Monoclonal antibody-targeted superantigens: a different class of anti-tumor agents.

Dohlsten, Mikael; Hedlund, Gunnar; Åkerblom, Eva; Lando, Peter A.; Kalland, Terje

doi:10.1073/pnas.88.20.9287

Cited by 94 publications

(71 citation statements)

References 41 publications

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“…mixed with chromium labelled Calu-1 cells and human SEA reactive T cells (Dohlsten et al, 1991). 5T4FabV13-SEA D227A mediated a specific T cell killing of Calu-1 cells ( Figure 3A) and was 10 5 times more effective than control Fab-SEA D227A , as determined by the EC 50 value.…”

Section: Cytotoxicity Of 5t4fabv13-sea D227a To Nsclc and Mhc Class Imentioning

confidence: 96%

“…The cells were isolated by density centrifugation over Ficoll-Paque cushion and incubated in complete R-medium (RPMI-1640 supplemented with 10% fetal calf serum (Gibco BRL, Life Technologies, UK), 1 mM glutamine, 10 mM Hepes buffer, 1 mM sodium pyruvate (HyClone Europe, UK), 50 µM 2-mercaptoethanol (ICN Biomedicals INC. Costa Mesa CA), 0.1 M NaHCO 3 (Seromed Biochrome), 0.1 mg ml -1 gentamycine (Biological Industries, Kibbutz Beit Haemek, Israel). SEA activated T cell lines were produced by activation of PBMC using 2 × 10 6 cells ml -1 with mitomycin C-treated BSM cells preincubated with 100 ng ml -1 SEA in medium with 10% FCS (Dohlsten et al, 1991). The T cell lines were restimulated biweekly with 20 U ml -1 IL-2, weekly with mitomycin C treated SEA coated BSM cells (Van De Griend et al, 1984) and cultivated for 4-12 weeks before being used in the assay.…”

Section: Cellsmentioning

confidence: 99%

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Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

et al. 2001

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Summary Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEA D227A bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a K d of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEA D227A tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEA D227A induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10 -10 M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEA D227A against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEA D227A . Thus, 5T4FabV13-SEA D227A has highly attractive properties for therapy of human NSCLC.

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Section: Cytotoxicity Of 5t4fabv13-sea D227a To Nsclc and Mhc Class Imentioning

confidence: 96%

Section: Cellsmentioning

confidence: 99%

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

et al. 2001

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“…Activation leads to the expression of perforin and the production of cytotoxic and proinflammatory cytokines and thus death of the APC (Fischer et al, 1990;Dohlsten et al, 1991b). Targeting of superantigens towards tumours induces a strong, local cytotoxic T-cell attack, which directly kills tumour cells and leads to inflammation and the local accumulation of tumouricidal cytokines (Dohlsten et al, 1991a(Dohlsten et al, , 1994(Dohlsten et al, , 1995Litton et al, 1997Litton et al, ,1999.…”

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confidence: 99%

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

et al. 2007

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In a phase II study, 43 renal cell carcinoma patients were treated with individualised doses of ABR-214936; a fusion of a Fab recognising the antigen 5T4, and Staphylococcal enterotoxin A. Drug was given intravenously on 4 consecutive days, treatment was repeated 1 month later. Treatment was associated with moderate fever and nausea, but well tolerated. Of 40 evaluable patients, 28 had disease control at 2 months, and at 4 months, one patient showed partial response (PR) and 16 patients stable disease. Median survival, with minimum follow-up of 26 months was 19.7 months with 13 patients alive to date. Stratification by the Motzer's prognostic criteria highlights prolonged survival compared to published expectation. Patients receiving higher drug exposure had greater disease control and lived almost twice as long as expected, whereas the low-exposure patients survived as expected. Sustained interleukin-2 (IL-2) production after a repeated injection appears to be a biomarker for clinical effect, as the induced-IL-2 level on the day 2 of treatment correlated with survival. The high degree of disease control and the prolonged survival suggest that this treatment can be effective. These findings will be used in the trial design for the next generation of drug, with reduced antigenicity and toxicity.

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“…Cytokines can suppress tumor growth both directly and synergistically. 31 In addition, cytokines can induce LAK activity, activate natural killer cells and macrophages, [32][33][34] facilitate penetration of high molecular weight proteins and upregulate cell adhesion molecules and MHC class II expression on tumor cells. These factors favor additional fusion protein interactions with subsequent SADCC 30,35 and recruit peripheral blood cells into this inflammatory milieu.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy by membrane-expressed superantigen for α-fetoprotein-producing hepatocellular carcinoma

Sun²,

Li³

et al. 2006

Gene Ther

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Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant, which can stimulate T cells bearing certain T-cell receptor b-chain variable regions, when bound to major histocompatibility complex II molecules. In vivo administration of intact superantigen in sufficient therapeutic amounts risks unwanted cytotoxicity against normal cells. In this study, we used SEA fused with CD80 transmembrane region (named as SEAtm) driven by a-fetoprotein (AFP) enhancer/ promoter to reduce toxicity and to improve safety and efficiency in the application of SEA. We demonstrated that SEAtm by adenovirus from the AFP enhancer/promoter (AdAFPSEA) could be expressed on the surface of AFPproducing cell line Hepa1-6 instead of non-AFP-producing cell lines. Hepa1-6 infected by recombinant adenovirus stimulated proliferation of splenocytes and activated CD4 + and CD8 + T cells in vitro. After AdAFPSEA was injected into the subcutaneously established hepatoma in vivo, the expression of SEA was detected in tumor tissues, which subsequently induced tumor-specific cytotoxic T cells in spleen. Moreover, hepatocellular carcinoma (HCC) xenografts were suppressed by treatment with AdAFPSEA and the survival time of treated mice was prolonged. These findings suggest that membrane-expressed SEA by adenovirus from AdAFPSEA can generate stronger local and systemic antitumor responses against HCC.

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Monoclonal antibody-targeted superantigens: a different class of anti-tumor agents.

Abstract: The bacterial superantigen staphylococcal enterotoxin (SE) A (SEA) directs cytotoxic T lymphocytes (CTLs) expressing particular sequences of the T-cell receptor (TCR)

Cited by 94 publications

References 41 publications

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

Gene therapy by membrane-expressed superantigen for α-fetoprotein-producing hepatocellular carcinoma

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