TY - JOUR
T1 - Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell–dependent cytotoxicity
AU - Bhatt, Shruti
AU - Parvin, Salma
AU - Zhang, Yu
AU - Cho, Hyun Mi
AU - Kunkalla, Kranthi
AU - Vega, Francisco
AU - Timmerman, John M.
AU - Shin, Seung Uon
AU - Rosenblatt, Joseph D.
AU - Lossos, Izidore S.
N1 - Funding Information:
This study was supported by the Lymphoma Research Foundation (I.S.L.), the Dwoskin Family, Recio Family, Greg Olsen, and
Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/4/20
Y1 - 2017/4/20
N2 - 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 (aCD20-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 g production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments. Further, the aCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life. In vivo aCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors. Collectively, the dual functional ability of the aCD20-IL-21 fusokine to induce direct apoptosis and activate immune effector cells may provide benefit over existing treatments for NHL.
AB - 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 (aCD20-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 g production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments. Further, the aCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life. In vivo aCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors. Collectively, the dual functional ability of the aCD20-IL-21 fusokine to induce direct apoptosis and activate immune effector cells may provide benefit over existing treatments for NHL.
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U2 - 10.1182/blood-2016-09-738211
DO - 10.1182/blood-2016-09-738211
M3 - Article
C2 - 28137826
AN - SCOPUS:85027587666
SN - 0006-4971
VL - 129
SP - 2246
EP - 2256
JO - Blood
JF - Blood
IS - 16
ER -