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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Published in:Blood Vol. 129; no. 16; p. 2246
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 20.04.2017
Subjects:
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
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Summary: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.
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2016-09-738211