Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell-dependent cytotoxicity

In spite of newly emerging therapies and the improved survival of patients with non-Hodgkin lymphoma (NHL), relapses or primary refractory disease are commonly observed and associated with dismal prognosis. Although discovery of the anti-CD20 antibody rituximab has markedly improved outcomes in B-ce...

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Vydáno v:	Blood Ročník 129; číslo 16; s. 2246
Hlavní autoři:	Bhatt, Shruti, Parvin, Salma, Zhang, Yu, Cho, Hyun-Mi, Kunkalla, Kranthi, Vega, Francisco, Timmerman, John M, Shin, Seung-Uon, Rosenblatt, Joseph D, Lossos, Izidore S
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 20.04.2017
Témata:	Animals Antibodies, Monoclonal, Murine-Derived - genetics Antibodies, Monoclonal, Murine-Derived - immunology Antigens, CD20 - genetics Antigens, CD20 - immunology Antineoplastic Agents - immunology Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacokinetics Apoptosis - drug effects B-Lymphocytes - drug effects B-Lymphocytes - immunology B-Lymphocytes - pathology Cytotoxicity, Immunologic - drug effects Gene Expression Half-Life Humans Interferon-gamma - biosynthesis Interferon-gamma - immunology Interleukins - genetics Interleukins - immunology Killer Cells, Natural - drug effects Killer Cells, Natural - immunology Killer Cells, Natural - pathology Lymphoma, Non-Hodgkin - drug therapy Lymphoma, Non-Hodgkin - genetics Lymphoma, Non-Hodgkin - immunology Lymphoma, Non-Hodgkin - pathology Mice Mice, Inbred BALB C Mice, Transgenic Molecular Targeted Therapy Receptors, Interleukin-21 - genetics Receptors, Interleukin-21 - immunology Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - immunology Recombinant Fusion Proteins - pharmacokinetics Signal Transduction
ISSN:	1528-0020, 1528-0020
On-line přístup:	Zjistit podrobnosti o přístupu
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Popis
Shrnutí:	In spite of newly emerging therapies and the improved survival of patients with non-Hodgkin lymphoma (NHL), relapses or primary refractory disease are commonly observed and associated with dismal prognosis. Although discovery of the anti-CD20 antibody rituximab has markedly improved outcomes in B-cell NHL, rituximab resistance remains an important obstacle to successful treatment of these tumors. To improve the efficacy of CD20-targeted therapy, we fused interleukin 21 (IL-21), which induces direct lymphoma cytotoxicity and activates immune effector cells, to the anti-CD20 antibody (αCD20-IL-21 fusokine). We observed substantially enhanced IL-21R-mediated signaling by the fusokine compared with native IL-21 at equimolar concentrations. Fusokine treatment led to direct apoptosis of lymphoma cell lines and primary tumors that otherwise were resistant to native IL-21 treatment. In addition to direct cytotoxicity, the fusokine enhanced NK cell activation, effector functions, and interferon γ production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments. Further, the αCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life. In vivo αCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors. Collectively, the dual functional ability of the αCD20-IL-21 fusokine to induce direct apoptosis and activate immune effector cells may provide benefit over existing treatments for NHL.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1528-0020 1528-0020
DOI:	10.1182/blood-2016-09-738211