Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein

Williams, Daniel W.; Parker, Karen; Bacha, P.; Bishai, William R.; Borowski, M; Genbauffe, Frank; Strom, Terry B.; Murphy, John R.

doi:10.1093/protein/1.6.493

Cited by 232 publications

(96 citation statements)

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“…39 Patients with HL have been treated with recombinant fusion toxins such as DAB 389 IL-2 or DAB 486 IL-2 which are composed of a deletion mutant of diphtheria toxin (DAB) and IL-2. 40 LeMaistre et al 41,42 conducted two studies with DAB 486 IL-2 in hematologic neoplasia expressing the IL-2 receptor without clinical response in four patients with HL. In contrast, one CR lasting more than 2 years in 1/4 HL patients was achieved with DAB 486 IL-2.…”

Section: Figurementioning

confidence: 99%

Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin

Schnell¹,

Vitetta

Schindler

et al. 2000

Leukemia

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The anti-CD25 immunotoxin RFT5.dgA was constructed by coupling the monoclonal antibody RFT5 via a sterically hindered disulfide linker to deglycosylated ricin A-chain and was administered to patients with relapsed Hodgkin's lymphoma in four bolus infusions over 7 days (day 1, 3, 5 and 7). The maximum tolerated dose in these patients as defined in a previous phase I study was 15 mg/m 2 . Subsequently, further patients were enrolled at the maximum tolerated dose and a total of 18 patients were treated at this level. All patients had signs of progressive disease and were heavily pretreated. Sideeffects in this trial were moderate and related to vascular leak syndrome. Five of 18 patients experienced NCI grade III toxicities including weakness, edema, dyspnea, and myalgia. Eleven of 16 (69%) patients receiving two or more cycles produced human anti-ricin antibodies and human anti-mouse antibodies (у1.0 g/ml). Seventeen of 18 patients were evaluable for clinical response. These included two partial remissions. One patient demonstrated minor response and five patients stable diseases. We conclude that RFT5.dgA is of moderate clinical efficacy in this group of heavily pretreated refractory patients. Leukemia (2000) 14, 129-135.

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Section: Figurementioning

confidence: 99%

Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin

Schnell¹,

Vitetta

Schindler

et al. 2000

Leukemia

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“…The dual specificity may be allowed by the relatively long linker between the antibody domains and the IL-2 moiety allowing the amino-terminal end of IL-2 freedom to interact with the low affinity receptor. Work with diptheria toxin-IL-2 fusion proteins has demonstrated the importance of this mobility in allowing this interaction to occur effectively (Williams et al, 1987;Kiyokawa et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…IL-2 has been successfully incorporated into a number of fusion proteins. Fusion proteins consisting of IL-2 linked to bacterial toxins have been produced in bacteria and have been demonstrated to be toxic to IL-2 receptor bearing cells (Lorderboum-Galski et Williams et al, 1987). With the aim of concentrating IL-2 activity in the tumour, two different antibody-IL-2 fusion proteins have already been described.…”

mentioning

confidence: 99%

A recombinant single-chain antibody interleukin-2 fusion protein

Savage

Spooner

et al. 1993

Cell Biophysics

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SummaryRecombinant interleukin-2 (rIL-2) therapy has been shown to be of value in the treatment of some cases of melanoma and renal cell carinoma. However its use can be limited by severe systemic toxicity. Targeting rIL-2 to the tumour should improve the anti-tumour immune response and decrease the systemic toxicity. With this aim we have employed recombinant DNA techniques to construct a single chain antibody interleukin-2 fusion protein (SCA-IL-2).The protein used in this model system comprises the variable domains of the anti-lysozyme antibody D1.3 fused to human IL-2. It has been expressed by secretion from Escherichia coli and the purified product possesses antigen binding specificity and retains the immunostimulatory activities of rIL-2.This approach can be taken to generate SCA-IL-2 proteins that bind to appropriate cellular antigens. In vivo administration of a tumour binding SCA-IL-2 should result in a localised high concentration of IL-2 in tumour tissues, maximising the anti-tumour immune response, whilst keeping systemic side effects to a minimum.

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“…Ontak (DAB 389 IL-2, Denileukin Diftitox) is a recombinant DNA-derived fusion protein containing the catalytic and membrane translocation domains of diphtheria toxin (fragments A and B) and the complete amino-acid sequences of IL-2. 18 Ontak selectively targets the highaffinity IL-2 receptor expressed on malignant and activated cells. 19 The drug is marketed by Ligand Pharmaceuticals, San Diego, CA, USA and was approved in 1999 by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed or refractory CTCL.…”

Section: Allodepletionmentioning

confidence: 99%

A comparison of an anti-CD25 immunotoxin, Ontak and anti-CD25 microbeads for their ability to deplete alloreactive T cells in vitro

Vaclavkova

Cao

et al. 2006

Bone Marrow Transplant

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Ex vivo depletion of alloreactive CD25 þ T cells from a stem cell transplant (SCT) can reduce the incidence of graft-versus-host disease (GVHD) while preserving antimicrobial and perhaps antileukemia activity. However, the most effective methods for allodepleting T cells prior to transplant have not been determined. In this study, we have compared three agents that deplete CD25 þ activated, alloreactive T cells. These included Ontak (Denileukin Diftitox), an IL-2 fusion toxin, anti-CD25 microbeads (MACS), an anti-CD25 immunotoxin (IT) and a combination of the IT and MACS. Peripheral blood mononuclear cells (PBMCs) activated in a primary mixed lymphocyte reaction (MLR) were allodepleted using optimal amounts of each agent, and the cells were then analyzed by flow cytometry. The treated cells were examined both for remaining alloreactivity and for the preservation of third party reactivity by testing them in a secondary MLR. Our data demonstrate that both the anti-CD25 IT and the anti-CD25 MACS were equally effective in depleting CD4 þ CD25 þ cells and in sparing T cells that were reactive with third party cells. The anti-CD25 IT was, however, superior in depleting alloreactive CD8 þ CD25 þ cells. In contrast, Ontak did not eliminate alloreactive cells and the Ontak-treated cells retained significant reactivity against the original stimulator cells.

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Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein

Cited by 232 publications

References 0 publications

Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin

Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin

A recombinant single-chain antibody interleukin-2 fusion protein

A comparison of an anti-CD25 immunotoxin, Ontak and anti-CD25 microbeads for their ability to deplete alloreactive T cells in vitro

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