The diphtheria toxin/urokinase fusion protein (DTAT) is selectively toxic to CD87 expressing leukemic cells.
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 (> or =5000 receptors/cell). DTAT cytotoxicity (IC(50)< or =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.
Ramage
Jason G
JG
Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Boulevard, 27157, Winston-Salem, NC, USA
Vallera
Daniel A
DA
Black
Jennifer H
JH
Aplan
Peter D
PD
Kees
Ursula R
UR
Frankel
Arthur E
AE
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001752:Blast Crisis / Q000473:pathology; D002051:Burkitt Lymphoma / Q000473:pathology; D005434:Flow Cytometry; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D007951:Leukemia, Myeloid / Q000473:pathology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D009101:Multiple Myeloma / Q000473:pathology; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020298:U937 Cells / Q000187:drug effects
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; C471586:diphtheria toxin-urokinase fusion protein, human