RJ. Immunotoxins for Targeted Cancer Therapy. AAPS Journal. 2006; 8(3): E532-E551.

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Clinical Trials [14 Associated Clinical Trials listed on BioPortfolio]

Collection of Human Samples to Study Hairy Cell and Other Leukemias, and to Develop Recombinant Immunotoxins for Cancer Treatment

Background: - Researchers who are studying hairy cell leukemia, and how the disease compares with other disorders, are interested in obtaining additional samples from leukemia patients an...

Multi-Tracer PET in Early Phase Trials

The treatment of cancer is increasingly aimed at molecular targets derived from studies of the oncogenes and tumor suppressors known to be involved in the development of human cancers. The...

Immunotoxin in Treating Patients With Leukemia or Lymphoma

RATIONALE: Immunotoxins can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. PURPOSE: Phase I trial to study the effecti...

Denileukin Diftitox in Treating Patients With Non-Hodgkin's Lymphoma

RATIONALE: Immunotoxins such as denileukin diftitox can locate cancer cells and kill them without harming normal cells. This may be an effective treatment for non-Hodgkin's lymphoma. PURP...

Immunotoxin Therapy in Treating Patients With Malignant Glioma

RATIONALE: Immunotoxins can locate tumor cells and kill them without harming normal cells. This may be an effective treatment for malignant glioma. PURPOSE: Phase I/II trial to study the ...

Immunotoxin Therapy in Treating Children With Progressive or Recurrent Glioblastoma Multiforme or Anaplastic Astrocytoma

RATIONALE: Immunotoxins can locate tumor cells and kill them without harming normal cells. Immunotoxin therapy may be an effective treatment for glioblastoma multiforme and anaplastic astr...

Immunotoxin Therapy in Treating Patients With Advanced Solid Tumors

RATIONALE: Immunotoxins can locate tumor cells and kill them without harming normal cells. Immunotoxin therapy may be effective in treating advanced solid tumors. PURPOSE: This phase I tr...

Safety and Efficacy Study to Treat Recurrent Grade 4 Malignant Brain Tumors

Immunotoxins can locate tumor cells and kill them without harming normal cells. Immunotoxin therapy may be effective in treating malignant glioma.

Anti-CD19 and Anti-CD22 Immunotoxins in Treating Patients With Refractory or Relapsed B-Cell Acute Lymphoblastic Leukemia

RATIONALE: Immunotoxins, such as anti-CD19 and anti-CD22, can find cancer cells that express CD19 and CD22 and kill them without harming normal cells. This may be an effective treatment fo...

Immunotoxin Therapy, Paclitaxel, Carboplatin, and Bevacizumab in Treating Patients With Advanced Non-Small Cell Lung Cancer

RATIONALE: Immunotoxins can find certain tumor cells and kill them without harming normal cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to s...

PubMed Articles [9 Associated PubMed Articles listed on BioPortfolio]

Immunotoxin therapy for hematologic malignancies: where are we heading?

The identification of numerous unique targets in recent years has led to the development of various immunotoxins (ITs) for treating hematological malignancies. Some of these ITs have advanced to clini...

Methylation-Associated Partial Down-Regulation of Mesothelin Causes Resistance to Anti-Mesothelin Immunotoxins in a Pancreatic Cancer Cell Line.

Anti-mesothelin Pseudomonas exotoxin A-based recombinant immunotoxins (RITs) present a potential treatment modality for pancreatic ductal adenocarcinoma (PDAC). To study mechanisms of resistance, the ...

Design and evaluation of a peptide-based immunotoxin for breast cancer therapeutics.

Immunotoxins are chimeric proteins comprising a specific cellular targeting domain linked to a cytotoxic factor. Here we describe the design and use of a novel, peptide-based immunotoxin that can init...

Angiogenin Mutants as Novel Effector Molecules For the Generation of Fusion Proteins With Increased Cytotoxic Potential.

Human cytolytic fusion proteins (hCFPs) are therapeutically efficacious recombinant polypeptides comprising a target cell-specific binding component and a human effector domain that induces apoptosis....

Functional Characterization of Sticholysin I and W111C Mutant Reveals the Sequence of the Actinoporin's Pore Assembly.

The use of pore-forming toxins in the construction of immunotoxins against tumour cells is an alternative for cancer therapy. In this protein family one of the most potent toxins are the actinoporins,...

Triterpenoid saponin augmention of saporin-based immunotoxin cytotoxicity for human leukaemia and lymphoma cells is partially immunospecific and target molecule dependent.

Abstract Context: Saponinum album (SA) is a complex mixture of triterpenoid saponins previously shown to augment the cytotoxicity of the type I ribosome-inactivating protein saporin and an EGF-saporin...

Effect of Antigen Shedding on Targeted Delivery of Immunotoxins in Solid Tumors from a Mathematical Model.

Most cancer-specific antigens used as targets of antibody-drug conjugates and immunotoxins are shed from the cell surface (Zhang & Pastan (2008) Clin. Cancer Res. 14: 7981-7986), although at widely va...

Pokeweed Antiviral Protein, a Ribosome Inactivating Protein: Activity, Inhibition and Prospects.

Viruses employ an array of elaborate strategies to overcome plant defense mechanisms and must adapt to the requirements of the host translational systems. Pokeweed antiviral protein (PAP) from Phytola...

Systematic comparison of single-chain Fv antibody-fusion toxin constructs containing Pseudomonas Exotoxin A or saporin produced in different microbial expression systems.

Antibodies raised against selected antigens over-expressed at the cell surface of malignant cells have been chemically conjugated to protein toxin domains to obtain immunotoxins (ITs) able to selectiv...

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Medical and Biotech [MESH] Definitions

Semisynthetic conjugates of various toxic molecules, including RADIOACTIVE ISOTOPES and bacterial or plant toxins, with specific immune substances such as IMMUNOGLOBULINS; MONOCLONAL ANTIBODIES; and ANTIGENS. The antitumor or antiviral immune substance carries the toxin to the tumor or infected cell where the toxin exerts its poisonous effect.

Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (IMMUNOTOXINS) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (see RADIOTHERAPY).


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