Expression of HER2 in Human Gastric Cancer Cells Directly Correlates with Antitumor Activity of a Recombinant Disulfide-Stabilized Anti-HER2 Immunotoxin

Shinohara, Hisashi; Morita, Shinsho; Kawai, Masaru; Miyamoto, Akiko; Sonoda, Toyooki; Pastan, Ira; Tanigawa, Nobuhiko

doi:10.1006/jsre.2001.6305

Cited by 29 publications

(22 citation statements)

References 15 publications

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“…Multiple conjugates of antibodies and chemotherapeutic agents (immunoconjugates) have a proven ability to inhibit growth of a host of xenografted tumors. Some examples of targeted TAAs are Her-2/neu (13,14), prostate stem cell antigen (15), mucine type glycoproteins (16), epidermal growth factor receptor (17), carcinoembryonic antigen (18), CD22 (19), and Lewis y (Le y ; 20). To achieve a cytotoxic effect, antibodies against these surface antigens were conjugated to pseudomonas exotoxin (14), maytansin (15,16), calicheamicin (19), Rnase (17), Vinca alkaloids (18), or doxorubicin (20).…”

Section: Introductionmentioning

confidence: 99%

Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193- N -Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts

Boghaert¹,

Sridharan²,

Armellino³

et al. 2004

Clinical Cancer Research

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Section: Introductionmentioning

confidence: 99%

Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193- N -Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts

Boghaert¹,

Sridharan²,

Armellino³

et al. 2004

Clinical Cancer Research

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“…Previous studies have shown the potent in vitro and in vivo xenograft efficacy of immunotoxins containing murine scFv e23 (12,13). However, in cancer patients, i.v.…”

Section: Discussionmentioning

confidence: 99%

“…To enhance its clinical potential, cell-surface Her2/ neu has been targeted using antibody-drug conjugates (9) or immunotoxins, composed of plant or bacterial toxins linked with a targeting molecule composed of monoclonal antibodies or antibody fragments (10,11). Previously, a recombinant, murine antiHer2/neu single-chain antibody (scFv), designated e23, has been fused to catalytic toxins such as Pseudomonas exotoxin A and diphtheria toxin (DT) to specifically target Her2/neu-expressing cells (12,13). A major drawback of such proteins is their potential for immune response after repeated administration.…”

Section: Introductionmentioning

confidence: 99%

Construction and Characterization of Novel, Recombinant Immunotoxins Targeting the Her2/neu Oncogene Product: In vitro and In vivo Studies

Cao

Marks

et al. 2009

Cancer Research

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The goal of this study was to characterize a series of antiHer2/neu immunotoxin constructs to identify how different antibodies and linker choices affect the specificity and cytotoxicity of these proteins. We constructed a series of immunotoxins containing either the human single-chain antibody (scFv) C6.5 or the murine scFv e23 fused to the highly toxic recombinant gelonin (rGel) molecule. Based on the flexible GGGGS linker (L), the fusion construct C6.5-L-rGel was compared with e23-L-rGel to evaluate the specific cytotoxic effects against Her2/neu-positive and Her2/neu-negative tumor cells. Both constructs retained the specificity of the original antibody as well as the biological activity of rGel toxin. The two constructs displayed similar cytotoxicity against different carcinoma cells. We additionally introduced the modified linkers TRHRQPRGWEQL (Fpe) and AGNRVRRSVG (Fdt), which contained furin cleavage sites, to determine the effect of these design changes on stability and cell killing efficiency. The introduction of furin cleavage linkers (Fpe or Fdt) into the molecules resulted in dissimilar sensitivity to protease cleavage compared with the constructs containing the L linker, but very similar intracellular rGel release, cytotoxic kinetics, and induction of autophagic cell death in vitro. Xenograft studies with SKOV3 ovarian tumors were done using various C6.5/rGel constructs. C6.5-L-rGel was more efficient in tumor inhibition than constructs containing furin linkers, attributing to a higher stability in vivo of the L version. Therefore, our studies suggest that human C6.5-L-rGel may be an effective novel clinical agent for therapy of patients with Her2/neuoverexpressing malignancies. [Cancer Res 2009;69(23):8987-95]

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“…Over the last decade, the protein has been engineered to minimize its size while retaining its potency at ADP ribosylation of elongation factor 2, which arrests protein synthesis (17,18). To efficiently enter cells it requires a targeting moiety and then can translocate to the cytosol where it exerts its cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…To efficiently enter cells it requires a targeting moiety and then can translocate to the cytosol where it exerts its cytotoxicity. PE38 has been fused to several ligands such as the Fv portion of erb B2 antibodies (18) and cytokines, including interleukin 4 (13) and interleukin 13 (19). PE38 has also been fused to the EGFR ligand TGF-␣ (14), enabling its use in the treatment of tumors expressing high levels of EGFR.…”

Section: Discussionmentioning

confidence: 99%

Abrogation of Head and Neck Squamous Cell Carcinoma Growth by Epidermal Growth Factor Receptor Ligand Fused to Pseudomonas Exotoxin Transforming Growth Factor α-PE38

Thomas

Zeng

Epperly

et al. 2004

Clinical Cancer Research

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Purpose: This study was undertaken to determine whether low intratumoral doses of the epidermal growth factor receptor ligand-transforming growth factor ␣ (TGF-␣) fused to Pseudomonas exotoxin (TGF-␣-PE38)-abrogated head and neck squamous cell carcinoma (HNSCC) tumor growth in vitro and in vivo.Experimental Design: In vitro cytotoxicity assays were carried out to determine the sensitivity of HNSCC cells to TGF-␣-PE38. TGF-␣-PE38-treated HNSCC cells were examined by immunoblotting for cleaved poly(ADP-ribose) polymerase to evaluate apoptosis. Nude mice bearing established HNSCC xenografts were treated with several doses of TGF-␣-PE38 to evaluate the antitumor efficacy in vivo. Tumor sections were stained with terminal deoxynucleotidyl transferase-mediated nick end labeling for apoptosis. To determine the effect of oral administration of TGF-␣-PE38, gavage injections of TGF-␣-PE38 were administered, and the esophagus and surrounding soft tissue were then stained for apoptotic cells.Results: HNSCC cell lines examined were sensitive to low doses of TGF-␣-PE38 (EC 50 in the range of 1.6 to 10 ng/mL). HNSCC cells treated with TGF-␣-PE38 undergo apoptosis. Antitumor effects were observed using 0.1 and 0.03 g of TGF-␣-PE38 administered intratumorally. At these doses, the treatment was well tolerated. Tumors treated with the toxin had a higher number of apoptotic cells compared with the control tumors. No apoptotic cells were observed in the pharyngoesophageal tissues of the mice after gavage administration of the toxin suggesting that the toxin could be orally administered without toxicity.Conclusions: These results indicate that topical or intratumoral administration of low doses of TGF-␣-PE38 may demonstrate antitumor effects in HNSCC without associated systemic toxicity.

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Expression of HER2 in Human Gastric Cancer Cells Directly Correlates with Antitumor Activity of a Recombinant Disulfide-Stabilized Anti-HER2 Immunotoxin

Cited by 29 publications

References 15 publications

Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193- N -Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts

Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193- N -Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts

Construction and Characterization of Novel, Recombinant Immunotoxins Targeting the Her2/neu Oncogene Product: In vitro and In vivo Studies

Abrogation of Head and Neck Squamous Cell Carcinoma Growth by Epidermal Growth Factor Receptor Ligand Fused to Pseudomonas Exotoxin Transforming Growth Factor α-PE38

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