Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis.
The Ki-1 antigen (CD30) is an established therapeutic target in patients with Hodgkin lymphoma and anaplastic large-cell lymphoma. We have recently shown that CD30 is expressed abundantly in the cytoplasm of neoplastic mast cells (MCs) in patients with advanced systemic mastocytosis (SM). In the current study, we asked whether CD30 is expressed on the surface of neoplastic MCs in advanced SM, and whether this surface structure may serve as therapeutic target in SM. As assessed by flow cytometry, CD30 was found to be expressed on the surface of neoplastic MCs in 3 of 25 patients (12%) with indolent SM, 4 of 7 patients (57%) with aggressive SM, and 4 of 7 patients (57%) with MC leukemia. The immature RAS-transformed human MC line MCPV-1.1 also expressed cell surface CD30, whereas the KIT-transformed MC line HMC-1.2 expressed no detectable CD30. The CD30-targeting antibody-conjugate brentuximab-vedotin inhibited proliferation in neoplastic MCs, with lower IC50 values obtained in CD30(+) MCPV-1.1 cells (10 µg/mL) compared with CD30(-) HMC-1.2 cells (>50 µg/mL). In addition, brentuximab-vedotin suppressed the engraftment of MCPV-1.1 cells in NSG mice. Moreover, brentuximab-vedotin produced apoptosis in all CD30(+) MC lines tested as well as in primary neoplastic MCs in patients with CD30(+) SM, but did not induce apoptosis in neoplastic MCs in patients with CD30(-) SM. Furthermore, brentuximab-vedotin was found to downregulate anti-IgE-induced histamine release in CD30(+) MCs. Finally, brentuximab-vedotin and the KIT D816V-targeting drug PKC412 produced synergistic growth-inhibitory effects in MCPV-1.1 cells. Together, CD30 is a promising new drug target for patients with CD30(+) advanced SM.
Department of Internal Medicine I, Division of Hematology and Hemostaseology and.
Katharina
K
Blatt
Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;
Sabine
S
Cerny-Reiterer
Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany;
Juliana
J
Schwaab
Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany;
Karl
K
Sotlar
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;
Gregor
G
Eisenwort
Department of Internal Medicine I, Division of Hematology and Hemostaseology and.
Gabriele
G
Stefanzl
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria;
Gregor
G
Hoermann
Department of Laboratory Medicine, Hanusch Hospital, Vienna, Austria;
Matthias
M
Mayerhofer
Department of Internal Medicine I, Division of Hematology and Hemostaseology and Department of Internal Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria;
Mathias
M
Schneeweiss
Department of Internal Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria; Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria; and.
Sylvia
S
Knapp
Institute of Laboratory Animal Science and.
Thomas
T
Rülicke
Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria; Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine, Vienna, Austria.
Emir
E
Hadzijusufovic
Department of Internal Medicine I, Division of Hematology and Hemostaseology and.
Karin
K
Bauer
Department of Internal Medicine I, Division of Hematology and Hemostaseology and.
Dubravka
D
Smiljkovic
Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine, Vienna, Austria.
Michael
M
Willmann
Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany;
Andreas
A
Reiter
Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany;
Hans-Peter
HP
Horny
Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;
Peter
P
Valent
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000079963:Brentuximab Vedotin; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007150:Immunohistochemistry; D017730:Ki-1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016133:Polymerase Chain Reaction
D018796:Immunoconjugates; D017730:Ki-1 Antigen; D000079963:Brentuximab Vedotin