Identification of the Antigenic Epitopes in Staphylococcal Enterotoxins A and E and Design of a Superantigen for Human Cancer Therapy

Erlandsson, Eva; Andersson, Kerstin; Cavallin, Anders; Nilsson, Anneli; Larsson-Lorek, Ulla; Niss, Ulf; Sjoberg, A; Wallén-Öhman, Marie; Antonsson, Per; Walse, Björn; Forsberg, G.

doi:10.1016/j.jmb.2003.09.009

Cited by 27 publications

(19 citation statements)

References 43 publications

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“…Therefore, in parallel to the clinical trials of ABR-214936, novel superantigen variants with low reactivity to human anti-SEA antibodies have been designed (Erlandsson et al, 2003). The removal of the link between anti-SEA titre and dose should allow every patient to receive an optimal dose and thus improve the efficacy of treatment.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…2 Immunotoxins have demonstrated significant antitumor effects in preclinical models and in clinical trials. [3][4][5] ABR-217620 (5T4FabV18-staphylococcal enterotoxin E [SEA/E-120] or naptumomab estafenatox) is a novel immunotoxin with a distinct mechanism of action and consists of a recombinant fusion protein developed from ABR-214936, 6 consisting of a mutated variant of the superantigen (SAg) SEA/E-120 7 linked to a fragment antigen binding (Fab) moiety of a monoclonal antibody recognizing the tumor-associated oncofetal trophoblast glycoprotein antigen 5T4. [8][9][10] The proposed mechanism of action is Fab targeting of ABR-217620 to tumor where the SAg portion of the fusion protein elicits a potent tumoricidal cytotoxic T proof-of-mechanism cell response (Fig 1).…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10] The proposed mechanism of action is Fab targeting of ABR-217620 to tumor where the SAg portion of the fusion protein elicits a potent tumoricidal cytotoxic T proof-of-mechanism cell response (Fig 1). 11 Preclinical evaluation 7 suggests several advantages for ABR-217620 over the predecessor compound ABR-214936, 12,13 including reduced binding to preformed anti-SAg antibodies, lower toxicity,…”

Section: Introductionmentioning

confidence: 99%

Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer

Borghaei

Alpaugh

Hedlund

et al. 2009

JCO

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A B S T R A C T PurposeTwo phase I studies were conducted of ABR-217620 alone or in combination with docetaxel. This is a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to fragment antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T4. Patients and MethodsPatients with non-small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose escalation monotherapy [MONO] study). Doses were selected based on individual patient anti-SEA/E-120 titers pretreatment. Patients with NSCLC received 4 daily, escalating doses of ABR-217620 followed by docetaxel in 21-day cycles (ABR-217620 dose escalation combination with docetaxel [COMBO] study). ResultsThirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 g/kg (NSCLC and PC) and 15 g/kg (RCC). Dose-limiting toxicities (DLTs) in the MONO study were fever, hypotension, acute liver toxicity, and vascular leak syndrome. In the COMBO study, the MTD was 22 g/kg (neutropenic sepsis). Adverse events included grade 1 to 2 fever, hypotension, nausea, and chills. Treatment caused a systemic increase of inflammatory cytokines and selective expansion of SEA/E-120 reactive T-cells. Tumor biopsies demonstrated T-cell infiltration after therapy. Fourteen patients (36%) had stable disease (SD) on day 56 of the MONO study. Two patients (15%) in the COMBO study had partial responses, one in a patient with progressive disease on prior docetaxel, and five patients (38%) had SD on day 56. ConclusionABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.

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“…Synthetic fusion proteins, MHC class II-independent and tumor-specific, have been evaluated successfully. 23,24,[51][52][53][54][55] In summary, the preclinical findings indicate that SEB could be a useful agent for treatment of bladder cancer and that a clinical phase I evaluation appears warranted. …”

Section: Discussionmentioning

confidence: 98%

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer

Perabo

Willert

Wirger

et al. 2005

Intl Journal of Cancer

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Superantigens are potent activators of T lymphocytes; therefore, their characteristics can be exploited in diseases where immunomodulation is known to be effective. In this study, we evaluated a new approach for the intravesical therapy of superficial bladder cancer. We investigated in coculture experiments if staphylococcal enterotoxin B (SEB)-activated PBMCs are able to induce apoptosis in human transitional cell carcinoma (TCC) cells. Additionally, we tested the toxicity and efficacy of SEB dissolved in NaCl 0.9% administered intravesically once weekly for 6 weeks in a rat bladder cancer model. To validate the coculture in vitro findings, we evaluated tumor stage, grade, apoptotic cells in the urothelium and stroma of the bladder and infiltration of the bladder wall by lymphocytes, macrophages and mononuclear cells. Coculture experiments revealed that SEB-activated PBMCs are able to kill TCC cells by inducing apoptosis. The intravesical toxicity study with a maximum dose of 100 mg/ml SEB demonstrated no side effects. In the intravesically SEB-treated animals (10 mg/ml), only 3 tumors remained vs. 15 persisting tumors in the control group. The remaining tumors of the therapy group showed a significant amount of apoptosis and granulocytes, mainly in the urothelium, whereas no relevant apoptosis or infiltration of the bladder with lymphocytes or macrophages was found in the control group. These preclinical findings suggest that SEB might be an interesting candidate for further clinical evaluation. ' 2005 Wiley-Liss, Inc.Key words: bladder cancer; superantigen; staphylococcal enterotoxin B; apoptosis; Fas ligand At initial presentation, approximately 50-70% of all bladder tumors are superficial, stage Tis (carcinoma in situ) or Ta (papillary) and T1 tumors confined to the mucosa or submucosa. 1 In the majority of these patients, tumors can be resected but have a high risk of recurrence, thus requiring adjuvant treatment. 2 The objective of intravesical therapy is to reduce recurrence or to eradicate Tis in patients when it is not possible to resect completely. The most common immunotherapeutic agent used is BCG, an attenuated strain of Mycobacterium bovis. The exact mechanism by which BCG exerts its antitumor effect remains unknown. However, cytotoxic activity of activated T lymphocytes within a complex local immune response against bladder cancer cells and secretion of several cytokines involved in the local immune response were demonstrated in in vitro cultures and in the urothelium of BCG-treated patients. [3][4][5][6] Other extremely potent activators of T lymphocytes are superantigens. Superantigens are proteins or peptide factors produced by various microorganisms like bacteria, mycoplasma or viruses. Staphylococcal enterotoxins are a family of structurally related proteins produced by Staphylococcus aureus. These compounds, m.w. 24-30 kDa, include the classical groups (A-E), the recently discovered enterotoxins G-Q and TSST-1. Streptococcal superantigens include the pyrogenic exotoxins A (and antigenic va...

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Identification of the Antigenic Epitopes in Staphylococcal Enterotoxins A and E and Design of a Superantigen for Human Cancer Therapy

Cited by 27 publications

References 43 publications

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

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

Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer

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