Immunotoxins:Is there a clinical value?

Gottstein, Claudia; Winkler, U.; Bohlen, Heribert; Diehl, Volker; Engert, Andreas

doi:10.1093/annonc/5.suppl_1.s97

Cited by 13 publications

(4 citation statements)

References 39 publications

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“…These characteristics ensure that only tumors get killed and normal tissues are spared. Saporin is a ribosomal inhibiting protein toxin and, although useful for research studies, has not proved itself for clinical application, due to its size and immunogenecity (28). Immunotoxins must not be immunogenic (as is often the case for protein toxins) and should retain the desired characteristics of the antibody (stability, affinity, selectivity, and function).…”

Section: Discussionmentioning

confidence: 99%

Targeting of the Receptor Protein Tyrosine Phosphatase β with a Monoclonal Antibody Delays Tumor Growth in a Glioblastoma Model

Foehr¹,

Lorente²,

Kuo³

et al. 2006

Cancer Research

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The receptor protein tyrosine phosphatase B (RPTPB) is a functional biomarker for several solid tumor types. RPTPB expression is largely restricted to the central nervous system and overexpressed primarily in astrocytic tumors. RPTPB is known to facilitate tumor cell adhesion and migration through interactions with extracellular matrix components and the growth factor pleiotrophin. Here, we show that RPTPB is expressed in a variety of solid tumor types with low expression in normal tissue. To assess RPTPB as a potential target for treatment of glioblastoma and other cancers, antibodies directed to RPTPB have been developed and profiled in vitro and in vivo. The recombinant extracellular domain of human short RPTPB was used to immunize mice and generate monoclonal antibodies that selectively recognize RPTPB and bind to the antigen with low nanomolar affinities. Moreover, these antibodies recognized the target on living tumor cells as measured by flow cytometry. These antibodies killed glioma cells in vitro when coupled to the cytotoxin saporin either directly or via a secondary antibody. Finally, in vivo studies showed that an anti-RPTPB immunotoxin (7E4B11-SAP) could significantly delay human U87 glioma tumors in a mouse xenograft model. Unconjugated 7E4B11 provides a modest but statistically significant tumor growth delay when delivered systemically in mice bearing U87 glioma tumors. (Cancer Res 2006; 66(4): 2271-8)

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Section: Discussionmentioning

confidence: 99%

Targeting of the Receptor Protein Tyrosine Phosphatase β with a Monoclonal Antibody Delays Tumor Growth in a Glioblastoma Model

Foehr¹,

Lorente²,

Kuo³

et al. 2006

Cancer Research

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“…PE contains a KDEL-like C-terminal sequence that can bind the KDEL-receptor in the Golgi that is proposed to carry PE out of the Golgi to the endoplasmic reticulum for efficient transport to the cytosol. A number of fusion proteins that contain PE domain III with a KDEL peptide linked to various ligands, including transforming growth factor a, EGF, Tfn, EGF-like domain of heregulins, IL-2, IL-4, IL-6, etc., have been studied (Pai and Pastan, 1993;Gottstein et al, 1994;Thrush et al, 1996). The cytotoxicity of all the fusion proteins are increased when the carboxyl terminus is attached with a KDEL.…”

Section: Others Introduction Of Kdel Peptidementioning

confidence: 99%

Enhancement of immunotoxin activity using chemical and biological reagents

1997

Br J Cancer

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Summary One of the major discoveries of effective therapeutics is the use of targeted treatment, such as antibody-directed toxins, i.e. immunotoxins; however, this medicine delivery strategy is still at a developmental stage. A number of problems need to be resolved; one is their inefficacy when applied in vivo. Research has stimulated interest in this area through the use of chemical reagents and other moieties to increase the activity of immunotoxins. In this article, reagents that can potentiate the cytotoxicity of immunotoxins are reviewed and the mechanisms that increase activity of immunotoxins are discussed. Lysosomotropic amines, especially ammonium chloride and chloroquine, may raise the pH value of the lysosome in which the conjugates enter. Carboxylic ionophores, e.g. monensin, can influence Golgi vacuolation, which may facilitate the routing of conjugates, augmenting activity. Calcium channel antagonists may increase immunotoxin killing through morphological or other mechanisms that are not yet well understood. Viral particles and surface structure can enhance the cytotoxicity of conjugates, probably through the mechanism of disrupting endosomes. In addition, cytokines, 3-adrenergic blockers, immunosuppressive agents (cyclosporin A) and some antibiotics (daunorubicin) can be used to increase the effect of immunotoxins.

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“…Preparing immunotoxins by chemical crosslinking of toxin and targeting components is still a compromise between high product stability in the blood circle and loss of function due to irreversible coupling (16,17). In some approaches with recombinant ricin, similar problems were observed which led to the hypothesis that intracellular release of the effector domain from the targeting domain is necessary to ensure toxin activity (18,19).…”

mentioning

confidence: 99%