The diphtheria toxin/urokinase fusion protein (DTAT) is selectively toxic to CD87 expressing leukemic cells

Jason G. Ramage; Daniel A. Vallera; Jennifer H. Black; Peter D. Aplan; Ursula R. Kees; Arthur E. Frankel

doi:10.1016/S0145-2126(02)00077-2

The diphtheria toxin/urokinase fusion protein (DTAT) is selectively toxic to CD87 expressing leukemic cells

Jason G. Ramage, Daniel A. Vallera, Jennifer H. Black, Peter D. Aplan, Ursula R. Kees, Arthur E. Frankel

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Diphtheria fusion proteins are a novel class of agents for the treatment of chemotherapy resistant acute myelogenous leukemia (AML). We prepared diphtheria toxin/urokinase fusion protein (DTAT) composed of the amino terminal fragment of the urokinase-type plasminogen activator (uPA) fused to the catalytic and translocation domains of diphtheria toxin (DT) and assessed its activity on leukemic cell lines. The number of uPA receptors (uPAR or CD87) was measured using a phycoerythrin conjugated monoclonal antibody to CD87 and flow cytometry. Seven of 23 cell lines (30%) showed CD87 expression (≥5000 receptors/cell). DTAT cytotoxicity (IC₅₀≤30pM) was observed in all seven of these samples and none of the 16 samples with low or absent CD87 expression. There was a significant correlation between DTAT sensitivity and CD87 density (P=0.0007). These results show that specific CD87 binding is one factor important in the sensitivity of patient's leukemic blasts to DTAT and demonstrate for the first time that the CD87/uPAR can be used as a target for fusion protein therapy of AML.

Original language	English (US)
Pages (from-to)	79-84
Number of pages	6
Journal	Leukemia research
Volume	27
Issue number	1
DOIs	https://doi.org/10.1016/S0145-2126(02)00077-2
State	Published - Jan 1 2003

Bibliographical note

Funding Information:
This work was supported by the Leukemia and Lymphoma Society (LSA6114 to A. Frankel) and the National Institutes of Health (R01CA76,178, R21CA90,550, and R01CA090,263 to A. Frankel).

Keywords

Acute myeloid leukemia
Diphtheria fusion protein
Urokinase receptor

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/S0145-2126(02)00077-2

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abstract = "Diphtheria fusion proteins are a novel class of agents for the treatment of chemotherapy resistant acute myelogenous leukemia (AML). We prepared diphtheria toxin/urokinase fusion protein (DTAT) composed of the amino terminal fragment of the urokinase-type plasminogen activator (uPA) fused to the catalytic and translocation domains of diphtheria toxin (DT) and assessed its activity on leukemic cell lines. The number of uPA receptors (uPAR or CD87) was measured using a phycoerythrin conjugated monoclonal antibody to CD87 and flow cytometry. Seven of 23 cell lines (30%) showed CD87 expression (≥5000 receptors/cell). DTAT cytotoxicity (IC50≤30pM) was observed in all seven of these samples and none of the 16 samples with low or absent CD87 expression. There was a significant correlation between DTAT sensitivity and CD87 density (P=0.0007). These results show that specific CD87 binding is one factor important in the sensitivity of patient's leukemic blasts to DTAT and demonstrate for the first time that the CD87/uPAR can be used as a target for fusion protein therapy of AML.",

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AU - Aplan, Peter D.

AU - Kees, Ursula R.

AU - Frankel, Arthur E.

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N2 - Diphtheria fusion proteins are a novel class of agents for the treatment of chemotherapy resistant acute myelogenous leukemia (AML). We prepared diphtheria toxin/urokinase fusion protein (DTAT) composed of the amino terminal fragment of the urokinase-type plasminogen activator (uPA) fused to the catalytic and translocation domains of diphtheria toxin (DT) and assessed its activity on leukemic cell lines. The number of uPA receptors (uPAR or CD87) was measured using a phycoerythrin conjugated monoclonal antibody to CD87 and flow cytometry. Seven of 23 cell lines (30%) showed CD87 expression (≥5000 receptors/cell). DTAT cytotoxicity (IC50≤30pM) was observed in all seven of these samples and none of the 16 samples with low or absent CD87 expression. There was a significant correlation between DTAT sensitivity and CD87 density (P=0.0007). These results show that specific CD87 binding is one factor important in the sensitivity of patient's leukemic blasts to DTAT and demonstrate for the first time that the CD87/uPAR can be used as a target for fusion protein therapy of AML.

AB - Diphtheria fusion proteins are a novel class of agents for the treatment of chemotherapy resistant acute myelogenous leukemia (AML). We prepared diphtheria toxin/urokinase fusion protein (DTAT) composed of the amino terminal fragment of the urokinase-type plasminogen activator (uPA) fused to the catalytic and translocation domains of diphtheria toxin (DT) and assessed its activity on leukemic cell lines. The number of uPA receptors (uPAR or CD87) was measured using a phycoerythrin conjugated monoclonal antibody to CD87 and flow cytometry. Seven of 23 cell lines (30%) showed CD87 expression (≥5000 receptors/cell). DTAT cytotoxicity (IC50≤30pM) was observed in all seven of these samples and none of the 16 samples with low or absent CD87 expression. There was a significant correlation between DTAT sensitivity and CD87 density (P=0.0007). These results show that specific CD87 binding is one factor important in the sensitivity of patient's leukemic blasts to DTAT and demonstrate for the first time that the CD87/uPAR can be used as a target for fusion protein therapy of AML.

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The diphtheria toxin/urokinase fusion protein (DTAT) is selectively toxic to CD87 expressing leukemic cells

Abstract

Bibliographical note

Keywords

UN SDGs

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